Antibodies to IL-6 and use thereof

• US 20100150829A1
• Filed: 11/24/2009
• Published: 06/17/2010
• 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: Latham, John, Jensen, Anne Elisabeth Carvalho, Garcia-Martinez, Leon, Litton, Mark, Schatzman, Randall, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Smith, Jeffrey T.L.
• Granted Patent: US 9,452,227 B2
• Time in Patent Office: Days
• US Class Current: 424/1.490
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 51/1033 against receptors for cytokines, lymphokines or interferons
• 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 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• 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
• CPC Class Codes: G01N 2333/5412 IL-6
• CPC Class Codes: G01N 2800/7095 Inflammation
• CPC Class Codes: G01N 33/6869 Interleukin
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as an Ab1 antibody or antibody fragment having binding specificity for IL-6 to prevent or treat disease or to improve survivability or quality of life of a patient in need thereof. In preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level, reduced serum albumin level, elevated D-dimer or other coagulation cascade related protein(s), cachexia, fever, weakness and/or fatigue prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, and others.

Claims

1-200. -200. (canceled)

201. A method of preventing, treating, or diagnosing a disease or condition associated with IL-6, comprising administration of an anti-IL-6 antibody or antibody fragment to a subject in need thereof, wherein the antibody or antibody fragment comprises:

a variable light chain polypeptide comprising;

a polypeptide having at least 75% identity to SEQ ID NO;

709, and

a variable heavy chain polypeptide comprising;

a polypeptide having at least 75% identity to SEQ ID NO;

657, and;

wherein the Ab1 antibody or antibody fragment specifically binds to IL-6 and antagonizes one or more activity associated with IL-6 and specifically binds to the same epitope on human IL-6 polypeptide as an anti-IL-6 antibody comprising the variable light chain polypeptide in SEQ ID NO;

709 and the variable heavy chain polypeptide in SEQ ID NO;

657.

202. The method of claim 201, wherein the light chain or the heavy chain each possess at least 85% sequence identity to the light chain and heavy chain polypeptides respectively comprised in SEQ ID NO:

709 and 657.

203. The method of claim 201, wherein the light chain or the heavy chain each possess at least 90% sequence identity to the light chain and heavy chain polypeptides respectively comprised in SEQ ID NO:

709 and 657.

204. The method of claim 201 wherein said antibody comprises light chain CDR1, CDR2 and CDR3 polypeptides and heavy chain CDR1, CDR2 and CDR3 polypeptides wherein at least 4 of said CDR polypeptides are identical to those on SEQ ID NO:

4, 5 and 6 and SEQ ID NO;

7, 8 or 120 and 9 respectively

205. The method of claim 201 wherein said antibody comprises light chain CDR1, CDR2 and CDR3 polypeptides and heavy chain CDR1, CDR2 and CDR3 polypeptides wherein at least 5 of said 6 CDR polypeptides are identical to those on SEQ ID NO:

4, 5 and 6 and SEQ ID NO;

7, 8 or 120 and 9 respectively.

206. The method of claim 201 wherein said antibody comprises light chain CDR1, CDR2 and CDR3 polypeptides and heavy chain CDR1, CDR2 and CDR3 polypeptides wherein all of said 6 CDR polypeptides are identical to those on SEQ ID NO:

4, 5 and 6 and SEQ ID NO;

7, 8 or 120 and 9 respectively.

207. The method of claim 201 wherein the antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.

208. The method of claim 201 wherein the antibody or antibody fragment has a binding affinity (Kd) for IL-6 of less than about 50 picomolar, or a rate of dissociation (K_off) from IL-6 of less than or equal to 10⁻

4 S<sup>−

1</sup>.

209. The method of claim 201, wherein the Ab1 antibody or antibody fragment 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 consisting essentially of the polypeptides of SEQ ID NO:

702 and SEQ ID NO;

704 or the polypeptides of SEQ ID NO;

2 and SEQ ID NO;

3.

210. The method of claim 209, wherein said binding to the same linear or conformational epitope(s) and/or competition for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or fragment thereof is ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide and 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 of the human IL-6 polypeptide in SEQ ID NO:

1.

211. The method of claim 201 wherein the antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

212. The method of claim 201 wherein the antibody is selected from a human, humanized, single chain, or chimeric antibody and the antibody fragment is selected from a Fab, Fab′

, F(ab′

)₂, Fv, or scFv.

213. The method of claim 201, wherein the one or more activity associated with IL-6 is an in vivo activity comprising:

decreased serum albumin;

elevated C-reactive protein (“

CRP”

);

fatigue;

fever;

anorexia (loss of appetite);

weight loss;

cachexia;

weakness;

decreased Glasgow Prognostic Score (“

GPS”

);

elevated serum D-dimer;

abnormal coagulation profile;

or any combination thereof.

214. The method claim 201 wherein the disease or condition associated with IL-6 is comprising:

cancer;

a disease or condition associated with hypercoagulation;

a disease or condition associated with elevated serum CRP;

a disease or condition associated with hypoalbuminemia;

an inflammatory disorder;

a viral disorder;

a wasting syndrome;

an autoimmune disorder;

or any combination thereof.

215. The method of claim 201 wherein the disease or condition associated with IL-6 is comprising:

general fatigue, exercise-induced fatigue, cancer-related fatigue, inflammatory disease-related fatigue, chronic fatigue syndrome, cancer-related cachexia, cardiac-related cachexia, respiratory-related cachexia, renal-related cachexia, age-related cachexia, rheumatoid arthritis, systemic lupus erythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), Sjogren'"'"'s syndrome, adult onset Still'"'"'s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis, Paget'"'"'s disease of bone, osteoarthritis, multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, prostate cancer, leukemia, renal cell cancer, multicentric Castleman'"'"'s disease, ovarian cancer, drug resistance in cancer chemotherapy, cancer chemotherapy toxicity, ischemic heart disease, atherosclerosis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer'"'"'s disease, cerebrovascular disease, fever, acute phase response, allergies, anemia, anemia of inflammation (anemia of chronic disease), hypertension, depression, depression associated with a chronic illness, thrombosis, thrombocytosis, acute heart failure, metabolic syndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, transplant rejection, graft versus host disease (GVHD), cytokine storm, avian influenza, H1N1 influenza, porcine influenza, H5N1 influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, or systemic inflammatory response syndrome (SIRS).

216. The method of claim 214 wherein the disease or condition associated with hypercoagulation is comprising:

cancer, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest, long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic stroke, acute coronary occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial cannulae, occluded venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia, thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), atrial fibrillation, implantation of a prosthetic heart valve, genetic susceptibility to thrombosis, factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism, platelet-receptor polymorphism, trauma, fractures, burns, or any combination thereof.

217. The method of claim 214 wherein the disease or condition associated with elevated serum CRP is comprising:

chronic inflammatory diseases, 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, hepatitis B, hepatitis C, other organ specific autoimmune diseases, burns, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, allergic asthma, other allergic conditions or any combination thereof.

218. The method of claim 214 wherein the disease or condition associated with hypoalbuminemia is comprising:

cancer, advanced cancer, rheumatoid arthritis, AIDS, heart disease, liver disease, dehydration, malnutrition, lead exposure, malaria, respiratory disease, old age, hypothyroidism, tuberculosis, hypopituitarism, neurasthenia, hypernatremia, hyponatremia, renal disease, splenica, ankylosing spondylitis, failure to thrive (faltering growth), inflammatory bowel disease, celiac'"'"'s disease, trauma, burns, or any combination thereof.

219. The method of claim 218, wherein the cancer is comprising:

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.

220. The method of claim 201 wherein prior to administration of the antibody or antibody fragment the subject has exhibited or is at risk for developing one or more of the following symptoms:

decreased serum albumin;

elevated serum C-reactive protein (“

CRP”

);

fatigue;

fever;

anorexia (loss of appetite);

weight loss;

cachexia;

weakness;

decreased Glasgow Prognostic Score (“

GPS”

);

elevated serum D-dimer;

abnormal coagulation profile; and

any combination thereof.

221. The method of claim 201 wherein the therapeutically effective amount is between about 0.1 and 20 mg/kg of body weight of recipient subject.

222. The method of claim 201, wherein the subject'"'"'s coagulation profile is assessed prior to treatment by measurement of the subject'"'"'s serum level of one or more of D-dimer, Factor II, Factor V, Factor VIII, Factor IX, Factor XI, Factor XII, F/fibrin degradation products, thrombin-antithrombin III complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor.

223. The method of claim 201, further comprising:

measuring the subject'"'"'s international normalized ratio (INR) prior to administration of the Ab1 antibody or antibody fragment, and administering to the subject the antibody or antibody fragment if the subject'"'"'s INR is less than about 0.9.

224. The method of claim 201, further comprising:

measuring the subject'"'"'s body temperature prior to administration of the antibody or antibody fragment, and administering the antibody or antibody fragment if the subject'"'"'s body temperature higher than about 38°

C.

225. The method of claim 201, further comprising:

measuring the subject'"'"'s body weight prior to administration of the Ab1 antibody or antibody fragment, and administering the antibody or antibody fragment if the subject'"'"'s weight has declined by approximately 5% or more within approximately 30 days, or if the subject'"'"'s lean body mass index is less than about 17 kg/m² (male subject) or less than about 14 kg/m² (female subject).

226. The method of claim 201, further comprising:

measuring the subject'"'"'s muscular strength prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 antibody or antibody fragment if the subject'"'"'s muscular strength has declined by greater than approximately 20% within approximately 30 days.

227. The method of claim 201 wherein the subject has exhibited an elevated serum D-dimer level prior to treatment.

228. The method of claim 201 wherein the subject has exhibited an elevated serum C-reactive protein (CRP) level prior to treatment.

229. The method of claim 201 wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period selected from approximately four weeks, approximately eight weeks, approximately twelve weeks and approximately sixteen weeks.

230. The method of claim 201, wherein the antibody or antibody fragment is administered in a diagnostically effective amount for detection of IL-6 expressing disease sites.

231. The method of claim 230, wherein the antibody or antibody fragment is directly or indirectly coupled to a radionuclide, fluorophore, or other detectable label that facilitates detection of the antibody at IL-6 expressing disease sites.

232. The method of claim 230, which is used to detect IL-6 expressing tumors or metastases.

233. The method of claim 230, which is used to detect the presence of sites of inflammation associated with IL-6 expressing cells.

234. The method of claim 230, wherein the results are used to facilitate design of an appropriate therapeutic regimen.

235. The method of claim 234, wherein said therapeutic regimen includes radiotherapy, chemotherapy or a combination thereof.

236. The method of claim 201, wherein the antibody or antibody fragment is co-administered with another therapeutic agent comprising:

chemotherapy agents, statins, cytokines, immunosuppressive agents, gene therapy agents, anti-coagulants, anti-cachexia agents, anti-weakness agent, anti-fatigue agent, anti-fever agent, anti-nausea agents, antiemetic agents, IL-6 antagonists, cytotoxic agents, analgesics, antipyretics, anti-inflammatory agents, antibiotics, antiviral agents, anti-cytokine agents, other therapeutic agents, or any combination thereof.

237. The method of claim 236, wherein the chemotherapy agent is selected from one of the following:

VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids, vinblastine, vincristine, vindesine, vinorelbine, 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-12, IL-2, 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;

the anti-coagulant is selected from;

abciximab (ReoPro™

), acenocoumarol, antithrombin III, argatroban, aspirin, bivalirudin (Angiomax™

), clopidogrel, dabigatran, dabigatran etexilate (Pradaxa™

/Pradax™

), desirudin (Revasc™

/Iprivask™

), dipyridamole, eptifibatide (Integrilin™

), fondaparinux, heparin, hirudin, idraparinux, lepirudin (Refludan™

), low molecular weight heparin, melagatran, phenindione, phenprocoumon, ticlopidine, tirofiban (Aggrastat™

), warfarin, ximelagatran, ximelagatran (Exanta™

/Exarta™

), or any combination thereof;

the statin is selected from;

atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or any combination thereof;

the another therapeutic agent is an antagonist of a factor selected from tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, Interleukin 6, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof;

the anti-cachexia agent is selected from cannabis, dronabinol (Marinol™

), nabilone (Cesamet), cannabidiol, cannabichromene, tetrahydrocannabinol, Sativex, megestrol acetate, or any combination thereof;

the anti-nausea agent or antiemetic agent is selected from;

5-HT3 receptor antagonists, ajwain, alizapride, anticholinergics, antihistamines, aprepitant, benzodiazepines, cannabichromene, cannabidiol, cannabinoids, cannabis, casopitant, chlorpromazine, cyclizine, dexamethasone, dexamethasone, dimenhydrinate (Gravol™

), diphenhydramine, dolasetron, domperidone, dopamine antagonists, doxylamine, dronabinol (Marinol™

), droperidol, emetrol, ginger, granisetron, haloperidol, hydroxyzine, hyoscine, lorazepam, meclizine, metoclopramide, midazolam, muscimol, nabilone (Cesamet), nk1 receptor antagonists, ondansetron, palonosetron, peppermint, Phenergan, prochlorperazine, Promacot, promethazine, Pentazine, propofol, sativex, tetrahydrocannabinol, trimethobenzamide, tropisetron, nandrolone, stilbestrol, thalidomide, lenalidomide, ghrelin agonists, myostatin antagonists, anti-myostatin antibodies, selective androgen receptor modulators, selective estrogen receptor modulators, angiotensin AII antagonists, beta two adenergic receptor agonists, beta three adenergic receptor agonists, or any combination thereof;

the another therapeutic agent is selected from tamoxifen, BCL-2 antagonists, estrogen, bisphosphonates, teriparatide, strontium ranelate, sodium alendronate (Fosamax), risedronate (Actonel), raloxifene, ibandronate (Boniva), Obatoclax, ABT-263, gossypol, gefitinib, epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib, epidermal growth factor receptor inhibitors, psoralens, trioxysalen, methoxsalen, bergapten, retinoids, etretinate, acitretin, infliximab (Remicade®

), adalimumab, infliximab, etanercept, Zenapax™

, Cyclosporine, Methotrexate, granulocyte-colony stimulating factor, filgrastim, lenograstim, Neupogen, Neulasta, 2-Arylpropionic acids, Aceclofenac, Acemetacin, Acetylsalicylic acid (Aspirin), Alclofenac, Alminoprofen, Amoxiprin, Ampyrone, Arylalkanoic acids, Azapropazone, Benorylate/Benorilate, Benoxaprofen, Bromfenac, Carprofen, Celecoxib, Choline magnesium salicylate, Clofezone, COX-2 inhibitors, Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Ethenzamide, Etodolac, Etoricoxib, Faislamine, fenamic acids, Fenbufen, Fenoprofen, Flufenamic acid, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indometacin, Indoprofen, Kebuzone, Ketoprofen, Ketorolac, Lornoxicam, Loxoprofen, Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid, Meloxicam, Metamizole, Methyl salicylate, Mofebutazone, Nabumetone, Naproxen, N-Arylanthranilic acids, Oxametacin, Oxaprozin, Oxicams, Oxyphenbutazone, Parecoxib, Phenazone, Phenylbutazone, Phenylbutazone, Piroxicam, Pirprofen, profens, Proglumetacin, Pyrazolidine derivatives, Rofecoxib, Salicyl salicylate, Salicylamide, Salicylates, Sulfinpyrazone, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid, Tolfenamic acid, Tolmetin, and Valdecoxib. Antibiotics include Amikacin, Aminoglycosides, Amoxicillin, Ampicillin, Ansamycins, Arsphenamine, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Carbacephem, Carbapenems, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalothin, Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefepime, Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftobiprole, Ceftriaxone, Cefuroxime, Cephalosporins, Chloramphenicol, Cilastatin, Ciprofloxacin, Clarithromycin, Clindamycin, Cloxacillin, Colistin, Co-trimoxazole, Dalfopristin, Demeclocycline, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin, Ertapenem, Erythromycin, Ethambutol, Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Geldanamycin, Gentamicin, Glycopeptides, Herbimycin, Imipenem, Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Macrolides, Mafenide, Meropenem, Meticillin, Metronidazole, Mezlocillin, Minocycline, Monobactams, Moxifloxacin, Mupirocin, Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin, Penicillins, Piperacillin, Platensimycin, Polymyxin B, Polypeptides, Prontosil, Pyrazinamide, Quinolones, Quinupristin, Rifampicin, Rifampin, Roxithromycin, Spectinomycin, Streptomycin, Sulfacetamide, Sulfamethizole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Sulfonamides, Teicoplanin, Telithromycin, Tetracycline, Tetracyclines, Ticarcillin, Timidazole, Tobramycin, Trimethoprim, Trimethoprim-Sulfamethoxazole, Troleandomycin, Trovafloxacin, and Vancomycin. Active agents also include Aldosterone, Beclometasone, Betamethasone, Corticosteroids, Cortisol, Cortisone acetate, Deoxycorticosterone acetate, Dexamethasone, Fludrocortisone acetate, Glucocorticoids, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Steroids, and Triamcinolone. Antiviral agents include abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, an antiretroviral fixed dose combination, an antiretroviral synergistic enhancer, arbidol, atazanavir, atripla, brivudine, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitor, ganciclovir, gardasil, ibacitabine, idoxuridine, imiquimod, immunovir, indinavir, inosine, integrase inhibitor, interferon, interferon type I, interferon type II, interferon type III, lamivudine, lopinavir, loviride, maraviroc, MK-0518, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, or any combination thereof;

the cytotoxic agent, chemotherapeutic agent, or immunosuppressive agent is selected from comprising;

1-dehydrotestosterone, 1-methylnitrosourea, 5-fluorouracil, 6-mercaptopurine, 6-mercaptopurine, 6-thioguanine, Abatacept, abraxane, acitretin, aclarubicin, Actinium-225 (²²⁵Ac), actinomycin, Adalimumab, adenosine deaminase inhibitors, Afelimomab, Aflibercept, Afutuzumab, Alefacept, alitretinoin, alkyl sulfonates, alkylating agents, altretamine, alvocidib, aminolevulinic acid/methyl aminolevulinate, aminopterin, aminopterin, amrubicin, amsacrine, amsacrine, anagrelide, Anakinra, anthracenediones, anthracyclines, anthracyclines, anthracyclines, anthramycin (AMC);

antimytotic agents, antibiotics, anti-CD20 antibodies, antifolates, Anti-lymphocyte globulin, Antimetabolites, Anti-thymocyte globulin, arsenic trioxide, Aselizumab, asparaginase, asparagine depleters, Astatine-211 (²¹¹At) Atlizumab, Atorolimumab, atrasentan, Avastin™

, azacitidine, Azathioprine, azelastine, aziridines, Basiliximab, BAYX antibodies, Belatacept, Belimumab, belotecan, bendamustine, Bertilimumab, bexarotene, bisantrene, Bismuth-213 (²¹³Bi), Bismuth-212 (²¹²Bi), bleomycin, bleomycin, bleomycin, BLyS antibodies, bortezomib, busulfan, busulfan, Calcineurin inhibitors, calicheamicin, camptothecin, camptothecins, capecitabine, carboplatin (paraplatin), carboquone, caminomycin, carmofur, carmustine, carmustine (BSNU), CAT antibodies, CD11a antibodies, CD147/Basigin antibodies, CD154 antibodies, CD18 antibodies, CD20 antibodies, CD23 antibodies, CD3 antibodies, CD4 antibodies, CD40 antibodies, CD62L/L-selectin antibodies, CD80 antibodies, CDK inhibitors, Cedelizumab, celecoxib, Certolizumab pegol, chlorambucil, chlorambucils, Ciclosporin, cis-dichlorodiamine platinum (II) (DDP) cisplatin, cladribine, Clenoliximab, clofarabine, colchicin, Complement component 5 antibodies, Copper-67 (⁶⁷Cu), corticosteroids, CTLA-4 antibodies, CTLA-4 fusion proteins, Cyclophilin inhibitors, cyclophosphamides, cyclothosphamide, cytarabine, cytarabine, cytochalasin B, cytotoxic ribonucleases, dacarbazine, Daclizumab, dactinomycin, dactinomycin (actinomycin D), daunorubicin, daunorubicin, daunorubicin (formerly daunomycin), decitabine, Deforolimus, demecolcine, detorubicin, dibromomannitol, diethylcarbamazine, dihydrofolate reductase inhibitors, dihydroxy anthracin dione, diphtheria toxin, DNA polymerase inhibitors, docetaxel, Dorlimomab aritox, Dorlixizumab, doxorubicin (adriamycin), DXL625, Eculizumab, Efalizumab, efaproxiral, EGFR antagonists, elesclomol, elsamitrucin, Elsilimomab, emetine, endothelin receptor antagonists, epipodophyllotoxins, epirubicin, epothilones, Erbitux™

, Erlizumab, estramustine, Etanercept, ethidium bromide, etoglucid, etoposide, etoposide phosphate, Everolimus, Faralimomab, farnesyltransferase inhibitors, FKBP inhibitors, floxuridine, fludarabine, fluorouracil, Fontolizumab, fotemustine, Galiximab, Gallium-67 (⁶⁷Ga), Gantenerumab, Gavilimomab, gemcitabine, glucocorticoids, Golimumab, Gomiliximab, gramicidin D, Gusperimus, Herceptin®

, hydrazines, hydroxyurea, hypomethylating agents, idarubicin, Idarubicine, ifosfamide, IL-1 antagonists, IL-1 receptor antagonists, IL-12, IL-12 antibodies, IL-12R antagonists, IL-13 antibodies, IL-2, IL-2 inhibitors, IL-2 receptor/CD25 antibodies, IL-6 antibodies, imatinib mesylate, Immunoglobulin E antibodies, IMP dehydrogenase inhibitors, Infliximab, Inolimomab, Integrin antibodies, Interferon antibodies, interferons, Interleukin 5 antibodies, Interleukin-6 receptor antibodies, interleukins, Iodine-125 (¹²⁵I), Iodine-131 (¹³¹I), Ipilimumab, irinotecan, ixabepilone, Keliximab, larotaxel, Lead-212 (²¹²Pb), Lebrilizumab, Leflunomide, Lenalidomide, Lerdelimumab, leucovorine, LFA-1 antibodies, lidocaine, lipoxygenase inhibitors, lomustine (CCNU), lonidamine, lucanthone, Lumiliximab, Lutetium-177 (¹⁷⁷Lu), Macrolides, mannosulfan, Maslimomab, masoprocol, mechlorethamine, melphalan, Mepolizumab, mercaptopurine, Metelimumab, Methotrexate, microtubule assembly inhibitors, microtubule stability enhancers, mithramycin, mitobronitol, mitoguazone, mitomycin, mitomycin C, mitotane, mitoxantrone, Morolimumab, mTOR inhibitors, Muromonab-CD3, mustines, Mycophenolic acid, mytotane (O,P′

-(DDD)), Natalizumab, nedaplatin, Nerelimomab, nimustine, nitrogen mustards, nitrosoureas, nordihydroguaiaretic acid, oblimersen, ocrelizumab, Ocrelizumab, Odulimomab, ofatumumab, olaparib, Omalizumab, ortataxel, Otelixizumab, oxaliplatin, oxaliplatin, paclitaxel (taxol), Pascolizumab, PDGF antagonists, pegaspargase, pemetrexed, Pentostatin, Pertuzumab, Pexelizumab, phosphodiesterase inhibitors, Phosphorus-32 (³²P), Pimecrolimus Abetimus, pirarubicin, pixantrone, platins, plicamycin, poly ADP ribose polymerase inhibitors, porfimer sodium, porphyrin derivatives, prednimustine, procaine, procarbazine, procarbazine, propranolol, proteasome inhibitors, pseudomonas exotoxin, Pseudomonas toxin, purine synthesis inhibitors, puromycin, pyrimidine synthesis inhibitors, radionuclides, radiotherapy, raltitrexed, ranimustine, Reslizumab, retinoid X receptor agonists, retinoids, Rhenium-186 (¹⁸⁶Re), Rhenium-188 (¹⁸⁸Re), ribonucleotide reductase inhibitors, ricin, Rilonacept, Rituxan®

, Rovelizumab, rubitecan, Ruplizumab, Samarium-153 (¹⁵³Sm), satraplatin, Scandium-47 (⁴⁷Sc), selective androgen receptor modulators, selective estrogen receptor modulators, seliciclib, semustine, sex hormone antagonists, Siplizumab, Sirolimus, steroid aromatase inhibitors, steroids, streptozocin, streptozotocin, Tacrolimus, talaporfin, Talizumab, taxanes, taxols, tegafur, Telimomab aritox, temoporfin, temozolomide, temsirolimus, Temsirolimus, Teneliximab, teniposide, Teplizumab, Teriflunomide, tesetaxel, testolactone, tetracaine, Thalidomide, thioepa chlorambucil, thiopurines thioguanine, ThioTEPA, thymidylate synthase inhibitors, tiazofurin, tipifarnib, T-lymphocyte antibodies, TNF antagonists, TNF antibodies, TNF fusion proteins, TNF receptor fusion proteins, TNF-alpha inhibitors, Tocilizumab, topoisomerase inhibitors, topotecan, Toralizumab, trabectedin, Tremelimumab, treosulfan, tretinoin, triazenes, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosfamide, tumor antigen specific monoclonal antibodies, tyrosine kinase inhibitors, uramustine, Ustekinumab, valrubicin, Valrubicine, Vapaliximab, VEGF antagonists, Vepalimomab, verteporfin, vinblastine, vinca alkaloids, vincristine, vindesine, vinflunine, vinorelbine, Visilizumab, vorinostat, Yttrium-88 (⁸⁸Y), Yttrium-90 (⁹⁰Y), Zanolimumab, zileuton, Ziralimumab, Zolimomab aritox, zorubicin, Zotarolimus, or any combination thereof;

the another active agent is one or more agonist, antagonist, or modulator of a factor selected from;

TNF-alpha, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-18, IFN-alpha, IFN-gamma, BAFF, CXCL13, IP-10, VEGF, EPO, EGF, HRG, Hepatocyte Growth Factor (HGF), Hepcidin, or any combination thereof.

238. The method of claim 201 wherein the antibody or antibody fragment is directly or indirectly coupled to one or more of said another therapeutic agent or a to a detectable label.

239. The method of claim 238 wherein the detectable label is comprising:

fluorescent dyes, bioluminescent materials, radioactive materials, chemiluminescent moieties, streptavidin, avidin, biotin, radioactive materials, enzymes, substrates, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase, luciferase, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin, dansyl chloride, luminol, luciferin, aequorin, Iodine 125 (¹²⁵I), Carbon 14 (¹⁴C), Sulfur 35 (³⁵S), Tritium (³H), Phosphorus 32 (³²P), or any combination thereof.

240. The method of claim 201, wherein the antibody comprises:

(a) light and heavy chain polypeptides comprising;

SEQ ID NO;

709 and SEQ ID NO;

657;

SEQ ID NO;

702 and SEQ ID NO;

704;

SEQ ID NO;

706 and SEQ ID NO;

708;

SEQ ID NO;

20 and SEQ ID NO;

19;

or SEQ ID NO;

2 and SEQ ID NO;

3;

(b) or a polypeptide having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to any of the polypeptides of (a).

241. A therapeutic or diagnostic composition comprising an anti-IL-6 antibody and another therapeutic or diagnostic compound,

wherein the anti-IL-6 antibody comprises:

a light chain polypeptide comprising;

a polypeptide having at least 75% identity to SEQ ID NO;

709, a polypeptide encoded by a polynucleotide that has at least 75% identity to the polynucleotide of SEQ ID NO;

723, a polypeptide encoded by a polynucleotide that hybridizes under medium stringency conditions to a polynucleotide having the sequence of the reverse complement of SEQ ID NO;

723, or a polypeptide encoded by a polynucleotide that hybridizes under high stringency conditions to a polynucleotide having the sequence of the reverse complement of SEQ ID NO;

723; and

a heavy chain polypeptide comprising;

a polypeptide having at least 75% identity to SEQ ID NO;

657, a polypeptide encoded by a polynucleotide that has at least 75% identity to the polynucleotide of SEQ ID NO;

700, a polypeptide encoded by a polynucleotide that hybridizes under medium stringency conditions to a polynucleotide having the sequence of the reverse complement of SEQ ID NO;

700, or a polypeptide encoded by a polynucleotide that hybridizes under high stringency conditions to a polynucleotide having the sequence of the reverse complement of SEQ ID NO;

700;

wherein the Ab1 antibody or antibody fragment specifically binds to IL-6 and antagonizes one or more activity associated with IL-6;

and wherein the another therapeutic compound comprising;

chemotherapy agents, statins, cytokines, gene therapy agents, anti-coagulants, anti-cachexia agents, anti-weakness agent, anti-fatigue agent, anti-fever agent, anti-nausea agents, antiemetic agents, IL-6 antagonist, a cytotoxic agent, another therapeutic compound, or any combination thereof.

242. The composition of claim 241 wherein the antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.

243. The composition of claim 241, wherein the antibody or antibody fragment 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 consisting essentially of the polypeptides of SEQ ID NO:

702 and SEQ ID NO;

704 or the polypeptides of SEQ ID NO;

2 and SEQ ID NO;

3.

244. The composition of claim 243, wherein said binding to the same linear or conformational epitope(s) and/or competition for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or fragment thereof is ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide and 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 of SEQ ID NO:

1.

245. The composition of claim 241, wherein the Ab1 antibody or antibody fragment is aglycosylated.

246. The composition of claim 241, wherein the antibody or antibody fragment is a human, humanized, single chain, or chimeric antibody or comprises a Fab, Fab′

, F(ab′

)₂, Fv, or scFv.

247. The composition of claim 241, wherein the antibody or antibody fragment is directly or indirectly coupled to one or more of said another therapeutic agent or a detectable label.

248. The composition of claim 241, wherein the antibody comprises:

(a) light and heavy chain polypeptides comprising;

SEQ ID NO;

709 and SEQ ID NO;

657;

SEQ ID NO;

702 and SEQ ID NO;

704;

SEQ ID NO;

706 and SEQ ID NO;

708;

SEQ ID NO;

20 and SEQ ID NO;

19;

or SEQ ID NO;

2 and SEQ ID NO;

3;

(b) a polypeptide having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to any of the polypeptides of (a).