ANTIBODIES TO IL-6 AND USE THEREOF

• US 20100129357A1
• Filed: 07/14/2009
• Published: 05/27/2010
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Jensen, Ann Elisabeth Carvalho, Smith, Jeffrey T. L., Latham, John, Garcia-Martinez, Leon, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Ojala, Ethan
• Granted Patent: US 8,323,649 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• 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 39/39533 against materials from animals
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/569 Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• 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: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• 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 cogulation 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. A method of preventing, treating, or diagnosing a disease or condition associated with IL-6, comprising administration of an Ab1 antibody or antibody fragment to a subject in need thereof, wherein the Ab1 antibody or antibody fragment comprises:

a light chain polypeptide selected from the group consisting of;

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

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

698, 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;

698, and 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;

698; and

a heavy chain polypeptide selected from the group consisting of;

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, and 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.

2. The method of claim 1, wherein the light chain polypeptide includes one or more substitutions within the light chain framework region(s) relative to the light chain framework region sequences of SEQ ID NO:

699.

3. The method of claim 2 wherein one or more of the substitutions within the light chain framework region(s) is substitution with the sequence of a corresponding position of a donor sequence, wherein the donor sequence is selected from the group consisting of:

SEQ ID NO;

2;

a human, rabbit, or a non-human primate light chain sequence; and

a light chain of any of Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36,

wherein the substitution results in replacement, insertion, and/or deletion of one or more amino acids, and

wherein the corresponding position is determined by sequence alignment between the framework region of SEQ ID NO;

699 and the donor sequence.

4. The method of claim 1, wherein the heavy chain polypeptide includes one or more substitutions within the heavy chain framework region(s) relative to the heavy chain framework region sequences of SEQ ID NO:

657.

5. The method of claim 4 wherein one or more of the substitutions within the heavy chain framework region(s) is substitution with the sequence of a corresponding position of a donor sequence, wherein the donor sequence is selected from the group consisting of:

SEQ ID NO;

3;

a human, rabbit, or a non-human primate heavy chain sequence; and

a heavy chain of any of Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36,

wherein the substitution results in replacement, insertion, and/or deletion of one or more amino acids, and

wherein the corresponding position is determined by sequence alignment between the framework region of SEQ ID NO;

657 and the donor sequence.

6. The method of claim 1, wherein the light chain polypeptide comprises one or more Ab1 light chain CDR polypeptide selected from the group consisting of:

a light chain CDR1 having at least 72.7% identity (identical to at least 8 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 85.7% identity (identical to at least 6 out of 7 residues) to SEQ ID NO;

5;

a light chain CDR3 having at least 50% identity (identical to at least 6 out of 12 residues) to SEQ ID NO;

6;

a light chain CDR1 having at least 90.9% similarity (similar to at least 10 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 100% similarity (similar to at least 7 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 66.6% similarity (similar to at least 8 out of 12 residues) to SEQ ID NO;

6;

and wherein the heavy chain polypeptide comprises one or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 80% identity (identical to at least 4 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 50% identity (identical to at least 8 out of 16 residues) to SEQ ID NO;

120;

a heavy chain CDR3 having at least 33.3% identity (identical to at least 4 out of 12 residues) to SEQ ID NO;

9;

a heavy chain CDR1 having at least 100% similarity (similar to at least 5 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 56.2% similarity (similar to at least 9 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 50% similarity (similar to at least 6 out of 12 residues) to SEQ ID NO;

9.

7. The method of claim 1, wherein the light chain polypeptide comprises one or more Ab1 light chain CDR polypeptide selected from the group consisting of:

a light chain CDR1 having at least 81.8% identity (identical to at least 9 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 71.4% identity (identical to at least 5 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 83.3% identity (identical to at least 10 out of 12 residues) to SEQ ID NO;

6;

and wherein the heavy chain polypeptide comprises one or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 60% identity (identical to at least 3 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 87.5% identity (identical to at least 14 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 83.3% identity (identical to at least 10 out of 12 residues) to SEQ ID NO;

9.

8. The method of claim 6, any wherein the Ab1 antibody or antibody fragment comprises at least two of said light chain CDR polypeptides and at least two of said heavy chain CDR polypeptides.

15. The method of claim 1, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.

16. The method of claim 1, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 25 days in a healthy human subject.

17. The method of claim 1, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 30 days in a healthy human subject.

18. The method of claim 1, wherein the Ab1 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>.

19. The method of claim 1, 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.

20. The method of claim 19, 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.

21. The method of claim 1, wherein the Ab1 antibody or antibody fragment is aglycosylated.

22. The method of claim 1, wherein the Ab1 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

23. The method of claim 1, wherein the Ab1 antibody or antibody fragment is a human, humanized, single chain, or chimeric antibody.

24. The method of claim 1, wherein the Ab1 antibody or antibody fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, and scFv.

25. The method of claim 1, wherein said Ab1 antibody or antibody fragment further comprises a human F_c.

26. The method of claim 25, wherein said human F_c is derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

27. The method of claim 1, wherein the one or more activity associated with IL-6 is an in vivo activity selected from the group consisting of:

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; and

any combination thereof.

28. The method of claim 1, wherein one or more of the one or more activity associated with IL-6 is an in vitro activity selected from the group consisting of:

stumultion of proliferation of T1165 cells;

binding of IL-6 to IL-6R;

activation (dimerization) of the gp130 signal-transducing glycoprotein;

formation of IL-6/IL-6R/gp130 multimers;

stimulation of haptoglobin production by HepG2 cells modified to express human IL6 receptor; and

any combination thereof.

29. The method of claim 1, wherein the Ab1 antibody or antibody fragment is expressed from a recombinant cell.

30. The method of claim 29 wherein the cell is selected from a mammalian, yeast, bacterial, and insect cell.

31. The method of claim 30 wherein the cell is a yeast cell.

32. The method of claim 31 wherein the cell is a diploidal yeast cell.

33. The method of claim 31 wherein the yeast cell is a Pichia yeast.

34. The method of claim 1, wherein the disease or condition associated with IL-6 is selected from the group consisting of:

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; and

any combination thereof.

35. The method of claim 1 wherein the disease or condition associated with IL-6 is selected from the group consisting of:

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, and systemic inflammatory response syndrome (SIRS).

36. The method of claim 34 wherein the disease or condition associated with hypercoagulation is selected from the group consisting of:

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, and any combination thereof.

37. The method of claim 34 wherein the disease or condition associated with elevated serum CRP is selected from the group consisting of:

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 Mediterrean fever, autoimmune thrombocytopenia, autoimmune hemolytic anemia, autoimmune thyroid diseases, pernicious anemia, vitiligo, alopecia areata, 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 obsructive pulmonary disease, allergic asthma, other allergic conditions or any combination thereof.

38. The method of claim 34 wherein the disease or condition associated with hypoalbuminemia is selected from the group consisting of:

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, and any combination thereof.

39. The method of claim 34, wherein the cancer is selected from the group consisting of:

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, and any combination thereof.

40. The method of claim 39, wherein the cancer is selected from the group consisting of:

Colorectal Cancer, Non-Small Cell Lung Cancer, Cholangiocarcinoma, Mesothelioma, Castleman'"'"'s disease, Renal Cell Carcinoma, and any combination thereof.

41. The method of claim 1 wherein prior to administration of the Ab1 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.

42. The method of claim 41 wherein said symptom is a side-effect of another therapeutic agent administered to the subject prior to, concurrent with, or subsequent to administration of the Ab1 antibody or antibody fragment.

43. The method of claim 1 wherein the Ab1 antibody or antibody fragment is administered in a therapeutically effective amount for prevention or treatment of one or more symptom associated with elevated IL-6.

44. The method of claim 43 wherein the therapeutically effective amount is between about 0.1 and 20 mg/kg of body weight of recipient subject

45. The method of claim 41 further comprising monitoring the subject to assess said symptom subsequent to administration of the Ab1 antibody.

46. The method of claim 41 wherein said symptom is exhibited prior to Ab1 antibody or antibody fragment administration.

47. The method of claim 46 wherein said symptom is improved or restored to a normal condition within approximately 1-5 weeks of Ab1 antibody administration.

48. The method of claim 47 wherein said symptom thereafter remains improved for an entire period intervening two consecutive Ab1 antibody administrations.

49. The method of claim 41, wherein the subject'"'"'s coagulation profile is assessed 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.

50. The method of claim 41, wherein the subject'"'"'s coagulation profile is assessed by a functional measurement of clotting ability.

51. The method of claim 50, wherein the functional measurement of clotting ability is selected from prothrombin time (PT), prothrombin ratio (PR), international normalized ratio (INR), or any combination thereof.

52. The method of claim 41, 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 Ab1 antibody or antibody fragment if the subject'"'"'s INR is less than about 0.9.

53. The method of claim 41, 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 Ab1 antibody or antibody fragment if the subject'"'"'s INR is less than about 0.5.

54. The method of claim 52, wherein the subject'"'"'s INR is raised to greater than approximately 0.9 within 4 weeks of administering to the subject the Ab1 antibody or antibody fragment.

55. The method of claim 41, further comprising:

measuring the subject'"'"'s serum D-dimer level prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 antibody or antibody fragment if the subject'"'"'s serum serum D-dimer level is above the normal reference range.

56. The method of claim 55, wherein the subject'"'"'s serum D-dimer level is lowered to less than the upper limit of the normal reference range within 4 weeks of administering to the subject the Ab1 antibody or antibody fragment.

57. The method of claim 41 that results in a prolonged improvement in the subject'"'"'s coagulation profile.

58. The method of claim 41, wherein the subject'"'"'s coagulation profile is measurably improved within about 2 weeks of administration of the Ab1 antibody or antibody fragment.

59. The method of claim 58, wherein the subject'"'"'s coagulation profile remains measurably improved approximately 12 weeks after administering to the subject the Ab1 antibody or antibody fragment.

60. The method of claim 41, further comprising:

measuring the subject'"'"'s body temperature prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 antibody or antibody fragment if the subject'"'"'s body temperature higher than about 38°

C.

61. The method of claim 41, further comprising:

measuring the subject'"'"'s body weight prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 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).

62. The method of claim 41, 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.

63. The method of claim 41, that results in a prolonged improvement in cachexia, weakness, fatigue, and/or fever in the subject.

64. The method of claim 41, wherein the subject'"'"'s body mass is raised by approximately 1 kilogram within approximately 4 weeks of administration of the Ab1 antibody or antibody fragment.

65. The method of claim 41, wherein the subject'"'"'s cachexia is measurably improved within about 4 weeks of Ab1 antibody or antibody fragment administration.

66. The method of claim 65, wherein the subject'"'"'s cachexia is assessed by measurement of the subject'"'"'s total body mass, lean body mass, lean body mass index, and/or appendicular lean body mass.

67. The method of claim 66, wherein the measurement of the subject'"'"'s body mass discounts (subtracts) the estimated weight of the subject'"'"'s tumor(s) and/or extravascular fluid collection(s).

68. The method of claim 66, wherein the subject'"'"'s cachexia remains measurably improved approximately 8 weeks after Ab1 antibody or antibody fragment administration.

69. The method of claim 41, wherein the subject'"'"'s weakness is measurably improved within about 2 weeks of Ab1 antibody or antibody fragment administration.

70. The method of claim 69, wherein the subject'"'"'s weakness is measured by the hand grip strength test.

71. The method of claim 70, wherein the subject'"'"'s hand grip strength is improved by at least about 15%.

72. The method of claim 70, wherein the subject'"'"'s hand grip strength is improved by at least about 20%.

73. The method of claim 69, wherein the subject'"'"'s weakness remains measurably improved approximately 12 weeks after Ab1 antibody or antibody fragment administration.

74. The method of claim 41, wherein the subject'"'"'s fatigue is measurably improved within about 1 week of Ab1 antibody or antibody fragment administration.

75. The method of claim 74, wherein the subject'"'"'s fatigue is measured by the FACIT-F FS test.

76. The method of claim 75, wherein the subject'"'"'s FACIT-F FS score is improved by at least about 10 points.

77. The method of claim 74, wherein the subject'"'"'s fatigue remains measurably improved approximately 12 weeks after anti-IL-6 antibody administration.

78. The method of claim 41, wherein the subject'"'"'s fever is measurably improved within about 1 week of Ab1 antibody or antibody fragment administration.

79. The method of claim 78, wherein the subject'"'"'s fever remains measurably improved approximately 12 weeks after Ab1 antibody or antibody fragment administration.

80. The method of claim 41, wherein said subject exhibits an elevated serum CRP level prior to administration of the Ab1 antibody or antibody fragment.

81. The method of claim 41 wherein said subject exhibits a reduced serum albumin level prior to administration of the Ab1 antibody or antibody fragment.

82. The method of claim 41, whereby the subject'"'"'s Glasgow Prognostic Score (GPS) is improved.

83. The method of claim 41, further comprising:

measuring the subject'"'"'s serum CRP level prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 antibody or antibody fragment if the subject'"'"'s serum CRP level is at least approximately 5 mg/L.

84. The method of claim 41, wherein the subject'"'"'s serum CRP level is reduced to less than approximately 10 mg/L within 1 week of administration of the Ab1 antibody or antibody fragment.

85. The method of claim 41, wherein the subject'"'"'s serum CRP level is reduced to less than approximately 5 mg/L within 1 week of administration of the Ab1 antibody or antibody fragment.

86. The method of claim 41, wherein the subject'"'"'s serum CRP level is reduced to less than approximately 1 mg/L within 1 week of administration of the Ab1 antibody or antibody fragment.

87. The method of claim 41, that results in a prolonged reduction in serum CRP level of the subject.

88. The method of claim 84, wherein 14 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

89. The method of claim 84, wherein 21 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

90. The method of claim 84, wherein 28 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

91. The method of claim 84, wherein 35 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

92. The method of claim 84, wherein 42 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

93. The method of claim 84, wherein 49 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

94. The method of claim 84, wherein 56 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum CRP level remains less than approximately 10 mg/L.

95. The method of claim 41, further comprising:

measuring the subject'"'"'s serum albumin level prior to administration of the Ab1 antibody or antibody fragment, and administering the Ab1 antibody or antibody fragment if the subject'"'"'s serum albumin level is less than approximately 35 g/L.

96. The method of claim 95, wherein the subject'"'"'s serum albumin level is increased to greater than approximately 35 g/L within about 5 weeks of administration of the Ab1 antibody or antibody fragment.

97. The method of claim 41, that results in a prolonged increase in serum albumin level of the subject.

98. The method of claim 97, wherein 42 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum albumin level remains above 35 g/L.

99. The method of claim 97, wherein 49 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum albumin level remains above 35 g/L.

100. The method of claim 97, wherein 56 days after Ab1 antibody or antibody fragment administration the subject'"'"'s serum albumin level remains above 35 g/L.

101. The method of claim 41, wherein the subject'"'"'s serum albumin level is increased by about 5 g/L within approximately 5 weeks of administering the Ab1 antibody or antibody fragment.

102. The method of claim 41 further comprising monitoring the subject to assess coagulation profile.

103. The method of claim 41 wherein the subject has exhibited an elevated serum D-dimer level prior to treatment.

104. The method of claim 41 wherein the subject has exhibited an elevated serum C-reactive protein (CRP) level prior to treatment.

105. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period of approximately four weeks.

106. The method of claim 105, wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period of approximately eight weeks.

107. The method of claim 106, wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period of approximately twelve weeks.

108. The method of claim 107, wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period of approximately sixteen weeks.

109. The method of claim 1, wherein the Ab1 antibody or antibody fragment is administered in a diagnostically effective amount for detection of IL-6 expressing disease sites.

110. The method of claim 109, wherein the Ab1 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.

111. The method of claim 109, which is used to detect IL-6 expressing tumors or metastases.

112. The method of claim 109, which is used to detect the presence of sites of inflammation associated with IL-6 expressing cells.

113. The method of claim 109, wherein the results are used to facilitate design of an appropriate therapeutic regimen.

114. The method of claim 109, wherein said therapeutic regimen includes radiotherapy, chemotherapy or a combination thereof.

115. The method of claim 1, wherein the Ab1 antibody or antibody fragment is co-administered with another therapeutic agent selected from the group consisting of:

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, and any combination thereof.

116. The method of claim 115, wherein the chemotherapy agent is selected from the group consisting of:

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, and any combination thereof.

117. The method of claim 115, wherein the anti-coagulant is selected from the group consisting of:

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), and any combination thereof.

118. The method of claim 115, wherein the statin is selected from the group consisting of:

atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and any combination thereof.

119. The method of claim 115, wherein the another therapeutic agent is an antagonist of a factor selected from the group consisting of tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, Interleukin 6, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof.

120. The method of claim 115, wherein the anti-cachexia agent is selected from the group consisting of:

cannabis, dronabinol (Marinol), nabilone (Cesamet), cannabidiol, cannabichromene, tetrahydrocannabinol, Sativex, megestrol acetate, and any combination thereof.

121. The method of claim 115, wherein the anti-nausea agent or antiemetic agent is selected from the group consisting of:

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 All antagonists, beta two adenergic receptor agonists, beta three adenergic receptor agonists, and any combination thereof.

122. The method of claim 115, wherein the another therapuetic agent is selected from the group consisting of 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, Tinidazole, 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, imunovir, 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, and any combination thereof.

123. The method of claim 115, wherein the cytotoxic agent, chemotherapeutic agent, or immunosuppressive agent is selected from the group consisting of:

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, carminomycin, 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-α

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, and any combination thereof.

124. The method of claim 115, wherein the another active agent is one or more agonist, antagonist, or modulator of a factor selected from the group consisting of:

TNF-α

, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-18, IFN-α

, IFN-γ

, BAFF, CXCL13, IP-10, VEGF, EPO, EGF, HRG, Hepatocyte Growth Factor (HGF), Hepcidin, and any combination thereof.

125. The method of claim 115, wherein the IL-6 antagonist is selected from the group consisting of:

anti-IL-6 antibodies or fragments thereof, antisense nucleic acids, polypeptides, small molecules, and any combination thereof.

126. The method of claim 125, wherein the antisense nucleic acid comprises at least approximately 10 nucleotides of a sequence encoding IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, or SYK.

127. The method of claim 125, wherein the antisense nucleic acid comprises DNA, RNA, peptide nucleic acid, locked nucleic acid, morpholino (phosphorodiamidate morpholino oligo), glycerol nucleic acid, threose nucleic acid, or any combination thereof.

128. The method of claim 125, wherein the anti-IL-6 antibody or fragment thereof is selected from the group consisting of:

Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, an IL-6 binding fragment of any of the foregoing, a variant of any of the foregoing, and any combination thereof.

129. The method of claim 125, wherein the IL-6 antagonist polypeptide comprises a fragment of a polypeptide having a sequence selected from the group consisting IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, and SYK.

130. The method of claim 129, wherein the fragment is at least 40 amino acids in length.

131. The method of claim 125, wherein the IL-6 antagonist comprises a soluble IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, SYK, or any combination thereof.

132. The method of claim 115, wherein the IL-6 antagonist is coupled to a half-life increasing moiety.

133. The method of claim 115, wherein the Ab1 antibody or antibody fragment is directly or indirectly coupled to one or more of said another therapeutic agent.

134. The method of claim 1, wherein the Ab1 antibody or antibody fragment is directly or indirectly coupled to a detectable label.

135. The method of claim 134 wherein the detectable label is selected from the group consisting of:

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), and any combination thereof.

136. The method of claim 1, wherein the Ab1 antibody is administered to the subject in the form of one or more nucleic acids that encode the Ab1 antibody.

137. The method of claim 136 wherein the one or more nucleic acids are introduced into the recipient as a virus, liposome, cationic lipid complex, cationic polymer complex, or nanoparticle complex.

138. The method of claim 136 wherein the one or more nucleic acids are comprised of yeast or human preferred codons.

139. The method of claim 136 wherein the one or more nucleic acids are comprised in a vector.

140. The method of claim 139 wherein the vector is a plasmid or recombinant viral vector.

141. The method of claim 136 wherein the one or more nucleic acids comprise the heavy and light chain polynucleotide sequences of SEQ ID NO:

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11.

142. The method of claim 1, wherein the Ab1 antibody comprises:

(a) light and heavy chain polypeptides selected from the group consisting of;

SEQ ID NO;

699 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; and

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);

(c) a polynucleotide that hybridizes under moderately or highly stringent hybridization conditions to any of the the heavy and light chain polynucleotide sequences of SEQ ID NO;

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11;

(d) a polynucleotide having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to any of the the heavy and light chain polynucleotide sequences of SEQ ID NO;

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11;

(e) a polypeptide encoded by any of the polynucleotides of (c) or (d).

9. A method of preventing or treating a disease or condition associated with IL-6, comprising administration of an Ab1 antibody or antibody fragment to a subject in need thereof, wherein the Ab1 antibody or antibody fragment comprises:

two or more Ab1 light chain CDR polypeptides selected from the group consisting of;

a light chain CDR1 having at least 72.7% identity (identical to at least 8 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 85.7% identity (identical to at least 6 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 50% identity (identical to at least 6 out of 12 residues) to SEQ ID NO;

6;

and two or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 80% identity (identical to at least 4 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 50% identity (identical to at least 8 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 33.3% identity (identical to at least 4 out of 12 residues) to SEQ ID NO;

9;

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

11. The method of claim 9 wherein said Ab1 antibody or antibody fragment comprises said light chain CDR1, said light chain CDR3, said heavy chain CDR2, and said heavy chain CDR3.

12. The method of claim 9 wherein said Ab1 antibody or antibody fragment comprises said light chain CDR1, said light chain CDR2, said light chain CDR3, said heavy chain CDR1, said heavy chain CDR2, and said heavy chain CDR3.

13. The method of claim 9 wherein said light and heavy chain CDR polypeptides are comprised in an antibody or antibody fragment selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, scFv, IgNAR, SMIP, camelbodies, and nanobodies.

14. The method of claim 9 wherein the framework regions (FRs) 1, 2, 3 and 4 in the variable light and heavy regions of said Ab1 antibody or antibody fragment, respectively, are human FRs which are unmodified or which have each been modified by the substitution of at most 2 or 3 human FR residues with the corresponding FR residues of the parent rabbit antibody light or heavy chain of SEQ ID NO:

2 and SEQ ID NO;

3, respectively,

wherein said human light chain FRs 1, 2 and 3 have been derived from a human variable light chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the subsequence of the parent rabbit antibody light chain of SEQ ID NO;

2 extending from the beginning of FR1 to the end of FR3; and

wherein said human light chain FR4 has been derived from a human variable light chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the parent rabbit antibody light chain FR4 contained in SEQ ID NO;

2; and

wherein said human heavy chain FRs 1, 2 and 3 have been derived from a human variable heavy chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the subsequence of the parent rabbit antibody heavy chain of SEQ ID NO;

3 extending from the beginning of FR1 to the end of FR3; and

wherein said human heavy chain FR4 has been derived from a human variable heavy chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the parent rabbit antibody heavy chain FR4 contained in SEQ ID NO;

3.

10. A method of preventing or treating a disease or condition associated with IL-6, comprising administration of an Ab1 antibody or antibody fragment to a subject in need thereof, wherein the Ab1 antibody or antibody fragment comprises:

two or more Ab1 light chain CDR polypeptides selected from the group consisting of;

a light chain CDR1 having at least 90.9% similarity (similar to at least 10 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 100% similarity (similar to at least 7 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 66.6% similarity (similar to at least 8 out of 12 residues) to SEQ ID NO;

6;

and two or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 100% similarity (similar to at least 5 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 56.2% similarity (similar to at least 9 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 50% similarity (similar to at least 6 out of 12 residues) to SEQ ID NO;

9;

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

143. A therapeutic composition comprising an Ab1 antibody and another therapeutic compound,

wherein the Ab1 antibody comprises:

a light chain polypeptide selected from the group consisting of;

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

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

698, 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;

698, and 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;

698; and

a heavy chain polypeptide selected from the group consisting of;

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, and 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 selected from the group consisting of;

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, and any combination thereof.

144. The composition of claim 143, wherein the light chain polypeptide includes one or more substitutions within the light chain framework region(s) relative to the light chain framework region sequences of SEQ ID NO:

699.

145. The composition of claim 144, wherein one or more of the substitutions within the light chain framework region(s) is substitution with the sequence of a corresponding position of a donor sequence, wherein the donor sequence is selected from the group consisting of:

SEQ ID NO;

2;

a human, rabbit, or a non-human primate light chain sequence; and

a light chain of any of Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36,

wherein the substitution results in replacement, insertion, and/or deletion of one or more amino acids, and

wherein the corresponding position is determined by sequence alignment between the framework region of SEQ ID NO;

699 and the donor sequence.

146. The composition of claim 145, wherein the heavy chain polypeptide includes one or more substitutions within the heavy chain framework region(s) relative to the heavy chain framework region sequences of SEQ ID NO:

657.

147. The composition of claim 146, wherein one or more of the substitutions within the heavy chain framework region(s) is substitution with the sequence of a corresponding position of a donor sequence, wherein the donor sequence is selected from the group consisting of:

SEQ ID NO;

3;

a human, rabbit, or a non-human primate heavy chain sequence; and

a heavy chain of any of Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36,

wherein the substitution results in replacement, insertion, and/or deletion of one or more amino acids, and

wherein the corresponding position is determined by sequence alignment between the framework region of SEQ ID NO;

657 and the donor sequence.

148. The composition of claim 143, wherein the light chain polypeptide comprises one or more Ab1 light chain CDR polypeptide selected from the group consisting of:

a light chain CDR1 having at least 72.7% identity (identical to at least 8 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 85.7% identity (identical to at least 6 out of 7 residues) to SEQ ID NO;

5;

a light chain CDR3 having at least 50% identity (identical to at least 6 out of 12 residues) to SEQ ID NO;

6;

a light chain CDR1 having at least 90.9% similarity (similar to at least 10 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 100% similarity (similar to at least 7 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 66.6% similarity (similar to at least 8 out of 12 residues) to SEQ ID NO;

6;

and wherein the heavy chain polypeptide comprises one or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 80% identity (identical to at least 4 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 50% identity (identical to at least 8 out of 16 residues) to SEQ ID NO;

120;

a heavy chain CDR3 having at least 33.3% identity (identical to at least 4 out of 12 residues) to SEQ ID NO;

9;

a heavy chain CDR1 having at least 100% similarity (similar to at least 5 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 56.2% similarity (similar to at least 9 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 50% similarity (similar to at least 6 out of 12 residues) to SEQ ID NO;

9.

149. The composition of claim 143, wherein the light chain polypeptide comprises one or more Ab1 light chain CDR polypeptide selected from the group consisting of:

a light chain CDR1 having at least 81.8% identity (identical to at least 9 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 71.4% identity (identical to at least 5 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 83.3% identity (identical to at least 10 out of 12 residues) to SEQ ID NO;

6;

and wherein the heavy chain polypeptide comprises one or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 60% identity (identical to at least 3 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 87.5% identity (identical to at least 14 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 83.3% identity (identical to at least 10 out of 12 residues) to SEQ ID NO;

9.

150. The composition of claim 148, wherein the Ab1 antibody or antibody fragment comprises at least two of said light chain CDR polypeptides and at least two of said heavy chain CDR polypeptides.

155. The composition of claim 147, wherein said light and heavy chain CDR polypeptides are comprised in an antibody or antibody fragment selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, scFv, IgNAR, SMIP, camelbodies, and nanobodies.

157. The composition of claim 143, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 22 days in a healthy human subject.

158. The composition of claim 143, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 25 days in a healthy human subject.

159. The composition of claim 143, wherein the Ab1 antibody or antibody fragment has an in vivo half-life of at least about 30 days in a healthy human subject.

160. The composition of claim 143, wherein the Ab1 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⁻

4S<sup>−

1</sup>.

161. The composition of claim 143, 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.

162. The composition of claim 161, 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.

163. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is aglycosylated.

164. The composition of claim 143, wherein the Ab1 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

165. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is a human, humanized, single chain, or chimeric antibody.

166. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fv, and scFv.

167. The composition of claim 143, wherein said Ab1 antibody or antibody fragment further comprises a human F_c.

168. The composition of claim 167, wherein said human F_c is derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

169. The composition of claim 143, wherein the one or more activity associated with IL-6 is an in vivo activity selected from the group consisting of:

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; and

any combination thereof.

170. The composition of claim 143, wherein one or more of the one or more activity associated with IL-6 is an in vitro activity selected from the group consisting of:

stumultion of proliferation of T1165 cells;

binding of IL-6 to IL-6R;

activation (dimerization) of the gp130 signal-transducing glycoprotein;

formation of IL-6/IL-6R/gp130 multimers;

stimulation of haptoglobin production by HepG2 cells modified to express human IL6 receptor; and

any combination thereof.

171. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is expressed from a recombinant cell.

172. The composition of claim 171, wherein the cell is selected from a mammalian, yeast, bacterial, and insect cell.

173. The composition of claim 172, wherein the cell is a yeast cell.

174. The composition of claim 173, wherein the cell is a diploidal yeast cell.

175. The composition of claim 174, wherein the yeast cell is a Pichia yeast.

176. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is co-administered with another therapeutic agent selected from the group consisting of:

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, and any combination thereof.

177. The composition of claim 176, wherein the chemotherapy agent is selected from the group consisting of:

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, and any combination thereof.

178. The composition of claim 176, wherein the anti-coagulant is selected from the group consisting of:

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), and any combination thereof.

179. The composition of claim 176, wherein the statin is selected from the group consisting of:

atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and any combination thereof.

180. The composition of claim 176, wherein the another therapeutic agent is an antagonist of a factor selected from the group consisting of tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, Interleukin 6, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof.

181. The composition of claim 176, wherein the anti-cachexia agent is selected from the group consisting of:

cannabis, dronabinol (Marinol), nabilone (Cesamet), cannabidiol, cannabichromene, tetrahydrocannabinol, Sativex, megestrol acetate, and any combination thereof.

182. The composition of claim 176, wherein the anti-nausea agent or antiemetic agent is selected from the group consisting of:

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, and any combination thereof.

183. The composition of claim 176, wherein the another therapuetic agent is selected from the group consisting of 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, Tinidazole, 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, imunovir, 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, and any combination thereof.

184. The composition of claim 176, wherein the cytotoxic agent, chemotherapeutic agent, or immunosuppressive agent is selected from the group consisting of:

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 (²¹¹ At), 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, carminomycin, 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-α

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, and any combination thereof.

185. The composition of claim 176, wherein the another active agent is one or more agonist, antagonist, or modulator of a factor selected from the group consisting of:

TNF-α

, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-18, IFN-α

, IFN-γ

, BAFF, CXCL13, IP-10, VEGF, EPO EGF, HRG, Hepatocyte Growth Factor (HGF), Hepcidin, and any combination thereof.

186. The composition of claim 176, wherein the IL-6 antagonist is selected from the group consisting of:

anti-IL-6 antibodies or fragments thereof, antisense nucleic acids, polypeptides, small molecules, and any combination thereof.

187. The composition of claim 186, wherein the antisense nucleic acid comprises at least approximately 10 nucleotides of a sequence encoding IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, or SYK.

188. The composition of claim 186, wherein the antisense nucleic acid comprises DNA, RNA, peptide nucleic acid, locked nucleic acid, morpholino (phosphorodiamidate morpholino oligo), glycerol nucleic acid, threose nucleic acid, or any combination thereof.

189. The composition of claim 186, wherein the anti-IL-6 antibody or fragment thereof is selected from the group consisting of:

Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, an IL-6 binding fragment of any of the foregoing, a variant of any of the foregoing, and any combination thereof.

190. The composition of claim 186, wherein the IL-6 antagonist polypeptide comprises a fragment of a polypeptide having a sequence selected from the group consisting IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, and SYK.

191. The composition of claim 190, wherein the fragment is at least 40 amino acids in length.

192. The composition of claim 186, wherein the IL-6 antagonist comprises a soluble IL-6, IL-6 receptor alpha, gp130, p38 MAP kinase, JAK1, JAK2, JAK3, SYK, or any combination thereof.

193. The composition of claim 176, wherein the IL-6 antagonist is coupled to a half-life increasing moiety.

194. The composition of claim 173, wherein the Ab1 antibody or antibody fragment is directly or indirectly coupled to one or more of said another therapeutic agent.

195. The composition of claim 143, wherein the Ab1 antibody or antibody fragment is directly or indirectly coupled to a detectable label.

196. The composition of claim 195 wherein the detectable label is selected from the group consisting of:

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), and any combination thereof.

197. The composition of claim 143, wherein the Ab1 antibody is administered to the subject in the form of one or more nucleic acids that encode the Ab1 antibody.

198. The composition of claim 197, wherein the one or more nucleic acids are introduced into the recipient as a virus, liposome, cationic lipid complex, cationic polymer complex, or nanoparticle complex.

199. The composition of claim 197, wherein the one or more nucleic acids are comprised of yeast or human preferred codons.

200. The composition of claim 197, wherein the one or more nucleic acids are comprised in a vector.

201. The composition of claim 197, wherein the vector is a plasmid or recombinant viral vector.

202. The composition of claim 197, wherein the one or more nucleic acids comprise the heavy and light chain polynucleotide sequences of SEQ ID NO:

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11.

203. The composition of claim 143, wherein the Ab1 antibody comprises:

(a) light and heavy chain polypeptides selected from the group consisting of;

SEQ ID NO;

699 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; and

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);

(c) a polynucleotide that hybridizes under moderately or highly stringent hybridization conditions to any of the the heavy and light chain polynucleotide sequences of SEQ ID NO;

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11;

(d) a polynucleotide having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to any of the the heavy and light chain polynucleotide sequences of SEQ ID NO;

698 and SEQ ID NO;

700;

SEQ ID NO;

701 and SEQ ID NO;

703;

SEQ ID NO;

705 and SEQ ID NO;

707;

SEQ ID NO;

720 and SEQ ID NO;

724; and

SEQ ID NO;

10 and SEQ ID NO;

11;

(e) a polypeptide encoded by any of the polynucleotides of (c) or (d).

151. A therapeutic composition comprising an Ab1 antibody and another therapeutic compound,

wherein the Ab1 antibody comprises:

two or more Ab1 light chain CDR polypeptides selected from the group consisting of;

a light chain CDR1 having at least 72.7% identity (identical to at least 8 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 85.7% identity (identical to at least 6 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 50% identity (identical to at least 6 out of 12 residues) to SEQ ID NO;

6;

and two or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 80% identity (identical to at least 4 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 50% identity (identical to at least 8 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 33.3% identity (identical to at least 4 out of 12 residues) to SEQ ID NO;

9;

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 selected from the group consisting of;

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, and any combination thereof.

153. The composition of claim 151, wherein said Ab1 antibody or antibody fragment comprises said light chain CDR1, said light chain CDR3, said heavy chain CDR2, and said heavy chain CDR3.

154. The composition of claim 151, wherein said Ab1 antibody or antibody fragment comprises said light chain CDR1, said light chain CDR2, said light chain CDR3, said heavy chain CDR1, said heavy chain CDR2, and said heavy chain CDR3.

156. The composition of claim 151, wherein the framework regions (FRs) 1, 2, 3 and 4 in the variable light and heavy regions of said Ab1 antibody or antibody fragment, respectively, are human FRs which are unmodified or which have each been modified by the substitution of at most 2 or 3 human FR residues with the corresponding FR residues of the parent rabbit antibody light or heavy chain of SEQ ID NO:

2 and SEQ ID NO;

3, respectively,

wherein said human light chain FRs 1, 2 and 3 have been derived from a human variable light chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the subsequence of the parent rabbit antibody light chain of SEQ ID NO;

2 extending from the beginning of FR1 to the end of FR3; and

wherein said human light chain FR4 has been derived from a human variable light chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the parent rabbit antibody light chain FR4 contained in SEQ ID NO;

2; and

wherein said human heavy chain FRs 1, 2 and 3 have been derived from a human variable heavy chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the subsequence of the parent rabbit antibody heavy chain of SEQ ID NO;

3 extending from the beginning of FR1 to the end of FR3; and

wherein said human heavy chain FR4 has been derived from a human variable heavy chain antibody sequence that has been selected from a library or database of human germline antibody sequences based on its high level of homology (relative to other human germline antibody sequences contained in the library or database) to the parent rabbit antibody heavy chain FR4 contained in SEQ ID NO;

3.

152. A therapeutic composition comprising an Ab1 antibody and another therapeutic compound,

wherein the Ab1 antibody comprises:

a light chain CDR1 having at least 90.9% similarity (similar to at least 10 out of 11 residues) to SEQ ID NO;

4;

a light chain CDR2 having at least 100% similarity (similar to at least 7 out of 7 residues) to SEQ ID NO;

5; and

a light chain CDR3 having at least 66.6% similarity (similar to at least 8 out of 12 residues) to SEQ ID NO;

6;

and two or more Ab1 heavy chain CDR polypeptide selected from the group consisting of;

a heavy chain CDR1 having at least 100% similarity (similar to at least 5 out of 5 residues) to SEQ ID NO;

7;

a heavy chain CDR2 having at least 56.2% similarity (similar to at least 9 out of 16 residues) to SEQ ID NO;

120; and

a heavy chain CDR3 having at least 50% similarity (similar to at least 6 out of 12 residues) to SEQ ID NO;

9;

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 selected from the group consisting of;

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, and any combination thereof.