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    • 专利摘要:
    The present invention relates to a pharmaceutical composition for oral administration, comprising an anti-tumor necrosis factor alpha (TNFα) antibody, preferably a monoclonal antibody produced in the milk of a transgenic non-human animal, and which can be combined in a controlled manner. advantageously with caprylic acid, and is preferably in a form suitable for release of the targeted antibody at the level of the intestine.
    公开号:FR3022462A1
    申请号:FR1455582
    申请日:2014-06-18
    公开日:2015-12-25
    发明作者:Abdessatar Sami Chtourou
    申请人:LFB SA；
    IPC主号:
    专利说明:

    [0001] The present invention relates to the oral administration of an anti-tumor necrosis factor alpha (TNFa) antibody. The targeted therapeutic applications include the treatment of inflammatory bowel diseases, such as Crohn's disease. BACKGROUND OF THE INVENTION TNFα is a pro-inflammatory cytokine that is secreted by and interacts with cells of the immune system. TNFa has been shown to be involved in many human diseases, including chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, and multiple sclerosis. Several anti-TNFa antibodies are currently under development. Two antibodies are already commercially available: infliximab (Remicade®), and adalimumab (Humira®), in injectable forms subcutaneously or intravenously. However, several studies have reported that anti-TNFa antibody therapy, particularly systemic, may have undesirable side effects, including the occurrence of bacterial infections such as tuberculosis (Jarequi-Amezaga et al., Journal of Crohn's and Colitis). , 2013, 7 (3): 208-212), or Listeria infections (Abreu et al., Journal of Crohn's and colitis, 2013, 7 (2): 175-182) or Candida (Huang et al. Journal of Pediatric Gastroenterology and Nutrition, 2013, 56 (4): e23-6). Anti-TNFa polyclonal antibody formulations for oral administration are under development. However, there is still a need to improve the efficacy and / or safety of oral anti-TNFα antibodies. SUMMARY OF THE INVENTION The inventors now propose a pharmaceutical composition for oral administration, comprising an anti-tumor necrosis factor alpha (TNFa) antibody, preferably a monoclonal antibody produced in the milk of a non-human transgenic animal, and which can advantageously be combined with caprylic acid. Preferably, the composition is in a form suitable for a release of the targeted antibody in the intestine. In a preferred embodiment, the anti-TNFα antibody is adalimumab or has the protein sequence of adalimumab.
    [0002] The composition is useful especially in the treatment of an inflammatory disease, preferably an inflammatory bowel disease, more preferably Crohn's disease. DETAILED DESCRIPTION OF THE INVENTION Definitions: The term "treatment" or "treating" means an improvement, prophylaxis, or reversal of a disease or disorder, or at least one symptom that can be discerned from it, or an improvement, prophylaxis, or inversion of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible in or by the subject being treated. The term "treatment" or "treating" further includes the inhibition or slowing down of the progression of a disease or disorder, physically, for example, the stabilization of a discernible symptom, physiologically, e.g. a physical parameter, or both. For the purposes of the present invention, the term "patient" means any mammal, and more particularly human beings, men or women, regardless of age.
    [0003] The term "inflammatory disease" includes any disease with an inflammatory component, preferably inflammatory bowel diseases, including inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. Also included are juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylarthritis.
    [0004] The terms "combination" and "co-administration" refer to the administration of anti-TNFa antibody and caprylic acid as a single formulation or as two separate formulations. Administration can be simultaneous or sequential, in any order. Both agents can be administered simultaneously or successively.
    [0005] Anti-TNFa Antibody: By "anti-TNFα antibody" is meant any antibody that binds specifically to human TNFα. Preferably, the antibody dissociates from human TNFα according to the following constants: Kd less than 1 × 10 -5 M (preferably less than 1 × 10 -5 M, preferably less than 1 × 10 -5 M, preferably less than 1 × 10 -11 M) and Koff of 1x10-3 s-1 or less, both determined by a surface plasmon resonance test ("plasmon surface resonance"). Preferably, the antibody is neutralizing, in particular, neutralizing the biological function of TNFa by blocking its interaction with the p55 and p75 TNF receptors on the cell surface. The neutralization capacity of the antibody can be assayed by a standard assay, for example, the antibody neutralizes the cytotoxicity of human TNFα in a standard L929 in vitro test, with an IC50 of 1x10-7M or less, preferably less than 1x10. -8M, 1x10-9M, or 1x10-1 ° M ,. Preferably it is a monoclonal antibody. The antibody may be an antibody of a mammal such as a mouse, or perhaps preferably humanized, or entirely human.
    [0006] In a preferred embodiment, the anti-TNFα antibody is a human monoclonal antibody. The anti-TNFα antibody preferentially used is adalimumab or has the protein sequence of adalimumab, that is to say comprises the light chain sequence SEQ ID NO: 1 and the heavy chain sequence SEQ ID NO: 2.
    [0007] 15 SEQ ID NO found: 1 1 DIQMTQSPSS LSASVGDRVT ITCRASQGIR NYLAWYQQKP GKAPKLLIYA ASTLQSGVPS 61 RFSGSGSGTD FTLTISSLQP EDVATYYCQR YNRAPYTFGQ GTKVEIKRTV AAPSVFIFPP 121 SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 181 LSKADYEKHK VYACEVTHQG LSSPVTKSFN GBER 20 SEQ ID NO: 2 1 EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYAMHWVRQA PGKGLEWVSA ITWNSGHIDY 61 ADSVEGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAKVS The use of adalimumab is an immunoglobulin G (IgG) consisting of two kappa light chains and two heavy IgG1 chains. The antibody may also be infliximab or golimumab, for example.
    [0008] The antibody used in the invention can be produced by any technique known to those skilled in the art, preferably it is a recombinant antibody. In a particular embodiment, the antibody can thus be produced recombinantly in a host cell, transformed with one or more vectors that allow the expression and / or secretion of the nucleotide sequences coding for the heavy chain and or the light chain of the antibody. The vector generally comprises a promoter, translation initiation and termination signals, as well as appropriate transcriptional regulatory regions. It is stably maintained in the host cell and may optionally have particular signals that specify the secretion of the translated protein. These different elements are selected and optimized by those skilled in the art depending on the cellular host used. Such vectors are prepared by methods commonly used by those skilled in the art, and the resulting clones can be introduced into a suitable host by standard methods, such as lipofection, electroporation, the use of polycationic agents, thermal shock, or chemical methods. The cellular host may be selected from prokaryotic or eukaryotic systems, for example bacterial cells but also yeast cells or animal cells, in particular mammalian cells. Preferred mammalian cells for the production of the monoclonal antibody are the YB2 / 0 rat line, the CHO hamster line, in particular the CHO dhfr- and CHO Lec13 lines, PER.C6TM (Crucell), 293, K562, NSO, SP2 / 0, BHK or COS. Insect cells can also be used.
    [0009] Another mode of production is the expression of the recombinant antibody in transgenic organisms, for example in plants (Ayala M, Gavilondo J, Rodriguez M, Fuentes A, Enriquez G, Perez L, Cremata J, Pujol M. Production of plantibodies in Nicotiana plants, Methods Mol Biol 2009; 483: 103-34.) Or especially in the milk of transgenic animals such as rabbit, goat or pig (Pollock, DP, JP Kutzko, E. Birck -Wilson, JL Williams, Y.
    [0010] Echelard and H.M. Meade. (1999). Transgenic milk as a method for the production of recombinant antibodies. Journal of Immunological Methods. 231: 147-157). According to a preferred embodiment, the antibody is produced in the milk of non-human transgenic mammals genetically modified to produce this glycoprotein. The mammal may be for example a goat, sheep, females of buffalo, buffalo, camel, llama, mouse, rat, or a cow, sow, rabbit, or mare. Preferably, it is transgenic goat's milk.
    [0011] The secretion of the antibody by the mammary glands, allowing its presence in the milk of the transgenic mammal, involves controlling the expression of the antibody in a tissue-dependent manner. Such control methods are well known to those skilled in the art. Expression control is performed through sequences allowing the expression of the glycoprotein in a particular tissue of the animal. These include promoter sequences of "WAP", "(3-casein)," (3-lactoglobulin) and optionally signal peptide-type sequences, and preferably the antibody is produced in the mammary glands. a transgenic goat, using an expression vector comprising the sequence of the two chains, under the control of a 5 '(3-casein) promoter A method of extracting proteins of interest from animal milk transgenic is described in EP 0 264 166. Advantageously, more than 4 grams of antibody per liter of milk is produced, advantageously more than 5, 10, 15, 20, 25, 30, 35 grams per liter, advantageously up to 70 grams per liter.
    [0012] Advantageously, the antibody produced by animal transgenesis, in particular in the mammary glands of a transgenic goat, is in the form of a population of anti-TNFα antibodies which exhibit glycosylation with a high level of galactosylation, for example greater than 60%, preferably greater than 70%, more preferably at least 80%. According to yet another particular aspect, the fucosylation rate of all the antibodies in the population is at least 50%, and in particular at least 60%. In another particular aspect, the population comprises antibodies that comprise mono-galactosyl N-glycans. In another particular aspect, the population comprises antibodies that include bi-galactosyl N-glycans.
    [0013] According to another particular aspect, the ratio of the level of galactosylation of the antibodies of the population and the fucosylation rate of the antibodies of the population is between 1.0 and 1.4. In another particular aspect, at least 35% of the antibodies in the population comprise bi-galactosyl N-glycans and at least 25% of the antibodies in the population comprise mono-galactosyl N-glycans.
    [0014] In another particular aspect, the sialylation rate of the antibodies is at least 50%, preferably at least 70%, or at least 90%. In yet another particular aspect, the antibodies are fully sialylated.
    [0015] The biosynthesis of N-glycans is not regulated by coding, as is the case with proteins, but is primarily dependent on the expression and activity of specific glycosyltransferases in a cell. Thus, a glycoprotein, such as the Fc fragment of an antibody, normally exists as a heterogeneous population of glycoforms that carry different glycans on the same protein backbone. A highly galactosylated antibody population is an antibody population in which the galactosylation level of all antibodies in the population is at least 50%, at least 60%, at least 70% at least 80%, at least 90%, up to 100% galactosylation.
    [0016] According to a particular mode of the highly galactosylated antibody population, the level of galactosylation of all the antibodies in the population is at least 60%. The galactosylation rate can be determined with the following formula: (Gal number) * (% relative area) 1 = 1 * 100 n% relative area) n (number of A) i = 1 in which: 15 - "n" represents the number of N-glycans analyzed on a chromatogram, for example a normal phase high performance liquid chromatography spectrum (NP HPLC), - "Gal number" represents the number of galactoses on the antenna of glycine corresponding to peak, 20 - "number of A" represents the number of N-acetylglucosamine units on the antenna of the glycan form corresponding to the peak (excluding the two N-acetylglucosamine units of the structure common structure of glycan), and - "% relative area" is the percentage of the area under the corresponding peak 25. The level of galactosylation of the antibodies of the antibody population can be determined, for example, by releasing the N-glycans from the antibodies, by solving the N-glycans on a chromatogram, by identifying the N-glycanic oligosaccharide motif which corresponds to a specific peak, determining the intensity of the peak and applying the data to the formula mentioned above.
    [0017] Antibodies that are galactosyl include antibodies that have monogalactosyl N-glycans and bi-galactosyl N-glycans. According to a particular aspect of the highly galactosylated antibody population, the population comprises antibodies which include mono-galactosyl N-glycans, which may or may not be sialylated. According to a particular aspect of the highly galactosylated antibody population, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, up to 100% of the N-glycans of the antibodies include mono-galactosylated glycans. According to still a particular embodiment of the invention, in the highly galactosylated antibody population, at least 25% of the antibodies comprise mono-galactosyl N-glycans. In a particular aspect of the highly galactosylated antibody population, the population includes antibodies that include bi-galactosylated N-glycans, which may or may not be sialylated. According to a particular aspect of the highly galactosylated antibody population, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, up to 100% of the N-glycans of the antibodies include big-lactated N-glycans. According to another particular embodiment of the invention, in the highly galactosylated antibody population, at least 35% of the antibodies comprise bi-galactosylated N-glycans. In yet another aspect of the highly galactosylated antibody population, the population comprises antibodies that include mono-galactosylated N-glycans, which may or may not be sialylated, and antibodies that include bi-galactosylated N-glycans, which may or may not be sialylated.
    [0018] According to a particular aspect of the highly galactosylated antibody population, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, up to 99% of the N-glycans of the antibodies comprise mono-galactosylated N-glycans, and at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60% at least 70%, at least 80%, at least 90%, up to 99% of the N-glycans of the antibodies include bigalactosyl N-glycans.
    [0019] According to another particular aspect of the highly galactosylated antibody population, at least 25% of the antibodies comprise mono-galactosylated N-glycans, and at least 35% of the antibodies comprise bi-galactosylated N-glycans.
    [0020] In a preferred embodiment, the anti-TNFα antibody is produced by the mammary epithelial cells of a transgenic mammal for the mammary gland production of exogenous anti-TNFα antibodies and possibly also transgenic for the production of sialylenes. transferase. Therapeutic antibodies thus produced have a high level of galactosylation, and possibly increased levels of alpha-2,6 sialic acid terminal linkages on their Fc-linked glycans residues. In some embodiments, the antibody has a high mannose glycosylation profile. As used herein, a "high mannose glycosylation profile" refers to an antibody that contains at least one oligomannose or antibody composition in which at least 30% of the antibody contains at least one oligomannose. In some embodiments at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the antibodies' sugars are non-fucosylated oligomannoses. In other embodiments less than 50%, 40%, 30%, 20%, 10%, 5% or less of the sugars of the antibodies contain fucose. In another embodiment, the antibodies have a low fucose content and a high oligomannose content. Thus, in other embodiments, at least 30%, 40%, 50%, 60%, 70%, 80% or 90% or more of the antibodies' sugars are oligomannose and less than 50%. %, 30%, 20%, 10% or 5% of the sugars of the antibodies contain fucose. Thus, in another embodiment at least 30%, 40%, 50%, 60%, 70%, 80% or 90% or more of the antibodies' sugars are non-fucosylated oligomannose and less than 50%. %, 30%, 20%, 10% or 5% of the sugars of the antibodies contain fucose. In a particular aspect, mannose-containing oligosaccharides range from ManS to Man9, with the number as an indicator of the number of mannose residues. For example, oligosaccharides containing mannose may include ManS, Man6, Man7, Man8 and Man9. In some embodiments, the antibody, such as transgenically produced adalimumab, has a high content of Man6. In some embodiments, the major sugar is ManS. In some embodiments, at least 10%, 15%, or more of the sugars are ManS. Advantageously, at least 20% of the sugars are ManS. In other embodiments, the major sugar is Man6. In some embodiments, at least 10%, 15%, or more of the sugars of the transgenically produced antibody are Man6.
    [0021] Advantageously, at least 20% of the sugars are of Man6. In other embodiments, the major sugar is Man7. In some embodiments, at least 10%, 15% or more of the sugars are Man7. Advantageously, at least 20% of the sugars are Man7.
    [0022] Antibodies which have a high galactose or mannose profile, as described above, are particularly preferred in that they have a high affinity for the FcγRIIIa receptor (CD16). High affinity means an affinity at least equal to 2x106 M-1, preferably at least 2x107 2x108 M-1 or 2x109 M-1, as determined by Scatchard analysis or BlAcore technology (Label-free surface plasmon resonance based 10 technology). This receptor is found on many immune cells, including natural killer cells, macrophages, neutrophils, and mast cells. This affinity for CD16 allows an improvement in complement dependent (CDC), or antibody-dependent cellular (ADCC) or target cell phagocytosis activities, as compared to non-highly galactosylated or non-highly labeled antibodies. mannose. In some embodiments, anti-TNFα antibody populations produced in mammary gland epithelial cells are superior, in terms of binding to soluble TNFα, to antibodies produced in cells that are not mammary gland epithelial cells. In some embodiments, populations of TNFα antibodies produced in mammary gland cells are superior, in terms of transmembrane TNFα binding, to antibodies produced in cells that are not mammary gland epithelial cells. Assays for determining the level of binding to soluble TNFα or transmembrane TNFα are well established (see, e.g., Horiuchi et al., Rheumatology et al., 49: 1215).
    [0023] Combination with caprylic acid: In a preferred embodiment, the anti-TNFα antibody, which is preferably a monoclonal antibody produced in the milk of a transgenic non-human animal, is administered in combination with caprylic acid. Caprylic acid, also called octanoic acid, is a linear, saturated fatty acid having eight carbon atoms.
    [0024] The caprylic acid can be used in acid form, or in the form of caprylate salt. Any pharmaceutically acceptable salt can be envisioned, for example sodium or caprylate potassium. According to the invention, the effect of caprylic acid is to provide an anti-septic activity (especially anti-bacterial, anti-fungal and anti-viral) in situ, and can advantageously prevent the risk of infections or superinfections following neutralization of TNFa in the intestinal lumen. Caprylic acid also makes it possible to improve the effectiveness of the antibody by protecting it against too rapid degradation in the gastrointestinal tract, which ultimately makes it possible to enhance the anti-inflammatory effect of the composition.
    [0025] The invention therefore also relates to a pharmaceutical composition for oral administration, comprising an anti-TNFa antibody and caprylic acid or a caprylate salt. Another object of the invention is an anti-TNFα antibody for use in the treatment of an inflammatory disease by oral administration, in combination with administration of caprylic acid (or caprylate salt) orally.
    [0026] Antibody and caprylic acid (or a caprylate salt) are intended for separate, simultaneous or sequential administration. Another object of the invention is a kit comprising, within the same package: a first container containing a pharmaceutical composition for oral administration, comprising an anti-TNFa antibody; A second container containing a pharmaceutical composition for oral administration comprising caprylic acid (or a caprylate salt). Anti-TNFa antibody and caprylic acid (or a caprylate salt) may be combined within the same pharmaceutical composition, or used as separate compositions, which may be administered simultaneously or sequentially. In particular they may be administered separately, ie either concomitantly or independently, for example with a time lag. Caprylic acid (or a caprylate salt) can be used in the invention as a pharmaceutical composition or dietary supplement type composition.
    [0027] Formulations and Therapeutic Applications: The compositions of the present invention may be in any of the galenical forms normally used for oral administration, especially in the form of tablets, capsules, capsules, powder or any form for solid oral preparation. 5 or in any form of oral preparation. In a preferred embodiment, the composition is in a dosage form adapted for targeted release in the intestine. By "intestine" is meant here all parts of the intestine, especially the colon. Such compositions are particularly useful in the treatment of inflammatory bowel diseases because they allow local action at the site of the infection (especially small intestine or colon). They also limit the passage of antibodies in the bloodstream, limiting the side effects related to anti-TNFa antibodies. There are several strategies for preparing orally administered drugs whose active ingredient (s) are released only at the level of the intestine, preferably at the level of the colon. Some strategies include covalent binding of the drug to a carrier, coating with pH-sensitive polymers. Also excipients and vehicles that are degraded by colon bacteria can be used. In a particular embodiment, the anti-TNFα antibody can be formulated in solid dosage forms, such as tablets or capsules, coated with pH-sensitive polymers. The pH is of the order of 1 to 3 in the stomach but it increases in the small intestine and the colon to reach values close to 7. The polymers most commonly used, insoluble in an acidic pH but soluble in a neutral or alkaline pH, are derivatives of methacrylic acid, especially polymers Eudragit® L and S.
    [0028] In another embodiment, formulations which are coated with degradable polymers by colonic microorganisms (more particularly by bacterial enzymes such as azoreductases and glycosidases), for example, azo polymers having a high degree of hydrophilic. Gels and hydrogels may also be used, including polysaccharide hydrogels.
    [0029] When the anti-TNFα antibody is associated with caprylic acid (or caprylate salt), the dosage form comprising the anti-TNFα antibody may be different from the dosage form comprising the optionally associated caprylic acid. Preferably the anti-TNFα antibody is administered in the form of a tablet or capsule. Preferably, caprylic acid is administered in capsule form. The compositions of the invention may comprise or be associated with other therapeutic agents, but this is not preferred. The compositions according to the invention advantageously comprise one or more excipients or vehicles, which are pharmaceutically acceptable. For example, saline, physiological, isotonic, buffered, etc. solutions compatible with pharmaceutical use and known to those skilled in the art may be mentioned. The compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles which can be used in formulations (liquid and / or injectable and / or solid) are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, etc. The compositions may optionally be formulated using dosage forms or devices providing sustained and / or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used.
    [0030] The doses administered may vary, inter alia, according to the weight and age of the patient, and the severity of the disease, appreciated by those skilled in the art. In a preferred embodiment, the dosage of the antibody is in the range of about 0.02 mg / kg to about 100 mg / kg of body weight, about 1 mg to about 8 g per day for a person of 55 to 80 mg / kg of body weight. kg.
    [0031] In a further preferred embodiment, the dosage of the antibody is in the range of about 0.16 mg / kg to about 32 mg / kg of body weight, from about 8.75 mg to about 2.5 g per day. . In a further preferred embodiment, the dosage of the antibody is in the range of about 0.16 mg / kg to about 13 mg / kg body weight, about 8.75 mg to about 1 g per day. In a further preferred embodiment, the dosage of the antibody is in the range of about 0.16 mg / kg to about 6.5 mg / kg of body weight, about 8.75 mg to about 520 mg. In a further preferred embodiment, the dosage of antibody 3022462 is in the range of about 0.16 mg / kg to about 3.2 mg / kg body weight, or about 8.75 mg to about 256 mg. In a further preferred embodiment, the dosage of the antibody is in the range of about 0.16 mg / kg to about 1.3 mg / kg body weight, about 8.75 mg to about 104 mg. In a further preferred embodiment, the dosage of the antibody is in the range of about 0.16 mg / kg to about 0.64 mg / kg of body weight, about 8.75 mg to about 51 mg. In general, advantageous doses are doses of 8 to 200 mg per day, preferably 8 to 35 or 15 to 70 mg per day. In a preferred embodiment, the dosage of caprylic acid (or caprylate salt) is in the range of from 0.01 mg / kg to about 500 mg / kg, for example 0.1 mg / kg to 300 mg. / kg, or about 0.1mg to 20g per day. The patient may receive, for example, a daily dose of anti-TNFα antibody (preferably adalimumab) of, for example, between 10 mg and 500 mg, preferably from 8 to 200 mg per day, preferably from 8 to 35 mg or 15 to 70 mg per day The administered dose of caprylic acid (or caprylate salt) may preferably be between 100 mg and 4 g, preferably 200 mg and 2 g, preferably between 300 mg and 1.5 g, preferably between 750 mg and 1250 mg, and more preferably between 900 mg and 1100 mg. It can be a daily dose or taken once or several times a week. In a particular embodiment, the antibody and caprylic acid (or caprylate salt) can be used in a caprylic acid / antibody mass ratio of at least 1: 1, preferably 5: 1, preferably 10: 1. / 1, preferably 15/1, preferably 20/1. When the two agents are administered sequentially, the dose is administered on the same day, by at least two separate administrations, or one of the agents is administered on the first day and the second on the next day, or the day of after for example. 25
    权利要求:
    Claims (2)
    [0001]
    REVENDICATIONS1. A pharmaceutical composition for oral administration, comprising a monoclonal antibody to tumor necrosis factor alpha (TNFα) produced in the milk of a transgenic non-human animal.
    [0002]
    2. Pharmaceutical composition according to claim 1, the composition being in a form suitable for a release of the targeted antibody in the intestine. . The pharmaceutical composition of claim 1 or 2, wherein the anti-TNFu antibody is adalimumab or has the protein sequence of adalimumab. 4. A phaia otic composition according to one of claims 1 to 3, wherein the transgenic non-human animal is a goat. 5. Pharmaceutical composition according to one of claims 1 to 4, further comprising caprylic acid or caprylate salt. 6. Pharmaceutical composition according to one of claims 1 to 5, for use in the treatment of an inflammatory disease. The pharmaceutical composition for use according to claim 6, wherein the inflammatory disease is an inflammatory bowel disease, such as Crohn's disease. Anti-TNFα antibodies for use in the treatment of inflammatory disease by oral administration, in combination with administration of caprylic acid or caprylate salt, preferably orally. Anti-TNFa antibody for use according to claim 8, wherein the inflammatory disease is inflammatory bowel disease, preferably Crohn's disease. Anti-TNFα antibody for use according to any one of claims 8 or 9, wherein said antibody is adalimumab or has the protein sequence of adalimumab. An anti-TNFa antibody for use according to any one of claims 8 to 10, wherein said antibody is a monoclonal antibody produced in the milk of a transgenic non-human animal, preferably a goat. An anti-TNFα antibody for use according to one of claims 8 to 11, wherein said antibody is in a form suitable for release of the targeted antibody at the level of the intestine. 13. Kit comprising, within the same package: A first container containing a pharmaceutical composition for oral administration, comprising an anti-TNFα antibody, which is preferably a monoclonal antibody produced in the milk of a transgenic non-human animal preferably a goat; A second container containing a pharmaceutical composition for oral administration comprising caprylic acid or a caprylate salt.
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    同族专利:
    公开号 | 公开日
    MX2016016918A|2017-03-27|
    KR20170016491A|2017-02-13|
    AU2015275926A1|2017-01-05|
    US20200331994A1|2020-10-22|
    CN106456765A|2017-02-22|
    EP3157954B1|2019-12-25|
    US20170121402A1|2017-05-04|
    AR100914A1|2016-11-09|
    FR3022462B1|2018-04-27|
    EP3157954A1|2017-04-26|
    CA2952327A1|2015-12-23|
    WO2015193622A1|2015-12-23|
    JP2017519767A|2017-07-20|
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    法律状态:
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    优先权:
    申请号 | 申请日 | 专利标题
    FR1455582|2014-06-18|
    FR1455582A|FR3022462B1|2014-06-18|2014-06-18|ORAL COMPOSITION OF ANTI-TNFALPHA ANTIBODY|FR1455582A| FR3022462B1|2014-06-18|2014-06-18|ORAL COMPOSITION OF ANTI-TNFALPHA ANTIBODY|
    KR1020177001091A| KR20170016491A|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies|
    MX2016016918A| MX2016016918A|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies.|
    CA2952327A| CA2952327A1|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies|
    ARP150101967A| AR100914A1|2014-06-18|2015-06-18|ORAL ANTI-TNF ANTIBODY COMPOSITION a|
    AU2015275926A| AU2015275926A1|2014-06-18|2015-06-18|Oral composition of anti-TNF alpha antibodies|
    PCT/FR2015/051616| WO2015193622A1|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies|
    US15/319,178| US20170121402A1|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies|
    JP2016573875A| JP2017519767A|2014-06-18|2015-06-18|Oral composition of anti-TNF alpha antibody|
    EP15738731.7A| EP3157954B1|2014-06-18|2015-06-18|Oral composition of anti-tnf alpha antibodies|
    CN201580031243.4A| CN106456765A|2014-06-18|2015-06-18|Oral composition of anti-TNF alpha antibodies|
    US16/697,519| US20200331994A1|2014-06-18|2019-11-27|Oral composition of anti-tnf alphaantibodies|
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