ANTAGONISTS OF IL-6 TO PREVENT OR TREAT CACHEXIA, WEAKNESS, FATIGUE AND/OR FEVER
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Accused Products
Abstract
The present invention is directed to therapeutic methods and compositions, especially subcutaneous and intravenous composition using antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat cachexia, fever, weakness and/or fatigue in 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. In another preferred embodiment, the patient'"'"'s survivability or quality of life will preferably be improved.
53 Citations
126 Claims
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1-101. -101. (canceled)
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102. A method of treating or inhibiting cachexia, weakness, fatigue, and/or fever in a patient diagnosed with an IL-6 associated disorder, comprising administering to the patient an anti-IL-6 antibody or antibody fragment, whereby the patient'"'"'s cachexia, weakness, fatigue, and/or fever is effectively treated or inhibited, and monitoring the patient to assess cachexia, weakness, fatigue, and/or fever, wherein the anti-IL-6 antibody or antibody fragment blocks the binding of human IL-6 to IL-6R1 and gp130, whereby the patient'"'"'s treating cachexia, weakness, fatigue, and/or fever is effectively treated or inhibited.
- View Dependent Claims (103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126)
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103. The method of claim 102, wherein the anti-human IL-6 antibody or antibody fragment competes with and/or binds the same epitope as an anti human 11-6 antibody comprising the variable heavy and light sequences respectively in SEQ ID NO:
- 3 and 2.
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104. The method of claim 103, wherein the anti-IL-6 antibody or fragment comprises the variable heavy chain in SEQ ID NO:
- 657 and the variable light chain in SEQ ID NO;
709 respectively or a antibody comprising variable heavy and/or light chain sequences comprising the same CDRs as the variable sequences in SEQ ID NO;
657 and 709.
- 657 and the variable light chain in SEQ ID NO;
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105. The method of claim 104, wherein the anti-IL-6 antibody or fragment 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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106. The method of claim 103, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same epitope on an intact IL-6 polypeptide or fragment thereof that is specifically bound by an antibody containing the variable heavy and light sequences in SEQ ID NO:
- 3 and 2 respectively, 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 each of the IL-6 fragments selected from those respectively consisting of 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 of SEQ ID NO;
1.
- 3 and 2 respectively, 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 each of the IL-6 fragments selected from those respectively consisting of 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 of SEQ ID NO;
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107. The method of claim 102, wherein the anti-IL-6 antibody or antibody fragment is aglycosylated and/or contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
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108. The method of claim 102, wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.
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109. The method of claim 102, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency of about every four weeks or eight weeks.
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110. The method of claim 102, wherein said antibody comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.
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111. The method of claim 102, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days, at least about 25 days or at least about 30 days.
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112. The method of claim 102, wherein the IL-6 antagonist is coadministered with a chemotherapy
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113. The method of claim 102, wherein the patient has been diagnosed with an autoimmune disorder, infectious disorder or cancer.
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114. The method of claim 102, wherein the antibody or fragment has variable heavy and light sequences contained at least 98% identical has the variable heavy and light sequences contained in SEQ ID NO:
- 19 or 20.
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115. The method of claim 102, which comprises intravenously or subcutaneously administering an anti-IL-6 antibody or antibody fragment having the same epitopic specificity as an antibody containing the variable light and heavy sequences in SEQ ID NO:
- 2 and 3 respectively by intravenously administering a dosage of about (+/−
20%>
) 80, 160 or 320 mg of said antibody to a patient in need thereof.
- 2 and 3 respectively by intravenously administering a dosage of about (+/−
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116. The method of claim 115, wherein the patient is administered said dosage every 8 weeks or 2 months.
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117. The method of claim 115, wherein said dosage is administered at least twice.
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118. The method of claim 115, wherein the first dosage is on day one and the second dosage during week 8 (8th week after day 0).
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119. The method of any one of claim 115, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 95% identical has the variable heavy and light sequences contained in SEQ ID NO:
- 19 or 20.
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120. The method of claim 119, wherein said anti-IL-6 antibody or antibody fragment contains the variable heavy and light sequences contained in SEQ ID NO:
- 19 or 20.
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121. The method of claim 102, wherein said anti-IL-6 antibody is comprised in a composition formulated for subcutaneous or intravenous injection.
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122. The method of claim 102, 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 Mullerian 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, Sezary 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, Waldenstrom'"'"'s macroglobulinemia, Warthin'"'"'s tumor, Wilms'"'"' tumor, or any combination thereof.
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123. The method of claim 112, wherein the chemotherapy agent is selected from VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids, vinblastine, 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.
- , Avastin™
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124. The method of claim 112, wherein the chemotherapy agent comprises an inhibitor of JAK1, JAK2, JAK3, or SYK.
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125. The method of claim 102, further comprising:
- measuring the patient'"'"'s body weight prior to administration of the anti-IL-6 antibody, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s weight has declined by greater than approximately 5% within approximately 30 days, or if the patient'"'"'s lean body mass index is less than about 17 kg/m<
2>
(male patient) or less than about 14 kg/m<
2>
(female patient).
- measuring the patient'"'"'s body weight prior to administration of the anti-IL-6 antibody, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s weight has declined by greater than approximately 5% within approximately 30 days, or if the patient'"'"'s lean body mass index is less than about 17 kg/m<
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126. The method of claim 102, further comprising:
- measuring the patient'"'"'s muscular strength prior to administration of the anti-IL-6 antibody, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s muscular strength has declined by greater than approximately 20% within approximately 30 days.
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103. The method of claim 102, wherein the anti-human IL-6 antibody or antibody fragment competes with and/or binds the same epitope as an anti human 11-6 antibody comprising the variable heavy and light sequences respectively in SEQ ID NO:
Specification
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Current AssigneeVitaeris Inc. (CSL Limited)
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Original AssigneeAlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
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InventorsSmith, Jeffrey T.L., Latham, John A., Litton, Mark, Schatzman, Randall
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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 Current424/85.2
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CPC Class CodesA61K 2039/505 comprising antibodiesA61K 2039/545 characterised by the dose, ...A61K 31/454 containing a five-membered ...A61K 38/2013 IL-2A61K 38/208 IL-12A61K 39/3955 against proteinaceous mater...A61K 45/06 Mixtures of active ingredie...A61K 49/0004 Screening or testing of com...A61K 49/0058 AntibodiesA61K 51/1033 against receptors for cytok...A61P 1/02 Stomatological preparations...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 1/18 for pancreatic disorders, e...A61P 11/00 Drugs for disorders of the ...A61P 13/08 of the prostateA61P 13/12 of the kidneysA61P 15/06 Antiabortive agents; Labour...A61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 : AntipsoriaticsA61P 17/14 : for baldness or alopeciaA61P 19/00 : Drugs for skeletal disordersA61P 19/02 : for joint disorders, e.g. a...A61P 19/08 : for bone diseases, e.g. rac...A61P 19/10 : for osteoporosisA61P 21/00 : Drugs for disorders of the ...A61P 25/00 : Drugs for disorders of the ...A61P 25/24 : AntidepressantsA61P 25/28 : for treating neurodegenerat...A61P 29/00 : Non-central analgesic, anti...A61P 3/04 : Anorexiants; Antiobesity ag...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/04 : Antibacterial agentsA61P 31/12 : AntiviralsA61P 31/16 : for influenza or rhinovirusesA61P 31/18 : for HIVA61P 33/06 : AntimalarialsA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 5/14 : of the thyroid hormones, e....A61P 7/00 : Drugs for disorders of the ...A61P 7/02 : Antithrombotic agents; Anti...A61P 7/04 : Antihaemorrhagics; Procoagu...A61P 7/06 : AntianaemicsA61P 9/00 : Drugs for disorders of the ...A61P 9/02 : Non-specific cardiovascular...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesC07K 16/248 : IL-6C07K 16/462 : Igs containing a variable r...C07K 2317/24 : containing regions, domains...C07K 2317/33 : Crossreactivity, e.g. for s...C07K 2317/34 : Identification of a linear ...C07K 2317/41 : Glycosylation, sialylation,...C07K 2317/56 : variable (Fv) region, i.e. ...C07K 2317/565 : Complementarity determining...C07K 2317/76 : Antagonist effect on antige...C07K 2317/90 : characterized by (pharmaco)...C07K 2317/92 : Affinity (KD), association ...C07K 2317/94 : Stability, e.g. half-life, ...G01N 33/6863 : Cytokines, i.e. immune syst...Y02A 50/30 : Against vector-borne diseas...