Antagonists of IL-6 to raise albumin and/or lower CRP

• US 8,420,089 B2
• Filed: 11/24/2009
• Issued: 04/16/2013
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T. L.
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US12/624,965
• Publication Number:
  US 20110250201A1
• Time in Patent Office: 1,239 Days
• Field of Search: None
• US Class Current: 424/139.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

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.

Claims

1. 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/or (ii) the patient'"'"'s serum albumin level is increased, and further wherein the IL-6 antagonist comprises an anti-IL-6 antibody or antibody fragment which competes for binding to an intact human IL-6 polypeptide with an anti-IL-6 antibody comprising the VL and VH sequences in SEQ ID NO;

2 and 3 respectively, and wherein the administration of said antibody or antibody fragment improves the survivability or quality of life of a patient in need thereof by reducing the patient'"'"'s serum C-reactive protein (“

CRP”

) level and/or increasing the patient'"'"'s serum albumin level.

2. The method of claim 1 wherein said patient has (i) an elevated serum CRP level prior to treatment, and/or (ii) a reduced serum albumin level prior to treatment.

3. The method of claim 1 whereby the patient'"'"'s Glasgow Prognostic Score (GPS) is improved.

4. The method of claim 1 wherein the IL-6 antagonist comprises an anti-IL-6 antibody or antibody fragment which comprises 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 or 120 and 9 respectively.

5. The method of claim 4 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 not within the CDR'"'"'s which do not substantially affect IL-6 antibody binding relative to an anti-IL-6 antibody lacking said mutations.

6. The method of claim 5 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.

7. The method of claim 6 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.

8. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment specifically binds to a conformational epitope on an intact IL-6 polypeptide comprising the amino acid residues in SEQ ID NO:

1, wherein said conformational epitope comprises one or more residues within each of amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and amino acid residues 58-72 of SEQ ID NO;

1.

9. The method of claim 4, 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.

10. The method of claim 4 wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.

11. The method of claim 4 wherein the anti-IL-6 antibody or antibody fragment is a humanized antibody derived from a rabbit (parent) anti-IL-6 antibody.

12. The method of claim 1 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.

13. The method claim 4 wherein the administered antibody comprises the same CDRs specified in claim 4 and further comprises at least one of the variable heavy and light antibody sequences comprised in FIGS. 34-37.

14. The method of claim 4 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 in FIGS. 34-37.

15. The method of claim 14 wherein said antibody further comprises the heavy constant and light constant sequences in SEQ ID NO:

588 and SEQ ID NO;

586 respectively.

16. The method of claim 1 or 4 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.

17. The method of claim 1 or 4 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 Mü

llerian 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, Waldenstrom'"'"'s macroglobulinemia, Warthin'"'"'s tumor, Wilms'"'"' tumor, or any combination thereof.

18. The method of claim 4 wherein said anti-IL-6 antibody or antibody fragment further comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.

19. The method of claim 4 wherein the anti-IL-6 antibody or antibody fragment comprises a variable heavy or light polypeptide having at least 90% sequence homology to SEQ ID NO:

18, 19, 20, 657 or 709 or any of the variable heavy and variable light sequences contained in any one of FIGS. 34-37 and both the variable heavy and light chain polypeptides comprise the same CDRs set forth in claim 4.

20. The method of claim 4 wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

21. The method of claim 1 or 4 wherein the anti-IL-6 antibody or fragment is co-administered with another therapeutic agent.

22. The method of claim 21 wherein the other therapeutic 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.

23. The method of claim 1 or 4 wherein the anti-IL-6 antibody or antibody fragment is directly or indirectly attached to a detectable label or therapeutic agent.

24. The method of claim 1 or 4 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.

25. The method of claim 1 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.

26. The method of claim 1 wherein the patient'"'"'s serum CRP level is reduced to below 1 mg/L within 1 week of administration of the IL-antagonist.

27. The method of claim 1 that results in a prolonged reduction in serum CRP level of the patient.

28. The method of claim 1 wherein the patient'"'"'s serum CRP level is reduced to below 10 mg/L within about 1 week of IL-6 antagonist administration.

29. The method of claim 1 wherein at least after 14 days after IL-6 antagonist administration the patient'"'"'s serum CRP level remains below 10 mg/L.

30. The method of claim 1 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.

31. The method of claim 30 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.

32. The method of claim 1, that results in a prolonged increase in serum albumin level of the patient.

33. The method of claim 1 wherein at least after 42 days after IL-6 antagonist administration the patient'"'"'s serum albumin level remains above 35 g/L.

34. The method of claim 1 wherein the patient'"'"'s serum albumin level is increased by about 5 g/L within approximately 5 weeks of administering the IL-6 antagonist.

35. The method of claim 1 or 4 further comprising administration of one or more statins to the patient.

36. The method of claim 1, wherein the anti-IL-6 antibody or fragment inhibits the binding of IL-6 to gp130 and IL-6R1.