Stable igg4 antibodies

Abstract

The present invention relates to stabilized IgG4 antibodies, to methods of producing such antibodies and to uses of such antibodies as a medicament. In a main aspect, the invention relates to a stabilized IgG4 antibody, comprising a heavy chain and a light chain, wherein said heavy chain comprises a human IgG4 constant region having a substitution of the Arg residue at position (409), the Phe residue at position (405) or the Lys residue at position (370).

1 . A stabilized IgG4 antibody for use as a medicament, comprising a heavy chain and a light chain, wherein said heavy chain comprises a human IgG4 constant region having a substitution of the Arg residue at position 409, the Phe residue at position 405 or the Lys residue at position 370, wherein said antibody optionally comprises one or more further substitutions, deletions and/or insertions, with the proviso that if the antibody has a residue selected from the group consisting of: Lys, Ala, Thr, Met and Leu at the position corresponding to 409, then the antibody does not comprise a Cys-Pro-Pro-Cys sequence in the hinge region. 
     
     
         2 . The stabilized IgG4 antibody of  claim 1 , wherein said heavy chain comprises a human IgG4 constant region having a residue selected from the group consisting of: Lys, Ala, Thr, Met and Leu at the position corresponding to 409 and/or a residue selected from the group consisting of: Ala, Val, Gly, He and Leu at the position corresponding to 405, and wherein said antibody optionally comprises one or more further substitutions, deletions and/or insertions, but does not comprise a Cys-Pro-Pro-Cys sequence in the hinge region. 
     
     
         3 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a Lys, Ala, Thr, Met or Leu residue at the position corresponding to 409. 
     
     
         4 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a Lys, Thr, Met or Leu residue at the position corresponding to 409. 
     
     
         5 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a Lys, Met or Leu residue at the position corresponding to 409. 
     
     
         6 . The stabilized IgG4 antibody of  claim 1 , wherein the CH3 region of the antibody has been replaced by the CH3 region of human IgG1, of human IgG2 or of human IgG3. 
     
     
         7 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody at the position corresponding to 405 has a residue which has a lower mass than Phe. 
     
     
         8 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises an Ala or Leu residue at the position corresponding to 405. 
     
     
         9 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a Thr residue at the position corresponding to 370. 
     
     
         10 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody does not comprise a substitution of the Leu residue at the position corresponding to 235 by a Glu. 
     
     
         11 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody does comprise a substitution of the Leu residue at the position corresponding to 235 by a Glu. 
     
     
         12 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises one or more of the following substitutions: an Ala at position 234, an Ala at position 236, an Ala at position 237, an Ala at position 297, an Ala or Val at position 318, an Ala at position 320, an Ala or Gln at position 322. 
     
     
         13 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody does not comprise a Cys-Pro-Pro-Cys sequence in the hinge region. 
     
     
         14 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a CXPC or CPXC sequence in the hinge region, wherein X can be any amino acid except for proline. 
     
     
         15 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody does not comprise an extended IgG3-like hinge region. 
     
     
         16 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a CPSC sequence in the hinge region. 
     
     
         17 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a constant heavy chain region comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:39, 40 and 41 or a variant of said amino acid sequence having less than 25 substitutions, deletions and/or insertions compared to said amino acid sequence. 
     
     
         18 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody is less efficient in mediating CDC and/or ADCC than a corresponding IgG1 or IgG3 antibody having the same variable regions. 
     
     
         19 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a constant heavy chain region comprising the amino acid sequence set forth in SEQ ID NO:40. 
     
     
         20 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody is selected from the group consisting of: a human antibody, a humanized antibody and a chimeric antibody. 
     
     
         21 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a human kappa light chain. 
     
     
         22 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody comprises a human lambda light chain. 
     
     
         23 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody is a bivalent antibody. 
     
     
         24 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody is a full-length antibody. 
     
     
         25 . The stabilized IgG4 antibody of  claim 1 , wherein said antibody is linked to a compound selected from the group consisting of: a cytotoxic agent; a radioisotope; a prodrug or drug, such as a taxane; a cytokine; and a chemokine. 
     
     
         26 . The stabilized IgG4 antibody of  claim 1 , wherein the antibody binds an antigen selected from the group consisting of: erythropoietin, beta-amyloid, thrombopoietin, interferon-alpha (2a and 2b), interferon-beta (1b), interferon-gamma, TNFR I (CD120a), TNFR II (CD120b), IL-IR type 1 (CD121a), IL-IR type 2 (CD121b), IL-2, IL2R (CD25), IL-2R-beta (CD123), IL-3, IL-4, IL-3R (CD123), IL-4R (CD124), IL-5R (CD125), IL-6R-alpha (CD126), -beta (CD130), IL-8, IL-10, IL-Il, IL-15, IL-15BP, IL-15R, IL-20, IL-21, TCR variable chain, RANK, RANK-L, CTLA4, CXCR4R, CCR5R, TGF-beta1, -beta2,-beta3, G-CSF, GM-CSF, MIF-R (CD74), M-CSF-R (CD115), GM-CSFR (CD116), soluble FcRI, sFcRII, sFcRIII, FcRn, Factor VII, Factor VIII, Factor IX, VEGF, VEGFxxxb, alpha-4 integrin, Cd 11a, CD18, CD20, CD38, CD25, CD74, FcalphaRI, FcepsilonRI, acetyl choline receptor, fas, fasL, TRAIL, hepatitis virus, hepatitis C virus, envelope E2 of hepatitis C virus, tissue factor, a complex of tissue factor and Factor VII, EGFr, CD4, CD28, VLA-I, 2, 3, or 4, LFA-I, MAC-I, 1-selectin, PSGL-I, ICAM-I, P-selectin, periostin, CD33 (Siglec 3), Siglec 8, TNF, CCL1, CCL2, CCL3, CCL4, CCL5, CCLU, CCL13, CCL17, CCL18, CCL20, CCL22, CCL26, CCL27, CX3CL1, LIGHT, EGF, VEGF, TGFalpha, HGF, PDGF, NGF, complement or a related components such as: CIq, C4, C2, C3, C5, C6, C7, C8, C9, MBL, factor B, a Matrix Metallo Protease such as any of MMP1 to MMP28, CD32b, CD200, CD200R, Killer Immunoglobulin-Like Receptors (KIRs), NKG2D and related molecules, leukocyte-associated immunoglobulin-like receptors (LAIRs), Iv49, PD-L2, CD26, BST-2, ML-IAP (melanoma inhibitor of apoptosis protein), cathepsin D, CD40, CD40R, CD86, a B cell receptor, CD79, PD-I and a T cell receptor. 
     
     
         27 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds an alpha-4 integrin and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma and sepsis. 
     
     
         28 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds VLA-I, 2, 3, or 4 and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis, COPD and sepsis. 
     
     
         29 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds a molecule selected from the group consisting of: LFA-I, MAC-I, 1-selectin and PSGL-I and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis, and COPD. 
     
     
         30 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds a molecule selected from the group consisting of: LFA-I, MAC-I, 1-selectin and PSGL-I and is for use in the treatment of a disease selected from the group consisting of ischemia-reperfusion injury, cystic fibrosis, osteomyelitis, glomerulonepritis, gout and sepsis. 
     
     
         31 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD18 and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis and COPD. 
     
     
         32 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds Cd 11a and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis and COPD. 
     
     
         33 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds ICAM-I and is for use in the treatment of inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis and COPD. 
     
     
         34 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds P-selectin and is for use in the treatment of cardiovascular diseases, post-thrombotic vein wall fibrosis, ischemia reperfusion injury, inflammatory diseases or sepsis. 
     
     
         35 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds periostin and is for use in the treatment of malignant diseases and/or metastising diseases, such as ovary cancer, endometrial cancer, NSCLC, glioblastoma, brain-related tumors, breast cancer, OSCC, colon cancer, pancreatic cancer, HNSCC, kidney cancer, thymoma, lung cancer, skin cancer, larynx cancer, liver cancer, parotid tumors, gastric cancer, esophagus cancer, prostate cancer, bladder cancer and cancer of the testis. 
     
     
         36 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD33 (Siglec 3), is optionally coupled to a toxin, cytotoxic or cytostatic drug, and is for use in the treatment of tumors expressing CD33 or acute myeloid leukemia. 
     
     
         37 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds Siglec 8 and is for use in the treatment of: asthma, inflammatory or autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis and COPD. 
     
     
         38 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds TNF and is for use in the treatment of: inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, atopic dermatitis, COPD and sepsis. 
     
     
         39 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CCL1, CCL2, CCL3, CCL4, CCL5, CCLU, CCL13, CCL17, CCL18, CCL20, CCL22, CCL26, CCL27 or CX3CL1 and is for use in the treatment of: atopic dermatitis, inflammatory and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, type-1 diabetes, SLE, psoriasis, COPD and sepsis. 
     
     
         40 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds LIGHT and is for use in the treatment of a disease selected from the group consisting of: hepatitis, inflammatory bowel disease, GVHD and inflammation. 
     
     
         41 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds EGF, VEGF, TGFalpha or HGF and is for use in the treatment of: malignant diseases, such as solid cancers. 
     
     
         42 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds PDGF and is for use in the treatment of: diseases in which abnormal cell proliferation cell migration and/or angiogenesis occurs, such as atherosclerosis, fibrosis, and malignant diseases. 
     
     
         43 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds NGF and is for use in the treatment of: neurological diseases, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, or cancer, such as prostate cancer. 
     
     
         44 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds complement or a related components such as: CIq, C4, C2, C3, C5, C6, C7, C8, C9, MBL, or factor B and is for use in: diseases in which complement and related components play a detrimental role, such as organ transplant rejection, multiple sclerosis, Guillain-Barre syndrome, hemolytic anemia, Paroxysmal Nocturnal Hemoglobinuria, stroke, heart attacks, burn injuries, age-related macular degeneration, asthma, lupus, arthritis, myasthenia gravis, anti-phospholipid syndrome, sepsis and ischemia reperfusion injury. 
     
     
         45 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds a Matrix Metallo Protease such as any of MMP1 to MMP28 and is for use in the treatment of: inflammatory and autoimmune diseases, cancer, including metastatic cancer; arthritis, inflammation, cardiovascular diseases, cerebrovascular diseases such as stroke or cerebral aneurysms, pulmonary diseases such as asthma, ocular diseases such as corneal wound healing or degenerative genetic eye diseases, gastrointestinal diseases such as inflammatory bowel disease or ulcers, oral diseases such as dental caries, oral cancer or periodontitis, ischemia repoerfusion injury or sepsis. 
     
     
         46 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD32b and is for use in enhancement of T-cell responses to tumor antigens and ADCC/phagocytosis by macrophages, in combination with another therapeutic antibody; vaccination, immunotherapy of B-cell lymphoma's, asthma or allergy. 
     
     
         47 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD200 or CD200R and is for use in the treatment of: asthma, rheumatoid arthritis, GVHD, other autoimmune diseases, or cancer, such as solid tumors or lymphomas. 
     
     
         48 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds Killer Immunoglobulin-Like Receptors (KIRs), NKG2D or related molecules, leukocyte-associated immunoglobulin-like receptors (LAIRs), or Iy49 and is for use in the treatment of: cancer, such as solid tumors or lymphomas; asthma, rheumatoid arthritis, GVHD or other autoimmune diseases. 
     
     
         49 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds PD-L2 and is for use in the treatment of: cancer, asthma, or for use in vaccine enhancement. 
     
     
         50 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD26 and is for use in the treatment of: atherosclerosis, GVHD, or auto-immune diseases. 
     
     
         51 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds BST-2 and is for use in the treatment of: asthma, atherosclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative cholitis, atopic dermatitis, sepsis or inflammation. 
     
     
         52 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds ML-IAP (melanoma inhibitor of apoptosis protein) and is for use in the treatment of melanoma. 
     
     
         53 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds cathepsin D and is for use in the treatment of: malignant diseases such as breast cancer, ovarian cancer, glioma, NSCLC, bladder cancer, endometrial cancer, liver cancer, sarcoma, gastric cancer, SCCHN, prostate cancer or colorectal cancer. 
     
     
         54 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD40 or CD40R and is for use in the treatment of: cancer, in particular B-cell lymphomas, B-cell-related or -mediated diseases, autoimmune diseases such as psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease or ulcerative cholitis. 
     
     
         55 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD86 and is for use in conjunction with organ transplantation. 
     
     
         56 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds a B cell receptor and is for use in the treatment of: B-cell-related or -mediated diseases, such as B cell lymphoma's, leukemia, autoimmune diseases, inflammation or allergy. 
     
     
         57 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD79 and is for use in the treatment of B-cell-related or -mediated diseases, such as B-cell lymphomas, leukemia, autoimmune diseases, inflammation or allergy. 
     
     
         58 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds a T cell receptor and is for use in the treatment of T-cell-related or -mediated diseases, such as T-cell lymphomas, leukemia, autoimmune diseases, inflammation or allergy. 
     
     
         59 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds FcalphaRI and is for use in the treatment of a disease or disorder selected from: allergic asthma or other allergic diseases such as allergic rhinitis, seasonal/perennial allergies, hay fever, nasal allergies, atopic dermatitis, eczema, hives, urticaria, contact allergies, allergic conjunctivitis, ocular allergies, food and drug allergies, latex allergies, or insect allergies, or IgA nephropathy, such as IgA pemphigus. 
     
     
         60 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD25 and is for use in the treatment of a disease or disorder selected from the group consisting of: transplant rejection, graft-versus-host disease, inflammatory, immune or autoimmune diseases, inflammatory or hyperproliferative skin disorders, lymphoid neoplasms, malignancies, hematological disorders, skin disorders, hepato-gastrointestinal disorders, cardiac disorders, vascular disorders, renal disorders, pulmonary disorders, neurological disorders, connective tissue disorders, endocrinological disorders, viral infections. 
     
     
         61 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds IL-15 or the IL15 receptor and is for use in the treatment of a disease or disorder selected from the group consisting of: arthritides, gout, connective disorders, neurological disorders, gastrointestinal disorders, hepatic disorders, allergic disorders, hematologic disorders, skin disorders, pulmonary disorders, malignant disorders, endocrinological disorders, vascular disorders, infectious disorders, kidney disorders, cardiac disorders, circulatory disorders, metabolic disorders, bone, disorders and muscle disorders. 
     
     
         62 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds IL-8 and is for use in the treatment of a disease or disorder selected from the group consisting of: palmoplantar pustulosis (PPP), psoriasis, or other skin diseases, inflammatory, autoimmune and immune disorders, alcoholic hepatitis and acute pancreatitis, diseases involving IL-8 mediated angiogenesis. 
     
     
         63 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD20 and is for use in the treatment of a disease or disorder selected from the group consisting of: rheumatoid arthritis, (auto)immune and inflammatory disorders, non-Hodgkin's lymphoma, B-CLL, lymphoid neoplasms, malignancies and hematological disorders, infectious diseases and connective disorders, neurological disorders, gastrointestinal disorders, hepatic disorders, allergic disorders, hematologic disorders, skin disorders, pulmonary disorders, malignant disorders, endocrinological disorders, vascular disorders, infectious disorders, kidney disorders, cardiac disorders, circulatory disorders, metabolic disorders, bone and muscle disorders, and immune mediated cytopenia. 
     
     
         64 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD38 and is for use in the treatment of a disease or disorder selected from the group consisting of: tumorigenic disorders, immune disorders in which CD38 expressing B cells, plasma cells, monocytes and T cells are involved, acute respiratory distress syndrome and choreoretinitis, rheumatoid arthritis, inflammatory, immune and/or autoimmune disorders in which autoantibodies and/or excessive B and T lymphocyte activity are prominent, skin disorders, immune-mediated cytopenias, connective tissue disorders, arthritides, hematologic disorders, endocrinopathies, hepato-gastrointestinal disorders, nephropathies, neurological disorders, cardiac and pulmonary disorders, allergic disorders, ophthalmologic disorders, infectious diseases, gynecological-obstetrical disorders, male reproductive disorders, transplantation-derived disorders, 
     
     
         65 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds EGFr and is for use in the treatment of a disease or disorder selected from the group consisting of: cancers (over)expressing EGFr and other EGFr related diseases, such as autoimmune diseases, psoriasis, inflammatory arthritis. 
     
     
         66 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD4 and is for use in the treatment of a disease or disorder selected from the group consisting of: rheumatoid arthritis, (auto)immune and inflammatory disorders, cutaneous T cell lymphomas, non-cutaneous T cell lymphomas, lymphoid neoplasms, malignancies and hematological disorders, infectious diseases, and connective disorders, neurological disorders, gastrointestinal disorders, hepatic disorders, allergic disorders, hematologic disorders, skin disorders, pulmonary disorders, malignant disorders, endocrinological disorders, vascular disorders, infectious disorders, kidney disorders, cardiac disorders, circulatory disorders, metabolic disorders, bone disorders, muscle disorders, immune mediated cytopenia, and HIV infection/AIDS. 
     
     
         67 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds CD28 and is for use in the treatment of a disease or disorder selected from the group consisting of: an inflammatory disease, autoimmune disease and immune disorder. 
     
     
         68 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds tissue factor, or a complex of Factor VII and tissue factor and is for use in the treatment of a disease or disorder selected from the group consisting of: vascular diseases, such as myocardial vascular disease, cerebral vascular disease, retinopathy and macular degeneration, and inflammatory disorders. 
     
     
         69 . The stabilized IgG4 antibody of  claim 26 , wherein the antibody binds PD-I and is for use in the treatment of HIV-I/AIDS. 
     
     
         70 . An isolated stabilized IgG4 antibody, comprising a heavy chain and a light chain, wherein said heavy chain comprises a human IgG4 constant region having a substitution of the Arg residue at position 409, the Phe residue at position 405 or the Lys residue at position 370, wherein said antibody optionally comprises one or more further substitutions, deletions and/or insertions, with the proviso that if the antibody has a residue selected from the group consisting of: Lys, Ala, Thr, Met and Leu at the position corresponding to 409, then the antibody does not comprise a Cys-Pro-Pro-Cys sequence in the hinge region and the proviso that the antibody does not comprise both a Lys at position 409 and a Leu at position 309. 
     
     
         71 . The stabilized IgG4 antibody of  claim 70 , wherein said heavy chain comprises a human IgG4 constant region having a residue selected from the group consisting of: Lys, Ala, Thr, Met and Leu at the position corresponding to 409 and/or a residue selected from the group consisting of: Ala, VaI, GIy, He and Leu at the position corresponding to 405, and wherein said antibody optionally comprises one or more further substitutions, deletions and/or insertions, but does not comprise a Cys-Pro-Pro-Cys sequence in the hinge region. 
     
     
         72 . A pharmaceutical composition comprising a stabilized IgG4 antibody as defined in  claim 1 . 
     
     
         73 . Use of a stabilized IgG4 antibody as defined in  claim 24  for the preparation of a medicament for the treatment of a disease or disorder as defined in said claim. 
     
     
         74 . A method for producing a stabilized IgG4 antibody of  claim 1 , said method comprising expressing a nucleic acid construct encoding said antibody in a host cell and optionally purifying said antibody. 
     
     
         75 . The method of  claim 74 , wherein said stabilized IgG4 antibody does not comprise both a Lys at position 409 and a Leu at position 309.