Antibodies to IL-6 and use thereof

• US 20100290993A1
• Filed: 05/21/2008
• Published: 11/18/2010
• Est. Priority Date: 05/21/2007
• Status: Abandoned Application

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Ojala, Ethan, Carvalho, Anne Elisabeth, Latham, John, Garcia-Martinez, Leon, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Smith, Jeffrey T.L.
• Application Number:
  US12/601,295
• Publication Number:
  US 20100290993A1
• Time in Patent Office: Days
• US Class Current: 424/9.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 2317/20 : characterized by taxonomic origin
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V_H, V_L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

Claims

1-133. -133. (canceled)

134. An isolated or recombinant anti-human IL-6 antibody or antibody fragment which specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or fragment thereof as an anti-human IL-6 antibody 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, and Ab36.

135. The anti-human IL-6 antibody or fragment of claim 134 which specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or a fragment thereof as Ab1.

136. The anti-human IL-6 antibody of claim 134 which specifically binds to the same linear or conformational epitopes on an intact IL-6 polypeptide or fragment thereof that is (are) specifically bound by Ab1 and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in IL-6 fragments selected from those respectively encompassing amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72.

137. The anti-human IL-6 antibody of claim 134 which comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in an anti-human IL-6 antibody 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, and Ab36.

138. The anti-human IL-6 antibody of claim 137 which comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in Ab 1.

139. The anti-human IL-6 antibody of claim 138 wherein all of the CDRs are identical to the CDRs contained in an anti-human IL-6 antibody selected from the group consisting of Ab 1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, Ab 11, 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.

140. The anti-human IL-6 antibody of claim 138 wherein all of the CDRs are identical to the CDRs contained in Ab1.

141. The anti-human IL-6 antibody or fragment of claim 140 which is aglycosylated.

142. The anti-human IL-6 antibody or fragment of claim 134 which is aglycosylated.

143. The anti-human IL-6 antibody of claim 134 which contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

144. The anti-human IL-6 antibody or fragment of claim 134 which is a human, humanized, single chain or chimeric antibody.

145. The anti-human IL-6 antibody or fragment of claim 140 which is a human, humanized, single chain or chimeric antibody.

146. The anti-human IL-6 antibody of claim 145 wherein the antibody comprises light and heavy framework regions and the framework regions (FRs) in the variable light region and the variable heavy regions of said antibody respectively are human FRs which are unmodified or which have been modified by the substitution of at most 2 or 3 human FR residues in the variable light or heavy chain region with the corresponding FR residues of the parent rabbit antibody, and wherein said human FRs have been derived from human variable heavy and light chain antibody sequences which have been selected from a library of human germline antibody sequences based on their high level of homology to the corresponding rabbit variable heavy or light chain regions relative to other human germline antibody sequences contained in the library.

147. The anti-human IL-6 antibody or fragment of claim 134 which specifically binds to IL-6 expressing human cells and/or to circulating soluble IL-6 molecules in vivo.

148. The anti-human IL-6 antibody or fragment of claim 140 which specifically binds to IL-6 expressing human cells and/or to circulating soluble IL-6 molecules in vivo.

149. The anti-human IL-6 antibody or fragment of claim 147 which specifically binds to IL-6 expressed on or by human cells in a patient with a disease associated with cells that express IL-6.

150. The anti-human IL-6 antibody or fragment of claim 147 which specifically binds to IL-6 expressed on or by human cells in a patient with a disease associated with cells that express IL-6.

151. The anti-human IL-6 antibody or fragment of claim 149 which specifically binds to IL-6 expressed on or by human cells in a patient with a disease associated with cells that express IL-6.

152. The anti-human IL-6 antibody or fragment of claim 150 which specifically binds to IL-6 expressed on or by human cells in a patient with a disease associated with cells that express IL-6.

153. The anti-human IL-6 antibody or fragment of claim 134 which is directly or indirectly attached to a detectable label or therapeutic agent.

154. The anti-human IL-6 antibody or fragment of claim 140 which is directly or indirectly attached to a detectable label or therapeutic agent.

155. A recombinant cell which expresses an antibody or antibody fragment according to claim 134.

156. A recombinant cell which expresses an antibody or antibody fragment according to claim 140.

157. A method of treatment comprising administering to a patient with a disease or condition associated with IL-6 expressing cells a therapeutically effective amount of at least one anti-human IL-6 antibody or fragment according to claim 134.

158. A method of treatment comprising administering to a patient with a disease or condition associated with IL-6 expressing cells a therapeutically effective amount of at least one anti-human IL-6 antibody or fragment according to claim 140.

159. The method of claim 157 wherein the disease is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS)

160. The method of claim 158 wherein the disease is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

161. The method of claim 157 wherein the disease or condition is a cancer, autoimmune disease, or inflammatory condition.

162. The method of claim 158 wherein the disease or condition is a cancer, autoimmune disease, or inflammatory condition.

163. The method of claim 157 wherein the treatment further includes the administration of another therapeutic agent or regimen selected from chemotherapy, radiotherapy, cytokine administration or gene therapy.

164. The method of claim 158 wherein the treatment further includes the administration of another therapeutic agent or regimen selected from chemotherapy, radiotherapy, cytokine administration or gene therapy

165. The method of claim 157 which is used to treat a side effect of cancer or viral infection.

166. The method of claim 158 which is used to treat a side effect of cancer or viral infection.

167. The method of claim 165 wherein the side effect is fatigue or weight loss (wasting syndrome).

168. The method of claim 166 wherein the side effect is fatigue or weight loss (wasting syndrome).

169. An isolated anti-IL-6 antibody according to claim 134 comprising a V_H polypeptide sequence selected from the group consisting of:

SEQ ID NO;

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO;

571; and

further comprising a V_L polypeptide sequence selected from the group consisting of;

SEQ ID NO;

2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO;

570 or a variant thereof wherein one or more of the framework residues (FR residues) in said V_{H or} V_L polypeptide has been substituted with another amino acid residue resulting in an anti-IL-6 antibody that specifically binds IL-6.

170. The isolated antibody of claim 169 wherein one or more of said FR residues are substituted with an amino acid present at the corresponding site in a parent rabbit anti-IL-6 antibody from which the complementarity determining regions (CDRs) contained in said V_{H or} V_L polypeptides have been derived or by a conservative amino acid substitution.

171. An antibody according to claim 169, wherein said antibody is humanized or chimeric.

172. An antibody according to claim 171, wherein said chimeric antibody comprises a human F_c.

173. An antibody according to claim 172, 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.

174. The antibody of claim 169, wherein said antibody binds at least one of soluble IL-6, cell-surface expressed IL-6, IL-6/IL-6R, IL-6/IL-6R/gp130 complexes and or multimers thereof and/or antagonizes the biological effects of one or more of the foregoing.

175. An isolated anti-IL-6 antibody comprising a polypeptide sequence having at least 90% or greater homology to any one of the polypeptide sequences of claim 169.

176. The antibody of claim 169, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

7</sup>, 10<sup>−

7</sup>, 5×

10<sup>−

8</sup>, 10<sup>−

8</sup>, 5×

10<sup>−

9</sup>, 10<sup>−

9</sup>, 5×

10<sup>−

10</sup>, 10¹⁰, 5×

10¹¹, 10<sup>−

11</sup>, 5×

10<sup>−

12</sup>, 10<sup>−

12</sup>, 5×

10<sup>−

13</sup>, or 10<sup>−

13</sup>.

177. The antibody of claim 140, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

7</sup>, 10<sup>−

7</sup>, 5×

10<sup>−

8</sup>, 10<sup>−

8</sup>, 5×

10<sup>−

9</sup>, 10<sup>−

9</sup>, 5×

10<sup>−

10</sup>, 10<sup>−

10</sup>, 5×

10<sup>−

11</sup>, 10<sup>−

11</sup>, 5×

10<sup>−

12</sup>, 10<sup>−

12</sup>, 5×

10<sup>−

13</sup>, or 10<sup>−

3</sup>.

178. The antibody of claim 140, wherein said antibody binds to 1L-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

10</sup>.

179. The antibody of claim 134, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

10</sup>.

180. The antibody of claim 134, wherein said antibody binds to IL-6 with an off-rate (K_off) of less than or equal to 10⁻

4 S<sup>−

1</sup>, 5×

10<sup>−

5</sup> S<sup>−

1</sup>, 10<sup>−

5</sup> S<sup>−

1</sup>, 5×

10<sup>−

6</sup> S<sup>−

1</sup>, 10⁶ S¹, 5×

10<sup>−

7</sup> S<sup>−

1</sup>, or 10<sup>−

7</sup> S<sup>−

1</sup>.

181. The antibody of claim 140, wherein said antibody binds to IL-6 with an off-rate (K_off) of less than or equal to 10⁻

4 S<sup>−

1</sup>, 5×

10<sup>−

5</sup> S<sup>−

1</sup>, 10<sup>−

5</sup> S<sup>−

1</sup>, 5×

10<sup>−

6</sup> S<sup>−

1</sup>, 10<sup>−

6</sup> S<sup>−

1</sup>, 5×

10<sup>−

7</sup> S<sup>−

1</sup>, or 10<sup>−

7</sup> S<sup>−

1</sup>.

182. The antibody of claim 134, wherein said antibody does not have binding specificity for IL-6R or gp130.

183. The antibody of claim 140, wherein said antibody does not have binding specificity for IL-6R or gp130.

184. The antibody of claim 134, wherein said antibody inhibits the association of IL-6 with IL-6R, and/or the production of IL-6/IL-6R/gp 130 complexes and/or the production of IL-6/IL-6R/gp 130 multimers

185. The antibody of any one of claim 140, wherein said antibody inhibits the association of IL-6 with IL-6R, and/or the production of IL-6/IL-6R/gp 130 complexes and/or the production of IL-6/IL-6R/gp 130 multimers.

186. The antibody of claim 184, wherein the IL-6R is soluble IL-6R (sIL-6R).

187. The antibody of claim 185, wherein the IL-6R is soluble IL-6R (sIL-6R).

188. An antibody fragment according to claim 134, wherein said fragment is selected from an F_ab fragment, an F_ab′

fragment, or an F<sub>(ab′

)2</sub> fragment.

189. An antibody fragment according to claim 140, wherein said fragment is selected from an F_ab fragment, an F_ab′

fragment, or an F<sub>(ab′

)2</sub> fragment.

190. An antibody according to claim 134, wherein said antibody further comprises an effector moiety.

191. An antibody according to claim 140, wherein said antibody further comprises an effector moiety.

192. A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6a therapeutically effective amount of the antibody according to claim 134.

193. A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6a therapeutically effective amount of the antibody according to claim 140.

194. The method of claim 192, wherein said disease or disorder associated with IL-6 is cancer associated fatigue or cachexia or arthritis

195. The method of claim 193, wherein said disease or disorder associated with IL-6 is cancer associated fatigue or cachexia or arthritis

196. The method of claim 192, wherein said disease or disorder associated with IL-6 is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

197. The method of claim 193, wherein said disease or disorder associated with IL-6 is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

204. An isolated anti-IL-6 antibody or antibody fragment according to claim 134 comprising one or more of the CDRs contained in the V_H polypeptide sequences selected from the group consisting of:

SEQ ID NO;

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO;

571 and/or one or more of the CDRs contained in the V_L polypeptide sequence consisting of;

2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO;

570.

206. The antibody of claim 204, wherein said antibody is humanized.

208. The antibody of claim 206, wherein said chimeric antibody comprises a human F_c.

210. The antibody of claim 206 which comprises a single chain antibody.

212. The antibody of claim 210 wherein said human F_c is derived from human IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

214. An isolated anti-IL-6 antibody comprising a V_L or V_H polypeptide sequence having at least 90% or greater homology to any one of the polypeptide sequences recited in claim 206.

216. A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6a therapeutically effective amount of an antibody according to claim 204.

218. The method of claim 216, wherein said disease or disorder associated with IL-6 is cancer-associated fatigue, cachexia or arthritis.

220. The method of claim 216, wherein said disease or disorder associated with IL-6 is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

222. An isolated or recombinant polynucleotide encoding an antibody sequence according to claim 204.

224. A vector or host cell containing a polynucleotide according to claim 222.

225. A pharmaceutical or diagnostic composition containing at least one IL-6 antibody or fragment according to one of claim 134 and a pharmaceutically acceptable carrier.

226. A pharmaceutical or diagnostic composition containing at least one IL-6 antibody or fragment according to one of claim 140 and a pharmaceutically acceptable carrier.

227. An antibody according to claim 134 which comprises a single chain antibody selected from scFv, camelbody, nanobody, IgNAR, SMIP, and combinations thereof

228. An antibody according to claim 140 which comprises a single chain antibody selected from scFv, camelbody, nanobody, IgNAR, SMIP, and combinations thereof

198. An isolated polynucleotide comprising a polynucleotide encoding a anti-IL-6 V_H antibody amino acid sequence selected from SEQ ID NO:

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO;

571 or a humanized variant of any of the foregoing sequences.

199. The isolated polynucleotide of claim 198 wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody V_H polypeptide or a conservative amino acid substitution.

200. A vector or host cell comprising the polynucleotide sequence of claim 198.

201. A vector or host cell comprising the polynucleotide sequence of claim 199.

202. An isolated or recombinant polynucleotide comprising the polynucleotide sequence encoding an anti-IL-6 V_L antibody amino acid sequence of 2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO:

570 or encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody V_L polypeptide or a conservative amino acid substitution.

203. The method of claim 202, wherein said polynucleotide comprises a sequence encoding the polypeptides contained in SEQ ID NO:

2 and SEQ ID NO;

3;

SEQ ID NO;

2 and SEQ ID NO;

18;

SEQ ID NO;

2 and SEQ ID NO;

19;

SEQ ID NO;

20 and SEQ ID NO;

3;

SEQ ID NO;

20 and SEQ ID NO;

18;

SEQ ID NO;

20 and SEQ ID NO;

19;

SEQ ID NO;

21 and SEQ ID NO;

22;

SEQ ID NO;

37 and SEQ ID NO;

38;

SEQ ID NO;

53 and SEQ ID NO;

54;

SEQ ID NO;

69 and SEQ ID NO;

70;

SEQ ID NO;

85 and SEQ ID NO;

86;

SEQ ID NO;

101 and SEQ ID NO;

102;

SEQ ID NO;

101 and SEQ ID NO;

117;

SEQ ID NO;

101 and SEQ ID NO;

118;

SEQ ID NO;

119 and SEQ ID NO;

102;

SEQ ID NO;

119 and SEQ ID NO;

117;

SEQ ID NO;

119 and SEQ ID NO;

118;

SEQ ID NO;

122 and SEQ ID NO;

123;

SEQ ID NO;

138 and SEQ ID NO;

139;

SEQ ID NO;

154 and SEQ ID NO;

155;

SEQ ID NO;

170 and SEQ ID NO;

171;

SEQ ID NO;

186 and SEQ ID NO;

187;

SEQ ID NO;

202 and SEQ ID NO;

203;

SEQ ID NO;

218 and SEQ ID NO;

219;

SEQ ID NO;

234 and SEQ ID NO;

235;

SEQ ID NO;

250 and SEQ ID NO;

251;

SEQ ID NO;

266 and SEQ ID NO;

267;

SEQ ID NO;

282 and SEQ ID NO;

283;

SEQ ID NO;

298 and SEQ ID NO;

299;

SEQ ID NO;

314 and SEQ ID NO;

315;

SEQ ID NO;

330 and SEQ ID NO;

331;

SEQ ID NO;

346 and SEQ ID NO;

347;

SEQ ID NO;

362 and SEQ ID NO;

363;

SEQ ID NO;

378 and SEQ ID NO;

379;

SEQ ID NO;

394 and SEQ ID NO;

395;

SEQ ID NO;

410 and SEQ ID NO;

411;

SEQ ID NO;

426 and SEQ ID NO;

427;

SEQ ID NO;

442 and SEQ ID NO;

443;

SEQ ID NO;

458 and SEQ ID NO;

459;

SEQ ID NO;

474 and SEQ ID NO;

475;

SEQ ID NO;

490 and SEQ ID NO;

491;

SEQ ID NO;

506 and SEQ ID NO;

507;

SEQ ID NO;

522 and SEQ ID NO;

523;

SEQ ID NO;

538 and SEQ ID NO;

539;

SEQ ID NO;

554 and SEQ ID NO;

555;

or SEQ ID NO;

570 and SEQ ID NO;

571.

205. The antibody of claim 203, wherein said antibody is humanized.

207. The antibody of claim 205, wherein said chimeric antibody comprises a human F_c.

209. The antibody of claim 205 which comprises a single chain antibody.

211. The antibody of claim 209 wherein said human F_c is derived from human IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

213. An isolated anti-IL-6 antibody comprising a V_L or V_H polypeptide sequence having at least 90% or greater homology to any one of the polypeptide sequences recited in claim 205.

215. A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6a therapeutically effective amount of an antibody according to claim 203.

217. The method of claim 215, wherein said disease or disorder associated with IL-6 is cancer-associated fatigue, cachexia or arthritis.

219. The method of claim 215, wherein said disease or disorder associated with IL-6 is selected from 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), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

221. An isolated or recombinant polynucleotide encoding an antibody sequence according to claim 203.

223. A vector or host cell containing a polynucleotide according to claim 221.