ANTAGONISTS OF IL-6 TO RAISE ALBUMIN AND/OR LOWER CRP
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Accused Products
Abstract
The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 to improve survivability or quality of life of a patient in need thereof. In preferred embodiments, the anti-IL-6 antibodies will be humanized and/or will be aglycosylated. Also, in preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level or a reduced serum albumin level prior to treatment. In another preferred embodiment, the patient'"'"'s Glasgow Prognostic Score will be increased and survivability will preferably be improved.
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Citations
130 Claims
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1-90. -90. (canceled)
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91. A method of improving survivability or quality of life of a patient in need thereof, comprising administering to the patient an IL-6 antagonist, whereby (i) the patient'"'"'s serum C-reactive protein (“
- CRP”
) level is reduced, and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level and/or (ii) the patient'"'"'s serum albumin level is increased, and monitoring the patient to assess the increase in the patient'"'"'s serum albumin level. - View Dependent Claims (92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130)
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92. The method of claim 91 wherein said patient has (i) an elevated serum CRP level prior to treatment, and/or (ii) a reduced serum albumin level prior to treatment.
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93. The method of claim 91 whereby the patient'"'"'s Glasgow Prognostic Score (GPS) is improved.
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94. The method of claim 91 wherein the antagonist comprises an anti-IL-6 antibody or antibody fragment which specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or fragment thereof as an anti-IL-6 antibody comprising Ab1 wherein Ab1 comprises the VL and VH sequences in SEQ ID NO:
- 2 and 3 respectively or a humanized, chimeric, scFv or antibody fragment derived from Ab1 that specifically bind IL-6 which comprise the variable light chain CDR1, CDR2 and CDR3 polypeptides in SEQ ID NO;
4, 5 and 6 respectively and the variable heavy chain CDR1, CDR2 and CDR3 polypeptides in SEQ ID NO;
7, 8 and 9 respectively.
- 2 and 3 respectively or a humanized, chimeric, scFv or antibody fragment derived from Ab1 that specifically bind IL-6 which comprise the variable light chain CDR1, CDR2 and CDR3 polypeptides in SEQ ID NO;
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95. The method of claim 94 wherein the anti-IL-6 antibody comprises the variable heavy chain in SEQ ID NO:
- 657 and the variable light chain in SEQ ID NO;
709 respectively or a variant thereof wherein said variable heavy and/or light chain sequences comprise one or more substitution mutations which do not substantially affect IL-6 antibody binding relative to an anti-IL-6 antibody lacking said mutations.
- 657 and the variable light chain in SEQ ID NO;
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96. The method of claim 95 wherein the anti-IL-6 antibody comprises the variable heavy chain in SEQ ID NO:
- 657 and the variable light chain in SEQ ID NO;
709.
- 657 and the variable light chain in SEQ ID NO;
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97. The method of claim 96 wherein the anti-IL-6 antibody further comprises the heavy chain and light chain constant regions comprised in SEQ ID NO:
- 588 and SEQ ID NO;
586 respectively.
- 588 and SEQ ID NO;
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98. The method of claim 94, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitopes on an intact IL-6 polypeptide or fragment thereof that is (are) specifically bound by Ab1 and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in IL-6 fragments selected from those respectively encompassing amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72.
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99. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in Ab1.
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100. The method of claim 99 wherein all of the CDRs in the anti-IL-6 antibody or antibody fragment are identical to the CDRs contained in Ab1.
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101. The method of claim 94, wherein the anti-IL-6 antibody or antibody fragment is aglycosylated. and/or the anti-IL-6 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
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102. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.
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103. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment is a humanized antibody derived from a rabbit (parent) anti-IL-6 antibody.
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104. The method of claim 103 wherein the framework regions (FRs) in the variable light region and the variable heavy regions of said anti-IL-6 antibody or antibody fragment respectively are human FRs which are unmodified or which have been modified by the substitution of at most 2 or 3 human FR residues in the variable light or heavy chain region with the corresponding FR residues of the parent rabbit antibody, and wherein said human FRs have been derived from human variable heavy and light chain antibody sequences which have been selected from a library of human germline antibody sequences based on their high level of homology to the corresponding rabbit variable heavy or light chain regions relative to other human germline antibody sequences contained in the library.
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105. The method of claim 95 wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency selected from (i) at most once per period of approximately four weeks, (ii) at most once per period of approximately eight weeks, (iii) at most once per period of approximately twelve weeks, (iv) at most once per period of approximately sixteen weeks.
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106. The method of any one of claim 94 wherein the administered antibody comprises the same CDRs as Ab1 and at least one of the variable heavy and light antibody sequences comprised in
FIGS. 34-37 . -
107. The method of claim 112 wherein the antibody comprises the variable heavy and variable light sequences in SEQ ID NO:
- 657 or SEQ ID NO;
709 or any of the variable heavy and light antibody sequences comprised inFIGS. 34-37 .
- 657 or SEQ ID NO;
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108. The method of claim 107 wherein said antibody further comprises the heavy constant and light constant sequences in SEQ ID NO:
- 588 and SEQ ID NO;
586 respectively.
- 588 and SEQ ID NO;
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109. The method of claim 91 wherein the patient'"'"'s serum CRP level remains decreased and/or serum albumin level remains raised for an entire period intervening two consecutive anti-IL-6 antibody administrations.
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110. The method of claim 91 wherein the patient has been diagnosed with cancer selected from Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt'"'"'s lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman'"'"'s Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing'"'"'s sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget'"'"'s disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor, Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemangioblastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin'"'"'s lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi'"'"'s sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Miillerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic Disease, Myelodysplastic Syndromes, Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget'"'"'s disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter'"'"'s transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sé
- zary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenströ
m'"'"'s macroglobulinemia, Warthin'"'"'s tumor, Wilms'"'"' tumor, or any combination thereof.
- zary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenströ
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111. The method of claim 94 wherein said anti-IL-6 antibody or antibody fragment further comprises a human Fc derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.
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112. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment comprises a polypeptide having at least 90% sequence homology to SEQ ID NO:
- 19, 20 657 or 709 or any of the variable heavy and variable light sequences contained in any one of
FIGS. 34-37 .
- 19, 20 657 or 709 or any of the variable heavy and variable light sequences contained in any one of
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113. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.
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114. The method of claim 91 wherein the IL-6 antagonist is co-administered with a chemotherapy agent.
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115. The method of claim 114 wherein the chemotherapy agent is selected from VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids, mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone antagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF antagonists, IL-1 antagonists, interleukins, IL-12R antagonists, Toxin conjugated monoclonal antibodies, tumor antigen specific monoclonal antibodies, Erbitux™
- , Avastin™
, Pertuzumab, anti-CD20 antibodies, Rituxan®
, ocrelizumab, ofatumumab, DXL625, Herceptin®
, or any combination thereof. or comprises an inhibitor of JAK1, JAK2, JAK3, or SYK.
- , Avastin™
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116. The method of claim 94 wherein the anti-IL-6 antibody or antibody fragment is directly or indirectly attached to a detectable label or therapeutic agent.
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117. The method of claim 91 further comprising:
- measuring the patient'"'"'s serum CRP level prior to administration of the IL-6 antagonist, and administering the IL-6 antagonist if the patient'"'"'s serum CRP level is at least approximately 5 mg/L.
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118. The method of claim 91 wherein the patient'"'"'s serum CRP level is reduced to less than approximately 5 mg/L within 1 week of administration of the IL-6 antagonist.
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119. The method of claim 91 wherein the patient'"'"'s serum CRP level is reduced to below 1 mg/L within 1 week of administration of the IL-antagonist.
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120. The method of claim 91 that results in a prolonged reduction in serum CRP level of the patient.
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121. The method of claim 91 wherein the patient'"'"'s serum CRP level is reduced to below 10 mg/L within about 1 week of IL-6 antagonist administration.
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122. The method of claim 91 wherein at least after 14 days after IL-6 antagonist administration the patient'"'"'s serum CRP level remains below 10 mg/L.
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123. The method of claim 91 further comprising:
- measuring the patient'"'"'s serum albumin level prior to administration of the IL-6 antagonist, and administering the IL-6 antagonist if the patient'"'"'s serum albumin level is less than approximately 35 g/L.
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124. The method of claim 123 wherein the patient'"'"'s serum albumin level is increased to more than approximately 35 g/L within about 5 weeks of administration of the IL-6 antagonist.
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125. The method of claim 91, that results in a prolonged increase in serum albumin level of the patient.
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126. The method of claim 91 wherein at least after 42 days after IL-6 antagonist administration the patient'"'"'s serum albumin level remains above 35 g/L.
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127. The method of claim 91 wherein the patient'"'"'s serum albumin level is increased by about 5 g/L within approximately 5 weeks of administering the IL-6 antagonist.
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128. The method of claim 91 wherein the patient has been diagnosed with rheumatoid arthritis, cancer, advanced cancer, liver disease, renal disease, inflammatory bowel disease, celiac'"'"'s disease, trauma, burns, other diseases associated with reduced serum albumin, or any combination thereof.
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129. The method of claim 91 wherein the patient has been diagnosed with rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, systemic lupus erythematosis, Crohn'"'"'s disease, ulcerative colitis, pemphigus, dermatomyositis, polymyositis, polymyalgia rheumatica, giant cell arteritis, vasculitis, polyarteritis nodosa, Wegener'"'"'s granulomatosis, Kawasaki disease, isolated CNS vasculitis, Churg-Strauss arteritis, microscopic polyarteritis, microscopic polyangiitis, Henoch-Schonlein purpura, essential cryoglobulinemic vasculitis, rheumatoid vasculitis, cryoglobulinemia, relapsing polychondritis, Behcet'"'"'s disease, Takayasu'"'"'s arteritis, ischemic heart disease, stroke, multiple sclerosis, sepsis, vasculitis secondary to viral infection, Buerger'"'"'s Disease, cancer, advanced cancer, Osteoarthritis, systemic sclerosis, CREST syndrome, Reiter'"'"'s disease, Paget'"'"'s disease of bone, Sjogran'"'"'s syndrome, diabetes type 1, diabetes type 2, familial Mediterranean fever, autoimmune thrombocytopenia, autoimmune hemolytic anemia, autoimmune thyroid diseases, pernicious anemia, vitiligo, alopecia greata, primary biliary cirrhosis, autoimmune chronic active hepatitis, alcoholic cirrhosis, viral hepatitis including hepatitis B and C, other organ specific autoimmune diseases, burns, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, allergic asthma, other allergic conditions or any combination thereof.
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130. The method of any of claim 91 further comprising administration of one or more statins to the patient.
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92. The method of claim 91 wherein said patient has (i) an elevated serum CRP level prior to treatment, and/or (ii) a reduced serum albumin level prior to treatment.
- CRP”
Specification
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Current AssigneeVitaeris Inc. (CSL Limited)
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Original AssigneeBristol-Myers Squibb Company
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InventorsSMITH, Jeffrey T.L.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current424/135.1
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CPC Class CodesA61K 2039/505 comprising antibodiesA61K 2039/54 characterised by the route ...A61K 2039/545 characterised by the dose, ...A61K 31/7088 Compounds having three or m...A61K 38/16 Peptides having more than 2...A61K 38/2013 IL-2A61K 38/208 IL-12A61K 39/3955 against proteinaceous mater...A61K 45/00 Medicinal preparations cont...A61K 45/06 Mixtures of active ingredie...A61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 19/02 for joint disorders, e.g. a...A61P 19/08 for bone diseases, e.g. rac...A61P 25/00 Drugs for disorders of the ...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 35/04 specific for metastasisA61P 9/10 for treating ischaemic or a...C07K 16/248 : IL-6C07K 2317/24 : containing regions, domains...C07K 2317/34 : Identification of a linear ...C07K 2317/41 : Glycosylation, sialylation,...C07K 2317/76 : Antagonist effect on antige...C07K 2317/92 : Affinity (KD), association ...