• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
      RECOMBINANT MULTIMERIC STRUCTURE SPECIFIC TRAIL R2, ITS USE, NUCLEIC ACID MOLECULE THAT CODES IT, AS WELL AS COMPOSITION.The present invention relates to Tenascin-3 FnIII domain-based multimeric structures that specifically bind to the TRAIL 2 receptor (TRAIL R2), a cell membrane receptor involved in apoptosis. The invention also relates to variants designed with increased affinity for the target, increases stability and reduced immunogenicity. In addition, the present invention relates to multivalent structures designed as prophylactic, diagnostic or therapeutic agents and their uses against diseases caused by cells that express TRAIL R2, in particular a therapeutic use against cancer.
    公开号:BR112012026003A2
    申请号:R112012026003-0
    申请日:2011-04-12
    公开日:2020-09-01
    发明作者:Manuel Baca；Thomas Thirsted；Jeffrey Swers；David Tice
    申请人:Medimmune, Llc；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for "TRAIL R2 SPECIFIC RECOMBINANT MULTIMETER STRUCTURE, ITS USE, NUCLEIC ACID MOLECULE THAT CODES IT, WELL AS A COMPOSITION". 5 BACKGROUND OF THE INVENTION Reference to the Sequence Listing This request incorporates by reference a Sequence Listing submitted with this request through an EFS-Web text file entitled “2943.011PC02_sequence_listing.txt” created on April 12, 2011 and having a size of 211 kilobytes.
    Field of the invention The present invention relates in general to the field of antibody mimetics, specifically to multimeric structures based on the domain of fibronectin type III (Fn3) useful, for example, for the generation of products containing new characteristics of Link.
    In particular, the invention relates to specific multimeric structures of TRAIL R2 derived from the third domain of human Tenascin C FnIII and their uses for TRAIL R2 receptor detection and modulation of TRAIL R2-mediated function as a cancer treatment and other disorders.
    Prior Art Biomolecules capable of specific binding to a desired target epitope are of great importance as therapeutics, research, and medical diagnostic tools.
    A well-known example of this class of molecules is the antibody.
    Antibodies can be selected that link specifically and with affinity to almost any structural epitope.
    However, classic antibodies are structurally complex heterotretameric molecules that are difficult to express in simple eukaryotic systems.
    As a result, most antibodies are produced using complex and cell mammalian cell expression systems.
    Proteins containing three-dimensional structures relative to
    defined structures, commonly referred to as protein structures, can be used as reagents for the design of designed products.
    One particular area where such structures are useful is the antibody mimetic design field.
    Antibody mimetics, that is, 5 small non-antibody protein therapies, capitalize on the advantages of antibodies and antibody fragments, such as high affinity target binding and low immunogenicity and toxicity, while avoiding some deficiencies, such as the tendency for antibody fragments to aggregate and be less stable than full-length IgGs.
    These disadvantages can be addressed by using antibody fragments by removing parts of the native fold of the antibody.
    However, this usually causes aggregation when amino acid residues that could normally be hidden in a hydrophobic environment as an interface between variable and constant domains are exposed to the solvent.
    An example of antibody mimetic based on the structure is based on the structure of a type III fibronectin molecule (FnIII), a domain found widely across protein ranks and classes, as in mammalian blood and proteins structural.
    TRAIL (apoptosis-inducing linkage related to tumor necrosis factor, still referred to in the literature as Apo2L and TNFSF10) belongs to the tumor necrosis factor (TNF) superfamily and has been identified as an activator of programmed cell death, or apoptosis , in tumor cells.
    Both membrane-bound and soluble forms of TRAIL are able to trigger apoptosis through interaction with TRAIL receptors located in target cells.
    In humans, five receptors have been identified as having TRAIL binding activity.
    In the connection of TRAIL to TRAIL R1 or TRAIL R2, cell death related to caspase is triggered.
    In light of this cell death activity, therapeutic approaches based on TRAIL are being sought.
    Various therapeutic approaches based on TRAIL or TRAIL
    权利要求:
    Claims (11)
    [1]
    1. TRAIL R2 specific recombinant multimeric structure, characterized by the fact that it comprises at least two structures of Tn3 monomers, where 5 (a) each Tn3 monomer structure comprises seven beta strands designated A, B, C, D, E , F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, (b) the Tn3 monomer structures are connected in tandem, and (c) the recombinant multimeric structure specifically binds to TRAIL R2, where at least two Tn3 monomer structures comprise the amino acid sequence: I- EV (XAB) nALITW (XBC) nCELX1YGI (XCD) nTTIX2L (XDE) nYSI (XEF) nYEVSLIC (XFG) n KX3TFTT where XAB , XBC, XCD, XDE, XEF, and XFG represent the amino acid residues present in the AB, BC, CD, DE, EF, and FG loops, respectively, where X1 represents amino acid residue A or T, where X2 represents amino acid residue D or G, where X3 represents amino acid E or G, and where loop length n is an integer between 2 and 26.
    [2]
    2. Multimeric structure according to claim 1, characterized by the fact that handle AB comprises SEQ ID NO: 35, handle CD comprises SEQ ID NO: 37, and handle EF comprises SEQ ID NO:
    39.
    [3]
    3. Multimeric structure according to claim 1, characterized by the fact that the loop BC comprises a sequence selected from the group consisting of: SEQ ID NOs: 97, 98, or 168.
    [4]
    4. Multimeric structure according to claim 1, characterized by the fact that the DE loop comprises a sequence selected from the group consisting of: SEQ ID NOs: 102, 103, and 179.
    [5]
    5. Multimeric structure according to claim 1, characterized by the fact that the FG loop comprises a sequence selected from the group consisting of: SEQ ID NOs: 106, 108, 109, 169, and 170.
    [6]
    6. Multimeric structure according to claim 1, characterized by the fact that handle BC comprises SEQ ID NO: 97, handle DE comprises SEQ ID NO: 179, and handle FG comprises SEQ ID NO :
    170.
    [7]
    7. Multimeric structure according to claim 1, characterized by the fact that the structure comprises SEQ ID NO: 204.
    [8]
    8. Isolated nucleic acid molecule, characterized by the fact that it encodes the multimeric structure, as defined in claim 1.
    [9]
    9. Composition, characterized by the fact that it comprises the recombinant multimeric structure, as defined in claim 1, in a pharmaceutically acceptable excipient.
    [10]
    10. Use of a recombinant multimeric structure, as defined in any of claims 1 to 7, characterized by the fact that it is to prepare a composition to prevent, treat, alleviate, or control cancer; to diagnose or imagine the disease in a patient.
    [11]
    11. 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, disclosed or illustrated in the patent application.
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    法律状态:
    2020-09-15| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-11-17| 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. |
    2020-12-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
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    2021-12-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US32370810P| true| 2010-04-13|2010-04-13|
    US61/323,708|2010-04-13|
    PCT/US2011/032188|WO2011130328A1|2010-04-13|2011-04-12|Trail r2-specific multimeric scaffolds|
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