IL274870B2 - Dual variable region antibody-like binding proteins having cross-over binding region orientation - Google Patents

Dual variable region antibody-like binding proteins having cross-over binding region orientation

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Publication number
IL274870B2
IL274870B2 IL274870A IL27487020A IL274870B2 IL 274870 B2 IL274870 B2 IL 274870B2 IL 274870 A IL274870 A IL 274870A IL 27487020 A IL27487020 A IL 27487020A IL 274870 B2 IL274870 B2 IL 274870B2
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Israel
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length
amino acid
antibody
binding protein
acid residues
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IL274870A
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Hebrew (he)
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IL274870B1 (en
IL274870A (en
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Sanofi Sa
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=65657124&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IL274870(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from PCT/US2012/030948 external-priority patent/WO2012135345A1/en
Application filed by Sanofi Sa filed Critical Sanofi Sa
Publication of IL274870A publication Critical patent/IL274870A/en
Publication of IL274870B1 publication Critical patent/IL274870B1/en
Publication of IL274870B2 publication Critical patent/IL274870B2/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46Hybrid immunoglobulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241Tumor Necrosis Factors
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • C07K16/245IL-1
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • C07K16/247IL-4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46Hybrid immunoglobulins
    • C07K16/461Igs containing Ig-regions, -domains or -residues form different species
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46Hybrid immunoglobulins
    • C07K16/468Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07ORGANIC CHEMISTRY
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
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    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/522CH1 domain
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    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/524CH2 domain
    • CCHEMISTRY; METALLURGY
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    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/526CH3 domain
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    • C07ORGANIC CHEMISTRY
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    • C07K2317/53Hinge
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55Fab or Fab'
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/624Disulfide-stabilized antibody (dsFv)
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/626Diabody or triabody
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
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    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/66Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94Stability, e.g. half-life, pH, temperature or enzyme-resistance
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    • C07K2318/00Antibody mimetics or scaffolds

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  • Genetics & Genomics (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (25)

274870/2 WHAT IS CLAIMED IS:
1. An antibody-like binding protein comprising four polypeptide chains that form four antigen binding sites, wherein two polypeptide chains have a structure represented by the formula:VL1-L1-VL2-L2-CL [I]and two polypeptide chains have a structure represented by the formula: VH2-L3-VH1-L4-CH1-Fc [II]wherein:V L1 is a first immunoglobulin light chain variable domain;V L2 is a second immunoglobulin light chain variable domain;V H1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain;Fc is the immunoglobulin hinge region and CH2, CH3 immunoglobulin heavy chain constant domains; andL1, L2, L3, and L4 are amino acid linkers, whereinL2 is at least 1 amino acid residue in length, andL4 is at least 1 amino acid residue in length;and wherein the polypeptides of formula I and the polypeptides of formula II form a cross-over light chain-heavy chain pair.
2. An antibody-like binding protein comprising two polypeptide chains that form two antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:VL1-L1-VL2-L2-CL [I]and a second polypeptide chain has a structure represented by the formula: VH2-L3-VH1-L4-CH1 [II]wherein:V L1 is a first immunoglobulin light chain variable domain; 274870/2 V L2 is a second immunoglobulin light chain variable domain;V H1 is a first immunoglobulin heavy chain variable domain;V H2 is a second immunoglobulin heavy chain variable domain;C L is an immunoglobulin light chain constant domain;C H1 is the immunoglobulin CH1 heavy chain constant domain; andL 1, L2, L3, and L4 are amino acid linkers, whereinL2 is at least 1 amino acid residue in length, andL4 is at least 1 amino acid residue in length;and wherein the first and second polypeptides form a cross-over light chain-heavy chain pair.
3. The antibody-like binding protein of either claim 1 or 2, wherein:L1 is 3 to 12 amino acid residues in length;L2 is 3 to 14 amino acid residues in length;L3 is 1 to 8 amino acid residues in length; andL4 is 1 to 3 amino acid residues in length.
4. The antibody-like binding protein of either claim 1 or 2, wherein:L1 is 5 to 10 amino acid residues in length;L2 is 5 to 8 amino acid residues in length;L3 is 1 to 5 amino acid residues in length; andL4 is 1 to 2 amino acid residues in length.
5. The antibody-like binding protein of either claim 1 or 2, wherein:L1 is 1 to 3 amino acid residues in length;L2 is 1 to 4 amino acid residues in length;L3 is 2 to 15 amino acid residues in length; andL4 is 2 to 15 amino acid residues in length.
6. The antibody-like binding protein of any one of claims 1 or 2, wherein:L1 is 7 amino acid residues in length; 274870/2 L2 is 5 amino acid residues in length;L3 is 1 amino acid residue in length; and L4 is 2 amino acid residues in length.
7. The antibody-like binding protein of either claim 1 or 2, wherein:L1 is 1 amino acid residue in length;L2 is 2 amino acid residues in length;L3 is 7 amino acid residues in length; and L4 is 5 amino acid residues in length.
8. The antibody-like binding protein of either claim 1 or 2, wherein one or more of L1 or L3 is 0 amino acid residues in length.
9. The antibody-like binding protein of either claim 1 or 2, wherein the bindingprotein is capable of specifically binding one or more antigen targets.
10. The antibody-like binding protein of claim 9, wherein the one or more antigen targets is selected from the group consisting of B7.1, B7.2, BAFF, BlyS, C3, C5, CCL11 (eotaxin), CCL15 (MIP-1d), CCL17 (TARC), CCL19 (MIP-3b), CCL(MCP-1), CCL20 (MIP-3a), CCL21 (MIP-2), SLC, CCL24 (MPIF-2/eotaxin-2), CCL25 (TECK), CCL26 (eotaxin-3), CCL3 (MIP-1a), CCL4 (MIP-1b), CCL(RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CD3, CD19, CD20, CD24, CD40, CD40L, CD80, CD86, CDH1 (E-cadherin), Chitinase, CSF1 (M-CSF), CSF(GM-CSF), CSF3 (GCSF), CTLA4, CX3CL1 (SCYD1), CXCL12 (SDF1), CXCL13, EGFR, FCER1A, FCER2, HER2, IGF1R, IL-1, IL-12, IL13, IL15, IL17, IL18, IL1A, IL1B, IL1F10, IL1β, IL2, IL4, IL6, IL7, IL8, IL9, IL12/23, IL22, IL23, IL25, IL27, IL35, ITGB4 (b 4 integrin), LEP (leptin), MHC class II, TLR2, TLR4, TLR5, TNF, TNFα, TNFSF4 (OX40 ligand), TNFSF5 (CDligand), Toll-like receptors, TREM1, TSLP, TWEAK, XCR1 (GPR5/CCXCR1), DNGR-1(CLEC91), and HMGB1. 274870/2
11. The antibody-like binding protein of either claim 1 or 2, wherein the binding protein is bispecific and capable of binding two different antigen targets.
12. The antibody-like binding protein of claim 11, wherein the two different antigen targets are selected from the group consisting of IL4 and IL13, IGF1R and HER2, IGF1R and EGFR, EGFR and HER2, BK and IL13, PDL-1 and CTLA-4, CTLAand MHC class II, IL-12 and IL-18, IL-1α and IL-1β, TNFα and IL12/23, TNFα and IL-12p40, TNFα and IL1β, TNFα and IL-23, and IL17 and IL23.
13. The antibody-like binding protein of either claim 1 or 2, wherein at least one of the linkers selected from the group consisting of L1, L2, L3, and L4 contains at least one cysteine residue.
14. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody-like binding protein of any one of claims 1-13.
15. An expression vector comprising the nucleic acid molecule of claim 14.
16. An isolated host cell comprising the nucleic acid molecule of claim 14 or the expression vector of claim 15.
17. The host cell of claim 16, wherein the host cell is a mammalian cell or an insect cell.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody-like binding protein of any one of claims 1-13.
19. A method for making the antibody-like binding protein of any one of claims 1-comprising expressing in a cell a nucleic acid molecule of claim 14. 274870/2
20. The method of claim 19, wherein the first antibody variable domain and the second antibody variable domain in the antibody-like binding protein are the same, wherein the first antibody variable domain is VL1 and VH1 and the second variable antibody domain is VL2 and VH2.
21. The antibody-like binding protein of either claim 1 or 2, wherein L2 and L4 are both at least one amino acid in length, and(a) the length of L2 is at least twice the length of L4; or(b) the length of L4 is at least twice the length of L2.
22. The antibody-like binding protein of claim 1, wherein at least one of the first or second polypeptide chains further comprises a Fc that is an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains derived from a Fc domain.
23. The antibody-like binding protein of claim 22, wherein the Fc is linked to the carboxyl terminal region of the polypeptide chain.
24. The antibody-like binding protein of claim 22, wherein the Fc is linked to CL and/or CH1.
25. The antibody-like binding protein of claim 24, wherein the Fc of the first polypeptide is linked to CL and/or the Fc of the second polypeptide is linked to the CH1.
IL274870A 2011-03-28 2020-05-24 Dual variable region antibody-like binding proteins having cross-over binding region orientation IL274870B2 (en)

Applications Claiming Priority (3)

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US201161468276P 2011-03-28 2011-03-28
FR1160311 2011-11-14
PCT/US2012/030948 WO2012135345A1 (en) 2011-03-28 2012-03-28 Dual variable region antibody-like binding proteins having cross-over binding region orientation

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IL274870A IL274870A (en) 2020-07-30
IL274870B1 IL274870B1 (en) 2023-01-01
IL274870B2 true IL274870B2 (en) 2023-05-01

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KR (1) KR102240802B1 (en)
CL (1) CL2013002763A1 (en)
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014719A1 (en) * 1995-10-16 1997-04-24 Unilever N.V. A bifunctional or bivalent antibody fragment analogue
EP2050764A1 (en) * 2007-10-15 2009-04-22 sanofi-aventis Novel polyvalent bispecific antibody format and uses thereof
WO2011014659A2 (en) * 2009-07-29 2011-02-03 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101821288A (en) * 2007-06-21 2010-09-01 宏观基因有限公司 Covalent diabodies and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014719A1 (en) * 1995-10-16 1997-04-24 Unilever N.V. A bifunctional or bivalent antibody fragment analogue
EP2050764A1 (en) * 2007-10-15 2009-04-22 sanofi-aventis Novel polyvalent bispecific antibody format and uses thereof
WO2011014659A2 (en) * 2009-07-29 2011-02-03 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof

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MX2019009016A (en) 2019-09-10
HRP20210240T1 (en) 2021-04-02
IL274876A (en) 2020-07-30
PH12018501305A1 (en) 2020-01-27
IL274870B1 (en) 2023-01-01
IL274870A (en) 2020-07-30
HUE053139T2 (en) 2021-06-28
PT3199547T (en) 2021-02-02
KR102240802B1 (en) 2021-04-16
IL249369A0 (en) 2017-02-28
RU2019122155A (en) 2020-03-16
KR20190049902A (en) 2019-05-09
LT3199547T (en) 2021-02-25
ES2859906T3 (en) 2021-10-04
CL2013002763A1 (en) 2014-03-07
IL249369B (en) 2019-11-28

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