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    • 专利摘要:
      USE OF A DOSE OF ADJUVANT COUPLED WITH NANO SYNTHETIC VEHICLES AND AN DOSE OF ANTIGEN IN THE TREATMENT OF INFECTION, CANCER, ADDICTION, ASTHMA, PULMONARY DISEASES, DEGENERATIVE AND NON AUTOIMMUNEThe present invention relates to the use of an adjuvant dose coupled to synthetic nano vehicles and an antigen dose in the treatment of infection, cancer, addiction, asthma, pulmonary, degenerative and non-autoimmune diseases.
    公开号:BR112012029823A2
    申请号:R112012029823-2
    申请日:2011-05-26
    公开日:2020-09-01
    发明作者:Petr Il Yinskii；Grayson B. Lipford；Charles Zepp
    申请人:Selecta Biosciences, Inc.；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for "USE OF A
    DOSE OF ADJUVANT COUPLED TO NANO SYNTHETIC VEHICLES AND AN DOSE OF ANTIGEN IN THE TREATMENT OF INFECTION, CANCER, ADDICTION, ASTHMA, PULMONARY DISEASES, DEGENERATIVE AND 5 NON-AUTOIMMUNE ".
    RELATED REQUESTS This request claims priority under Art. 35 USC §119 of United States Provisional Orders 61/348713, filed May 26, 2010, 61/348717, filed May 26, 2010, 61/348728, deposited on May 26, 2010, and 61/358635, filed on June 25, 2010, the contents of which are fully incorporated here as a reference.
    BACKGROUND OF THE INVENTION Adjuvants are important components for most vaccination schedules currently used. They are also likely to be integrated into future vaccine products. Numerous new adjuvants are now being developed, and many of these have been shown to increase immunological responses to vaccines in research and clinical trials. However, adjuvant doses that are beneficial for increasing the immune response may be able to induce side effects in a significant group of patients. In fact, these two adjuvant capacities are inextricably linked, since the extended immune stimulation alone provides stimuli for the increase in vaccination, as well as its side effects (toxicities). Both of these processes are known to be driven by the release of inflammatory cytokines. Therefore, approaches that reduce the side effects of adjuvant administration and / or specifically increase certain immunological responses, will be of great clinical value. Therefore, what is needed are compositions and methods that effectively provide the desired immune response (s) that can reduce the frequency of adverse events associated with the use of adjuvant in vaccines.
    SUMMARY OF THE INVENTION The following sheet 1a / 72 follows
    1a / 72
    In one aspect, a method comprising providing an adjuvant dose and an antigen dose, in which at least a portion of the adjuvant dose is coupled to synthetic nanovehicles, and generating
    The following is a sheet 2/72 of an antibody titer against the antigen through administration of the
    Y if the adjuvant and the antigen dose for an individual, where the dose of the adjuvant is less than the separate dose of adjuvant which results in an antibody titer similar to that generated by administering the dose of the adjuvant and the dose of antigen for the individual. In one embodiment, the method additionally comprises choosing the dose of adjuvant as being less than a separate dose of adjuvant which results in an antibody titer similar to that generated by administering the dose of adjuvant and the dose of antigen for the individual. . 10 Preferably, the same entity performs each of the steps of these methods (that is, the same entity performs the supply, generation and / or choice of steps). In another aspect, a composition is provided further comprising the dose of the adjuvant as being less than a separate dose of adjuvant which results in an antibody titer similar to that generated by administering the dose of the adjuvant and the dose of antigen for the individual. In another aspect, a method is provided comprising providing an adjuvant dose, in which at least a portion of the adjuvant dose is coupled to synthetic nanocarriers, and generating a release of the systemic cytokine through administration of the adjuvant dose. to an individual, where the dose of the adjuvant is higher than a separate dose of adjuvant that results in a systemic cytokine release similar to that generated by administering the dose of the adjuvant to the individual. In one embodiment, the method additionally comprises the choice of adjuvant dose as being higher than the separate dose of adjuvant that results in the release of systemic cytokine similar to that generated by administering the dose of adjuvant to the individual. Preferably, the same entity performs each step of these methods (that is, the same entity performs the supply, generation and / or choice of the 30 SOS steps). In another aspect, a composition is provided comprising the adjuvant sweetness, being higher than a separate dose of adjuvant that results in the systemic cytokine release similar to that generated through the adjuvant
    ~ 3/72 administration of the adjuvant dose to the individual.
    W In one embodiment, The adjuvant (s) of any of the methods and compositions provided herein comprise a Toll-like receptor agonist 3, 4, 5, 7, 8, or 9, or a combination of them. In another embodiment, the adjuvant comprises an agonist of Toll-like receptors 3, an agonist of Toll-like receptors 7 and 8, or an agonist of Toll-like receptors 9. In yet another embodiment, the adjuvant comprises R848, immunostimulatory DNA, or immunostimulatory RNA. In a . In an additional embodiment, the adjuvant dose of any of the methods and compositions provided herein comprises two or more types of adjuvants. In one embodiment, a portion of the dose of the adjuvant is not coupled to the synthetic nanocarriers. In another modality of any of the methods and compositions provided here, more than one type of antigen is administered to the individual. In one embodiment, at least a portion of the dose of the antigen (s) is coupled to the synthetic nanovehicles. In another embodiment, at least a portion of the dose of the antigen (s) is not coupled to the synthetic nanocarriers. Still, in another embodiment, at least a portion of the dose of the antigen (s) is co-administered with the synthetic nanocarriers. In yet another embodiment, at least a portion of the dose of the antigen (s) is not co-administered with the synthetic nanocarriers. In one embodiment, the antigen (s) comprise a B cell antigen and / or a T cell antigen. In another embodiment, the T cell antigen comprises a B antigen. universal T cell or T-helper cell antigen- In yet another embodiment, the (S) antigen (s) comprise a B cell antigen or a T cell antigen and a cell antigen Universal T or helper T-30 cell antigen. In one embodiment, the auxiliary T cell antigen comprises a peptide obtained or derived from ovalbumin. In another embodiment, the peptide obtained or derived from ovalbumin comprises the sequence as defined in SEQ ID NO: 1, Yet, in another embodiment of any of the methods and compositions provided herein,. The antigen of universal T cells or the antigen of auxiliary T cells is coupled to synthetic nanoveicules by encapsulation. Yet, in another embodiment of any of the methods and compositions provided herein, the B cell antigen comprises nicotine. In an additional embodiment, the synthetic nanocarriers comprise nicotine and an unNersal T-cell antigen or T-helper cell antigen. Still in an additional modality, nicotine and / or the universal T cell antigen or the anti-
    F l The genius of auxiliary T cells are coupled to synthetic nanocars. In one embodiment, the universal T-cell antigen or T-helper cell antigen is coupled by encapsulation. In another embodiment of any of the methods and compositions provided, the adjuvant dose comprises R848 and the antigen dose comprises nicotine and a universal T cell antigen or a helper T cell antigen, wherein the nicotine and the universal T-cell antigen or auxiliary T-cell antigen are also coupled to the synthetic nanocarriers, and in which the synthetic nanocarriers comprise one or more polymers. 20 In another modality of any of the methods and compositions provided here, synthetic nanoveicules comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, emulsions based on surfactants, dendrimers, magnetic spheres, nanowires, virus-like particles , particles based on peptides or proteins, 25 nanoparticles that comprise a combination of nanomaterials, spheroidal nanoparticles, cuboidal nanoparticles, pyramidal nanoparticles, oblong nanoparticles, cylindrical nanoparticles, or toroidal nanoparticles. In one embodiment, the synthetic nanocarriers comprise one or more polymers. In another embodiment, the one or more polymers comprise a polyester. In yet another embodiment, one or more polymers comprise or additionally comprise a polyester coupled to a hydrophilic polymer. In yet another embodiment, the polyester comprises a poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), or polycaprolactone.
    In one embodiment, the hydrophilic polymer comprises a polyether.
    In another embodiment, the polyether comprises polyethylglycol.
    In an embodiment of any of the methods and compositions provided, at least one dosage form comprises the dosage of the adjuvant.
    In another embodiment, a vaccine comprises the dosage form (s).
    In yet another embodiment, 10 as, more than one, dosage forms comprise the dosage of adjuvant, and more than one dosage forms are co-administered.
    In an embodiment of any of the methods provided, the administration is made by a route that comprises the subcutaneous, intramuscular, intradermal, oral, intranasal, transmucosal, rectal administration; ophthalmic, transdermal or transcutaneous, or a combination thereof.
    In another modality of any of the methods provided, the individual has cancer, an infectious disease, a non-autoimmune metabolic disease, a degenerative disease, an addiction, an atopic condition, asthma, chronic obstructive pulmonary disease (COPD) or an infection chronic. 20 In another aspect, an adjuvant dose and antigen dose or an adjuvant dose, as defined with respect to any of the methods or compositions provided, are provided for use in therapy or prophylaxis.
    In yet another aspect, a dose of adjuvant 25 and a dose of antigen or a dose of adjuvant, as defined with respect to any of the methods or compositions provided, are provided for use in any of the methods provided.
    In yet another aspect, an adjuvant dose and an antigen dose or an adjuvant dose, as defined with respect to any of the methods or compositions provided, are provided for use in a cancer treatment method. , an infectious disease, a non-autoimmune metabolic disease, a degenerative disease, an addiction, an atopic condition, asthma; chronic obstructive pulmonary disease (COPD) or a chronic infection. In one embodiment, the com-. includes the administration of the dose (s) via a route that comprises subcutaneous, intramuscular, intradermal, oral, intranasal, trans-mucosal, rectal administration; ophthalmic, transdermal or transcutaneous, or a combination of these. In an additional aspect, the use of an adjuvant dose and an antigen dose or an adjuvant dose, as defined with respect to any of the methods or compositions provided, is provided. 10 supplied, for the manufacture of a medicine for use in any of the methods provided.
    - BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the systemic production of cytokines in mice after inoculation of the nanovehicles (NC). figure 1A, 1B and lC show the production of TNF-a, IL-6, IL-12 in the experimental groups, respectively. Sera from groups of three mice were pooled and analyzed by ELISA. Figure 2 shows the systemic production of | FN-Y in mice after inoculation of the NC. Sera from groups of three mice were pooled and analyzed by ELISA. Figure 3 shows the production of systemic IL-12 in mice after inoculation with TLR agonists free or coupled to NC. Sera from groups of two mice were pooled and analyzed by ELISA. Figure 4 shows the local induction of immune cytokines by TLR agonists free or coupled to NC. Each point represents an average of two separate mouse lymph nodes (LNS). Figure 5 shows the dynamics of the cell population in popIite lymph nodes after inoculation with free TLR 7/8 coupled R848 agonists. Three intact mice were sacrificed on different days 30 and the mean cell counts of their popliteal LN were considered to be "day 0" meaning "1" to which all other numbers were compared. Each bar in a group inoculated with R848- or NC- represented
    an average of two lymph nodes taken from independent animals. "¶ Figure 6 shows anti-nicotine antibody titers in mice immunized with NC containing surface nicotine and T-helper peptide OP-ll with or without R848. 5 Figure 7 shows that TNF-a and IL-6 were induced in sera from animals inoculated with NC-CpG and free CpG Figure 8 shows the induction of | FN-y and IL-12 in sera from animals inoculated with NC-CpG and Free CpG. DETAILED DESCRIPTION OF THE INVENTION
    W 10 Before describing the present invention in detail, it should be understood that this invention is not limited to particularly exemplary materials or process parameters, as they can obviously vary. It should also be understood that the terminology used here is intended only to describe particular modalities of the invention, and is not intended to limit the use of alternative terminology to describe the present invention- All publications, patents and patent applications mentioned here, either above or below, are incorporated by reference in their entirety, for all purposes. As used in the present description and the appended claims, the singular forms "one", "one" and "o / a" include plural referents, unless the content clearly dictates otherwise. For example, the reference to "a polymer" includes a mixture of two or more of these molecules, the reference to "a solvent" includes a mixture of two or more of these 25 solvents, the reference to "an adhesion agent "includes mixtures of two or more of these materials, and the like.
    INTRODUCTION The inventors have found, unexpectedly and surprisingly, that the above problems and limitations can be overcome by the practice of the invention disclosed here. The findings described here refer to the coupling of the adjuvant to the nanovehicles, and based on these findings, related methods and compositions are provided that
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    W are directed to generate desired immune responses through the selection of specific doses of the adjuvant coupled to the nanovehicles. In some-. but modalities, and depending on the desired immune response (s), these doses are lower than the doses of unattached adjuvant 5 to the nanoveicules in a similar context. In other modalities, these doses are higher than the doses of adjuvant not coupled to the naiciculos. In one respect, the inventors unexpectedly discovered that it is possible to provide methods, and related compositions, that comprise a method comprising administering a dose of adjuvant, when coupled to synthetic nanocarriers, which is less than one. separate dose of adjuvant that results in an immune response (for example, antibody titer) similar to that generated by administering the dose of adjuvant to an individual. Due to the stronger adjuvant effect 15 as a result of the coupling of at least a portion of an adjuvant dose to a synthetic nanocouple, less adjuvant can be used. Adjuvant doses, therefore, can be subtherapeutic or reduced toxicity doses, in which at least a portion of the adjuvant dose is coupled to synthetic nanocarriers. In another aspect, the invention relates to a composition comprising a dosage form comprising a subtherapeutic or reduced toxicity dose of adjuvant, and a pharmaceutically acceptable excipient, wherein at least one portion of the dose of the adjuvant is coupled to synthetic nanoveiculos. In yet another aspect, the invention relates to a method comprising administering a subtherapeutic or reduced toxicity dose of the adjuvant to an individual; in which at least a portion of the dose of the adjuvant is coupled to the synthetic nanocarriers. The coupling of adjuvants to the nanocarriers has been observed to provide a stronger adjuvant effect and to lead to a substantially greater antibody response when compared to the mixed adjuvant. Additionally, it was also observed that the coupled adjuvant results in a greater antibody response, even when a
    K substantially greater amount of free adjuvant (as much as 6 times greater) is used. See Example 11. This result is contrary to what is expected from the teachings provided in Diwan et al-, Current Drug Delivery, 2004, 1, 405-412, where it was found that the production of antibodies, particularly at higher doses. drops of the adjuvant, was greater when the adjuvant was given in solution, instead of with the delivery of particles. An opposite result, however, is described here. In another aspect, therefore, the inventors unexpectedly discovered that it is possible to provide methods, and related compositions.
    W lO nadas, which comprise a method comprising providing an adjuvant dose and an antigen dose, in which at least a portion of the adjuvant dose is coupled to synthetic nanocarriers, and generating an antibody titer against the antigen via administration of the adjuvant dose and antigen dose to an individual, where the dose of the adjuvant is less than the separate dose of adjuvant which results in an antibody titer similar to that generated by administering the dose of the adjuvant and antigen dose to the individual. In embodiments, the method further comprises choosing the adjuvant dose as being less than a separate dose of the adjuvant which results in an antibody titer similar to that generated by administering the adjuvant dose and the antigen dose to the individual (for example, a human). Preferably, the steps of the methods provided here are carried out by the same entity. In yet another aspect, the invention relates to a composition comprising an adjuvant dose and an antigen dose and a pharmaceutically acceptable excipient, wherein at least a portion of the adjuvant dose is coupled to synthetic nanocarriers, and wherein the dose of adjuvant is less than a separate dose of adjuvants which results in an antibody titer similar to that generated by administering the dose of adjuvant and the dose of antigen to an individual. 30 It has also been shown that coupling the adjuvant to nanovehicles can result in less induction of imecliata systemic cytokine than using the free adjuvant. Therefore, the coupling of the
    The "nanovehicle adjuvant may allow the use of a higher dose of adjuvant when compared to the separate adjuvant. In another aspect,. Y therefore, the invention relates to a method comprising providing a dose of adjuvant, in that at least a portion of the adjuvant dose is coupled to synthetic nanovehicles, generating an immune response (for example, a systemic cytokine release) by administering the adjuvant dose to an individual (for example, a human) , where the dose of the adjuvant is greater than a separate dose of adjuvant that results in an immune response similar to that generated by administering the dose of the adjuvant to the individual In modalities, the method comprises - additionally the choice of the adjuvant dose as being higher than a separate dose of adjuvant that results in an immune response (for example, the release of systemic cytokine) similar to that generated by administering the dose of the adjuvant to the individual. O. Preferably, the 15 steps of the methods provided here are performed by the same entity.
    In yet another aspect, the invention relates to a composition comprising a dosage form comprising a dose of adjuvant and a pharmaceutically acceptable excipient, wherein at least a portion of the dose of adjuvant is coupled to synthetic nanocarriers, and in that the dose of adjuvant 20 is higher than a separate dose of adjuvants that results in an immune response (eg, systemic cytokine release) similar to that generated by administering the dose of adjuvant to an individual.
    Collectively, with the findings provided here, it is now possible to select an adjuvant dose depending on the desired immune result that is specific to the use of adjuvant coupled to nano-vehicles. The dose may be a lower dose (in relation to the separate adjuvant) that generates antibody titers or that avoids unwanted systemic activity (while strongly potentiating local immunostimulatory effects). The 30 dose can be a larger one, which generates a similar systemic cytokine release profile in relation to the separate adjuvant.
    In an additional aspect, the administration of the compositions
    provided can be beneficial for any individual where modulation of an immune response is desired. In some embodiments, the individual is such that an inflammatory response is desired. In other embodiments, individuals are those in which a Th1 immune response is desired. In some modalities, individuals have or are at risk for cancer. In other modalities, individuals are or are at risk of having an infection or infectious disease. Still, in other modalities, individuals are or are at risk of having an atopic condition, asthma, chronic obstructive pulmonary disease (COPD) or a chronic infection. Methods for administering the compositions to such individuals are also provided. Examples 1-13 illustrate several embodiments of the present invention, including different formulations or aspects of the present invention. The compositions and methods described in the Examples are also provided here. The invention will now be described in more detail.
    DEFINITIONS An "adjuvant" means an agent that does not constitute a specific antigen, but enhances the resistance and longevity of the immune response to the antigen administered concurrently. Such adjuvants may include, but are not limited to, standard recognition receptor stimulators, such as Toll-like receptors, NOD-like RIGle receptors (NLR), mineral salts, such as alum, alum combined with lipid monophosphoryl ( MPL) A of enterobacteria, such as 25 Escherihia coli, Salmonella minnesota, Salmonella typhimurium, or Shigella flexneri or specifically with MPL® (AS04), MPL A of the above-mentioned bacteria, saponins, such as QS-21, Quil-A , ISCOMS, | SCOMATRlX®, emulsions such as MF59®, Montanide "ISA 51 and ISA 720, AS02 (QS21 + squalene + MPL"), AS15, liposomes and liposome formulations 30 such as ASOl, microparticles and microtransporters synthesized or specifically prepared such as outer membrane vesicles derived from bacteria (OMV) of N. gonorrheae, Chlamydia trachomatis and
    . 12/72
    M other, or chitosan particles, deposit forming agents, such as block Pluronic® copolymers, specifically modified or prepared peptides, such as muramyl dipeptide, aminoalkyl-glucosaminide 4-phosphates, such as RC529, or proteins, such as bacterial toxoids or toxin fragments. In embodiments, adjuvants comprise agonists for standard recognition receptors (PRR), including, but not limited to, Toll-like teceptors (TLRS), specifically TLRS 2, 3, 4, 5, 7, 8, 9 and / or their combinations. In other embodiments, the buy-10 adjuvants end with Toll 3-like receptor agonists, Toll-like 7 and 8 receptor agonists, or Toll-like 9 receptor agonists; preferably the cited adjuvants comprise imidazoquinolines; such as R848; adenine derivatives, such as those disclosed in U.S. patent documents 6,329,381 (Sumitorno Pharmaceutical Company), 15 Published US Patent Application 2010/0075995 to Biggadike et al., or WO 2010/018132 by Campos et al .; Immunostimulatory DNA; or immunostimulatory RNA. In specific embodiments, synthetic nanovehicles incorporate as adjuvants compounds that are agonists for Toll-like receptors (TLRS) 7 & 8 ("TLR 7/8 agonists"). Of use are the 20 TLR 7/8 agonist compounds disclosed in US Patent 6,696,076 to Tomai et al., Including, but not limited to, imidazoquinoline amines, imidazopyridine amines, fused 6,7-cycloalkylimidazopyridine amines and 1, 2-imidazoquinoline bridged. Preferred adjuvants comprise imiquimod and resiquimod (also known as R848). In specific embodiments, an adjuvant can be an agonist for the surface DC molecule CD40. In certain modalities, to stimulate immunity instead of tolerance, a synthetic nanovelcle incorporates an adjuvant that promotes DC maturation (necessary for the use of naive T cell primers) and the production of cytokines, such as type I interferons, that promote immune responses to antibodies. In embodiments, adjuvants may also comprise immunomostimulatory RNA molecules, such as, but not limited to, dsRNA, poly 1: C or poly 1: poly C 12U (dis
    Available as Ampligen®, both poly l: C and poly l: poly C12U being known.
    as TLR3 stimulants), and / or those disclosed in F. Heil et al., "Speci- -. es-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8" Science 303 (5663), 1526-1529 (2004): J. VoIlmer et al., "Lmmune modulation by chemically modified ribonucleosides and oligoribonucleotides" WO 2008033432 A2: A. Forsbach et al., "Lmmunostimulatory oligoribonucleotides containing specific sequence motif (s) and targeting the Toll- like receptor 8 pathway "WO 2007062107 A2: E. Uhlmann et al.," Modified oligoribonucleotide analogs with enhanced immunostimulatory activity "Pat. U.S. Appl. Publ. , 10 US 2006241076; G. Lipford et al., "Immune viral RNA oligonucleotides and use for treating cancer and infections" WO 2005097993 A2: G. Lipford et al., "Immunostimulatory G, U-containing oligoribonucleotides, com- positions, and screening methods" WO 2003086280 A2. In some modalities, an adjuvant may be a TLR-4 agonist, such as a bacterial lipopo-lysaccharide (LPS), VSV-G and / or HMGB-I. In some embodiments, adjuvants may comprise TLR-5 agonists, such as flagellin, or portions or derivatives thereof, including, but not limited to, those disclosed in US Patents 6,130,082, 6,585,980 and 7,192,725. In specific fashion, synthetic nanocarriers incorporate a ligand for the Toll-like receptor (TLR) -9, such as immunostimulatory DNA molecules comprising CpGs, which induce secretion of type I interferon and stimulate activation T and B cells, leading to increased antibody production and cytotoxic T cell responses (Krieg et a!., CpG motifs in bacterial DNA trigger direct B cell activation. Nature. 1995. 25 374: 546- 549; Chu et al. CpG oligodeosoxynucleotides act as adjuvants that bind to T helper immunity 1 (Thl) .j. Exp. Med. 1997- 186: 1623-1631; Lipford et al. Os o | igonuc | synthetic eotopes containing CpG promote cytotoxic B and T cell responses to protein antigen: a new class of vaccine adjuvants Eur. J. Immunol 1997. 30 27: 2340-2344: Roman et al. Immunostimulatory DNA sequences function as adjuvants promoters of T-helper T .. Nat. Med. 1997. 3: 849-854; Davis et al. pG is a potent immune enhancer
    .
    14/72 "of specificity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol. 1998. 160: 870-876; Lipford et al., Bacterial DNA as immune cell activator. Trends Microbiol. 1998. 6 : 496-500; US Patent 6,207,646 to Krieg et al .; US Patent 7,223,398 to Tuck et al .; 5 US 7,250,403 to Van Nest et al .; or US Patent 7,566,703 to Krieg et al. In some embodiments, adjuvants may be pro-inflammatory stimuli released by necrotic cells (eg, urate crystals). In some modalities, adjuvants can be activated components of the complement cascade (eg, CD21, CD35, etc.). adjuvants can be activated components of immune complexes.Adjuvants also include complement receptor agonists, such as a molecule that binds to CD21 or CD35. In some embodiments, the complement receptor agonist induces endogenous complement opsonization nanovdculonanoveí synthetic circle. In some modalities, adjuvants are cytokines, which are small proteins or biological factors (in the range of 5 KD-20 KD) that are released by cells and have specific effects on cell-cell interaction, communication and behavior of other cells. In some modalities, the cytokine receptor agonist is a small molecule, antibody, fusion protein, or aptamer. In embodiments, at least a part of the dose of the adjuvant can be coupled to synthetic nanocarriers, preferably, the entire dose of the adjuvant is coupled to synthetic nanocarriers. In embodiments, the adjuvant dose comprises two or more types of adjuvants. For example, and without limitation, adjuvants that act on different receptors, such as different TLR receptors, can be combined. As an example, in one embodiment, a TLR 7/8 agonist can be combined with a TLR 9 agonist. In another embodiment, a TLR 7/8 agonist can be combined with a TLR 4 agonist. , in another mode, a TLR 9 agonist can be combined with a TLR agonist
    3. The term "administered" or "administration" means providing M "
    a substance to an individual in a way that is pharmacologically useful. "Effective amount" is any amount of a composition that produces one or more desired immune responses.
    This amount can be for in vitro or in vivo purposes.
    For in vivo purposes, the amount 5 may be such that a physician may believe that there is a clinical benefit for an individual in need of an immune response.
    Such individuals include those who have or are at risk for cancer, an infectious infection or disease, atopic condition, asthma, chronic obstructive pulmonary disease (COPD) or a chronic infection. . 10 Effective amounts include those that involve the generation of an antibody titer and / or the systemic release of one or more cytokines.
    In modalities, the effective quantidacles include those that involve the production of a systemic cytokine release profile.
    In some modalities, one or more cytokines or cytokine release profile 15 comprises the systemic release of TNF-o, IL-6 and / or IL-12. In other modalities, one or more cytokines or cytokine release profile comprises the systemic release of | FN-y.
    IL-12 and / or IL-18. This can be monitored by routine methods.
    An amount that is effective to produce one or more desired immune responses can also be an amount of a composition provided herein that produces a desired therapeutic outcome or a desired therapeutic outcome.
    The effective amounts depend, of course, on the particular individual being treated; the severity of the condition, disease or disorder; the individual parameters of the patient, such as age, physical condition, size and weight; the duration of treatment; the nature of the concomitant therapy (if any); the route of administration and similar factors within the physician's knowledge and specialty.
    These factors are well known to those with common skill in the art and can be addressed with no more than routine experimentation.
    Generally, it is preferable that a "maximum dose" is used, that is, the maximum safe dose according to medical opinion.
    It will be understood by those of ordinary skill in the art, however, that a patient may insist on the lowest dose or the dose
    The tolerable for medical reasons, psychological reasons or for almost any other reason.
    In modalities, the selection of doses of adjuvant (s), coupled to nanoveiculos depends on a comparison with the doses of adjuvant (s) separately (that is, not coupled to nanoveiculos) that generate a res - similar immune system (with or without antigen). As used here, the term "similar immune response" includes the immune responses that a physician would expect to see result in a comparable therapeutic outcome in an individual.
    Similar immune responses also include immune responses, which are the same type of response (for example, the induction of the same specific cytokine or set of cytokines, the generation of the same type of antibody titer, etc.), whose level is not considered to be statistically different.
    It can be determined by in vitro or in vivo techniques whether or not a similar immune response is generated.
    For example, it can be determined whether or not a similar immune response is generated by measuring the immune response (for example, antibody titer or cytokine release (s)) in an individual, by administering the separate dose of adjuvant ( with or without antigen) to the individual.
    The individual is not necessarily the same individual for which the composition of the invention comprising an adjuvant coupled to the nanoveiculone vehicle is administered in the methods of the invention.
    The individual, for example, can be an individual or individuals from the clinical trial, to whom the separate adjuvant dose has been previously administered.
    The individual can also be an individual or individuals in an animal model to whom the separate adjuvant dose has been previously administered.
    The determination of the immune response in the individual can also be determined by measuring the response of cells isolated from one individual, or cells from another individual or individuals, which are brought into contact with the separate adjuvant dose (with or without antigen). The other individual or individuals may again be individuals from previous clinical trials or animal model individuals.
    In modalities, the comparison is based on the measurement of a
    .- immune response (eg, particular type of antibody titer, particular level of cytokine, levels of a set of cytokines) can be made within the first 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 12, 15, 17, 20, 25, 30, 35, 40 or more hours after immunization with the separate adjuvant dose.
    In 5 other modalities, the immune response is measured within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40 or more days after immunization.
    Assays to determine whether an immune response is similar or not are known to those skilled in the art.
    In addition, examples of such tests are described in more detail in the Examples. . 10 Whether or not a separate dose of adjuvant (with or without antigen) generates a similar immune response can also be determined by what a physician would expect in relation to the immune response (or level of immune response) based on results from previous trials in vitro and / or in vivo (in other individuals). Such results may include the results of clinical trials where effective doses have been determined.
    Accordingly, the separate adjuvant dose that is used in the comparison is an amount that a doctor expects to be effective in producing the immune response or therapeutic effect.
    In another embodiment, the separate adjuvant dose that is used in the comparison is the separate adjuvant dose that a doctor expects to be the maximum tolerated dose.
    In embodiments, the dose of coupled adjuvant is 1-time, 2 times, 3 times, 4 times, 5 times or 6 times less than a separate dose of adjuvant which is an effective amount to generate an immune response or therapeutic result provided herein. .
    In other embodiments, the dose of coupled adjuvant is at least 1-time, 2 times, 3 times, 4 times, 5 times or 6 times less than a separate dose of adjuvant which is a maximum tolerated dose.
    In other embodiments, the dose of coupled adjuvants is greater than the dose of separate adjuvant which is an amount effective to generate an immune response or therapeutic result provided herein.
    In 30 other embodiments, the dose of coupled adjuvant is greater than a dose of separate adjuvant which is a maximum tolerated dose.
    In general, the doses of the adjuvant (s) or antigen (s) of the compounds
    . positions of the invention can range from about 0.001 µg / kg to about 100 mg / kg.
    In some embodiments, doses can vary from about -. from 0.01 µg / kg to about 10 mg / kg.
    Still, in other modalities, doses can vary from about 0.1 µg / kg to about 5 mg / kg, about 15 µg / kg to about 1 mg / kg, about 10 µg / kg up to about 0.5 mg / kg or about 100 µg / kg to about 0.5 mg / kg.
    In additional embodiments, doses can vary from about 0.1 µg / kg to about 100 µg / kg.
    In addition, in additional modalities, doses can vary from about 30 µg / kg to about 300 µg / kg.
    Alternatively, the dose can be administered with, 10 based on the number of synthetic nanocarriers.
    For example, useful doses include more than 106, 107, 108, 109 or 1010 synthetic nanocars per dose.
    Other examples of useful doses include from about 1X106 to about 1X1010, about 1X107 to about 1X109 or about 1X108 to about 1x109 synthetic nanocars per dose. 15 In modalities, the dose is a "subtherapeutic dose", which means an amount (for example, specified number of units of mass) of an adjuvant (or adjuvants) that provides a desired therapeutic result in which the subtherapeutic dose is an amount that is numerically less than would be required to provide substantially the same therapeutic result if administered separately.
    In this context, "separate" or "separately" means that the adjuvant (or adjuvants) is not (SãO) coupled (s) to a synthetic vehicle nanocouple.
    In one embodiment, the sub-therapeutic dose of R848 comprises 0.01 micrograms / kg to 100 micrograms / kg, preferably 0.1 micro-25 grams / kg to 10 micrograms / kg, of R848. In one embodiment, the subtherapeutic dose of CPG containing oligonucleotides comprises from 0.001 µg / kg to 2 mg / kg, preferably from about 0.01 µg / kg to 0.1 mg / kg, of CpG containing oligonucleotides.
    In yet another embodiment, the subtherapeutic dose of an immunologically active nucleic acid or derivative thereof ranges from 0.001 µg / kg to 2 mg / kg, preferably from 0.01 µg / kg to 0.1 mg / kg. kg.
    In another embodiment, a subtherapeutic dose of MPL "comprises from 0.001 µg / kg to 0.5 mg / kg.
    In other modalities, the dose is a "reduced toxicity dose", which means a dose of an adjuvant that provides a certain systemic cytokine release, preferably a certain systemic cytokine release profile, in which the dose of reduced toxicity is greater than the dose of adjuvant that would be necessary to provide substantially the same determined systemic cytokine release, preferably a certain systemic cytokine release profile, when administered separately.
    In this context, "separately" means that the adjuvant is not coupled to a synthetic nanoveiculone vehicle. , 10 Additionally, the "systemic cytokine release profile" means a systemic cytokine release pattern, in which the pattern comprises measured cytokine levels for several different systemic cytokines.
    In one embodiment, the reduced toxicity dose of R848 ranges from 0.01 micrograms / kg to 100 micrograms / kg, preferably 15 0.1 micrograms / kg to 10 micrograms / kg, of R848. In one embodiment, the reduced toxicity dose of CpG containing Igonucleotides comprises from 0.001 µg / kg to 2 mg / kg, preferably 0.01 µg / kg to 0.1 mg / kg, of oligonucleotide containing CpG.
    In another embodiment, the subtherapeutic dose of MPL® comprises from 0.001 µg / kg 20 to 0.5 mg / kg. "Antibody response" means any immune response that results in the production or stimulation of B cells and / or the production of antibodies.
    The "antibody titer" means the production of a measurable level of antibodies.
    Preferably, the antibody response or generation of the antibody titer is in a human.
    In some embodiments, antibodies are antibodies of a certain isotype, such as IgG or a subclass thereof.
    Methods of measuring antibody titers are known in the art and include immunosorbent enzyme binding assays (ELISA). Methods for measuring antibody titers are also described in some detail in the Examples.
    Preferably, the antibody response, or the antibody titer, is specific for an antigen.
    This antigen can be co-administered with the nanoveicle coupled with the adjuvant, but it can also not be co-administered. "Antigen" means a B cell antigen or a T cell antigen.
    In modalities, the antigens are coupled to the synthetic nanoveiculos.
    In other modalities, the antigens are not coupled to the 5 synthetic nanovehicles.
    In modalities, the antigens are co-administered with the synthetic nanovehicles.
    In other modalities, antigens are not co-administered with synthetic nanovehicles.
    The term "antigen type (s)" means molecules that share the same, or substantially the same, antigenic characteristics.
    In modalities, the antigens. 10 of the compositions provided are associated with the disease or condition being treated.
    For example, the antigen can be an allergen (for the treatment of an allergy or an allergic condition), a cancer-associated antigen (for the treatment of cancer or tumor), an infectious agent antigen (for the treatment of an infection, infectious disease or chronic infectious disease), etc. "At least a portion of the dose" means at least some portion of the dose, varying to include the entire dose.
    An "at risk" individual is one in which a doctor believes there is a possibility of having a disease or condition as provided herein. 20 "B cell antigen" means any antigen that is recognized by a B cell, and triggers an immune response in the B cell (for example, an antigen that is specifically recognized by a B cell receptor in a cell B). In some embodiments, an antigen that is a T cell antigen is also a B cell antigen. 25 In other embodiments, the T cell antigen is also not a B cell antigen.
    B cell antigens include, but are not limited to, proteins, peptides, small molecules and carbohydrates.
    In some embodiments, the B-cell antigen comprises a non-protein antigen (that is, neither a protein nor a peptide antigen). In some 30 modalities, the B cell antigen comprises a carbohydrate associated with an infectious agent.
    In some embodiments, the B cell antigen comprises a glycoprotein or glycopeptide associated with an infectious agent.
    The infectious agent can be a bacterium, virus, fungus, protozoa, parasite or prion.
    In some embodiments, the B cell antigen comprises a poorly immunogenic antigen.
    In some modalities, the B cell antigen comprises an abused substance or a portion thereof.
    In some embodiments, the B cell antigen comprises an addictive substance or a portion thereof.
    Addictive substances include, but are not limited to, nicotine, a narcotic, cough suppressants, a tranquilizer and a sedative.
    In some embodiments, the B cell antigen comprises a toxin, such as a toxin from a chemical weapon or from natural sources, or a pollutant.
    The B cell antigen may also comprise a dangerous environmental agent.
    In other modalities, the B cell antigen comprises an alloantigen, an allergen, a contact sensitizer, a degenerative disease antigen, a hapine, an infectious disease antigen, a cancer antigen, an antigen 15 from atopic disease, an autoimmune disease antigen, an addictive substance, a xenoantigen, or a metabolic disease enzyme or its enzyme product. "Choosing" means making a selection, either directly on its own or indirectly, such as, but not limited to, an unrelated third party 20 that takes action based on someone's words or actions.
    Generally, the same entity (for example, the individual, group of individuals acting in concert, or organization) provides a composition provided here and generates the desired immune response by administering the composition after having also selected the appropriate dose of the composition. composition.
    The term "co-administered" means administering two or more substances to an individual in a way that is time correlated, preferably sufficiently correlated over time, to provide a modulation of the immune response.
    In modalities, co-administration 30 can occur through the administration of two or more substances in the same dosage form.
    In other modalities, co-administration may include administration of two or more substances in different dosage forms, but within a certain period of time, preferably within 1 month, more preferably within 1 week, even more preferably within 1 day, and even more preferably within 1 hour. 5 The term "couple" or "couple" or "couple" (and the like) means the chemical association of one entity (for example, a portion) with another.
    In some modalities, the coupling is covalent, meaning that the coupling occurs in the context of the presence of a covalent bond between the two entities.
    In non-covalent modalities, the non-. 10 covalent is mediated by non-covalent interactions including, but not limited to, load interactions, affinity interactions, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, TT stacking interactions, link interactions by hydrogen, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, and / or their combinations.
    In embodiments, encapsulation is a form of coupling.
    In modalities, at least a portion of the dose of the adjuvant (s) is coupled to synthetic nanocarriers, preferably, the entire dose of the adjuvant (s) is coupled to synthetic nanocarriers.
    In modalities, at least a portion of dose 20 of the adjuvant (s) is not coupled to the synthetic nanocarriers.
    The term "dosage form" means a pharmacologically and / or immunologically active material in a medium, vehicle, vehicle or device suitable for administration to an individual.
    In embodiments, at least one dosage form of the invention may comprise a dose of one adjuvant or multiple adjuvants.
    In embodiments, more than one dosage form comprises an adjuvant dose, preferably in such embodiments more than one dosage form are co-administered.
    The term "Encapsulate" means to encompass within a synthetic nanocarrier, preferably completely encompassed within a synthetic nanocarrier.
    Most or all of a substance that is encased is not exposed to the local environment external to the synthetic nanoveicle.
    Encapsulation is distinct from adsorption, which places most or all of a substance on the surface of a synthetic nanoveicle, and leaves the substance exposed to the external environment of the synthetic nanoveicle. 5 "Generate" means to cause an action to occur, such as an antibody titer against an antigen or systemic cytokine release, either directly by itself, or indirectly, such as, but not limited to, an unrelated third party who takes action based on someone's words or deeds. , 10 An "infection" or "infectious disease" is any condition or disease caused by a microorganism, pathogen or other agent, such as a bacterium, fungus, prion or virus.
    The term "isolated nucleic acid" means a nucleic acid that is separated from its native environment and comes in a quantity sufficient to permit its identification or use.
    An isolated nucleic acid may be such that it is (i) amplified in vitro by, for example, polymerase chain reaction (PCR): (ii) produced recombinantly by cloning; (iii) purified, as by gel sieving and separation; or (iv) synthesized by, for example, chemical synthesis.
    An isolated nucleic acid is such that it is easily manipulated by recombinant DNA techniques well known in the art.
    Thus, a nucleotide sequence contained in a vector in which the 5 'and 3' restriction sites are known or for which the sequences of the polymerase chain reaction (PCR) primers have been revealed, is considered isolated but a sequence of acid nucleic acid existing in its native state in its natural host is not.
    An isolated nucleic acid can be substantially purified, but it need not be.
    For example, a nucleic acid that is isolated within a vector or expression vector is not pure, as it can comprise only a small percentage of the material in the cell where it resides.
    Such a nucleic acid is isolated, however, as the term is used in the present document because it is easily manipulated by common techniques known to those skilled in the art.
    None of the nucleic acids provided herein can be isolated.
    In some embodiments, the antigens in the compositions provided herein are present in the form of an isolated nucleic acid, such as a -. isolated nucleic acid encoding an antigenic peptide, polypeptide, or protein. 5 The term "isolated peptide, polypeptide or protein" means a polypeptide (or peptide or protein) that is separated from its native environment and is present in sufficient quantity to allow its identification or use. This means, for example, that the polypeptide (or peptide or protein) can be (i) selectively produced by expression cloning. 10 are either (ii) purified by chromatography or electrophoresis.
    Isolated peptides, proteins or polypeptides can be, but need not be, substantially pure.
    Since an isolated peptide, polypeptide or protein can be mixed with a pharmaceutically acceptable carrier in a pharmaceutical preparation, the polypeptide (or peptide or protein) can comprise only a small percentage by weight of the preparation.
    The polypeptide (or peptide or protein) is, however, isolated insofar as it has been separated from substances with which it may be associated in living systems, that is, isolated from other proteins (or peptides or polypeptides). Any of the peptides, polypeptides or proteins provided herein can be isolated.
    In some embodiments, the antigens in the compositions provided herein are in the form of peptides, polypeptides or proteins. "The maximum dimension of a synthetic nanocarrier" means the largest dimension of a nanocarrier measured along any axis of the synthetic nanocarrier. "The minimum size of a synthetic nanocarrier" means the smallest dimension of a synthetic nanocarrier measured along any axis of the synthetic nanocarrier.
    For example, for a synthetic spheroidal nanocarrier, the maximum and minimum dimensions of a synthetic nanocarrier would be substantially identical, and would be the size of its diameter.
    Similarly, for a cuboidal synthetic nanocarrier, the minimum dimension of a synthetic nanocarrier would be the smallest of its height, width or length, while the maximum dimension of a nanocarrier
    synthetic .r would be the largest of its height, width or length. In a modality, a minimum dimension of at least 75%, preferably at least 80%, more preferably at least 9Õ ° / o, of the synthetic nanocars in a sample, based on the total number of synthetic nanocars. 5 tetics in the sample, is greater than 100 nm. In one embodiment, a maximum dimension of at least 75%, preferably at least 8O'Yo, more preferably, at least 90%, of the synthetic nanocarriers in a sample, based on the total number of synthetic nanocarriers in the sample, is equal to or less than 5 µm. Preferably, a minimum size of 10 at least 75%, preferably at least 80 ° / 0, more preferably at least 90%, of the synthetic nanocars in a sample, based on the total number of synthetic nanocars in the sample, is greater than 110 nm, more preferably greater than 120 nm, more preferably greater than 130 nm, and more preferably, preferably greater than 150 nm. The 15 ratios of the aspects of the maximum and minimum dimensions of the inventive synthetic nanocarriers may vary, depending on the modality. For example, the aspect ratios of the maximum to minimum dimensions of synthetic nanocars can vary from 1: 1 to 1,000,000: 1, preferably from 1: 1 to
    100,000: 1, more preferably from 1: 1 to 1000: 1, still more preferably 20 from 1: 1 to 100: 1, and even more preferably from 1: 1 to 10: 1. Preferably, the maximum dimension of at least 75%, preferably at least 80%, more preferably, at least 90%, of the synthetic nanocarriers in a sample, based on the total number of synthetic nanocarriers in the sample, is equal to or less than 3 µm, more preferably equal to 25 or less than 2 µm, more preferably equal to or less than 1 µm, more preferably equal to or less than 800 nm, more preferably equal to or less than 600 nm and , even more preferably, equal to or less than 500 nm. In the preferred embodiments, a maximum size of at least 75%, preferably at least 8Õ ° / o, more preferably at least 30 90%, of the synthetic nanocars in a sample, based on the total number of synthetic nanocars in the sample, is equal to or greater than 100 nm, more preferably, equal to or greater than 120 nm, more preferably,
    equal to or greater than 130 nm, more preferably equal to or greater than 140 nm and, most preferably, equal to or greater than 150 nm.
    The measurement of the dimensions of a synthetic nanocarrier is obtained by suspending the synthetic nanocells in a liquid medium (usually aqueous) and using 5 dynamic light scattering (for example, using a Brookhaven ZetaPALS instrument). "Pharmaceutically acceptable carrier or excipient" means a pharmacologically inactive material used in conjunction with the synthetic nanocarriers cited to formulate the compositions of the invention.
    The pharmaceutically acceptable vehicles or excipients comprise a variety of materials known in the art, including, but not limited to, saccharides (such as glucose, lactose, and the like), preservatives such as antimicrobial agents, reconstitution aids, dyes, solutions - saline tion (as phosphate buffer) and buffers.
    In some embodiments, pharmaceutically acceptable carriers or excipients comprise calcium carbonate, calcium phosphate, various diluents, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
    The "individual" means animals, including warm-blooded mammals, such as humans and primates; birds; domestic or farm animals such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; wild animals and zoo gardens; and the like. 25 The "synthetic nanocouple (s)" means (m) a discrete object that is not found in nature and that has at least one dimension that is less than or equal to 5 microns in size.
    Albumin nanoparticles are usually included as synthetic nanocarriers, however in certain embodiments, synthetic nanocarriers do not comprise nanocarrier particles.
    In modalities, the synthetic nanoveiculos of the invention do not include chitosan.
    A synthetic nanocarrier can be, but is not limited to, one or a plurality of lipid-based nanoparticles (eg liposomes) (also referred to herein as lipid nanoparticles, that is, nanoparticles where most of the material that its structure are iipids), polymeric nanoparticles, metallic nanoparticles, emulsions based on 5 surfactant, dendrimers, magnetic metal spheres (buckyballs), daffodils, virus-like particles (that is, particles that are mainly made up of viral structural proteins but which are not infectious or have "low infectivity", particles based on peptides or proteins (also referred to here as protein particles, that is, particles on-10 of most materials that make up its structure are peptides or proteins) (such as albumin nanoparticles) and / or nanoparticles that are developed using a combination of nanomaterials, such as lipid nanoparticles os-polymers.
    Synthetic nanocars can be a variety of different shapes, including, but not limited to, 15 spheroidal, cuboidal, pyramidal, oblong, cylindrical, toroidal and the like.
    The synthetic nanoveicles according to the invention comprise one or more surfaces, including, but not limited to internal surfaces (surfaces generally facing an interior portion of the synthetic nanoveicle) and external surfaces (surfaces generally facing an environment). 20 external part of the synthetic nanoveicule). Exemplary synthetic nanoveicles that can be adapted for use in the practice of the present invention include: (1) the biodegradable nanoparticles disclosed in US Patent 5,543,158 by Gref et al-, (2) the polymeric nanoparticles of the Publication of US Patent Application 20060002852 by Saltzman et al., (4) the 25 nanoparticles built lithographically from US Patent Application Publication 20090028910 by DeSimone et al., (5) the disclosure of WO 2009/051837 by von Andrian et al., or (6) the nanoparticles disclosed in US Patent Application Publication 2008/0145441 by Penades et al.
    The synthetic nanovehicles according to the invention which have a minimum size of about 100 nm or less, preferably less than or equal to 100 nm, do not comprise a surface with hydroxyl groups that activate the complement or alternatively comprise a surface that it consists essentially of portions that are not hydroxyl groups that activate the complement.
    In a preferred embodiment, synthetic nano-vehicles according to the invention that have a minimum dimension of about 100 nm or less, preferably equal to or less than 100 5 nm, do not comprise a surface that substantially activates the compound. - complement or alternatively comprise a surface that consists essentially of portions that do not substantially activate the complement.
    In a preferred embodiment, the synthetic nanocarriers according to the invention, which have a minimum dimension of about 100 nm or less,, 10 preferably equal to or less than 100 nm, do not comprise a surface that activates the complement or alternatively comprise a surface that consists essentially of portions that do not activate the complement.
    In modalities, synthetic nanovehicles can have an aspect ratio greater than 1: 1, 1: 1,2, 1: 1,5, 1: 2, 1: 3, 1: 5, 1: 7, or higher to 1:10. 15 "Systemic cytokine fiberation" means the systemic release of one or more particular cytokines.
    In some modalities, systemic cytokine release is a certain profile of systemic cytokine release.
    In some modalities, the release of particular systemic cytokines, preferably a certain systemic release profile of 20 cytokines is found in a human being.
    In modalities, the compositions and methods provided here (where, at least, a portion of an adjuvant dose is coupled to nanoveiculos) results in a certain systemic cytokine release profile in an individual.
    The term "separate" or "separately" is also used to refer to the adjuvant that is not coupled to any synthetic nanovehicles.
    In addition, the "systemic cytokine release profile" means a systemic cytokine release pattern, in which the pattern comprises levels of cytokines measured for several different systemic cytokines.
    In some embodiments, the particular systemic cytokine release profile comprises the systemic release of TNF-cx, IL-6 and / or IL-12. In other modalities, the particular systemic profile of cytokine release comprises the systemic release of lFN-y, IL12 and / or IL-18.
    ,. "T cell antigen" means any antigen that is recognized by, and triggers, an immune response in a T cell (for example, an antigen that is specifically recognized by a T cell receptor in a T cell or a cell NKT via presentation of the antigen or a portion thereof to a molecule of the Class I or Class II major histocompatibility complex (MHC), or attached to a CD1 complex). In some embodiments, an antigen, which is a T cell antigen, is also a B cell antigen.
    In other embodiments, the T cell antigen is also not a B cell antigen.
    Cell T-cell antigens are usually proteins, polypeptides or peptides.
    T cell antigens can be an antigen that stimulates a CD8 + T cell response, a CD4 + T cell response, or both.
    Therefore, nanovehicles, in some modalities, can effectively stimulate both types of responses. 15 In some embodiments, the T cell antigen is a "universal" T cell antigen, or T cell memory antigen, (that is, one for which an individual has a pre-existing memory and which can be used to potentiate the help of T cells to an unrelated antigen, for example an unrelated B cell antigen). Universal T cell antigens include tetanus toxoid, as well as one or more peptides derived from tetanus toxoid, Epstein-8arr virus, or influenza virus.
    Universal T cell antigens also include a component of the influenza virus, such as hemagglutinin, neuraminidase, or nuclear protein, or one or more peptides derived therefrom.
    In some modalities, the universal T cell antigen is not the one that is presented in a complex with an MHC molecule.
    In some embodiments, the universal T cell antigen is not complexed with an MHC molecule for presentation to an auxiliary T cell.
    Accordingly, in some embodiments, the universal T cell antigen is not an auxiliary T cell antigen.
    However, in other embodiments, the universal T cell antigen is an auxiliary T cell antigen.
    In modalities, an auxiliary T cell antigen can
    comprise one or more peptides obtained or derived from tetanus toxoid, Epstein-8arr virus, influenza virus, respiratory syncytial virus, measles virus, mumps virus, rubella virus, cytomegalovirus, adenovirus, diphtheria toxoid, or a PADRE peptide (known from the work of Sette et 5 al.
    US patent 7,202,351). In other embodiments, a helper T cell antigen may comprise ovalbumin or a peptide obtained or derived therefrom.
    Preferably, ovalbumin comprises the amino acid sequence as defined in Accession No. AAB59956, NP_ 990483.1, AA-A48998 or CAA2371. In other embodiments, the peptide obtained or derived 10 from ovalbumin comprises the following amino acid sequence: H-lle-Ser- G | nA | a-Va | -His-A | a-Ala-His-A | aG | u - | e-Asn-G | u-Ala-G | i-Arg-OH (SEQ ID NO: 1). In other embodiments, an auxiliary T cell antigen may comprise one or more lipids, or ghcolipids, including, but not limited to: α-galactosylceramide (a-GalCer), α-linked glycosphingolipids (from Sphin-15 gomonas spp .), ga | actosi | diaci | g | icerols (from Borrelia burgdorferi), lipophosphoglycan (from Leishmania donovani) and phosphatidylinositol tetramanoside (PIM4) (from Mycobacterium leprae). For additional lipids and / or glycolipids useful as an auxiliary T cell antigen, see V.
    Cerundolo et al., "Harnessing invariant NKT cells in vaccination strategies." Nature Rev mmun, 9: 28-38 (2009). 20 In modalities, CD4 + T cell antigens can be derived from a CD4 + T cell antigen that is obtained from a source, such as a natural source.
    In such embodiments, CD4 + T cell antigen sequences, such as peptides that bind to MHC |, may have at least 70 ° / 0, 80 ° / 0, 90 ° / 0, or 95% identity with 25 the antigen obtained from the source.
    In modalities, the T cell antigen, preferably a universal T cell antigen or auxiliary T cell antigen, can be coupled to, or decoupled from, the synthetic nanoveicle.
    In some embodiments, the universal T cell antigen or the auxiliary T cell antigen is encapsulated in the synthetic nanovehicles of the inventive positions.
    The term "vaccine" means a composition of matter that improves the immune response to a particular pathogen or disease-
    A vaccine typically contains factors that stimulate the individual's immune system to recognize a specific antigen as foreign and eliminate it from the individual's body.
    A vaccine also establishes an immunological "memory" so that the antigen is quickly recognized and a response is triggered if the person is exposed to it again.
    Vaccines can be prophylactic (for example, to prevent future infection by any pathogen), or therapeutic (for example, a vaccine against a specific tumor antigen for the treatment of cancer or against an antigen derived from an infectious agent for treatment) , 10 of an infection or infectious disease). In embodiments, the vaccine can comprise dosage forms according to the invention.
    Preferably, in some embodiments, vaccines comprise an adjuvant (or adjuvants) coupled to a synthetic nanocarrier.
    In specific embodiments, the compositions of the invention incorporate adjuvants comprising agonists for Toll-like receptors (TLRS) 7 & 8 ("TLR 7/8 agonists"). Of utility are the TLR 7/8 agonist compounds disclosed in US Patent 6,696,076 to Tomai et al., Including, but not limited to, imidazoquinoline amines, imidazopyridine amines, fused 6,7-cycloalkylimidazopyridine amines and 20 amines 1,2-bridged imidazoquinoline.
    Preferred adjuvants comprise imiquimod and R848. In specific embodiments, the compositions of the invention incorporate adjuvants that comprise a ligand for the Toll-like receptor (TLR) -9, such as immunostimulatory DNA molecules 25 comprising CpGs, which induce secretion of type I interferon and stimulates the activation of T and B cells, leading to an increase in the production of antibodies and the responses of cytotoxic T cells (Krieg et al ,, CpG motifs in bacterial DNA trigger direct B cell activation.
    Nature. 1995. 374: 546-549; Chu et al.
    CpG oligodeosoxynucleotides act as adjuvants that bind to auxiliary T immunity 1 (Thl). J.
    Exp.
    Med. 1997. 186: 1623-1631; Lipford et al.
    Synthetic oligonucleotides containing CpG promote cytotoxic B and T cell responses to protein antigen: a new class of additives
    ^
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    -r vaccine youth.
    Eur.
    J. Immunol. 1997. 27: 2340-2344; Roman et al.
    At
    -. immunostimulatory DNA sequences function as adjuvants promoting T-helper T.
    Nat.
    Med. 1997. 3: 849-854; Davis et al.
    CpG DNA is a potent enhancer of specific immunity in mice immunized 5 with recombinant hepatitis B surface antigen - J. Immunol. 1998. 160: 870-876; Lipford et al., Bacterial DNA as immune cell activator.
    Trends Microbiol. 1998. 6: 496-500. In embodiments, CpGs may comprise modifications designed to enhance stability, such as phosphorothioate bonds, or other modifications, such as modified bases.
    See, for e-. 10 for example, US Patents 5,663,153, 6,194,388, 7,262,286 and 7,276,489. In certain embodiments, to stimulate immunity rather than tolerance, a composition provided here incorporates an adjuvant that promotes DC maturation (necessary for the use of pure T cell primers) and the production of cytokines, such as interferons from type I, which promote the 15 immune responses to antibodies and antiviral immunity.
    In some embodiments, the adjuvant comprises a TLR-4 agonist, such as a bacterial lipopolysaccharide (LPS), VSV-G and / or HMGB-I.
    In some modalities, adjuvants comprise cytokines, which are small proteins or biological factors (in the range of 5 KD-20 KD) that are released by the 20 cells and have specific effects on the cell-cell interaction, the community cation and behavior of other cells.
    In some embodiments, adjuvants comprise pro-inflammatory stimuli released by necrotic cells (eg, urate crystals). In some embodiments, adjuvants comprise activated components of the complement cascade (for example, CD21, CD35, etc.). In some embodiments, adjuvants comprise activated components of immune complexes.
    Adjuvants also include those that comprise complement receptor agonists, such as a molecule that binds to CD21 or CD35. In some embodiments, the complement 30 receptor agonist induces the endogenous opsonization of the complement of the nanoveicle.
    Adjuvants also include those that comprise cytokine receptor agonists, such as a cytokine.
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    W In some embodiments, the cytokine receptor agonist is. a small molecule, antibody, fusion protein, or aptamer. In modalities, adjuvants may also comprise immunomostimulatory RNA molecules, such as, but not limited to, dsRNA, or poly 5 l: C (a TLR3 stimulant), and / or those disclosed in F. Heil et al. , "Species-Specific Recognition of Single-Stranded RNA via Toll-like Receiver 7 and 8" Science 303 (5663), 1526-1529 (2004); J. Vollmer et al., "Immune modulation by chemically modified ribonucleosides and oligoribonucleotides" WO 2008033432 A2; A. Forsbach et al., "Lmmunostimulatory oligoribonucleo-, 10 tides containing specific sequence motif (s) and targeting the Toll-like receptor 8 pathway" WO 2007062107 A2; E. Uhlmann et al., "Modified oligoribonucleotide analogs with enhanced immunostimulatory activity" Pat. U.S. AppI. Publ. US 2006241076; G. Lipford et al., "Immune viral RNA oligonucleotides and use for treating cancer and infections" WO 2005097993 A2; 15 G. Lipford et al., "Immunostimulatory G, U-containing oligoribonucleotides, compositions, and screening methods" WO 2003086280 A2. In some embodiments, adjuvants comprise gel-type adjuvants (for example, aluminum hydroxide, aluminum phosphate, calcium phosphate, etc.), microbial adjuvants (for example, immunomodulachlor DNA sequences that include CpG motifs: molecules immunostimulatory RNAs; endotoxins such as monophosphoryl lipid A; exotoxins such as cholera toxin, E. coli thermolabile toxin and pertussis toxin; muramyl dipeptide, etc.); oil-emulsion and emulsifier-based adjuvants (eg Freund's Adjuvant, MF59 [Novartis], SAF, 25 etc.); adjuvant particles (for example, liposomes, biodegradable microspheres, saponins, etc.); synthetic adjuvants (e.g., non-ionic block copolymers, muramyl peptide analogs, polyphosphazene, synthetic polynucleotides, etc.), and / or combinations thereof. COMPOSITIONS OF THE INVENTION 30 A wide variety of synthetic nanocarriers can be used according to the invention. In some modalities, synthetic nanovehicles are spheres or spheroids. In some modalities, nanovelcu-
    -the synthetic ones are flat or in the form of a plate- In some embodiments, the synthetic nanoveiculos are cubes or cuboid.
    In some modalities, synthetic nanovehicles are oval or elliptical.
    In some modalities, synthetic nanovehicles are cylindrical, conical or pyramidal. 5 In some modalities, it is desirable to use a population of synthetic nanocarriers that is relatively uniform in terms of size, shape and / or composition, so that each synthetic nanocarrier has similar properties.
    For example, at least 80%, at least 90 ° / j or at least 95% of synthetic nanocars, based on. 10 total number of synthetic nanocars, can have a minimum or maximum dimension that falls within 5 ° / 0, 10 ° / j, or 20 ° 6 of the average diameter or average dimension of synthetic nanocars.
    In some modalities, a population of synthetic nano vehicles can be heterogeneous with respect to size, shape and / or composition. 15 Synthetic nanocarriers can be solid or empty and can comprise one or more layers.
    In modalities, each layer has a unique composition and unique properties in relation to the other layer (s). To give just one example, synthetic nanocars can have a central structure / cover, where the core is a layer (for example, a polymeric core) and the cover is a second layer (for example, a monolayer or lipid bilayer) . Synthetic nanocars can comprise a plurality of different layers.
    In some embodiments, synthetic nanovehicles may optionally comprise one or more lipids.
    In some embodiments, a synthetic nanocarrier may comprise a liposome.
    In some embodiments, a synthetic nanocarrier may comprise a lipid bilayer. In some embodiments, a synthetic nanocarrier may comprise a lipid monolayer.
    In some embodiments, a synthetic nanocarrier may comprise a micelle.
    In some embodiments, a synthetic molecule may comprise a core comprising a polymeric matrix surrounded by a lipid layer (e.g., lipid bilayers, lipid monolayer, etc.). In some modalities, a single nanoveicle
    .
    The synthetic material may comprise a non-polymeric nucleus (for example, metallic particles, quantum particles, ceramic particles, bone particles, viral particles, proteins, nucleic acids, carbohydrates, etc.), surrounded by a lipid layer (for example, example, lipid bilayer, lipid monolayer, 5 etc.). In some embodiments, synthetic nanocarriers may comprise one or more polymeric polymers or matrices. In some embodiments, such a polymer or polymeric matrix may be surrounded by a coating layer (e.g., liposome, lipid monolayer, 10 ca, micelle, etc.). In some embodiments, various elements of the synthetic nanocarriers may be coupled with the polymer or polymeric matrix. In some embodiments, an element, such as an immunocharacteristic surface, target portion, antigen, adjuvant and / or oligonucleotide, can be covalently associated with a polymeric matrix. In some modalities, the covalent association is mediated by a ligand. In some embodiments, an element may be non-covalently associated with a polymeric matrix. For example, in some embodiments, an element can be encapsulated inside, surrounded by, and / or dispersed through a polymer matrix. Alternatively or additionally, an element can be associated with a polymeric matrix by hydrophobic interactions, charge interactions, van der Waals forces, etc. A wide variety of polymers and niethodes for forming polymer matrices there are conventionally known. In general, a polymeric matrix comprises one or more polymers. The polymers can be natural or unnatural (synthetic) polymers. The polymers can be homopolymers or copolymers comprising two or more monomers. In terms of the sequence, copolymers can be random, block, or comprise a combination of random and block sequences. Typically, the polymers according to the present invention are organic polymers. Examples of polymers suitable for use in the present invention include, but are not limited to, polyethylenes, polycarbonates
    .
    36/72 '(eg poly (1,3-dioxane-2-one)), polyanhydrides (eg poly (sebaceous anhydride)), polypropylfumerates, polyamides (eg polycaprolactam), polyacetals, polyethers , polyesters (eg, polylactide, polyglycolide, pol | i | actide-co-g | icicide, polycaprolactone, polyhydroxy acid (eg, poly 5 (B-hydroxy | canoe))), poly (orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphate, polyacrylate, polymethacrylate, polyurea, polystyrene, polyamine, polylysine, polylysine-PEG copolymers, poly (ethyleneimine), polyester polyethylene (polyethylene) compounds According to pre-, 10 this invention includes polymers that have been approved for use in humans by the US Food and Drug Administration (FDA) under 21 CFR § 177.2600, including, but not limited to, polyesters (for example, polylactic acid, poly (lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly (1,3-dioxane-2one)); polyanhydrides (for example, poly-15 (sebaceic anhydride)): polyethers (for example, polyethylene |): polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates. In some embodiments, the polymers can be hydrophilic. For example, polymers can comprise anionic groups (for example, phosphate group, sulfate group, carboxylate group); cationic groups 20 (for example, quaternary amine group); or polar groups (e.g., hydroxyl group, thiol group, amine group). In some embodiments, a synthetic nanocouple comprising a hydrophilic polymeric matrix generates a hydrophilic environment in the synthetic nanocarrier. In some embodiments, the polymers may be hydrophobic. In some embodiments, a synthetic nanovelcle 25 comprising a hydrophobic polymeric matrix generates a hydrophobic environment in the synthetic nanocarrier. The selection of the hydrophilicity or hydrophobicity of the polymer can have an impact on the nature of the materials that are incorporated (eg coupled) within the synthetic nanoveicle. In some embodiments, the polymers can be modified 30 with one or more portions and / or functional groups. A variety of portions or functional groups can be used in accordance with the present invention. In some embodiments, polymers can be modified V
    37/72 r with po | ieti | enog | ico | (PEG), with a carbohydrate, and / or with acyclic polyacetals derived from polysaccharides (Papisov, 2001, ACS Symposium Series, 786: 301). Some modalities can be done using the general teachings of US Patent No. 5543158 to Gref et al., Or Publication WO 5 WO2009 / 051837 by Von Andrian et al.
    In some embodiments, the polymers can be modified with a lipid or fatty acid group.
    In some embodiments, a fatty acid group may be one or more of butyric, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, benign, OL1. 10 lignoceric.
    In some embodiments, a group of fatty acids may be one or more of palmitoleic, oleic, vaccenic, linoleic, alpha-linoleic, gamma-linoleic, arachidonic, gadoleic, arachidonic, eicosapentaenoic, or docosahexaenoic or erucic acid.
    In some embodiments, the polymers may be polyesters, 15 including copolymers comprising units of lactic acid and glycolic acid, such as, for example, poly (lactic acid-co-glycolic acid) and polyQactide-co-glycolide, collectively referred to here as "PLGA"; and homopollomers comprising glycolic acid units, referred to herein as "PGA," and lactic acid units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D, L-lactic acid, poly-L-lactide, poly-D-lactide and poly-D, L-lactide, collectively referred to herein as "PLA." In some embodiments, exemplary polyesters include, for example, polyhydroxy acids; PEG copolymers and lactide and glycolide copolymers (for example, PLA-PEG cup-limers, PGA-PEG copolymers PLGA-PEG copolymers and their 25 derivatives.
    In some embodiments, polyesters include, for example, poly (caprolactone), copolymers of poly (caprolactone) -PEG, poIi (L-lactide-co-L-lysine), poly (serine ester), poly (4-ester) -hydroxy-L-proline), poly [a- (4-aminobutyl) -L-glycolic acid], and their derivatives.
    In some embodiments, a polymer can be PLGA.
    PL-30 GA is a biocompatible and biodegradable copolymer of lactic acid and glycolic acid, and various forms of PLGA are characterized by the lactic acid: glycolic acid ratio.
    Lactic acid can be L-lactic acid,
    D-lactic acid, or D, L-lactic acid.
    The degradation rate of PLGA can be adjusted by changing the proportion of lactic acid: glycolic acid.
    In some embodiments, the PLGA to be used in accordance with the present invention is characterized by a lactic acid: glycolic acid ratio of approximately 85:15, approximately 75:25, approximately 60:40, approximately 50: 50, approximately 40:60, approximately 25:75, or approximately 15:85. In some embodiments, the polymers can be one or more acrylic polymers.
    In certain embodiments, acrylic polymers include, for example, copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (acrylic acid) ), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, methacrylate copolymer, aminoacrylate copolymer glycidyl, polycyanoacrylates, and combinations comprising one or more of the polymers mentioned above.
    The acrylic polymer can comprise the fully polymerized copolymers of esters of acrylic and methacrylic acid with a low content of quaternary ammonia groups.
    In some embodiments, the polymers can be cationic polymers.
    In general, cationic polymers are able to condense and / or protect negatively charged strands from nucleic acids (e.g.
    DNA, or its derivatives). Amine-containing polymers, such as polyl (lysine) (Zauner et al., 1998, Adv.
    Drug Del.
    Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6: 7), poly (ethylene imine) (PEI: Boussif et al., 1995, Proc.
    Natl.
    Acad.
    Sci., USA, 1995, 92: 7297), and polyl (amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc.
    Natl.
    Acad.
    Sci., USA, 93: 4897; Tang et al., 1996, Bioconjugate Chem., 7: 703; and Haensler et al., 1993, Bioconjugate Chem., 4: 372) are positively charged at physiological pH, form ionic pairs with nucleic acids and mediate transfection in a variety of cell lines.
    In modalities, the nanovehicles
    synthetics of the invention may not comprise (or may exclude) cationic polymers.
    In some embodiments, the polymers can be degradable polyesters comprising cationic side chains (Putnam et al., 1999, 5 Macromolecules, 32: 3658; Barrera et al., 1993, J.
    Am.
    Chem.
    Soc., 115: 11010: Kwon et al., 1989, Macromolecules, 22: 3250; Lim et al., 1999, J.
    Am.
    Chem.
    Soc., 121: 5633; and Zhou et al., 1990, Macromolecules, 23: 3399). Examples of these polyesters include poly (L-lactide-co-L-lysine) (Barrera et al., 1993, J.
    Am.
    Chem.
    Soc., 115: 11010), polo (serine ester) (Zhou et al., - 10 1990, Macromolecules, 23: 3399), poly (4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32: 3658; and Lim et al., 1999, j.
    Am.
    Chem.
    Soc.,
    "121: 5633), and poly (4-hydroxy-L-proline ester) (Putnam et al., 1999, Macro-molecules, 32: 3658; and Lim et al., 1999, J.
    Am.
    Chem.
    Soc., 121: 5633). The properties of these and other polymers and methods of preparation are well known in the art (see, for example, US Patents 6,123,727; 5,804,178; 5,770,417; 5,736,372; 5,716,404; 6,095,148; 5,837,752: 5,902,599; 5,696,175; 5,514,378; 5,512,600; 5,379,665; : 5,010,167; 4,806,621; 4,638,045; and 4,946,929; Wang et al., 2001, J.
    Am.
    Chem.
    Soc., 123: 9480; Lim et al., 2001, J.
    Am.
    Chem.
    Soc., 20 123: 2460; Langer, 2000, Acc.
    Chem.
    Res., 33:94; Langer, 1999, J.
    Control.
    Release, 62: 7; and Uhrich et al., 1999, Chem.
    Rev., 99: 3181) - More generally, a variety of methods for synthesizing certain suitable polymers is described in the Concise Encyclopedia of Science of Polymers and Polymeric Amines and Ammonium Salts, ed. by Goethals, Pergamon Press, 1980; Principles 25 of Polymerization by Odian, John Wiley & Sons, Fourth Edition, 2004: Conventional Polymer Chemistry by Allcock et al., Prentice-Hall, 1981; Deming et al., 1997, Nature, 390: 386; and in U.S.
    Patents 6,506,577, 6,632,922, 6,686,446, and 6,818,732. In some embodiments, the polymers can be straight or branched polymers.
    In some embodiments, the polymers can be dendrimers.
    In some embodiments, the polymers can be substantially cross-linked to each other.
    In some embodiments, polymers
    "
    .
    40/72 can be substantially free of crosslinking. In some embodiments, polymers can be used in accordance with the present invention without undergoing a crosslinking step. In addition, it is to be understood that the synthetic nanocarriers of the invention can comprise block copolymers, graft copolymers, homogenates, mixtures, and / or adducts of any of the above mentioned polymers or other polymers. Those skilled in the art will recognize that the polymers listed here represent an exemplary, non-comprehensive list of polymers that can be used in accordance with the present invention. , 10 In some embodiments, synthetic nanocars comprise one or more polymers. Polymeric synthetic nanoveicles, therefore, can also include those described in WO WO2009 / 051837 by Von Andrian et al., Including, but not limited to, those with one or more hydrophilic components. Preferably, the one or more polymers comprises (m) a polyester, such as a poly (lactic acid), poIi (glycolic acid), poIi (acetic-co-glycolic acid), or polycaprolactone. More preferably, the one or more polymers further comprise or comprise a polyester coupled to a hydrophilic polymer, such as a polyether. In embodiments, the polyether comprises the polyethylene glycol 20 Even more preferably, the one or more polymers comprise a polyester and a polyester coupled to a hydrophilic polymer, such as a polyether. In other embodiments, the one or more polymers are coupled to one or more antigens and / or one or more adjuvants. In embodiments, at least some of the polymers are coupled to the antigen (s) and / or at least 25 of the polymers are coupled to the adjuvant (s). Preferably, when there is more than one type of polymer, one of the types of polymer is coupled to the antigen (s). In modalities, one of the other types of polymers is coupled to the adjuvant (s). For example, in embodiments, when nano-vehicles comprise a polyester and a polyester coupled to a hydrophilic polymer, such as a polyether, the polyester is coupled to the adjuvant, while the polyester attached to the hydrophilic polymer, such as, for example, a polyester. polyether, is linked to the antigen (s) - In modalities, where nanovehicles
    .
    41/72 comprise an auxiliary T cell antigen, the auxiliary T cell antigen "0 can be encapsulated in the nanoveicle. In some embodiments, the synthetic nanocarriers may not comprise a polymeric component. In some embodiments, the 5 synthetic nanocarriers may comprise particles of metal, quantum dots, ceramic particles, etc. In some embodiments, a synthetic non-polymeric nanocarrier is an aggregate of non-polymeric components, such as an aggregate of metal atoms (for example, gold atoms)., 10 In some embodiments, synthetic nanovehicles may optionally comprise one or more amphiphilic entities In some embodiments, an amphiphilic entity can promote the production of nanoparticles with increased stability, improved uniformity, or increased viscosity. can be associated with the inner surface of a lipid membrane (for example, lipid bilayer, monoc beloved lipid, etc.). Many amphiphilic entities known in the art are suitable for use in the manufacture of synthetic nanovehicles according to the present invention. Such amphiphilic entities include, but are not limited to, phosphoglycerides; phosphatidylcholine; dipa | mitoylphosphatidi | co |ine (DPPC): dioleylphosphatidylethanolamine (DOPE): dioleyloxypropyltriethylammonium (DOTMA); dio | eoi | phosphatidine | co | ina; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidylglycerol (DPPG); hexanodecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; fat acids; fatty acid monoglycerides; diglycerides of fatty acids; fatty acid amides; sorbitan trioleate (Span® 85) glycocholate; sorbitan monolaurate (Span® 20); polysorbate 20 (Tween® 20); polysorbate 60 (Tween® 60); polysorbate 65 (Tween® 65); polysorbate 80 (Tween® 80): polysorbate 85 (Tween® 85): 30 polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (ce-
    ^ falina); cardiolipin; phosphatidic acid; cerebrosides; dicetylphosphate; dipalmi- toilphosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; palmitate -. acetyl; glycerol ricinoleate; hexadecyl stearate; isopropyl myristate; tiloxapol; po | i (ethyl | enogen |) 5000-phosphatidylethanolamine; poly (ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents having high surfactant properties; deoxycholates: cyclodextrins; chaotropic salts; ion pairing agents; and their combinations.
    A component of the amphiphilic entity can be a mixture of different amphiphilic entities.
    Technique experts will recognize that this is one. 10 exemplary, non-exhaustive list of substances with surfactant activity.
    Any amphiphilic entity can be used in the production of synthetic nanocars for use in accordance with the present invention.
    In some embodiments, synthetic nanocarriers may optionally comprise one or more carbohydrates.
    Carbohydrates can be natural or synthetic.
    A carbohydrate can be a derivatized natural carbohydrate.
    In certain embodiments, a carbohydrate comprises monosaccharides or disaccharides, including, but not limited to, glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid and galactonic acid, manuronic acid, glucosamine, galactosamine and neuramic acid.
    In certain modalities, a carbohydrate is a polysaccharide, including, but not limited to, pullulan, cellulose, microcrystalline cellulose, hydroxypropümetHcelulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, starch , hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, 25 N, O-carboxylmethyl chitosan, algin and alginic acid, starch, chitin, heparin, inulin, konjac, glucomannan, pustulan, heparin, hyaluronic acid, curdlaine and xanthan.
    In embodiments, the synthetic nanovehicles of the invention do not include (or specifically exclude) carbohydrates, such as, for example, a polysaccharide.
    In certain embodiments, the carbohydrate may comprise a carbohydrate derivative such as a sugar alcohol, including, but not limited to, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol.
    Compositions according to the invention comprise the
    _-J nine synthetic vehicles of the invention in combination with pharmaceutical excipients
    -. ceutically acceptable, such as preservatives, buffers, saline or phosphate buffered saline.
    The compositions can be made using conventional pharmaceutical manufacturing and composition techniques to arrive at useful dosage forms.
    In one embodiment, the inventive synthetic nano-vehicles are suspended in sterile saline solution for injection together with a preservative.
    In modalities, when preparing synthetic nanovehicles as vehicles for agents (for example, antigen or adjuvant) for use. For use in vaccines, methods of coupling the agents to synthetic nanovessels can be useful.
    If the agent is a small molecule, it may be an advantage to bind the agent to a polymer before the aggregation of the synthetic nanocarriers.
    In embodiments, it may also be an advantage to prepare synthetic nanocarriers with surface groups that are used to couple the agent to the synthetic nanocarrier using these surface groups instead of attaching the agent to a polymer and then using this polymer combined in the construction of synthetic nanocarriers.
    A variety of reactions can be used for the purpose of associating agents with synthetic nanovehicles. 20 In certain embodiments, the coupling can be a covalent bond.
    In embodiments, the peptides according to the invention can be covalently coupled to the outer surface through a 1,2,3-triazole linker formed by a 1,3-dipolar cycloaddition reaction of the azido groups on the nanoveicle surface with antigens or adjuvants of surface 25 containing an alkaline group or by 1,3-dipolar cycloaddition reaction of alkanes on the nanoveicule surface with antigens or adjuvants containing an azide group.
    Such cyclloading reactions are preferably carried out in the presence of a Cu (l) catalyst together with a suitable Cu (l) ligand and a reducing agent to reduce the Cu (ll) compound to the 30 Cu (l) active catalyst.
    This cycloaddition of azide-alkali catalyzed by Cu (l) (CuAAC) can also be referred to as a click reaction.
    Additionally, the covalent coupling can comprise a
    44/72 is a covalent linker comprising an amide linker, a disulfide linker, -. a thioether linker, a hydrazone linker, a hydrazide linker, an imine or oxime linker, a urea or thiourea linker, an amidine linker, an amine linker and a sulfonamide linker.
    5 An amide linker is formed through an amide bond between an amine in a component such as the antigen or the adjuvant with the carboxylic acid group of a second component, such as the nanowove. The amide bond in the linker can be made using any of the conventional amide bond formation reactions with the amino acids or. 10 suitably protected antigens or adjuvants and activated carboxylic acid such as the N-hydroxysuccinimide ester.
    A disulfide bond is made by forming a disulfide bond (S-S) between two sulfur atoms in the form, for example, of R1-S-S-R2. A disulfide bond can be formed by thiol exchange of an antigen or adjuvant containing a thiol / mercaptan group (-SH) with another thiol group activated in a polymer or nanoveicle or a nanoveicle containing thiol / mercaptan groups with an antigen or adjuvant containing the activated thiol group. A triazole binder, specifically a 1,2,3-triazole of the form Rj N —N Ç '20 R2, where R1 and R2 can be any chemical entities, is made by a 1,3-dipolar cycloaddition reaction of an azide Attached to a first component such as the nanoveicle with a terminal alkaline bonded to a second component, such as the peptide. The 1,3-dipolar cycloaddition reaction is carried out with or without a catalyst, preferably with a Cu (l) catalyst, which connects the two components through a 1,2,3-triazole function. This chemistry is described in detail by Sharpless et al., Angew. Chem. Int. Ed. 41 (14), 2596, (2002) and Meldal, et al., Chem. Rev., 2008, 108 (8), 2952-3015 and is usually referred to as a "click" reaction or CuAAC- In modalities, a polymer containing a group m
    45/72 azide or alkaline, terminal for the polymer chain.
    This polymer is then
    -. used to prepare a synthetic nanoveicle in such a way that a plurality of the alkaline or azide groups are positioned on the surface of that nanocele.
    Alternatively, the synthetic nanoveicle can be prepared by another route, and subsequently functionalized with alkali or azide groups.
    The antigen or adjuvant is prepared in the presence of either an alkaline (if the polymer contains an azide) or an azide group (if the polymer contains an alkali). The antigen and / or adjuvant is then left to react with the nanoveicle through a 1,3-dipolar cycloaddition reaction with or without. 10 is a catalyst that covalently couples the antigen or adjuvant to the particle via the 1,2,3-triazole 1,4-disubstituted linker.
    A thioether linker is made by forming a sulfur-carbon bond (thioether) in the form, for example, of R1-S-R2. The thioether can be made either by alkylating a thiol / mercaptan group (-SH) in a component such as the antigen or adjuvant with an alkylating group, such as halide or epoxide over a second component, such as the nano vehicle.
    Thioether linkers can also be formed by adding Michael of a thiol / mercaptan group on a component such as an antigen or an adjuvant to an electron-deficient alkene group on a second of the component, such as a polymer containing a maleimide group or a vinylsulfone group as Michael's acceptor.
    Otherwise, thioether linkers can be prepared by the radical thiol-ene reaction of a thiol / mercaptan group on a component such as an antigen or adjuvant with an alkene group on a second component such as a polymer 25 or a nanocarrier.
    A hydrazone linker is made by reacting a hydrocarbon group on a component such as the antigen or adjuvant with a chemical aldehyde / ketone group on the second component, such as the nanocove. 30 A hydrazide linker is formed by reacting a hydrazine group on one component and such as the antigen or adjuvant with a carboxylic acid group on the second component, such as
    it.
    Such a reaction is usually carried out using chemistry similar to the formation of the amide bond where the carboxylic acid is activated with an activating reagent.
    An imine or oxime ligand is formed by reacting an amine or N-alkoxyamine (or aminooxy) group on a component such as the antigen or adjuvant with an aldehyde or ketone group on the second component, such as like the nano-vehicle.
    A urea or thiourea ligand is prepared by reacting an amine group on a component such as the antigen or adjuvant with. 10 an isocyanate or thioisocyanate group on the second component, such as the nanoveicle.
    An amidine linker is prepared by reacting an amine group on one component such as the antigen or the adjuvant with an imidoester group on the second component, such as the nanoveicle. 15 An amine linker is prepared by the alkylation reaction of an amine group on a component such as the antigen or adjuvant with an alkylating group such as halide, epoxide or sulfonate ester on the second component, such as the nanove.
    Alternatively, an amine linker can also be made by reducing amination of an amine group on a component such as the antigen or adjuvant with an aldehyde or ketone group on the second component, such as the nanove with a suitable reducing reagent such as cyanoboro- sodium hydride or sodium triacetoxyborohydride.
    A sulfonamide linker is prepared by reacting an amine group on a component such as the antigen or adjuvant with a sulfonyl halide group (such as sulfonyl chloride) on the second component, such as the nanocarrier.
    A sulfone ligand is made by adding Michael from a nucleophile to a vinyl sulphonic.
    Both the vinylsulfone and the nucleophile can be on the surface of the nanoparticle or attached to the antigen or adjuvant.
    The antigen or adjuvant can also be conjugated to the nanoveicle using non-covalent conjugation methods.
    For example
    For example, a negatively charged antigen or adjuvant can be conjugated to a positively charged nanoveicle through electrostatic adsorption. An antigen or adjuvant containing a metal linker can also be conjugated to a nanoveicle containing a metal 5 complex via a metal-ligand complex. In embodiments, the antigen or adjuvant can be attached to a polymer, for example, to poly | acetic acid-b | hollow-po | ieti | enogen | prior to the assembly of the synthetic nanocarrier or the synthetic nanocarrier can be formed with groups reactive or activable on its surface. That last. In this case, the antigen or adjuvant can be prepared with a group that is compatible with the bonding chemistry that is presented by the surface of the synthetic nanovehicles. In other embodiments, agents, such as a peptide antigen, can be associated with VLPS or liposomes using suitable binding. A linker is a compound or reagent that is capable of coupling two molecules together. In one embodiment, the linker can be a homobifunctional or heterobifunctional reagent as described in Hermanson 2008. For example, a synthetic VLP or liposomal nanoveicle containing a carboxylic group on the surface, can be treated with a homobifunctional ligand, adipic dihydrazide ( ADH), in the presence of 20 EDC to form a synthetic synthetic nanocarrier with the ADH ligand. The resulting synthetic DNA linked to the ADH is then conjugated to an agent containing an acid group through the other end of the ADH linker in NC to produce the corresponding VLP conjugate or liposomal peptide. 25 For detailed descriptions of the available conjugation methods, see Hermanson GT "Bioconjugate Techniques", 2nd Edition Published by Academic Press, lnc., 2008. In addition to the covalent bond, the antigen or adjuvant can be coupled by adsorption to a preformed synthetic nanoveicle or can be coupled by encapsulation during the formation of the synthetic nanoveicle. METHODS OF MANUFACTURING AND USE OF THE METHODS OF THE INVENTION AND RELATED COMPOSITIONS
    .
    48/72 Synthetic nanocars can be prepared using a wide variety of methods known in the art. For example, synthetic nanocars can be formed by methods such as nanoprecipitation, focusing on the flow of fluid channels, spray drying, evaporation of the solvent from the single and double emulsion, solvent extraction, phase separation, grinding, procedures microemulsion, microfabrication, nanofabrication, sacrificial layers, simple and complex coacervation, and other methods well known to those of ordinary skill in the art. Alternatively or in addition, solvent syntheses. 10 aqueous and organic for monodisperse, conductive, magnetic, organic and other nanomaterials have been described (Pellegrino et - al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30 : 545; and Trindade et al., 2001, Chem. Mat., 13: 3843). Additional methods have been described in the bibliography (see, for example, Doubrow, Ed., "Microcapsules and 15 Nanoparticles in Medicine and Pharmacy," CRC Press, Boca Raton, 1992: Mathiowitz et al., 1987, j. Control. Release. , 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6: 275; and Mathiowitz et al., 1988, J. AppI. Polymer Sci., 35: 755, US Patents 5578325 and 6007845; P. Paolicelli et al ., "Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliv- 20 er Virus-like Particles" Nanomedicine. 5 (6): 843-853 (2010)). Various materials can be encapsulated in synthetic nanocars as desired, using a variety of methods, including, but not limited to, C. Astete et al., "Synthesis and characterization of PLGA nanoparticles" J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 25 (2006): K. Avgoustakis "Pegylated Poly (Lactide) and Poly (Lactide-Co-Glyco-Iide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery" Current Drug Delivery 1: 321-333 (2004 ); C. Reis et al., "Nanoencapsulation I. Methods for preparing drug-loaded polymeric na-noparticles" Nanomedicine 2: 8 - 21 (2006); P. Paolicehi et al., "Surface-30 modified PLGA-based Nanoparticles that can Efficiently Associate and Virus-like Particles" Nanomedicine. 5 (6): 843-853 (2010). Other methods suitable for encapsulating materials, such as oligonucleotides, in synthetic nanocarriers can be used, including without the limitation methods disclosed in United States Patent 6,632,671 to Unger (October 14, 2003). In certain embodiments, synthetic nano vehicles are prepared by a process of nanoprecipitation or spray drying.
    The conditions used in the preparation of synthetic nanovehicles can be changed in order to produce particles of the size or with the desired property (for example, hydrophobicity, hydrophilicity, external morphology, "adhesion", shape, etc.). The method of preparing synthetic nanocarriers. 10 cos and the conditions (for example, solvent, temperature, concentration, air flow rate, etc.) used may depend on the materials to be coupled to the synthetic nano-vehicles and / or the composition of the polymeric matrix.
    If the particles prepared by any of the above methods have a size range outside the desired range, the particles 15 can be sized, for example, using a sieve.
    The elements of the synthetic nanovehicles of the invention - such as the target portions, polymeric matrices, antigens, adjuvants and the like - can be coupled to the synthetic nanoveicle, for example, by one or more covalent connections, or they can be coupled by means of a 20 or more binders.
    Additional methods of functionalizing synthetic nanowells can be adapted from US Patent Application Publication 200610002852 by Saltzman et al., US Patent Application Publication 2009/0028910 to DeSimone et al., Or Publication of Application International Patent WO / 2008/127532 A1 to Murthy et al. 25 Alternatively or in addition, synthetic nanocarriers can be coupled to an element, such as immunocharacteristic surfaces, target portions, adjuvants, various antigens, etc. directly or indirectly, via non-covalent interactions.
    In non-covalent modalities, non-covalent bonding is mediated by non-covalent interactions including, 30 but not limited to charge interactions, affinity interactions, metallic coordination, physical adsorption, host-guest interactions, hydrophobic interactions, TT stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, and / or their combinations.
    Such couplings can be arranged to be on an external surface or an internal surface of a synthetic nanovehicle of the invention.
    In 5 modalities, encapsulation and / or absorption is a form of coupling.
    In embodiments, the synthetic nanovehicles of the invention can be combined with other adjuvants by mixing in the same vehicle or delivery system.
    Such adjuvants may include, but are not limited to. 10 to mineral salts, such as alum, alum combined with lipid monophosphoryl (MPL) A from Enterobacteria, such as Escherihia co / i, Salmone // a minnesota, Sa / mone // a {yphimurium, or Shige // af / exneri or specifically with MPL® (AS04), AS15, MPL A of the above mentioned bacteria, saponins, such as QS-21, Quil-A, ISCOMS, ISCOMATRIX "", and- 15 mulsions such as MF59®, Montanide ® ISA 51 and ISA 720, AS02 (QS21 + esceneno + MPL®), liposomes and liposomal formulations such as ASOl, microparticles and microtransporters synthesized or specifically prepared such as outer membrane vesicles derived from N. gononheae bacteria (OMV), Ch / amydia trachomatis and others, or chitosan particles, deposit forming agents, such as Pluronic® block copolymers, specifically modified or prepared peptides, such as muramyl dipeptide, aminoalkylglucosaminide 4-phosphates, such as RC529, or proteins , such as bacterial toxoids or fragments of toxin.
    Additional useful adjuvants can be found in WO 25 2002/032450: US 7,357,936 "Adjuvant Systems and Vaccines"; US 7,147,862 "Vaccine composition containing adjuvants"; US 6,544,518 "Vaccines"; US 5,750,110 "Vaccine composition containing adjuvants." The doses of these other adjuvants can be determined using studies of conventional dosing intervals.
    In modalities, the adjuvant that is not coupled to the said synthetic nanocarriers, if any, may be the same or different from the adjuvant that is coupled to the synthetic nanocarriers.
    . «In modalities, any adjuvant coupled to the nanoveiculos
    . Synthetic compounds of the invention can be different, similar or identical to those not coupled to a nanowatt (with or without antigen, using or not using another delivery vehicle) - Adjuvants (coupled and unattached) can be administered separately in one different time and / or in a different body location and / or by a different immunization route or with another synthetic nanoveicle carrying adjuvant (with or without antigen) administered separately at a different time and / or in a different body location and / or by an immunization route. 10 different.
    Populations of synthetic nanocars can be combined
    - designed to form pharmaceutical dosage forms according to the present invention, using traditional pharmaceutical mixing methods.
    These include a liquid-liquid mixture in which two or more suspensions, each containing one or more subsets of nanovehicles, are directly combined or are brought together through one or more containers containing diluent.
    Since synthetic nanocars can also be produced or stored in powder form, a dry powder-powder mixture could be carried out as could be the resuspension of two or more 20 powders in a common medium.
    Depending on the properties of the nanocars and their interaction potentials, there may be advantages attributed to one or the other mixing path.
    Typical compositions of the invention that can be used in the methods of the invention comprise synthetic nanocarriers which can comprise inorganic or organic buffers (e.g., sodium or potassium phosphate, carbonate, acetate, or citrate salts) and pH adjusting agents (eg hydrochloric acid, sodium or potassium hydroxide, citrate or acetate salts, amino acids and their salts), antioxidants (eg ascorbic acid, alpha-tocopherol), surfactants (eg polysorbate 20, polysorbate 30 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and / or cryo / lithium stabilizers (eg sucrose, lactose, mannitol, trehalose), osmotic regulating agents (eg salts or sugars), agents antibacterial
    &
    52/72 years (eg benzoic acid, phenol, gentamicin), antifoam agents (eg, polydimethylsilozone), preservatives (eg, thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity regulating agents (eg polyvinylpyrrolidone, poloxamer 488, carboxymethyl-5 cellulose) and co-solvents (e.g., glycerol, polyethylene, ethanol). The compositions that can be used in the methods according to the invention comprise synthetic nanovessels of the invention in combination with pharmaceutically acceptable excipients.
    The compositions can be made using conventional pharmaceutical manufacturing and composition techniques to arrive at useful dosage forms.
    Techniques suitable for use in the practice of the present invention can be found in the Industrial Mixing Manual: Science and Practice, Edited by Edward L.
    Paul, Victor A.
    Atiemo-Obeng, and Suzanne M.
    Kresta, 2004 John Wi-ley & Sons, lnc .; and Pharmaceutics: The Science of Dosage Form Design, 2 "15 Ed.
    Edited by M.E.
    Auten, 2001, Churchill Livingstone.
    In an embodiment, the inventive synthetic nanovehicles are suspended in sterile saline solution for injection together with a preservative.
    It is to be understood that the compositions of the invention that can be used in the methods of the invention can be made in any suitable manner, and the invention is in no way limited to the use of the compositions that can be produced using the methods described herein. - tos.
    Selecting an appropriate method may require attention to the properties of the particular portions being associated.
    In some embodiments, the synthetic nanovehicles of the invention are manufactured under sterile conditions or are terminally sterilized. This can ensure that the resulting compositions are sterile and non-infectious, thereby improving safety when compared to non-sterile compositions.
    This provides a valuable safety measure, especially when individuals who receive synthetic nanocarriers have immune defects, suffer from infection and / or are susceptible to infection.
    In some embodiments, the synthetic nanoveicules of the invention can be lyophilized and stored in suspension or in lyophilized powder depending on
    f
    53/72 given the formulation strategy to stay long periods without losing activity.
    Compositions that can be used in the methods of the invention can be administered by a variety of routes of administration, including, but not limited to, subcutaneous, intramuscular, intradermal, oral, intranasal, transmucosal, sublingual, rectal, ophthalmic, transdermal, transcutaneous or by a combination of these routes.
    The doses of the dosage forms contain varying amounts of populations of synthetic nanocars and / or varying amounts of. 10 adjuvants and / or antigens, according to the invention.
    The amount of synthetic nautical vehicles and / or adjuvants and / or antigens present in the dosage forms of the invention can be varied according to the nature of the adjuvants and / or the antigens, the therapeutic benefit to be achieved, and other such parameters .
    In some embodiments, doses of the dosage forms are sub-therapeutic or reduced toxicity doses.
    In other embodiments, doses are amounts effective to generate one or more immune responses as provided here.
    In some modalities, the immune response (s) is an antibody response or generation of an antibody titer and / or systemic release of cytokines.
    In modalities, dose interval studies can be conducted to determine the optimal therapeutic amount of the population of synthetic nanovehicles and / or the amount of adjuvants and / or antigens to be present in the dosage form.
    In embodiments, synthetic nanovehicles and / or adjuvants and / or antigens are present in dosage form in an amount effective to generate an immune response, as provided herein, upon administration to an individual.
    In some modalities, the individual is a human.
    It may be possible to determine the amounts of adjuvants and / or antigens effective to generate an immune response as provided herein using conventional dose range studies and techniques in individuals.
    The dosage forms of the invention can be administered at a variety of frequencies. In a preferred embodiment, at least one administration of the dosage form is sufficient to generate a pharmacologically relevant response.
    In a more preferred embodiment, at least two administrations, at least three administrations or at least four administrations, of the dosage form are used to ensure a pharmacologically relevant response. 5 The compositions and methods described herein can be used to induce, improve, stimulate, modulate, target or redirect an immune response.
    The compositions and methods described herein can be used in the diagnosis, prophylaxis and / or treatment of conditions such as cancer, infectious diseases, metabolic diseases, degenerative diseases, diseases. 10 autoimmune, inflammatory diseases, immunological diseases, or other diseases and / or conditions.
    The compositions and methods described herein can also be used for the prophylaxis or treatment of an addiction, such as a nicotine addiction or a narcotic.
    The compositions and methods described herein can also be used for the prophylaxis and / or treatment of a condition resulting from exposure to a toxin, dangerous substance, environmental toxin, or other harmful agent.
    In embodiments, the compositions and methods provided can be used to systemically induce cytokines, such as TNF-cx, IL-6 and / or IL-12, or IFN-y, IL-12 and / or IL-18. In other embodiments, the compositions and methods provided can be used to induce an antibody response or to generate an antibody titer.
    The immune responses as provided herein can be specific for an antigen, such as any of the antigens provided here, preferably for one or more antigens in a composition of the invention or which is administered according to a method of the invention, provided herein.
    The compositions and methods provided herein can be used on a wide variety of individuals.
    The individuals provided here may have or be at risk for cancer.
    Cancers include, but are not limited to, breast cancer; biliary tract cancer; bladder cancer; brain cancer including glioblastomas and medulloblastomas; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including lymphocytic and myelogenous leukemia, for example, CLL B cells; acute T-cell lymphoblastic leukemia / lymphoma; hairy cell leukemia: chronic myelogenous leukemia, multiple myeloma: leukemias associated with AIDS and adult T-cell leukemia / lymphoma; epithelial neoplasms including Bowen's disease and Paget's disease; liver cancer; lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cell carcinoma; ovarian cancer including those fronts of epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; . 10 sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma; testicular cancer including germinal tumors such as seminoma and non-seminoma (teratomas, choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullary carcinoma; and renal carcinoma including adenocarcinoma and Wilms' tumor.
    The individuals provided here may have or be at risk of having an infection or infectious disease.
    Infectious diseases or infections 20 include, but are not limited to, infectious viral diseases, such as AIDS, chicken pox (chickenpox), common cold, cytomegalovirus infection, Colorado tick fever, Dengue fever, Ebola hemorrhagic fever, Ebola disease hand, foot and mouth, Hepatitis, Herpes simplex, Herpes zoster, HPV, influenza (flu), Lassa fever, Measles, Marburg hemorrhagic fever, infectious nonucleosis, Mumps, Norovirus, Poliomyelitis, progressive multifocal leukoencephalopathy, rabies, rubella , SARS, smallpox (Variola), viral encephalitis, viral gastroenteritis, viral meningitis, viral pneumonia, West Nile disease and yellow fever; infectious bacterial diseases, such as anthrax, bacterial meningitis, botulism, brucellosis, campillobacteriosis, cat scratch disease, cholera, diphtheria, epidemic typhus, gonorrhea, impetigo, legellosis, Iepra (Hansen's disease), listerospirosis , Lyme disease, melioidosis, rheumatic fever, MRSA infection, nocardiosis, Pertussis (whooping cough), Plague, pneumococcal pneumonia, Psittacosis, Q fever, Malarial fever (RMSF), salmonellosis, scarlet fever, shigellosis. s ifilis, tetanus, trauma, tuberculosis, tularemia, typhoid fever, typhus and urinary tract infections: parasitic infectious diseases, such as African trypanosomiasis, amoebiasis, ascariasis, babesiosis, Chagas disease, Clonorchiasis, Cryptosporiditis yo if, Cysticercosis, Diphyllobotriase, Dracu nculiase, Echinococcosis, Fascioliasis, Fasciolopsiase, filariasis, free amoeba infection, giardlase, gnatosome tomiasis, hymenolepiasis, lsosporiasis, Kala azar, leishmaniasis, mycosis, malaria, Meiasis, malaria , nematode infection,. 10 scabies, schistosomiasis, teniasis, Toxocariase, toxoplasmosis, trichinellosis, trichinosis, tricuriasis, trichomoniasis and trypanosomiasis; fungal infectious disease, such as aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Tinea pedis (athlete's foot) and Tinea cruris; infectious diseases the prion, such as Alpers' disease, Fatal Family Insomnia 15, Gerstmann-Strãussler-Scheinker syndrome, Kuru and variant of Creutzfeldt-jakob disease. The individuals provided for here also include those who have or are at risk of having an atopic condition, such as, but not limited to, allergy, allergic asthma, or atopic dermatitis; asthma; chronic obstructive pulmonary disease (COPD, eg emphysema or chronic bronchitis); and chronic infections due to chronic infectious agents, such as chronic leishmaniasis, candidiasis or schistosomiasis and infections caused by plasmodium, Toxoplasma gondii, mycobacteria, HlV, HBV, HCV, EBV or CMV, or any of the above, or any subset of the same 25.
    EXAMPLES Example 1: Synthetic Nanoveicles with Covalently Coupled Adjuvants [Prophetic] Resiquimod (aka R848) is synthesized according to the synthesis 30 provided in Example 99 of US Patent 5,389,640 to Gerster et al. The PLA-R848 conjugate is prepared. The PO-PEG-nicotine conjugate is prepared. The PLA is prepared by ring-opening polymerization using
    D, L-lactide (MW = approximately 15 KD - 18 KD). The structure of the PLA is confirmed by NMR. Polyvinyl alcohol (Pm = 11 KD - 31 KD, 8S ° / hydrolyzed) was purchased from VWR scientific. These are used to prepare the following solutions: 5 1. PLA-R848 conjugate @ 100 mg / mL in methylene chloride
    2. P> -PEG-nicotine in methylene chloride @ 100 mg / mL,
    3. PLA in methylene chloride @ 100 mg / mL,
    4. Polyvinyl alcohol in water @ 50 mg / mL. Solution # 1 (0.25 to 0.75 ml), solution # 2 (0.25 ml) and solution. 10 tion # 3 (0.25 to 0.5 mL) are combined in a small flask with distilled water (0.5 mL) and the mixture is sonicated at an amplitude of 50 ° 6 for _ 40 seconds, using a Digital Sonifier Branson 250. To this emulsion was added solution # 4 (2.0 mL) and sonication at 35% amplitude for 40 seconds, using the Branson Digital 250 Sounder, forming the second emulsion. This was added to a beaker containing a phosphate buffer solution (30 ml), and this mixture was stirred at room temperature for 2 hours to form the nanovehicles. To wash the nanovessels, a portion of the nanovillage dispersion (7.0 mL) was transferred to a centrifuge tube and spun at 5.30 Og for one hour, the supernatant was removed, and the pellet was resuspended in 7, 0 mL of phosphate buffered saline. The centrifugation procedure was repeated and the pellet was resuspended in 2.2 mL of phosphate buffered saline for a final dispersion of the nanoveicle of about 10 mg / mL. Example 2: Synthetic Nanoveicles with Adjuvants Coupled with 25 Non-Covalently [Prophetic] Additives The loaded nanoveicles are made as follows:
    1. PLA-PEG-OMe in methylene chloride @ 100 mg / mL,
    2. PLA in methylene chloride @ 100 mg / mL,
    3. Cetyltrimethylammonium bromide (CTAB) in 5 mg / mL water 30 Solution # 1 (0.25 to 0.75 mL), solution # 2 (0.25 mL) and distilled water (0.5 mL) they are combined in a small bottle with distilled water (0.5 mL) and the mixture is sonicated at a 50% amplitude for 40 seconds, using a Branson 250 Digital Sonifier. To this emulsion, solution # 3 (2 , 0 mL) and sonication at 35% amplitude for 40 seconds, using the Branson Digital 250 Sounder, forming the second emulsion. This was added to a beaker containing a phosphate buffer solution (30 mL), and this mixture was stirred at room temperature for 2 hours to form the nanovehicles. To wash the nanovillage, a portion of the nanovillage dispersion (7.0 mL) was transferred to a centrifuge tube and spun at 5.30 Og for one hour, the supernatant was removed, and the pellet was resuspended in 7.0 mL of saline also. 10 point of phosphates. The centrifugation procedure was repeated and the pellet was resuspended in 2.2 ml of deionized water (Dl) for a final dispersion of the nanoveicle of about 10 mg / ml. In order to adsorb an antigen, in this case CpG DNA, to the nanocarriers, 1.0 ml of the nanocarriers loaded in 10 mg / mL Dl water are cooled on ice. To this chilled suspension 10 µg of CpG ODN 1826 DNA are added, and this mixture is incubated at 4 ° C for 4 hours. The nanovehicles are then isolated and washed as described above. Example 3: Composition with Synthetic Nanoveiculos and Decoupled Antigen (Prophetic) 20 Polyvinyl alcohol (Pm = 11 KD - 31 KD, 87-89% partially hydrolyzed) was purchased from JT Baker. The peptide ovalbumin 323-339, was purchased from Bachem Americas lnc. (3132 Kashiwa Street, Torrance CA
    90505. Order # 4065609). The conjugates PLGA-R848 (or PLA-R848) and PLA-PEG-antigen or PO-PEG-ligand or PLA-PEG-OMe are synthesized and purified. The materials described above were used to prepare the following solutions:
    1. PLA-R848 or PLGA-R848 conjugate in methylene chloride @ 100 mg / mL, 30 2. PLA-PEG-OMe in methylene chloride @ 100 mg / mL,
    3. PLA or PLGA in methylene chloride @ 100 mg / mL,
    4. Polyvinyl alcohol in 100 mM phosphate buffer pH 8 @ 50 mg / mL-
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    Solution # 1 (0.1 to 0.9 ml) and solution # 2 (0.01 to 0, 50 ml) were combined, optionally also including solution # 3 (0.1 to 0.89 ml), and then distilled water (0, 50 mL) was added in a small container and the mixture was sonicated at an amplitude of 50 ° / 0 for 40 seconds using a Branson Digital 250 Sounder. To this emulsion, solution # 4 (2.0 - 3.0 mL) and the sonication was performed with a 30 ° 6 amplitude for 40 seconds, using the Branson Digital 250 Sounder, forming the second emulsion. This was added to a beaker with agitation, containing a solution phosphate buffer 70 mM ph 8 (30 ml), and this. The mixture was stirred at room temperature for 2 hours to form the nanocarriers.
    To wash the nanocarriers, a portion of the nanocarrier dispersion (25 to 32 mL) was transferred to a 50 mL centrifuge tube and spun at 9,500 rpm (13.80Og) at 4 ° C for one hour, the supernatant was removed, and the pellet was resuspended in 25 to 32 mL of saline solution in the phosphate buffer.
    The centrifugation procedure was repeated and the pellet was resuspended in phosphate buffered saline to achieve a nominal final nanoveicle concentration of 10 mg / mL.
    The nanovehicles are combined with the required amount of sterile saline to reach a final concentration in a sterile vehicle, and then administered to an individual by subcutaneous or intramuscular injection using a conventional slip-on syringe or Luer lock .
    Example 4: Administration of Synthetic Nanoveiculi and Non-Co-administered Antigen (Prophetic) 25 The synthetic nanoveiculi of Example 3 are formulated in a sterile saline vehicle and then administered to an individual by subcutaneous or intramuscular injection using a conventional syringe slip-on tip or Luer lock.
    The individual is exposed to an environmental antigen (for example, pollen, animal antigens, etc.) that is not co-administered with synthetic nanocarriers.
    Any alteration in the immune response to the non-coadministered antigen that is due to the administration of the synthetic nanoveicules is observed.
    Example 5: Synthetic nanocarriers with Covalently Coupled Adjuvants The virus-like particles (VLP'S) received attention as nanovehicles for use in vaccines and for drug delivery. 5 Virus-like particles can also be used to provide covalently linked adjuvants.
    Virus-like particles can be made by a variety of methods, for example, as described in Biotechnology and Bioengineering 100 (1), 28, (2008). The covalent bond can be carried out as follows. . 10 A suspension of virus-like particles in PBS (1.0 mL, 300 µg / mL) is cooled on ice. To this is added the conjugate R-
    "848 (50 mg, described below) in PBS (0.5 ml). EDC hydrochloride (50 mg) is added and the mixture is stirred gently overnight at ice temperature.
    The resulting VLP conjugate is released from excess R848 conjugate by dialysis.
    The R848 conjugate is made as follows.
    R848 (5.0 gm, 1.59 X 10 "2 mol) and diglyclic anhydride (3.7 gm, 3.18 X 10" 2 moles) are combined
    in dimethylacetamide (10 mL). The solution is heated to 120 ° C for 2 hours.
    After cooling a little, 2-propanol (25 ml) is added, and the resulting solution is stirred on ice for 1 hour.
    The imides separate as a white solid which is isolated by filtration, washed with 2-propanol and dried.
    The yield of imide R848 is 6.45 gm (98%). Imide R848 (412 mg, 1.0 X 10 "soft) and 6-hydroxycaproic acid (132 mg, 1.0 X 10" 3 mol) are stirred in methylene chloride
    25 (5 ml). To this suspension is added 1,5,7-triazabicyclo [4.4,0] dec-5-ene (TBD, 278 mg, 2 x 10 "3 moles) after which the suspension is stirred overnight at room temperature .
    The resulting clear solution is diluted with methylene chloride (25 ml), and this solution is washed with 5% citric acid solution (2 x 25 ml). After drying over magnesium sulfate, the solution is filtered and evaporated in vacuo to provide the R848 conjugate used in the synthesis of antigen-VLP.
    The expected structure of the R848 conjugate is as follows:
    «61/72 h3ç, hc - + -—- ,, r
    Ç, 0, '"oEt h3c' n" , [i "" jA j: 'í ,, o ÍÍ "" "" "" "" "n" "" "" n "" "" "" " "" "" "" "" "" "o (chz} 5co2h h Example 6: Coupling the Nanoveicle with the Adjuvant R848 Prevents Systemic Production of Inflammatory Cytokines Groups of mice were injected subcutaneously into the hind limbs with 100 µg of nanoveicles (NC) coupled, non-5 coupled or mixed with nucleoside analogs of small molecules and a TLR 7/8 agonist and an adjuvant, R848, known. The amount of R-848 in the nanoveicules was 2-3% resulting in 2 -3 µg of R-848 coupled by injection, the amount of free R-848 used was 20 µg per injection.The mouse serum was removed by terminal bleeding and the systemic production of cytokines in the serum was measured in moments different by ELISA (BD Biosciences) .As seen in figures 1A-1C, a strong systemic production was observed production of the main pro-inflammatory cytokines TNF-a, IL-6 and IL-12 when mixed R848 (NC + R848) , although expression of TNF-a, IL-6 and IL-12 15 was not detected when two separate NC preparations were used coupled with R848 (NC-R848-1 and NC-R848-2). The difference in expression levels at peak cytokines was> 100-fold for TNF-a and IL-6, and> 50-fold for IL-12. The NC not coupled to R848 (marked only as NC) did not induce any systemic cytokines when used without being mixed with R848. Example 7: Coupling the Nanoveicle to Adjuvant R848 does not inhibit the Systemic Production of Immune Cytokines IFN-y While the initial pro-inflammatory cytokines are associated with side effects during immunization, the production of other cytokines, such as immune lFN-y it is known to be important in inducing an effective immune response. Thus, an assay was performed in the same way as Example 6. The systemic production of the immune cytokine lFN-y (as measured in the mouse serum by ELISA, BD Biosciences), which is instrumental for the
    «
    62/72 Thl immune response, was obeyed to reach the same level regardless of whether NC-R848 (containing 2 µg of R848) or NC with commuted R848 (20 µg) was used (figure 2). Additionally, the production of | FN-y by NP-R848 was spread over a wide time window. 5 Example 8: The Production of Systemic IL-12 by R848 and CpG Adjuvants is Abolished by Their Coupling to Nanovehicles The effect on the systemic induction of cytokines by coupling a TLR agonist with a nanoveicub has been shown not to be specific for a given TLR agonist.
    In this assay, groups of two _ 10 mice were inoculated by free agonists TLR R848 or CpG 1826 (20 µg each) and by the same molecules coupled to nanocarriers, NC-R848 (100 µg NC prep, containing a total of 3 µg of R848) or NC-CpG (100 µg of prep NC, containing a total of 5 µg of CpG 1826), and IL-12 in the serum measured at the times indicated in the combined rat sera (ELISA, BD Bi-15 osciences ). As seen in figure 3, peak levels of systemic IL-12 were 30 times higher than those of free R848 than for NC-R848 and 20-times higher than those obtained with free CpG 1826 compared to NC-CpG). Example 9: Local Induction of Immune Cytokines IFN-'y, IL-12 20 and IL-1 j3 is Strongly Increased by Coupling Adjuvant to Nanoveicles, When Adjuvant Is Saved When systemic induction of pro-inflammatory cytokines is associated with adverse effects of vaccination, the local induction of immune cytokines, such as lFN-y and 1L-1j3, is seen as essentially beneficial for the induction of the specific and localized immune response.
    In the test shown in figure 4, the mice were injected subcutaneously in the hind limb with free R848 and CpG adjuvants (20 µg) or coupled to NC (content in 2.5 -4 µg adjuvant), draining (popIíteal ) lymph nodes (LN) removed at the indicated times, incubated overnight in standard cell culture medium and cytokine production in cells measured by ELISA, as described above.
    The much stronger local induction of Thl lFNq 'cytokines (50-100-fold, figure 4A) and IL-12 (17-fold, figure 4B) and IL q
    63/72 cytokines related to lL-1j3 inflammasome (6-fold, figure 4C) was observed when NC-R848 was used compared to R848 (free (namely, the amounts of R848 present in NC-R848 were 5-10 times less than free R848. Similarly, NC-5 CpG was a much stronger inducer of local immune cytokines than free CpG (known to be extremely potent in this regard). IFN-y was 7-15 times higher than peak levels (figure 4A), IL-12 production was 4 times higher (figure 4B), and lL-1f3 production was 2 times higher (figure 4C). The amount of CpG 1826 present in NC-CpG.10 was 4-5 times less than that of free CpG 1826.
    Example 10: Stimulation of Local Lymph Nodes (LN) and ln- "reduction of Immune Cell Proliferation by R848 NC-coupled, but not by R848 Free Adjuvant The swelling of lymph nodes in drainage (lymphadenopathy) is an indicator of immune activation place.
    It results from the infiltration of LN by different cellular instruments for an innate and adaptive immune response.
    Mice were inoculated subcutaneously with NC-R848, NC only or with NC-R848 on the hind limbs as described above.
    Popliteal LNs were removed at the indicated times (figure 5), and the total number of cells was 20, as well as the population of separate immune cells counted.
    The hemocytometer was used for total cell count, and then the cell populations were differentially stained with cell surface markers and the percentage of positives for each population determined using FACS.
    DC: dendritic cells, mDC: myeloid DC, pDC: 25 plasmacytoid DC, Mph: macrophages, Gr: granulocytes, B: B cells, T: T cells, NK: natural killer cells- The following markers were used for collaboration: CD11C "(DC): CD11C" B220 "(mDC); CD11C" B220 "(pDC); F4 / 80 + / Gr1" (Mph); F4 / 80 "/ Gr1" (Gr); B220 "CD11c" (B cells); CD3 "(T cells); CD3" / CD49b "(NK cells). The main increase in the total number of cells in LN emptying was observed after injection with NC-R848 with DC, granulocytes, B- cells and NK cells showing the most pronounced effect (figure 5).
    q
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    Example 11: Response of the Superior Antibody to Nanocarriers with Conjugated Adjuvant versus Mixed Adjuvant Additives for Nanoveicule Formulations N1C, R848, OPj | The TFA amide salt of ovalbumin peptide 323-339 was purchased from Bachem Americas lnc. (3132 Kashiwa Street, Torrance CA 90505. Part # 4064565). PLA with an inherent viscosity of 0.19 dljg was purchased from Boehringer lngelheim (lngelheim Germany.
    Product code R202H.) A PLA-R848 conjugate with a molecular weight of approximately 2,500 Da and an R848 content of approximately was synthesized. 10 13.6% by weight by a ring opening process.
    PLA-PEG-Nicotine with a nicotine-terminated PEG block of approximately 3,500 "Da and the DL-PLA block of approximately 15,000 Da were synthesized.
    Polyvinyl alcohol (Pm = 11,000 - 31,000, 87-89 ° 6 hydrolyzate) was purchased from JT Baker.
    Baker (part number U232-08). 15 Methods for the Production of Nanoveicle N1C, R848, OPjI The solutions were prepared as follows: Solution 1: The ovalbumin peptide 323 - 339 @ 69 mg / mL was prepared in distilled water at room temperature.
    Solution 2: PLA-R848 @ 50 mg / mL, PLA @ 25 mg / mL and 20 PLA-PEG-Nicotine @ 25 mg / mL in dichloromethane were prepared by dissolving the polymers at 100 mg / mL, combining the PLA-R848 and PLA solutions in a 2: 1 ratio and then adding 1 part of PLA-PEG-Nicotine solution to 3 parts of PLA-R848 / PLA solution.
    Solution 3: Polyvinyl alcohol @ 50 mg / mL at 100 mM in deionized water.
    Solution 4: Phosphate buffer, 70 mM pH 8. A primary emulsion (Wl / O) was created first using Solution 1 and Solution 2. Solution 1 (0.1 mL) and solution 2 (1.0 mL) were combined in a small glass tube under pressure and sonicated at a 50% amplitude for 40 seconds, using a Branson Digital 250 Sounder. A secondary emission ( N1 / ONV2) was then formed by adding solution 3 ( 2.0 mL) to the primary emulsion and sonicating at 35%
    -
    for 40 seconds using the Branson Digital 250 Sounder. The secondary emulsion was added to a beaker containing 70 mM phosphate buffer solution (30 ml) in an open 50 ml beaker and was stirred at room temperature for 2 hours. to allow the dichloromethane to evaporate and the nanovehicles to form in suspension. A portion of the suspended nautilus was washed by transferring the suspension of nautilus to a centrifuge tube, rotating at 5,300 rcf for 60 minutes, removing the supernatant and resuspending the sediment in phosphate buffered saline. This washing procedure was repeated. 10, and then the pellet was resuspended in phosphate-buffered saline to achieve a nanocarrier suspension having a nominal concentration of 10 mg / ml in a polymer base. The suspension was stored frozen at -20 ° C until use.
    Table 1: Characterization of Nanoveicle N1c, R848, OP-II Nanoveicle ID effective diameter TLR Agonist, Peptide I Cells (nm) I% w / w Í T-helper, ° / 0 w / w I N1c, R848, OP -II I 234 I R848, 0.7 I Ova 323-339, 1.8 15 Materials for the Nanoveicule Formulations Nic, 0, OP-11 The TFA amide salt of ovalbumin peptide 323-339, was purchased from Bachem Americas lnc. (3132 Kashiwa Street, Torrance CA 90505. Part # 4064565). PLA with an inherent viscosity of 0.19 dljg was purchased from Boehringer lngelheim (lngelheim Germany. Product code 20 R202H.) PLA-PEG-Nicotine with a nicotine-terminated PEG block of approximately 3,500 Da and the block DL-PLA of approximately
    15,000 Da have been synthesized. Polyvinyl alcohol (PM = 11,000 - 31,000, 87-89% hydrolyzed) was purchased from J.T. Baker (part number U232-08). Nanoveiculo Production Methods Nic, 0, OP- | The solutions were prepared as follows: Solution 1: The ovalbumin peptide 323 - 339 @ 69mg / mL was prepared in 0.13 N hydrochloric acid at room temperature. Solution 2: PLA @ 75 mg / mL and PLA-PEG-Nicotine @ 25 mg / mL in dichloromethane were prepared by dissolving PLA @ 100 30 mg / mL in dichloromethane and PLA-PEG-Nicotine at 100 mg / mL in dichloro -
    Q 66/72 methane, then combining 3 parts of the PLA solution with 1 part of the PLA-PEG-Nicotine solution.
    Solution 3: Polyvinyl alcohol @ 50 mg / mL at 100 mM in deionized water.
    Solution 4: Phosphate buffer, 70 mM pH 8. 5 A primary emulsion (Wl / O) was created first using Solution 1 and Solution 2. Solution 1 (0.1 mL) and Solution 2 (1.0 mL ) were combined in a small glass tube under pressure and sonicated at a 50% amplitude for 40 seconds, using a Branson Digital 250 Sounder. A secondary emulsion (W1 / ONV2) was then formed by additives. 10 tion of solution 3 (2.0 mL) to the primary emulsion and sonicating at 35% amplitude for 40 seconds using the Branson Digital 250 Sounder. The secondary emulsion was added to a beaker containing 70 mM phosphate buffer solution (30 mL) in an open 50 mL beaker and was stirred at room temperature for 2 hours to allow the dichloromethane to evaporate and the nanovehicles to form in suspension. A portion of the suspended suspension was washed by transferring the suspension from suspension to centrifuge tubes, rotating at 5,300 rcf for 60 minutes, removing the supernatant and resuspending the sediment in phosphate buffered saline. This washing procedure was repeated, and then the pellet was resuspended in phosphate buffered saline to achieve a nanocarrier suspension having a nominal concentration of 10 mg / mL in a polymer base. The suspension was stored frozen at -20 ° C until use.
    Table 2: Characterization of Nanoveicle 25 Nanoveicle ID effective diameter TLR Agonist, I Cell Peptide (nm) | % w / w I T-auxiliaries, ° /) w / w I Nic, 0, OP-ll I 248 I None I Ova, 2.2 I (0 = no adjuvant) Results Antinicotin antibody titers in mice immunized with NC containing on the surface nicotine and OP-ll T-helper peptide with no R848 (5 animals / group; sc, 100 µg NC per injection, 3 times with
    4 weeks). Titers for the 26th and 40th days after the 1st "immunization are displayed (ELISA against polylysine-nicotine). Group 1: immunized with NP [N1c, R848, OPA] (3.1% of R848 NC-conjugated); group 2: immunized with NP [N1C, 0, OPAI] (without R848 linked to NC) administered with 20 µg of free R848. These results demonstrate that the conjugation of R848 with NC resulted in a stronger adjuvant effect than the use of R848 mixed with NC than that which does not contain R848. When identical amounts of two NCS, one containing nicotine on the surface, peptide 10 OP-11 T-helper and R848 (NC [N1C, R848, OPjI]), and another containing the same ingredients, but without R848 (NC [Nic, 0, OP-ll]) were used for the immunization of animals, a greater antibody response was observed for R848 than that conjugated to NC even if a substantially greater amount of free R848 ("6 times) was mixed with NP [N1C, 0, OPA] before immunization compared to the amount of NC-conjugated R848 (figure 6). Example 12: Nanoveiculos with Imprisoned Adjuvant Result in Less Induction of Systemic Proinflammatory Cytokine Materials for Nanoveicule Formulations The amide acetate salt of the ovalbumin peptide 323-339, was purchased from Bachem Americas lnc. (3132 Kashiwa Street, Torrance CA 90505- Product code 4065609.) The DNA oligonucleotide PS-1826 with a fully phosphorothed support structure containing a nucleotide sequence 5'-TCC ATG ACG TTC CTG ACG TT-3 'with a counter -Sodium ion was purchased from Oligos Etc (9775 SW Commerce Circle C-6, Wilsonville, OR 97070.) PLA with an inherent viscosity of 0.19 dljg was purchased from Boehringer lngelheim (lngelheim Germany. Product code R202H.) PLA-PEG-Nicotine with a nicotine-terminated PEG block of approximately 5,000 Da and the DL-PLA block of approximately 17,000 Da have been synthesized. Polyvinyl alcohol (Pm = 11,000 -
    31,000, 87-89% hydrolyzed) was purchased from JT Baker. Baker (part number U232-08).
    P 68/72 Methods for the Production of Nanoveicules The solutions were prepared as follows: Solution 1: Ovalbumin peptide 323 - 339 @ 70 mg / mL in diluted aqueous hydrochloric acid solution. The solution was prepared by dissolving the ovalbumin peptide in a 0.13 N hydrochloric acid solution at room temperature. Solution 2: 0.19-lV PLA @ 75 mg / ml and PLA-PEG-nicotine @ 25 mg / ml in dicbromethane. The solution was prepared by separately dissolving PLA @ 100 mg / ml in dichloromethane and PLA-PEG-nicotine @ 100 - 10 mg / ml in dichloromethane, then mixing the solutions, adding 3 parts of PLA solution for each part of P © solution -PEG-nicotine. Solution 3: Oligonucleotide (PS-1826) @ 200 mg / mL in purified water. The solution was prepared by dissolving the oligonucleotide in purified water at room temperature. 15 Solution 4: Same as solution 2. Solution 5: Polyvinyl alcohol @ 50 mg / mL at 100 mM in phosphate buffer pH 8. Two primary waters separated into oily emulsions were prepared. W1 / O2 was prepared by combining solution 1 (0.1 mL) and 20 solution 2 (1.0 mL) in a small tube under pressure and sonicated at 50% amplitude for 40 seconds, using a Branson Sonifier Digital 250. The W3 / O4 was prepared by combining solution 3 (0.1 ml) and solution 4 (1.0 ml) in a small tube under pressure and sonicated at an amplitude of 50 ° / j for 40 seconds, using a Branson 25 Digital 250 Sonifier. A third emulsion with two internal emulsion phases (Nv1 / o2, w3 / o4] nv5) emulsion was prepared by combining 0.5 mL of 1 each primary emulsion (W1 / O2 and W3 / O4) and solution 5 (3.0 mL) and sonicating at 30% amplitude for 60 seconds using the Branson Digital Sonifier
    250. 30 The third emulsion was then added to an open 50 ml beaker containing 70 mM phosphate buffer pH 8 (30 ml) and stirred at room temperature for 2 hours to evaporate the dichloromethane and
    the nanovehicles in aqueous suspension. A portion of the nanovehicles was washed by transferring the suspension to a centrifuge tube, rotating at 13,800 g for one hour, removing the supernatant and resuspending the pellet in phosphate buffered saline. The washing procedure was repeated and the pellet was resuspended in phosphate buffered saline for a final nanoveicle dispersion of about 10 mg / mL.
    The amounts of oligonucleotides and peptides in the nanoveicule were determined by HPLC analysis. The total dry nanoveicle mass. 10 per mL of the suspension was determined by a gravimetric method and was adjusted to 5 mg / mL. The particles were stored as suspensions - refrigerated until the moment of use.
    Table 3: Characterization of the Nanoveicule Nanove iculo effective diameter TLR Agonist, I Cells Peptide (nm) 1% w / w) T-helper, ° /) w / w I 232 I PS-1826, 6.4 I Ova, 2.2 Results 15 TNF-a and IL-6 were induced in sera from animals inoculated with NC-CpG and Free CpG. The groups of animals were inoculated (s. C.) either with 100 µg of NC-CpG (containing 5 ° / 0 CpG-1826) or with 5 µg of free CpG-1826. At different times, the post-inoculation serum was collected from the animals (3 / group) by terminal bleeding, stored together and subjected to analysis for the presence of cytokines in ELISA (BD). The results demonstrate that the trapping of the adjuvant within the NC results in a lower induction of immediate systemic proinflammatory cytokines than the use of a free adjuvant. When identical amounts of a CpG, NC-imprisoned or free adjuvant were used for inoculation, a substantially greater induction of TNF-a and IL-6 in the serum of animals was observed for free CpG compared to CpG trapped in NC (figure 7). Example 13: Nanovehicles with Imprisoned Adjuvant Results in Similar or Higher Systemic Induction of Immune Cytokines
    Materials for Nanoveicule Formulations The amide acetate salt of the ovalbumin peptide 323-339, was purchased from Bachem Americas lnc. (3132 Kashiwa Street, Torrance CA
    90505. Product code 4065609-) The DNA oligonucleotide PS-1826 5 with a fully phosphorothed support structure containing a 5'-TCC ATG ACG TTC CTG ACG TT-3 'nucleotide sequence with a sodium counterion was purchased from Oligos Etc (9775 SW Commerce Circle C-6, Wilsonville, OR 97070.) PLA with an intrinsic viscosity of 0.21 dljg was purchased from SurModics Pharmaceuticals (756 Tom Martin Drive,. 10 Birmingham, AL 35211. Product code 100 DL 2A). PLA-PEG-Nicotine with a PEG block with approximately 5,000 "Da nicotine termination and the DL-PLA block of approximately 17,000 Da have been synthesized. Polyvinyl alcohol (PM = 11-000 - 31,000, 87-89% hydrolyzed) was purchased from JT Baker (part number U232-08) 15 Methods for the Production of Nanoveicles The solutions were prepared as follows: Solution 1: Ovalbumin peptide 323 - 339 @ 35 mg / mL in diluted aqueous hydrochloric acid solution. The solution was prepared by dissolving the ovalbumin peptide in 0.13 N hydrochloric acid solution at room temperature Solution 2: 0.21-lV PLA @ 75 mg / mL and PLA-PEG-nicotine @ 25 mg / ml in dichloromethane The solution was prepared by separately dissolving PLA @ 100 mg / ml in dichloromethane and P © -PEG-nicotine @ 100 mgl ml in dichloromethane, then mixing the solutions, adding 3 parts 25 of PLA solution for each part of so | L | tion PO-PEG-nicotine Solution 3: Oligonucleotide (PS-1826) @ 200 mg / mL in purified water. o was prepared by dissolving the oligonucleotide in purified water at room temperature. Solution 4: The same as solution # 2. 30 Solution 5: Ávinyl polyvinyl @ 50 mg / mL at 100 mM in pH 8 phosphate buffer. Two primary waters separated into oily emulsions were
    The prepared. W1 / O2 was prepared by combining solution 1 (0.2 ml) and solution 2 (1.0 ml) in a small tube under pressure and sonicated at 50% amplitude for 40 seconds, using a Branson Digital Sonifier 250. W3 / O4 was prepared by combining solution 3 (0.1 ml) and 5 solution 4 (1.0 ml) in a small tube under pressure and sonicated at 50% amplitude for 40 seconds, using a Branson Digital 250 sonifier. A third emulsion with two internal emulsion phases ([W1 / O2, W3 / O4] / N5) emulsion was prepared by combining 0.55 ml of each primary emulsion ( N1 / O2 and W3 / O4) and solution 5 (3.0 mL) and sonicating
    P 10 to 30% amplitude for 60 seconds using Branson Digital Sonifier 250- The third emulsion was then added to an open 50 ml beaker containing 70 mM phosphate buffer pH 8 (30 ml) and stirred at room temperature for 2 hours to evaporate the dichloromethane and form the nanovehicles in aqueous suspension. A portion of the nanovelles was washed by transferring the suspension to a centrifuge tube, rotating at 13,800 g for one hour, removing the supernatant and resuspending the pellet in phosphate buffered saline. The washing procedure was repeated and the pellet was resuspended in 20 phosphate buffered saline solution for a final dispersion of the nanoveuge of about 10 mg / mL.
    The amounts of oligonucleotides and peptides in the nanocarrier were determined by HPLC analysis. The total dry nanoveicule mass per ml of the suspension was determined by a gravimetric method and was adjusted to 5 mg / ml. The particles were stored as refrigerated suspensions until the moment of use.
    Table 4: Characterization of the Nanoveicle Nanoveicle effective diameter TLR Agonist, Cell Peptide | (nm) ° 6p / p I T-auxiliaries, ° /) p / p I 217 PS-1826, 6.2 i Ova, not determined Results O lFN- y and IL-12 were induced in sera from animals inoculated with NC-CpG and free CpG. The groups of animals were inoculated (s. C.)
    either with 100 µg of NC-CpG (containing 6 ° /, CpG-1826) or with 6 µg of free CpG-1826. 24 hours after inoculation, serum was collected from animals (3 / group) by terminal bleeding, stored together and subjected to analysis for the presence of cytokines in ELISA (BD). 5 These results demonstrate that the imprisonment of the adjuvant in the nanovehicles results in a systemic induction similar or even longer to the immune cytokines in relation to the use of free adjuvants. When identical amounts of a CpG adjuvant, NC-trapped or free, were used to inoculate animals, a similar level of induction a. 10 long-term systemic lFN-Y and greater IL-12 induction in animal serum were observed (figure 8) - | q i4 ç; jq ¶ à 0
    S a to%
    权利要求:
    Claims (16)
    [1]
    1. Use of an adjuvant dose and an antigen dose, in which at least a portion of the adjuvant dose is coupled to synthetic nano-vehicles, characterized by the fact that it is for the manufacture of a medicine for use in a treatment of generating an antibody titer against the antigen by administering the adjuvant dose and the antigen dose to an individual, wherein the method comprises choosing the adjuvant dose as being less than a separate dose of adjuvant that results in an antibody titration similar to that generated by administering the dose of adjuvant and the dose of antigen to the individual.
    [2]
    2. Use of an adjuvant dose, in which at least a portion of the adjuvant dose is coupled to synthetic nano vehicles, characterized by the fact that it is for the manufacture of a medicine for use in a treatment to generate a systemic cytokine release by administering the dose of adjuvant to an individual, in which the method comprises choosing the dose of adjuvant as being higher than a separate dose of adjuvant that results in the release of systemic cytokine similar to that generated by administering the dose of adjuvant to the individual.
    [3]
    Use according to claim 1 or 2, characterized in that the adjuvant comprises a receptor agonist similar to Toll 3, 4, 5, 7, 8, or 9, or a combination of these, for example, an agonist of Toll-like receptors 3, an agonist of Toll-like receptors 7 and 8, or an agonist of Toll-like receptors 9, for example, comprising R848, immunostimulatory DNA, or immunostimulatory RNA.
    [4]
    Use according to any one of claims 1 to 3, characterized in that: (a) the dose of adjuvant comprises two or more types of adjuvants; and / or (b) a portion of the adjuvant dose is not coupled to any synthetic nano-vehicles / and / or (c) more than one type of antigen is administered to the individual; and / or (d) at least a portion of the dose of the antigen (s) is / are coupled to synthetic nano-vehicles, or at least a portion of the dose of the antigen (s) is not / are coupled to synthetic nano vehicles, or at least a portion of the dose of the antigen (s) is / are co-administered with synthetic nano vehicles, or at least a portion of the dose of the antigen (s) (s) is / are not co-administered with synthetic nano vehicles.
    [5]
    Use according to any one of claims 1 to 4, characterized by the fact that: (a) the antigen (s) comprises (s) a B cell antigen and / or a T cell antigen , optionally wherein the T cell antigen comprises a helper T cell antigen; or (b) the antigen (s) comprises (a) a B cell antigen or a T cell antigen and a helper T cell antigen.
    [6]
    6. Use according to any one of claims 1 to 5, characterized by the fact that the administration is done through a route that includes subcutaneous, intramuscular, intradermal, oral, intrascal, transmucosal, rectal administration; ophthalmic, transdermal or transcutaneous, or a combination of these.
    [7]
    Use according to any one of claims 1 to 6, characterized in that the synthetic nanoparticles comprise (a) lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, emulsions based on surfactants, dendrimers, spheres magnetic, nanowires, virus-like particles, peptide- or protein-based particles, nanoparticles that comprise a combination of nanoparticles, nanoparticles nanoparticles, cuboidal nanoparticles, pyramidal nanoparticles, nanostructure nanoparticles, nanoparticles, or toroidal nano particles; or (b) one or more polymer (s).
    [8]
    Use according to claim 7, characterized in that the one or more polymer (s) comprises (s) a polyester, optionally wherein the one or more polymer (s) comprises (s) or comprises ( m) still a polyester coupled to a hydrophilic polymer.
    [9]
    9. Use according to claim 8, characterized by the fact that the polyester comprises a poly (lactic acid), poly (glycolic acid),
    poly (lactic-co-glycolic acid), or polycaprolactone and / or the hydrophilic polymer comprises a polyether, for example, comprising polyethylene glycol.
    [10]
    Use according to any one of claims 1 to 9, characterized in that the dose form comprises the dose of adjuvant, optionally in which a vaccine comprises the form (s) of dosage .
    [11]
    Use according to claim 10, characterized by the fact that more than one dose form comprises the adjuvant dose, and more than one dose form is co-administered.
    [12]
    12. Use according to any one of claims 1 to 11, characterized by the fact that the individual has cancer, an infectious disease, a non-autoimmune metabolic disease, a degenerative disease, an addiction, a atopic condition, asthma, illness chronic obstructive pulmonary disease (COPD) or a chronic infection.
    [13]
    Use according to any one of claims 1 to 12, characterized by the fact that the antigen comprises nicotine.
    [14]
    Use according to any one of claims 1 to 13, characterized in that the adjuvant dose comprises R848 and the antigen dose comprises nicotine and an auxiliary T cell antigen, wherein nicotine and a T cell antigen auxiliary are further coupled to synthetic nano vehicles, and in which synthetic nano vehicles comprise one or more polymer (s), optionally in which the one or more polymer (s) comprises (m) a polyester coupled to a polymer hydrophilic.
    [15]
    Use according to claim 14, characterized in that the hydrophilic polymer comprises a polyether, for example, comprising a polyethylene glycol, and / or the polyester comprises a poly (lactic acid), poly (glycolic acid ), poly (lactic-co-glycolic acid), or polycaprolactone.
    [16]
    16. Invention, in any form of its embodiments or in any applicable category of claim, for example, product or process or use encompassed by the material initially described, revealed or illustrated in the patent application.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR7461M|1968-06-19|1970-01-05|
    GB1355961A|1970-02-27|1974-06-12|Wellcome Found|Preparation of immunosuppressive antilymphocytic serum|
    CH594444A5|1972-12-04|1978-01-13|Gerd Birrenbach|
    US3996355A|1975-01-02|1976-12-07|American Home Products Corporation|Permanent suspension pharmaceutical dosage form|
    DK143689C|1975-03-20|1982-03-15|J Kreuter|PROCEDURE FOR THE PREPARATION OF AN ADVERTISED VACCINE|
    US4756907A|1978-10-17|1988-07-12|Stolle Research & Development Corp.|Active/passive immunization of the internal female reproductive organs|
    US4946929A|1983-03-22|1990-08-07|Massachusetts Institute Of Technology|Bioerodible articles useful as implants and prostheses having predictable degradation rates|
    US6309669B1|1984-03-16|2001-10-30|The United States Of America As Represented By The Secretary Of The Army|Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix|
    US4638045A|1985-02-19|1987-01-20|Massachusetts Institute Of Technology|Non-peptide polyamino acid bioerodible polymers|
    US4631211A|1985-03-25|1986-12-23|Scripps Clinic & Research Foundation|Means for sequential solid phase organic synthesis and methods using the same|
    US4806621A|1986-01-21|1989-02-21|Massachusetts Institute Of Technology|Biocompatible, bioerodible, hydrophobic, implantable polyimino carbonate article|
    JPS63122620A|1986-11-12|1988-05-26|Sanraku Inc|Polylactic acid microsphere and production thereof|
    US5736372A|1986-11-20|1998-04-07|Massachusetts Institute Of Technology|Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure|
    US5804178A|1986-11-20|1998-09-08|Massachusetts Institute Of Technology|Implantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue|
    CA1340581C|1986-11-20|1999-06-08|Joseph P. Vacanti|Chimeric neomorphogenesis of organs by controlled cellular implantation using artificial matrices|
    FR2608988B1|1986-12-31|1991-01-11|Centre Nat Rech Scient|PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOPARTICLES|
    US5912017A|1987-05-01|1999-06-15|Massachusetts Institute Of Technology|Multiwall polymeric microspheres|
    US5229490A|1987-05-06|1993-07-20|The Rockefeller University|Multiple antigen peptide system|
    US5019379A|1987-07-31|1991-05-28|Massachusetts Institute Of Technology|Unsaturated polyanhydrides|
    US4950432A|1987-10-16|1990-08-21|Board Of Regents, The University Of Texas System|Polyene microlide pre-liposomal powders|
    US6130082A|1988-05-05|2000-10-10|American Cyanamid Company|Recombinant flagellin vaccines|
    US4929624A|1989-03-23|1990-05-29|Minnesota Mining And Manufacturing Company|Olefinic 1H-imidazoquinolin-4-amines|
    US5010167A|1989-03-31|1991-04-23|Massachusetts Institute Of Technology|Poly for biological application|
    US5114703A|1989-05-30|1992-05-19|Alliance Pharmaceutical Corp.|Percutaneous lymphography using particulate fluorocarbon emulsions|
    US5733572A|1989-12-22|1998-03-31|Imarx Pharmaceutical Corp.|Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles|
    US6005087A|1995-06-06|1999-12-21|Isis Pharmaceuticals, Inc.|2'-modified oligonucleotides|
    US6399754B1|1991-12-24|2002-06-04|Isis Pharmaceuticals, Inc.|Sugar modified oligonucleotides|
    GB9016885D0|1990-08-01|1990-09-12|Scras|Sustained release pharmaceutical compositions|
    US6699474B1|1990-08-20|2004-03-02|Erich Hugo Cerny|Vaccine and immunserum against drugs of abuse|
    US6608201B2|1992-08-28|2003-08-19|3M Innovative Properties Company|Process for preparing 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines|
    AT229943T|1991-03-01|2003-01-15|Minnesota Mining & Mfg|INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF 1-SUBSTITUTED, 2-SUBSTITUTED-1H-IMIDAZO CHINOLIN-4-AMINES|
    US5389640A|1991-03-01|1995-02-14|Minnesota Mining And Manufacturing Company|1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines|
    US5175296A|1991-03-01|1992-12-29|Minnesota Mining And Manufacturing Company|Imidazo[4,5-c]quinolin-4-amines and processes for their preparation|
    JP3296817B2|1991-04-02|2002-07-02|バイオテック・オーストラリア・ピーティーワイ・リミテッド|Oral distribution system suitable for fine particles|
    IL105325A|1992-04-16|1996-11-14|Minnesota Mining & Mfg|Immunogen/vaccine adjuvant composition|
    US6235313B1|1992-04-24|2001-05-22|Brown University Research Foundation|Bioadhesive microspheres and their use as drug delivery and imaging systems|
    CA2138997C|1992-06-25|2003-06-03|Jean-Paul Prieels|Vaccine composition containing adjuvants|
    WO1994002068A1|1992-07-21|1994-02-03|The General Hospital Corporation|System of drug delivery to the lymphatic tissues|
    GB9216082D0|1992-07-28|1992-09-09|Univ Nottingham|Lymphatic delivery composition|
    FR2695563B1|1992-09-11|1994-12-02|Pasteur Institut|Microparticles carrying antigens and their use for the induction of humoral or cellular responses.|
    AU4932493A|1992-09-25|1994-04-26|Dynagen, Inc.|An immunobooster for delayed release of immunogen|
    US5399665A|1992-11-05|1995-03-21|Massachusetts Institute Of Technology|Biodegradable polymers for cell transplantation|
    ES2131676T3|1993-01-11|1999-08-01|Dana Farber Cancer Inst Inc|INDUCTION OF RESPONSES WITH T CYTOTOXIC LYMPHOCYTES.|
    US5512600A|1993-01-15|1996-04-30|Massachusetts Institute Of Technology|Preparation of bonded fiber structures for cell implantation|
    US5811447A|1993-01-28|1998-09-22|Neorx Corporation|Therapeutic inhibitor of vascular smooth muscle cells|
    US5395937A|1993-01-29|1995-03-07|Minnesota Mining And Manufacturing Company|Process for preparing quinoline amines|
    US5514378A|1993-02-01|1996-05-07|Massachusetts Institute Of Technology|Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures|
    CA2151742C|1993-02-22|1999-05-25|Alfred A. Amkraut|Compositions for oral delivery of active agents|
    US5916539A|1993-03-02|1999-06-29|Silica Gel Ges. M.B.H.|Superparamagnetic particles, process for producing the same and their use|
    CH686761A5|1993-05-27|1996-06-28|Sandoz Ag|Pharmaceutical formulations.|
    US5543158A|1993-07-23|1996-08-06|Massachusetts Institute Of Technology|Biodegradable injectable nanoparticles|
    US5565215A|1993-07-23|1996-10-15|Massachusettes Institute Of Technology|Biodegradable injectable particles for imaging|
    US6007845A|1994-07-22|1999-12-28|Massachusetts Institute Of Technology|Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers|
    WO1995003035A1|1993-07-23|1995-02-02|Massachusetts Institute Of Technology|Polymerized liposomes with enhanced stability for oral delivery|
    WO1995007707A1|1993-09-14|1995-03-23|Cytel Corporation|Alteration of immune response using pan dr-binding peptides|
    US5798340A|1993-09-17|1998-08-25|Gilead Sciences, Inc.|Nucleotide analogs|
    US5500161A|1993-09-21|1996-03-19|Massachusetts Institute Of Technology And Virus Research Institute|Method for making hydrophobic polymeric microparticles|
    WO1995022963A1|1994-02-28|1995-08-31|Medinova Medical Consulting Gmbh|Drug targeting system, method for preparing same and its use|
    US5596091A|1994-03-18|1997-01-21|The Regents Of The University Of California|Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides|
    WO1995026204A1|1994-03-25|1995-10-05|Isis Pharmaceuticals, Inc.|Immune stimulation by phosphorothioate oligonucleotide analogs|
    GB9412273D0|1994-06-18|1994-08-10|Univ Nottingham|Administration means|
    US6207646B1|1994-07-15|2001-03-27|University Of Iowa Research Foundation|Immunostimulatory nucleic acid molecules|
    DK0772619T4|1994-07-15|2011-02-21|Univ Iowa Res Found|Immunomodulatory oligonucleotides|
    US6239116B1|1994-07-15|2001-05-29|University Of Iowa Research Foundation|Immunostimulatory nucleic acid molecules|
    US5716404A|1994-12-16|1998-02-10|Massachusetts Institute Of Technology|Breast tissue engineering|
    DE69630514D1|1995-01-05|2003-12-04|Univ Michigan|SURFACE-MODIFIED NANOPARTICLES AND METHOD FOR THEIR PRODUCTION AND USE|
    US5876727A|1995-03-31|1999-03-02|Immulogic Pharmaceutical Corporation|Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same|
    US6123727A|1995-05-01|2000-09-26|Massachusetts Institute Of Technology|Tissue engineered tendons and ligaments|
    US5866132A|1995-06-07|1999-02-02|Alberta Research Council|Immunogenic oligosaccharide compositions|
    WO1997004747A1|1995-07-27|1997-02-13|Dunn James M|Drug delivery systems for macromolecular drugs|
    WO1997007788A2|1995-08-31|1997-03-06|Alkermes Controlled Therapeutics, Inc.|Composition for sustained release of an agent|
    US6095148A|1995-11-03|2000-08-01|Children's Medical Center Corporation|Neuronal stimulation using electrically conducting polymers|
    US5902599A|1996-02-20|1999-05-11|Massachusetts Institute Of Technology|Biodegradable polymer networks for use in orthopedic and dental applications|
    US5874064A|1996-05-24|1999-02-23|Massachusetts Institute Of Technology|Aerodynamically light particles for pulmonary drug delivery|
    US5898031A|1996-06-06|1999-04-27|Isis Pharmaceuticals, Inc.|Oligoribonucleotides for cleaving RNA|
    WO1997047623A1|1996-06-10|1997-12-18|Cytos Pharmaceuticals Llc|Imidazole derivatives as protective agents in reperfusion injury and severe inflammatory responses|
    US5922695A|1996-07-26|1999-07-13|Gilead Sciences, Inc.|Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability|
    US6767702B2|1996-07-29|2004-07-27|Nanosphere, Inc.|Nanoparticles having oligonucleotides attached thereto and uses therefor|
    ES2188985T3|1996-08-30|2003-07-01|Jens Peter Furste|ENANTIOMERIC SELECTION AND ENANTIOMERIC EVOLUTION OF NUCLEIC ACIDS.|
    EP1006798A4|1996-09-05|2003-03-05|Massachusetts Inst Technology|Compositions and methods for treatment of neurological disorders and neurodegenerative diseases|
    CZ294563B6|1996-10-25|2005-02-16|Minnesota Mining And Manufacturing Company|Immune response modifier compounds for treatment of TH2 cell mediated and related diseases|
    US6042820A|1996-12-20|2000-03-28|Connaught Laboratories Limited|Biodegradable copolymer containing α-hydroxy acid and α-amino acid units|
    US6127533A|1997-02-14|2000-10-03|Isis Pharmaceuticals, Inc.|2'-O-aminooxy-modified oligonucleotides|
    AU738513B2|1997-02-28|2001-09-20|University Of Iowa Research Foundation, The|Use of nucleic acids containing unmethylated CpG dinucleotide in the treatment of LPS-associated disorders|
    WO1998040100A1|1997-03-10|1998-09-17|Ottawa Civic Loeb Research Institute|USE OF NUCLEIC ACIDS CONTAINING UNMETHYLATED CpG DINUCLEOTIDE AS AN ADJUVANT|
    US5989591A|1997-03-14|1999-11-23|American Home Products Corporation|Rapamycin formulations for oral administration|
    US6211159B1|1997-04-11|2001-04-03|University Of Toronto|Flagellin gene, FlaC of campylobacter|
    US7192725B2|2000-05-19|2007-03-20|University Of Toronto|Flagellin gene, flaC of Campylobacter|
    US6060082A|1997-04-18|2000-05-09|Massachusetts Institute Of Technology|Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery|
    WO1998052581A1|1997-05-20|1998-11-26|Ottawa Civic Hospital Loeb Research Institute|Vectors and methods for immunization or therapeutic protocols|
    US5985325A|1997-06-13|1999-11-16|American Home Products Corporation|Rapamycin formulations for oral administration|
    US5837752A|1997-07-17|1998-11-17|Massachusetts Institute Of Technology|Semi-interpenetrating polymer networks|
    US6989435B2|1997-09-11|2006-01-24|Cambridge University Technical Services Ltd.|Compounds and methods to inhibit or augment an inflammatory response|
    DE19745950A1|1997-10-17|1999-04-22|Dds Drug Delivery Service Ges|Drug carrier particle for site specific drug delivery, especially to CNS|
    ES2205573T3|1997-11-28|2004-05-01|Sumitomo Pharmaceuticals Company, Limited|NEW HETEROCICLIC COMPOUNDS.|
    US6197229B1|1997-12-12|2001-03-06|Massachusetts Institute Of Technology|Method for high supercoiled DNA content microspheres|
    US6254890B1|1997-12-12|2001-07-03|Massachusetts Institute Of Technology|Sub-100nm biodegradable polymer spheres capable of transporting and releasing nucleic acids|
    US6506559B1|1997-12-23|2003-01-14|Carnegie Institute Of Washington|Genetic inhibition by double-stranded RNA|
    FR2775435B1|1998-02-27|2000-05-26|Bioalliance Pharma|NANOPARTICLES COMPRISING AT LEAST ONE POLYMER AND AT LEAST ONE COMPOUND CAPABLE OF COMPLEXING ONE OR MORE ACTIVE INGREDIENTS|
    EP1064025B1|1998-03-09|2006-09-13|GlaxoSmithKline Biologicals S.A.|Combined vaccine compositions|
    US6232287B1|1998-03-13|2001-05-15|The Burnham Institute|Molecules that home to various selected organs or tissues|
    US6686446B2|1998-03-19|2004-02-03|The Regents Of The University Of California|Methods and compositions for controlled polypeptide synthesis|
    US6506577B1|1998-03-19|2003-01-14|The Regents Of The University Of California|Synthesis and crosslinking of catechol containing copolypeptides|
    US6632922B1|1998-03-19|2003-10-14|The Regents Of The University Of California|Methods and compositions for controlled polypeptide synthesis|
    DE69935507T2|1998-04-03|2007-12-06|University Of Iowa Research Foundation|METHOD AND PRODUCTS FOR STIMULATING THE IMMUNE SYSTEM BY IMMUNOTHERAPEUTIC OLIGONUCLEOTIDES AND CYTOKINES|
    CA2328602A1|1998-05-06|1999-11-11|University Of Iowa Research Foundation|Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides|
    SE9801923D0|1998-05-29|1998-05-29|Independent Pharmaceutical Ab|Nicotine vaccine|
    US6693086B1|1998-06-25|2004-02-17|National Jewish Medical And Research Center|Systemic immune activation method using nucleic acid-lipid complexes|
    US6242589B1|1998-07-14|2001-06-05|Isis Pharmaceuticals, Inc.|Phosphorothioate oligonucleotides having modified internucleoside linkages|
    NZ509853A|1998-07-29|2003-08-29|Chiron Corp|Microparticles with an adsorbent surface useful for delivering pharmaceuticals|
    DE19839214C1|1998-08-28|2000-05-25|Aventis Res & Tech Gmbh & Co|Process for the production of spherical microparticles with a smooth surface which consist wholly or partly of at least one water-insoluble linear polysaccharide, and microparticles obtainable by this process and their use|
    US6306640B1|1998-10-05|2001-10-23|Genzyme Corporation|Melanoma antigenic peptides|
    PL202399B1|1998-10-05|2009-06-30|Pharmexa As|Novel methods for therapeutic vaccination|
    CN100558401C|1998-10-16|2009-11-11|史密丝克莱恩比彻姆生物有限公司|Adjuvant system and vaccine|
    ES2313797T7|1998-11-02|2019-11-19|Alkermes Pharma Ireland Ltd|Multiparticulate modified release composition of methyl fenidate|
    US7521068B2|1998-11-12|2009-04-21|Elan Pharma International Ltd.|Dry powder aerosols of nanoparticulate drugs|
    US6232082B1|1998-12-01|2001-05-15|Nabi|Hapten-carrier conjugates for treating and preventing nicotine addiction|
    KR20010101420A|1999-01-08|2001-11-14|캐롤린 에이. 베이츠|Formulations and Methods for Treatment of Mucosal Associated Conditions With an Immune Response Modifier|
    US6486168B1|1999-01-08|2002-11-26|3M Innovative Properties Company|Formulations and methods for treatment of mucosal associated conditions with an immune response modifier|
    US6403779B1|1999-01-08|2002-06-11|Isis Pharmaceuticals, Inc.|Regioselective synthesis of 2′-O-modified nucleosides|
    DE19956568A1|1999-01-30|2000-08-17|Roland Kreutzer|Method and medicament for inhibiting the expression of a given gene|
    US6444192B1|1999-02-05|2002-09-03|The Regents Of The University Of California|Diagnostic imaging of lymph structures|
    US6558951B1|1999-02-11|2003-05-06|3M Innovative Properties Company|Maturation of dendritic cells with immune response modifying compounds|
    PT1154790E|1999-02-26|2005-03-31|Chiron Srl|REFORCO OF THE ACTIVITY BACTERICIDE OF ANTIGEN AGAINST NEISSERIA WITH OLIGONUCLEOTIDOS CONTAINING REASONS CG|
    US6110462A|1999-03-03|2000-08-29|The Scripps Research Institute|Enzymatic DNA molecules that contain modified nucleotides|
    US7238711B1|1999-03-17|2007-07-03|Cambridge University Technical Services Ltd.|Compounds and methods to inhibit or augment an inflammatory response|
    EP1326638B9|2000-10-18|2008-02-20|GlaxoSmithKline Biologicals S.A.|Vaccines against cancers|
    CZ303515B6|1999-04-19|2012-11-07|Smithkline Beecham Biologicals S. A.|Adjuvant compositions|
    US7390780B2|1999-04-23|2008-06-24|Alza Corporation|Gene delivery mediated by liposome-DNA complex with cleavable peg surface modification|
    US6800296B1|1999-05-19|2004-10-05|Massachusetts Institute Of Technology|Modification of surfaces using biological recognition events|
    US6331539B1|1999-06-10|2001-12-18|3M Innovative Properties Company|Sulfonamide and sulfamide substituted imidazoquinolines|
    US6815170B1|1999-06-30|2004-11-09|John Wayne Cancer Institute|Methods for lymph node identification|
    WO2001012071A1|1999-08-13|2001-02-22|Point Biomedical Corporation|Microparticles useful as ultrasonic contrast agents and for lymphatic system|
    RU2245149C2|1999-09-25|2005-01-27|Юниверсити Оф Айова Рисерч Фаундейшн|Immunostimulating nucleic acids|
    AT420657T|1999-10-12|2009-01-15|Ca Nat Research Council|ARCHAEOSOME AS AN ADJUVANTIA AND SUPPORT FOR AZELLULAR IMPULSES FOR THE INDUCTION OF A CYTOTOXIC T-LYMPHOCYTE IMMUNE RESPONSE|
    US7223398B1|1999-11-15|2007-05-29|Dynavax Technologies Corporation|Immunomodulatory compositions containing an immunostimulatory sequence linked to antigen and methods of use thereof|
    CA2391534A1|1999-11-15|2001-05-25|Drug Innovation & Design, Inc.|Selective cellular targeting: multifunctional delivery vehicles|
    US6248363B1|1999-11-23|2001-06-19|Lipocine, Inc.|Solid carriers for improved delivery of active ingredients in pharmaceutical compositions|
    AT409085B|2000-01-28|2002-05-27|Cistem Biotechnologies Gmbh|PHARMACEUTICAL COMPOSITION FOR IMMUNULATING AND PRODUCING VACCINES|
    US7097837B2|2001-02-19|2006-08-29|Pharmexa A/S|Synthetic vaccine agents|
    CN1406140A|2000-02-28|2003-03-26|吉倪塞思公司|Nano capsule encapsulation system and method|
    US7157437B2|2000-03-10|2007-01-02|Dynavax Technologies Corporation|Methods of ameliorating symptoms of herpes infection using immunomodulatory polynucleotide sequences|
    US20030129251A1|2000-03-10|2003-07-10|Gary Van Nest|Biodegradable immunomodulatory formulations and methods for use thereof|
    US7129222B2|2000-03-10|2006-10-31|Dynavax Technologies Corporation|Immunomodulatory formulations and methods for use thereof|
    SE0000933D0|2000-03-21|2000-03-21|Independent Pharmaceutica Ab|Method of producing 6-substituted -nicotine derivatives and intermediate compounds|
    AU2001249622B2|2000-03-30|2007-06-07|Massachusetts Institute Of Technology|RNA sequence-specific mediators of RNA interference|
    BRPI0115814B8|2000-12-01|2021-05-25|Europaeisches Laboratorium Fuer Molekularbiologie Embl|double-stranded RNA molecules, their method of preparation and pharmaceutical composition comprising them|
    EP1278542A2|2000-05-05|2003-01-29|Cytos Biotechnology AG|Molecular antigen arrays and vaccines|
    US6610713B2|2000-05-23|2003-08-26|North Shore - Long Island Jewish Research Institute|Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation|
    US20050032733A1|2001-05-18|2005-02-10|Sirna Therapeutics, Inc.|RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
    KR100865706B1|2000-09-26|2008-10-28|이데라 파마슈티칼즈, 인코포레이티드|Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes|
    AU2001297913A1|2000-10-13|2002-12-23|Ligocyte Pharmaceuticals, Inc.|Polyvalent nanoparticles|
    GB0025414D0|2000-10-16|2000-11-29|Consejo Superior Investigacion|Nanoparticles|
    EP2363424B1|2000-10-19|2016-08-10|Ecole Polytechnique Federale de Lausanne |Block copolymers for multifunctional self-assembled systems|
    US7592008B2|2000-11-20|2009-09-22|The Board Of Trustees Of The University Of Illinois, A Body Corporate And Politic Of The State Of Illinois|Membrane scaffold proteins|
    CA2598144A1|2000-12-08|2006-08-31|3M Innovative Properties Company|Compositions and methods for targeted delivery of immune response modifiers|
    DE60142410D1|2000-12-27|2010-07-29|Dynavax Tech Corp|IMMUNOMODULATORY POLYNUCLEOTIDES AND METHOD FOR THE USE THEREOF|
    GB0108364D0|2001-04-03|2001-05-23|Glaxosmithkline Biolog Sa|Vaccine composition|
    US8202979B2|2002-02-20|2012-06-19|Sirna Therapeutics, Inc.|RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid|
    US20050020525A1|2002-02-20|2005-01-27|Sirna Therapeutics, Inc.|RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
    US20030175950A1|2001-05-29|2003-09-18|Mcswiggen James A.|RNA interference mediated inhibition of HIV gene expression using short interfering RNA|
    WO2004030608A2|2001-06-05|2004-04-15|The Regents Of The University Of Michigan|Nanoemulsion vaccines|
    DE60140863D1|2001-06-10|2010-02-04|Noxxon Pharma Ag|Use of L polynucleotides for diagnostic imaging|
    EP2241309A3|2001-07-10|2012-12-26|Corixa Corporation|Methods for encapsulation of proteins and adjuants in microspheres|
    US20030133988A1|2001-08-07|2003-07-17|Fearon Karen L.|Immunomodulatory compositions, formulations, and methods for use thereof|
    US6818732B2|2001-08-30|2004-11-16|The Regents Of The University Of California|Transition metal initiators for controlled poly synthesis from beta-lactam monomers|
    US20080160089A1|2003-10-14|2008-07-03|Medivas, Llc|Vaccine delivery compositions and methods of use|
    US20030054042A1|2001-09-14|2003-03-20|Elaine Liversidge|Stabilization of chemical compounds using nanoparticulate formulations|
    WO2003037304A1|2001-11-02|2003-05-08|Wockhardt Limited|Controlled release compositions for macrolide antimicrobial agents|
    US8088388B2|2002-02-14|2012-01-03|United Biomedical, Inc.|Stabilized synthetic immunogen delivery system|
    ES2607431T3|2002-02-20|2017-03-31|Glaxosmithkline Biologicals Sa|Microparticles with molecules containing adsorbed polypeptides|
    US20030232013A1|2002-02-22|2003-12-18|Gary Sieckman|Therapeutic and diagnostic targeting of cancers cells with tumor homing peptides|
    ES2543710T3|2002-04-04|2015-08-21|Zoetis Belgium S.A.|Immunostimulatory oligonucleotides containing G and U|
    US20040038303A1|2002-04-08|2004-02-26|Unger Gretchen M.|Biologic modulations with nanoparticles|
    US7285289B2|2002-04-12|2007-10-23|Nagy Jon O|Nanoparticle vaccines|
    US20080233181A1|2002-04-12|2008-09-25|Nagy Jon O|Nanoparticle adjuvants for sub-unit vaccines|
    AU2003234196A1|2002-04-22|2003-11-03|University Of Florida|Functionalized nanoparticles and methods of use|
    US6824338B2|2002-05-28|2004-11-30|Satco, Inc.|Air transport modular container system|
    AU2003276131A1|2002-06-18|2003-12-31|Epigenesis Pharmaceuticals, Inc.|A dry powder oligonucleotide formulation, preparation and its uses|
    AU2003269904A1|2002-07-10|2004-01-23|The Ohio State University Research Foundation|Antigen-polymer compositions|
    EP1523334A2|2002-07-18|2005-04-20|Cytos Biotechnology AG|Hapten-carrier conjugates and uses thereof|
    US7427629B2|2002-08-15|2008-09-23|3M Innovative Properties Company|Immunostimulatory compositions and methods of stimulating an immune response|
    JP2006522823A|2003-04-10|2006-10-05|スリーエムイノベイティブプロパティズカンパニー|Delivery of immune response modulator compounds|
    US20040091503A1|2002-08-20|2004-05-13|Genitrix, Llc|Lectin compositions and methods for modulating an immune response to an antigen|
    US7488792B2|2002-08-28|2009-02-10|Burnham Institute For Medical Research|Collagen-binding molecules that selectively home to tumor vasculature and methods of using same|
    US20040152105A1|2002-09-06|2004-08-05|Cytos Biotechnology Ag.|Immune modulatory compounds and methods|
    US20060189554A1|2002-09-24|2006-08-24|Russell Mumper|Nanoparticle-Based vaccine delivery system containing adjuvant|
    US7008411B1|2002-09-30|2006-03-07|Advanced Cardiovascular Systems, Inc.|Method and apparatus for treating vulnerable plaque|
    NO20024755D0|2002-10-03|2002-10-03|Amersham Health As|Method|
    US7276489B2|2002-10-24|2007-10-02|Idera Pharmaceuticals, Inc.|Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends|
    US7670627B2|2002-12-09|2010-03-02|Salvona Ip Llc|pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients|
    AU2003300919A1|2002-12-11|2004-06-30|Coley Pharmaceutical Gmbh|5' cpg nucleic acids and methods of use|
    SE0203687D0|2002-12-13|2002-12-13|Ian Harwigsson Med Adagit Fa|Pharmaceutical Porous Particles|
    KR101178816B1|2002-12-23|2012-09-07|다이나박스 테크놀로지 코퍼레이션|Immunostimulatory sequence oligonucleotides and methods of using the same|
    AU2003300184B8|2002-12-30|2009-12-03|3M Innovative Properties Company|Immunostimulatory combinations|
    US20040156846A1|2003-02-06|2004-08-12|Triton Biosystems, Inc.|Therapy via targeted delivery of nanoscale particles using L6 antibodies|
    EP1592302A4|2003-02-13|2007-04-25|3M Innovative Properties Co|Methods and compositions related to irm compounds and toll-like receptor 8|
    DE602004008582T2|2003-02-17|2008-05-21|Peter Burkhard|PEPTIDIC NANOTEHICLES AS DRUG DISPENSING AND ANTIGEN DISPLAY SYSTEMS|
    US20060159655A1|2003-03-21|2006-07-20|Wyeth|Treating immunological disorders using agonists of interleukin-21 / interleukin-21 receptor|
    US20040191215A1|2003-03-25|2004-09-30|Michael Froix|Compositions for induction of a therapeutic response|
    AU2004224530A1|2003-03-26|2004-10-07|Ltt Bio-Pharma Co., Ltd.|Intravenous nanoparticles for targenting drug delivery and sustained drug release|
    CA2517675A1|2003-03-26|2004-10-07|Cytos Biotechnology Ag|Packaging of immunostimulatory oligonucleotides into virus-like particles: method of preparation and use|
    US7731967B2|2003-04-30|2010-06-08|Novartis Vaccines And Diagnostics, Inc.|Compositions for inducing immune responses|
    EP1631264B8|2003-06-02|2017-05-24|GlaxoSmithKline Biologicals SA|Immunogenic compositions based on microparticles comprising adsorbed toxoid and a polysaccharide-containing antigen|
    US7727969B2|2003-06-06|2010-06-01|Massachusetts Institute Of Technology|Controlled release nanoparticle having bound oligonucleotide for targeted delivery|
    US7149574B2|2003-06-09|2006-12-12|Palo Alto Investors|Treatment of conditions through electrical modulation of the autonomic nervous system|
    US20060182793A1|2003-07-22|2006-08-17|Cytos Biotechnology Ag|Cpg-packaged liposomes|
    US20050042298A1|2003-08-20|2005-02-24|Pardridge William M.|Immunonanoparticles|
    US20070014807A1|2003-09-03|2007-01-18|Maida Anthony E Iii|Multiplex vaccine|
    US7943179B2|2003-09-23|2011-05-17|Massachusetts Institute Of Technology|pH triggerable polymeric particles|
    US7771726B2|2003-10-08|2010-08-10|New York University|Use of synthetic glycolipids as universal adjuvants for vaccines against cancer and infectious diseases|
    WO2007089870A2|2006-01-31|2007-08-09|Medivas, Llc|Vaccine delivery compositions and methods of use|
    WO2005057163A2|2003-10-20|2005-06-23|William Marsh Rice University|Method to fabricate microcapsules from polymers and charged nanoparticles|
    CN1608675A|2003-10-22|2005-04-27|四川大学|Medicine-carrying nanometer polymer particle and its prepn and use|
    GEP20094767B|2003-10-30|2009-09-10|Coley Pharm Group Inc|C-class oligonucleotide analogs with enhanced immunostimulatory potency|
    CN1544638A|2003-11-28|2004-11-10|中国药科大学|Virus-like particle capable of carrying and loading polypeptide|
    US20070116768A1|2003-12-09|2007-05-24|Michael Chorny|Sustained release preparations composed of biocompatible complex microparticles|
    KR100581967B1|2003-12-18|2006-05-22|한국유나이티드제약 주식회사|Double pellet formulation of proton pump inhibitors and clarithromycin for the treatment of gastrointestinal ulcer, and method for producing the same|
    FR2863890B1|2003-12-19|2006-03-24|Aventis Pasteur|IMMUNOSTIMULATING COMPOSITION|
    PT1704585T|2003-12-19|2017-05-05|Univ North Carolina Chapel Hill|Methods for fabricating isolated micro- and nano- structures using soft or imprint lithography|
    US9040090B2|2003-12-19|2015-05-26|The University Of North Carolina At Chapel Hill|Isolated and fixed micro and nano structures and methods thereof|
    EP1550458A1|2003-12-23|2005-07-06|Vectron Therapeutics AG|Synergistic liposomal adjuvants|
    WO2005065418A2|2003-12-31|2005-07-21|Board Of Regents, The University Of Texas System|Compositions and methods of use of targeting peptides for diagnosis and therapy|
    US20070087986A1|2004-01-26|2007-04-19|Brett Premack|Compositions and methods for enhancing immunity by chemoattractant adjuvants|
    TW200533750A|2004-02-19|2005-10-16|Coley Pharm Group Inc|Immunostimulatory viral RNA oligonucleotides|
    AU2005244260B2|2004-04-09|2010-08-05|3M Innovative Properties Company|Methods, compositions, and preparations for delivery of immune response modifiers|
    EP1768998A2|2004-04-27|2007-04-04|Alnylam Pharmaceuticals Inc.|Single-stranded and double-stranded oligonucleotides comprising a 2-arylpropyl moiety|
    ES2246695B1|2004-04-29|2007-05-01|Instituto Cientifico Y Tecnologico De Navarra, S.A.|STIMULATING COMPOSITION OF THE IMMUNE RESPONSE THAT INCLUDES NANOPARTICLES BASED ON A COPYLIMER OF METHYL VINYL ETER AND MALEIC ANHYDRIDE.|
    DK1767216T3|2004-06-11|2012-09-03|Riken|Regulatory cell ligand drug contained in liposome|
    GB0413868D0|2004-06-21|2004-07-21|Chiron Srl|Dimensional anlaysis of saccharide conjugates|
    AU2005326322B2|2004-07-01|2009-02-05|Yale University|Targeted and high density drug loaded polymeric materials|
    US20080206270A1|2004-07-08|2008-08-28|Minev Boris R|Enhancing Class I Antigen Presentation With Synthetic Sequences|
    US8017151B2|2004-09-07|2011-09-13|Board Of Regents Of The University Of Nebraska By And Behalf Of The University Of Nebraska Medical Center|Amphiphilic polymer-protein conjugates and methods of use thereof|
    JP4769810B2|2004-09-14|2011-09-07|ノバルティスヴァクシンズアンドダイアグノスティクス，インコーポレイテッド|Imidazoquinoline compounds|
    CN1692943A|2004-09-17|2005-11-09|四川大学|Preparation and application of CpG DNA molecule anti-infection and immunity prepn|
    US9079765B2|2004-10-01|2015-07-14|Midatech Ltd.|Nanoparticles comprising antigens and adjuvants, and immunogenic structures|
    US20090004118A1|2004-10-07|2009-01-01|Shuming Nie|Multifunctional Nanoparticle Conjugates And Their Use|
    MY159370A|2004-10-20|2016-12-30|Coley Pharm Group Inc|Semi-soft-class immunostimulatory oligonucleotides|
    WO2007001448A2|2004-11-04|2007-01-04|Massachusetts Institute Of Technology|Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals|
    EP1814587A2|2004-11-05|2007-08-08|The General Hospital Corporation|Purposeful movement of human migratory cells away from an agent source|
    ES2434029T3|2004-11-15|2013-12-13|Novartis Vaccines And Diagnostics, Inc.|Immunogenic compositions containing anthrax antigen, biodegradable polymer microparticles, and immunological adjuvant containing polynucleotide|
    US20060111271A1|2004-11-24|2006-05-25|Cerny Erich H|Active and passive immunization against pharmacologically active hapten molecules using a synthetic carrier compound composed of similar elements|
    US20070292386A9|2004-12-02|2007-12-20|Campbell Robert L|Vaccine formulations for intradermal delivery comprising adjuvants and antigenic agents|
    AT544774T|2004-12-14|2012-02-15|Alnylam Pharmaceuticals Inc|RNAI MODULATION OF MLL-AF4 AND USES THEREOF|
    US20060257359A1|2005-02-28|2006-11-16|Cedric Francois|Modifying macrophage phenotype for treatment of disease|
    EP1866416A2|2005-03-22|2007-12-19|Medstar Health Inc.|Delivery systems and methods for diagnosing and treating cardiovascular diseases|
    US7709001B2|2005-04-08|2010-05-04|Wyeth Llc|Multivalent pneumococcal polysaccharide-protein conjugate composition|
    US20080305161A1|2005-04-13|2008-12-11|Pfizer Inc|Injectable depot formulations and methods for providing sustained release of nanoparticle compositions|
    CA2609788A1|2005-04-26|2006-11-02|Coley Pharmaceutical Gmbh|Modified oligoribonucleotide analogs with enhanced immunostimulatory activity|
    SG161311A1|2005-05-04|2010-05-27|Noxxon Pharma Ag|Novel use of spiegelmers|
    US20100062968A1|2005-05-10|2010-03-11|Bali Pulendran|Novel strategies for delivery of active agents using micelles and particles|
    WO2007003054A1|2005-07-06|2007-01-11|Shoichet Molly S|Method of biomolecule immobilization on polymers using click-type chemistry|
    CN103315944B|2005-08-12|2016-03-30|刘江|For lympha targeted method and apparatus|
    TWI382019B|2005-08-19|2013-01-11|Array Biopharma Inc|Aminodiazepines as toll-like receptor modulators|
    TW201402124A|2005-08-19|2014-01-16|Array Biopharma Inc|8-substituted benzoazepines as toll-like receptor modulators|
    CA2620182A1|2005-08-22|2007-03-01|Dennis A. Carson|Tlr agonists|
    JP2009507049A|2005-09-09|2009-02-19|北京徳科瑞医薬科技有限公司|Nanomicelle formulation of vinca alkaloid anticancer drug encapsulated in polyethylene glycol derivative of phospholipid|
    BRPI0622298A2|2005-11-25|2012-12-11|Coley Pharm Gmbh|oligoribonucleotide to stimulate production of a proinflammatory cytokine, use thereof and composition containing such oligoribonucleotide|
    WO2007064478A2|2005-11-28|2007-06-07|Nabi Biopharmaceuticals|Method for making nicotine hapten|
    EP1954252B1|2005-12-02|2016-02-03|GlaxoSmithKline Biologicals SA|Nanoparticles for use in immunogenic compositions|
    KR101552227B1|2006-06-12|2015-09-10|사이토스 바이오테크놀로지 아게|- processes for packaging oligonucleotides into virus-like particles of rna bacteriophages|
    AU2006325225B2|2005-12-14|2013-07-04|Cytos Biotechnology Ag|Immunostimulatory nucleic acid packaged particles for the treatment of hypersensitivity|
    WO2008071774A1|2006-12-14|2008-06-19|Cytos Biotechnology Ag|Purification process for coat protein of rna bacteriophages|
    WO2007070682A2|2005-12-15|2007-06-21|Massachusetts Institute Of Technology|System for screening particles|
    US7842312B2|2005-12-29|2010-11-30|Cordis Corporation|Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same|
    WO2007083316A2|2006-01-23|2007-07-26|Yissum Research Development Company Of The Hebrew University Of Jerusalem|Microspheres comprising nanocapsules containing a lipophilic drug|
    EP1986610B1|2006-02-10|2018-04-11|Biocompatibles UK Limited|Loading of hydrophobic drugs into hydrophilic polymer delivery systems|
    US8021689B2|2006-02-21|2011-09-20|Ecole Polytechnique Federale de Lausanne |Nanoparticles for immunotherapy|
    WO2007100699A2|2006-02-24|2007-09-07|Novartis Ag|Microparticles containing biodegradable polymer and cationic polysaccharide for use in immunogenic compositions|
    WO2007109810A2|2006-03-23|2007-09-27|Novartis Ag|Methods for the preparation of imidazole-containing compounds|
    ES2776100T3|2006-03-31|2020-07-29|Massachusetts Inst Technology|System for targeted delivery of therapeutic agents|
    US20100247653A1|2006-04-11|2010-09-30|Hans Lautenschlager|Nanoparticles containing nicotine and/or cotinine, dispersions, and use thereof|
    EP2019691B1|2006-05-15|2020-08-12|Massachusetts Institute of Technology|Polymers for functional particles|
    WO2007137117A2|2006-05-17|2007-11-29|Massachusetts Institute Of Technology|Aptamer-directed drug delivery|
    US20080014281A1|2006-06-16|2008-01-17|Florida Atlantic University|Chitin Micro-Particles As An Adjuvant|
    WO2007149802A2|2006-06-19|2007-12-27|3M Innovative Properties Company|Formulation for delivery of immune response modifiers|
    US9381477B2|2006-06-23|2016-07-05|Massachusetts Institute Of Technology|Microfluidic synthesis of organic nanoparticles|
    MX2009000035A|2006-06-26|2009-05-28|Mutual Pharmaceutical Co|Active agent formulations, methods of making, and methods of use.|
    US20100144845A1|2006-08-04|2010-06-10|Massachusetts Institute Of Technology|Oligonucleotide systems for targeted intracellular delivery|
    US20080171059A1|2006-08-07|2008-07-17|Shanshan Wu Howland|Methods and compositions for increased priming of t-cells through cross-presentation of exogenous antigens|
    JP2010500340A|2006-08-11|2010-01-07|パナセアバイオテックリミテッド|Particles for delivering active ingredients, methods for their production and compositions|
    US8945582B2|2006-09-07|2015-02-03|Glaxosmithkline Biologicals S.A.|Vaccine|
    WO2008033432A2|2006-09-12|2008-03-20|Coley Pharmaceutical Group, Inc.|Immune modulation by chemically modified ribonucleosides and oligoribonucleotides|
    EP2083857A4|2006-09-22|2010-03-24|Dana Farber Cancer Res Inc|Methods for treating mica-related disorders|
    WO2008043157A1|2006-10-12|2008-04-17|The University Of Queensland|Compositions and methods for modulating immune responses|
    WO2008147456A2|2006-11-20|2008-12-04|Massachusetts Institute Of Technology|Drug delivery systems using fc fragments|
    CA2671629C|2006-12-06|2017-08-15|Novartis Ag|Vaccines including antigen from four strains of influenza virus|
    WO2008073856A2|2006-12-08|2008-06-19|Massachusetts Institute Of Technology|Delivery of nanoparticles and/or agents to cells|
    EP1932516A1|2006-12-11|2008-06-18|Universiteit Utrecht Holding B.V.|Anti-inflammatory compounds containing compositions for treatment of cancer|
    US20080149123A1|2006-12-22|2008-06-26|Mckay William D|Particulate material dispensing hairbrush with combination bristles|
    JP5389668B2|2007-01-31|2014-01-15|チョンシー ユー|Positively charged water-soluble prodrugs of 1H-imidazo [4,5-c] quinolin-4-amine and related compounds with very high skin permeability|
    HUE025555T2|2007-02-07|2016-02-29|Univ California|Conjugates of synthetic tlr agonists and uses therefor|
    US9217129B2|2007-02-09|2015-12-22|Massachusetts Institute Of Technology|Oscillating cell culture bioreactor|
    US8889117B2|2007-02-15|2014-11-18|Yale University|Modular nanoparticles for adaptable vaccines|
    WO2008109852A2|2007-03-07|2008-09-12|Uti Limited Partnership|Compositions and methods for the prevention and treatment of autoimmune conditions|
    WO2008118861A2|2007-03-23|2008-10-02|The University Of North Carolina At Chapel Hill|Discrete size and shape specific organic nanoparticles designed to elicit an immune response|
    WO2008121926A1|2007-03-30|2008-10-09|Particle Sciences, Inc.|Particle formulations and uses thereof|
    WO2008124632A1|2007-04-04|2008-10-16|Massachusetts Institute Of Technology|Amphiphilic compound assisted nanoparticles for targeted delivery|
    WO2008124634A1|2007-04-04|2008-10-16|Massachusetts Institute Of Technology|Polymer-encapsulated reverse micelles|
    AU2008236566A1|2007-04-09|2008-10-16|Chimeros, Inc.|Self-assembling nanoparticle drug delivery system|
    CA2684052A1|2007-04-12|2008-10-23|Emory University|Novel strategies for delivery of active agents using micelles and particles|
    EP1982729A1|2007-04-20|2008-10-22|Cytos Biotechnology AG|Vaccination Regimen for B-Cell Vaccines|
    US20080294089A1|2007-06-06|2008-11-27|Biovaluation & Analysis, Inc.|Dendritic Polymers for Use in Acoustically Mediated Intracellular Drug Delivery in vivo|
    US20090047318A1|2007-08-16|2009-02-19|Abbott Cardiovascular Systems Inc.|Nanoparticle-coated medical devices and formulations for treating vascular disease|
    US8394914B2|2007-08-24|2013-03-12|Board Of Trustees Of Michigan State University|Functional polyglycolide nanoparticles derived from unimolecular micelles|
    WO2009027971A2|2007-08-27|2009-03-05|H2Q Water Industries Ltd.|Antimicrobial polymers|
    US20090130210A1|2007-09-11|2009-05-21|Raheja Praveen|Pharmaceutical compositions of sirolimus|
    EP2197457A4|2007-09-26|2010-10-27|Aparna Biosciences|Therapeutic and vaccine polyelectrolyte nanoparticle compositions|
    MX2010003642A|2007-10-12|2010-08-09|Massachusetts Inst Technology|Vaccine nanotechnology.|
    US8277812B2|2008-10-12|2012-10-02|Massachusetts Institute Of Technology|Immunonanotherapeutics that provide IgG humoral response without T-cell antigen|
    US8343497B2|2008-10-12|2013-01-01|The Brigham And Women's Hospital, Inc.|Targeting of antigen presenting cells with immunonanotherapeutics|
    US8591905B2|2008-10-12|2013-11-26|The Brigham And Women's Hospital, Inc.|Nicotine immunonanotherapeutics|
    US8343498B2|2008-10-12|2013-01-01|Massachusetts Institute Of Technology|Adjuvant incorporation in immunonanotherapeutics|
    WO2009069448A1|2007-11-28|2009-06-04|Toray Industries, Inc.|Adjuvant for japanese b encephalitis vaccine, and japanese b encephalitis vaccine|
    EP2244695A1|2007-12-07|2010-11-03|Novartis AG|Compositions for inducing immune responses|
    WO2009078754A1|2007-12-19|2009-06-25|Ardenia Investments, Ltd.|Drug delivery system for administration of poorly water soluble pharmaceutically active substances|
    JP6088123B2|2008-02-01|2017-03-01|アルファ−オー・ペプチドズ・アーゲーＡｌｐｈａ−Ｏ Ｐｅｐｔｉｄｅｓ Ａｇ|Self-assembling peptide nanoparticles useful as vaccines|
    EP2262489A2|2008-02-28|2010-12-22|Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts|Hollow nanoparticles and uses thereof|
    JP2011525477A|2008-03-04|2011-09-22|リクイディア・テクノロジーズ・インコーポレーテッド|Immunomodulator particles and method of treatment|
    CN101983063A|2008-04-01|2011-03-02|伊耐特医疗技术有限公司|Anti-infective agents and uses thereof|
    US20090297621A1|2008-06-03|2009-12-03|Abbott Cardiovascular Systems Inc.|Microparticles For The Treatment Of Disease|
    MX2010014018A|2008-06-16|2011-06-21|Bind Biosciences Inc|Drug loaded polymeric nanoparticles and methods of making and using same.|
    US8613951B2|2008-06-16|2013-12-24|Bind Therapeutics, Inc.|Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same|
    KR102080429B1|2008-06-26|2020-02-21|안테리오스, 인코퍼레이티드|Dermal delivery|
    WO2010003009A2|2008-07-01|2010-01-07|Emory University|Synergistic induction of humoral and cellular immunity by combinatorial activation of toll-like receptors|
    JP5667566B2|2008-08-06|2015-02-12|ノバルティス アーゲー|Microparticles for use in immunogenic compositions|
    KR20110042116A|2008-08-11|2011-04-22|글락소스미스클라인 엘엘씨|Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases|
    ES2433371T3|2008-08-11|2013-12-10|Glaxosmithkline Llc|Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases|
    MX2011001666A|2008-08-11|2011-03-24|Glaxosmithkline Llc|Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases.|
    WO2010018132A1|2008-08-11|2010-02-18|Smithkline Beecham Corporation|Compounds|
    US8323696B2|2008-08-29|2012-12-04|Ecole Polytechnique Federale De Lausanne|Nanoparticles for immunotherapy|
    WO2010039861A2|2008-09-30|2010-04-08|The Regents Of The University Of Michigan|Dendrimer conjugates|
    EP2172193A1|2008-10-02|2010-04-07|Capsulution Nanoscience AG|Improved nanoparticulate compositions of poorly soluble compounds|
    US10369204B2|2008-10-02|2019-08-06|Dako Denmark A/S|Molecular vaccines for infectious disease|
    US20100098770A1|2008-10-16|2010-04-22|Manikandan Ramalingam|Sirolimus pharmaceutical formulations|
    US20120015899A1|2008-10-25|2012-01-19|Plant Bioscience, Limited|Modified plant virus particles and uses therefor|
    JP5727937B2|2008-11-06|2015-06-03|ベンティアールエックス ファーマシューティカルズ， インコーポレイテッドＶｅｎｔｉＲｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ．|Method for synthesizing benzoacepine derivatives|
    CN101822838B|2009-03-05|2012-06-27|无锡纳奥生物医药有限公司|Nano-medicament carrier material for target recognition of tumor cell as well as preparation and application thereof|
    US20100233231A1|2009-03-10|2010-09-16|Roger Labrecque|Use of cryogenic processing to obtain a substantially-thickened formulation|
    CN102448491A|2009-04-01|2012-05-09|迈阿密大学|Vaccine compositions and methods of use thereof|
    CA2759332A1|2009-04-21|2010-10-28|Selecta Biosciences, Inc.|Immunonanotherapeutics providing a th1-biased response|
    GB0908129D0|2009-05-12|2009-06-24|Innovata Ltd|Composition|
    JP6297776B2|2009-05-27|2018-03-20|セレクタ バイオサイエンシーズ インコーポレーテッドＳｅｌｅｃｔａ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ．|Immunomodulators-polymer compounds|
    EA201270050A1|2009-06-19|2012-05-30|Сан Фарма Адвансед Ресёрч Компани Лтд.|NANODISPERSIA OF THE MEDICINE AND THE METHOD FOR ITS PREPARATION|
    EP2451485B1|2009-07-07|2016-03-02|The Research Foundation Of State University Of New York|Lipidic compositions for induction of immune tolerance|
    CA2771863A1|2009-08-26|2011-03-17|Selecta Biosciences, Inc.|Compositions that induce t cell help|
    ES2549924T3|2009-11-25|2015-11-03|Cytometix, Inc.|Arachidonic acid analogs and methods for analgesic treatment using the same|
    ES2780156T3|2009-12-15|2020-08-24|Pfizer|Therapeutic compositions of polymeric nanoparticles with high glass transition temperature or high molecular weight copolymers|
    WO2011085231A2|2010-01-08|2011-07-14|Selecta Biosciences, Inc.|Synthetic virus-like particles conjugated to human papillomavirus capsid peptides for use as vaccines|
    US20110229556A1|2010-03-19|2011-09-22|Massachusetts Institute Of Technology|Lipid-coated polymer particles for immune stimulation|
    US20110272836A1|2010-04-12|2011-11-10|Selecta Biosciences, Inc.|Eccentric vessels|
    US20110262491A1|2010-04-12|2011-10-27|Selecta Biosciences, Inc.|Emulsions and methods of making nanocarriers|
    WO2011150258A1|2010-05-26|2011-12-01|Selecta Biosciences, Inc.|Dose selection of adjuvanted synthetic nanocarriers|
    US20120064110A1|2010-08-20|2012-03-15|Selecta Biosciences, Inc.|Synthetic nanocarrier vaccines comprising peptides obtained or derived from human influenza a virus hemagglutinin|
    MX2013002173A|2010-08-23|2013-05-06|Selecta Biosciences Inc|Targeted multi-epitope dosage forms for induction of an immune response to antigens.|
    EP2640190A4|2010-11-05|2016-05-11|Selecta Biosciences Inc|Modified nicotinic compounds and related methods|
    WO2012092552A1|2010-12-30|2012-07-05|Selecta Biosciences, Inc.|Synthetic nanocarriers with reactive groups that release biologically active agents|
    MX366228B|2011-03-25|2019-07-03|Selecta Biosciences Inc|Osmotic mediated release synthetic nanocarriers.|
    EA201790030A1|2011-04-29|2017-09-29|Селекта Байосайенсиз, Инк.|NANOSEAGES CAUSING IMMUNE TOLERANCE TO REDUCE THE RESPONSE REACTION OF CYTOTOXIC T-LYMPHOCYTES|
    KR20140050698A|2011-07-29|2014-04-29|셀렉타 바이오사이언시즈, 인크.|Synthetic nanocarriers that generate humoral and cytotoxic t lymphocyte immune responses|
    WO2013036293A1|2011-09-06|2013-03-14|Selecta Biosciences, Inc.|Dendritic cell subsets for generating induced tolerogenic dendritic cells and related compositions and methods|
    CN105338968A|2013-05-03|2016-02-17|西莱克塔生物科技公司|Tolerogenic synthetic nanocarriers to reduce or prevent anaphylaxis in response to a non-allergenic antigen|
    WO2014197616A1|2013-06-04|2014-12-11|Selecta Biosciences, Inc.|Repeated administration of non-immunosupressive antigen specific immunotherapeutics|
    US20150359865A1|2014-06-17|2015-12-17|Selecta Biosciences, Inc.|Tolerogenic synthetic nanocarriers for t-cell-mediated autoimmune disease|
    US20150374815A1|2014-06-25|2015-12-31|Selecta Biosciences, Inc.|Methods and compositions for treatment with synthetic nanocarriers and immune checkpoint inhibitors|
    BR112017001245A2|2014-09-07|2017-12-05|Selecta Biosciences Inc|methods and compositions for attenuating immune responses of the antiviral transfer vector|
    BR112017008720A2|2014-11-05|2017-12-19|Selecta Biosciences Inc|methods and compositions related to rapamycin synthetic nanovoltaics in a supersaturated, stable state|
    US20160220501A1|2015-02-03|2016-08-04|Selecta Biosciences, Inc.|Tolerogenic synthetic nanocarriers to reduce immune responses to therapeutic proteins|EP1960009B1|2005-12-13|2011-11-23|The President and Fellows of Harvard College|Scaffolds for cell transplantation|
    HUE028978T2|2006-09-29|2017-02-28|Takeda Vaccines Inc|Norovirus vaccine formulations|
    US9770535B2|2007-06-21|2017-09-26|President And Fellows Of Harvard College|Scaffolds for cell collection or elimination|
    EP2190471A4|2007-09-18|2012-05-09|Ligocyte Pharmaceuticals Inc|Method of conferring a protective immune response to norovirus|
    CN102006891B|2008-02-13|2017-04-26|哈佛学院董事会|Continuous cell programming devices|
    US9370558B2|2008-02-13|2016-06-21|President And Fellows Of Harvard College|Controlled delivery of TLR agonists in structural polymeric devices|
    WO2009146456A1|2008-05-30|2009-12-03|President And Fellows Of Harvard College|Controlled release of growth factors and signaling molecules for promoting angiogenesis|
    US8492364B2|2008-07-21|2013-07-23|The Brigham And Women's Hospital, Inc.|Methods and compositions relating to synthetic β-1,6 glucosamine oligosaccharides|
    PE20110998A1|2008-12-09|2012-02-10|Coley Pharm Group Inc|IMMUNOSTIMULATORY OLIGONUCLEOTIDES|
    WO2010120749A2|2009-04-13|2010-10-21|President And Fellow Of Harvard College|Harnessing cell dynamics to engineer materials|
    CA2759332A1|2009-04-21|2010-10-28|Selecta Biosciences, Inc.|Immunonanotherapeutics providing a th1-biased response|
    JP6297776B2|2009-05-27|2018-03-20|セレクタ バイオサイエンシーズ インコーポレーテッドＳｅｌｅｃｔａ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ．|Immunomodulators-polymer compounds|
    CA2768552A1|2009-07-31|2011-02-03|President And Fellows Of Harvard College|Programming of cells for tolerogenic therapies|
    CA2771863A1|2009-08-26|2011-03-17|Selecta Biosciences, Inc.|Compositions that induce t cell help|
    EP2542230A4|2010-03-05|2013-08-28|Harvard College|Enhancement of skeletal muscle stem cell engrafment by dual delivery of vegf and igf-1|
    WO2011150258A1|2010-05-26|2011-12-01|Selecta Biosciences, Inc.|Dose selection of adjuvanted synthetic nanocarriers|
    EP2585053A4|2010-06-25|2014-02-26|Harvard College|Co-delivery of stimulatory and inhibitory factors to create temporally stable and spatially restricted zones|
    US11202759B2|2010-10-06|2021-12-21|President And Fellows Of Harvard College|Injectable, pore-forming hydrogels for materials-based cell therapies|
    EP2640190A4|2010-11-05|2016-05-11|Selecta Biosciences Inc|Modified nicotinic compounds and related methods|
    US9603894B2|2010-11-08|2017-03-28|President And Fellows Of Harvard College|Materials presenting notch signaling molecules to control cell behavior|
    US10647959B2|2011-04-27|2020-05-12|President And Fellows Of Harvard College|Cell-friendly inverse opal hydrogels for cell encapsulation, drug and protein delivery, and functional nanoparticle encapsulation|
    US9675561B2|2011-04-28|2017-06-13|President And Fellows Of Harvard College|Injectable cryogel vaccine devices and methods of use thereof|
    ES2878089T3|2011-04-28|2021-11-18|Harvard College|Injectable preformed macroscopic three-dimensional scaffolds for minimally invasive administration|
    EA201790030A1|2011-04-29|2017-09-29|Селекта Байосайенсиз, Инк.|NANOSEAGES CAUSING IMMUNE TOLERANCE TO REDUCE THE RESPONSE REACTION OF CYTOTOXIC T-LYMPHOCYTES|
    JP6062426B2|2011-06-03|2017-01-18|プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ|In situ antigen-producing cancer vaccine|
    EP2731621B1|2011-07-11|2017-11-01|Takeda Vaccines, Inc.|Parenteral norovirus vaccine formulations|
    KR20140050698A|2011-07-29|2014-04-29|셀렉타 바이오사이언시즈, 인크.|Synthetic nanocarriers that generate humoral and cytotoxic t lymphocyteimmune responses|
    US20130122106A1|2011-10-19|2013-05-16|Aphios Corporation|Dosage form, and methods of making and using the same, to produce immunization in animals and humans|
    EP2802350B1|2012-01-13|2017-12-20|President and Fellows of Harvard College|Controlled delivery of tlr agonists in structural polymeric devices|
    KR101822941B1|2012-02-06|2018-01-29|엘지전자 주식회사|Air cleaning filter and method for manufacturing the same|
    EP2634179A1|2012-02-28|2013-09-04|Sanofi|Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging|
    AU2013243955B2|2012-04-02|2018-02-22|Modernatx, Inc.|Modified polynucleotides for the production of oncology-related proteins and peptides|
    AU2013243949A1|2012-04-02|2014-10-30|Moderna Therapeutics, Inc.|Modified polynucleotides for the production of biologics and proteins associated with human disease|
    PL2838515T3|2012-04-16|2020-06-29|President And Fellows Of Harvard College|Mesoporous silica compositions for modulating immune responses|
    WO2014018931A1|2012-07-26|2014-01-30|The General Hospital Corporation|Methods and compositions for treating autoimmune disease|
    US10752949B2|2012-08-14|2020-08-25|10X Genomics, Inc.|Methods and systems for processing polynucleotides|
    US10323279B2|2012-08-14|2019-06-18|10X Genomics, Inc.|Methods and systems for processing polynucleotides|
    US10584381B2|2012-08-14|2020-03-10|10X Genomics, Inc.|Methods and systems for processing polynucleotides|
    KR101953374B1|2012-09-27|2019-02-28|고려대학교 산학협력단|Protein nanoparticle based multivalent vaccines|
    US9701998B2|2012-12-14|2017-07-11|10X Genomics, Inc.|Methods and systems for processing polynucleotides|
    CN103083663B|2013-02-04|2014-12-10|江苏省农业科学院|Immunity enhancing agent, inactivated vaccine, and preparation method thereof|
    US10206985B2|2013-02-05|2019-02-19|Nitto Denko Corporation|WT1 peptide cancer vaccine composition for mucosal administration|
    US9388465B2|2013-02-08|2016-07-12|10X Genomics, Inc.|Polynucleotide barcode generation|
    EP2968584A1|2013-03-11|2016-01-20|Cristal Delivery B.V.|Vaccination composition|
    US10258698B2|2013-03-14|2019-04-16|Modernatx, Inc.|Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions|
    CN105338968A|2013-05-03|2016-02-17|西莱克塔生物科技公司|Tolerogenic synthetic nanocarriers to reduce or prevent anaphylaxis in response to a non-allergenic antigen|
    AU2014292926B2|2013-07-25|2020-03-05|Exicure Operating Company|Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use|
    CN105764524A|2013-08-06|2016-07-13|约翰斯·霍普金斯大学|Methods of treatment of HPV related diseases|
    CN104338126B|2013-08-08|2018-05-04|中国科学院过程工程研究所|It is a kind of that there is the vaccine combination for treating or preventing HPV viruse and its application|
    EP3041938A1|2013-09-03|2016-07-13|Moderna Therapeutics, Inc.|Circular polynucleotides|
    AU2014315287A1|2013-09-03|2015-03-12|Moderna Therapeutics, Inc.|Chimeric polynucleotides|
    JP6543258B2|2013-09-16|2019-07-10|アストラゼネカ アクチボラグ|Therapeutic polymerizable nanoparticles and methods of making and using the same|
    WO2015066715A1|2013-11-04|2015-05-07|Viracell Advanced Products, Llc|Virus-like particles and methods related thereto|
    CN112870163A|2014-01-21|2021-06-01|安杰瑞姆生物科学公司|Hybrid, composition containing the hybrid, preparation method and use thereof|
    US10682400B2|2014-04-30|2020-06-16|President And Fellows Of Harvard College|Combination vaccine devices and methods of killing cancer cells|
    JP6581604B2|2014-06-04|2019-09-25|イグジキュア，インコーポレーテッドＥｘｉｃｕｒｅ，Ｉｎｃ．|Multivalent delivery of immunomodulators with liposomal globular nucleic acids for prophylactic or therapeutic applications|
    KR20180012857A|2015-06-12|2018-02-06|글락소스미스클라인 바이오로지칼즈 에스.에이.|Adenovirus polynucleotides and polypeptides|
    AU2015280417B2|2014-06-24|2020-01-30|The Trustees Of Princeton University|Process for encapsulating soluble biologics, therapeutics, and imaging agents|
    US20150374815A1|2014-06-25|2015-12-31|Selecta Biosciences, Inc.|Methods and compositions for treatment with synthetic nanocarriers and immune checkpoint inhibitors|
    CN106535933B|2014-08-04|2021-09-17|日东电工株式会社|Composition for promoting induction of immunity, which contains nuclear receptor ligand, and vaccine pharmaceutical composition|
    BR112017001245A2|2014-09-07|2017-12-05|Selecta Biosciences Inc|methods and compositions for attenuating immune responses of the antiviral transfer vector|
    GB201418004D0|2014-10-10|2014-11-26|Isis Innovation|Polymer adjuvant|
    WO2016073348A1|2014-11-03|2016-05-12|Albert Einstein College Of Medicine, Inc.|Modified paramagnetic nanoparticles for targeted delivery of therapeutics and methods thereof|
    RU2600031C2|2014-11-11|2016-10-20|Публичное акционерное общество "Фармсинтез"|Dosage form of specific immunobiological medicine for treating and preventing hiv infection and preparation method thereof|
    US11213593B2|2014-11-21|2022-01-04|Northwestern University|Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates|
    US10339559B2|2014-12-04|2019-07-02|Adobe Inc.|Associating social comments with individual assets used in a campaign|
    KR101586466B1|2014-12-31|2016-01-18|성균관대학교산학협력단|Immunoadjuvant and vaccine composition including the same|
    WO2016164705A1|2015-04-10|2016-10-13|Omar Abdel-Rahman Ali|Immune cell trapping devices and methods for making and using the same|
    KR101595949B1|2015-05-27|2016-02-19|성균관대학교산학협력단|Producing method of adjuvant composition and vaccine composition|
    CA2989332A1|2015-06-15|2016-12-22|Emory University|Multivalent enterovirus vaccine compositions and uses related thereto|
    BR112018000037A2|2015-07-02|2018-09-04|Medigen Inc|recombinant virus-like particles using bovine immunodeficiency virus gag protein , vaccine, transfer plasmid vector to produce bgag vlp, method for making bgag vlp, method for preparing the vaccine|
    WO2017021792A1|2015-08-06|2017-02-09|Glaxosmithkline Biologicals Sa|Tlr4 agonists and compositions thereof and their use in the treatment of cancer|
    AU2016378743A1|2015-12-22|2018-08-02|The Trustees Of Princeton University|Process for encapsulating soluble biologics, therapeutics, and imaging agents|
    CN106943597A|2016-01-07|2017-07-14|博笛生物科技（北京）有限公司|Anti-EGFR for treating tumour is combined|
    CN106943596A|2016-01-07|2017-07-14|博笛生物科技（北京）有限公司|Anti-CD 20 for treating tumour is combined|
    CN105535964B|2016-01-27|2019-01-18|苏文全|A kind of double stranded polynucleotide-epsilon-polylysine-sulfuric acid glycan compound and its preparation application method with immunoregulation effect|
    CN105664152B|2016-01-27|2019-01-18|苏文全|A kind of double stranded polynucleotide with immunoregulation effect-epsilon-polylysine compound and its preparation application method|
    DK3436054T3|2016-09-13|2019-11-11|Allergan Inc|STABILIZED NON-PROTEIN CLOSTRID TOXIN COMPOSITIONS|
    CN106496309A|2016-11-24|2017-03-15|北京开景基因技术有限公司|Microballoon antigen and preparation method thereof and the preparation method of anti-cotinine antibody|
    JP6625514B2|2016-11-24|2019-12-25|株式会社デンソーテン|Load drive control device|
    KR101996538B1|2017-02-13|2019-07-04|단디바이오사이언스 주식회사|Nanoemulsion containing imidazoquinoline-based material and uses thereof|
    CN106943592A|2017-03-02|2017-07-14|暨南大学|Application of the phosphonized chitosan as immunologic adjuvant in vaccine therapy|
    WO2019028387A1|2017-08-03|2019-02-07|Rita Elena Serda|Liposomal coated nanoparticles for immunotherapy applications|
    WO2019035963A1|2017-08-16|2019-02-21|Ohio State Innovation Foundation|Nanoparticle compositions for salmonella vaccines|
    CN107582564A|2017-09-14|2018-01-16|湖南晓林生物科技发展有限公司|A kind of medicine of targeted therapy thyroid cancer and preparation method thereof|
    US10590244B2|2017-10-04|2020-03-17|10X Genomics, Inc.|Compositions, methods, and systems for bead formation using improved polymers|
    CN111386134A|2017-10-04|2020-07-07|10X基因组学有限公司|Compositions, methods, and systems for bead formation using improved polymers|
    US10837047B2|2017-10-04|2020-11-17|10X Genomics, Inc.|Compositions, methods, and systems for bead formation using improved polymers|
    WO2019074842A1|2017-10-09|2019-04-18|Keith Black|Oncolytic cancer immunotherapies and methods of use|
    EP3625361A1|2017-11-15|2020-03-25|10X Genomics, Inc.|Functionalized gel beads|
    US10829815B2|2017-11-17|2020-11-10|10X Genomics, Inc.|Methods and systems for associating physical and genetic properties of biological particles|
    US20200306364A1|2017-11-30|2020-10-01|Ohio State Innovation Foundation|Mucoadhesive nanoparticle entrapped influenza virus vaccine delivery system|
    CN108379562B|2018-03-20|2021-11-12|苏州杰纳生物科技有限公司|Polymer nano adjuvant and preparation method and application thereof|
    CN112020823A|2018-05-10|2020-12-01|日产自动车株式会社|Motor system control method and motor system control device|
    EA038215B1|2018-06-09|2021-07-26|Федеральное государственное бюджетное научное учреждение "Федеральный научный центр исследований и разработки иммунобиологических препаратов им. М.П. Чумакова РАН"|Method for quantitative determination of yellow fever virus antigen by enzyme immunoassay using specific yolk antibodies and biotin-labelled detector antibodies|
    CN109187982B|2018-08-02|2021-06-04|浙江康佰裕生物科技有限公司|Method for screening and identifying TLR vaccine adjuvant|
    WO2020163512A1|2019-02-05|2020-08-13|The Brigham And Women's Hospital, Inc.|Polysaccharide compositions for use in treating filariasis|
    法律状态:
    2020-09-15| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-09-15| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-10-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 9A ANUIDADE. |
    2021-02-09| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2598 DE 20-10-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |
    2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US34871310P| true| 2010-05-26|2010-05-26|
    US34871710P| true| 2010-05-26|2010-05-26|
    US34872810P| true| 2010-05-26|2010-05-26|
    US61/348,717|2010-05-26|
    US61/348,713|2010-05-26|
    US61/348,728|2010-05-26|
    US35863510P| true| 2010-06-25|2010-06-25|
    US61/358,635|2010-06-25|
    PCT/US2011/038210|WO2011150258A1|2010-05-26|2011-05-26|Dose selection of adjuvanted synthetic nanocarriers|
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