ANTIBODIES TO IL-6 AND USE THEREOF

• US 20130034554A1
• Filed: 11/24/2010
• Published: 02/07/2013
• Est. Priority Date: 11/24/2009
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Alder Biopharmaceuticals, Inc. (Lundbeck Foundation)
• Inventors: Garcia-Martinez, Leon F., Olson, Katie, Dutzar, Benjamin H., Latham, John A., Kovacevich, Brian Robert, Litton, Mark, Schatzman, Randall, Jensen, Anne Elisabeth Carvalho, Smith, Jeffrey T.L.
• Granted Patent: US 9,775,921 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 49/0058 Antibodies
• CPC Class Codes: A61K 51/1033 against receptors for cytokines, lymphokines or interferons
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as an Ab1 antibody or antibody fragment having binding specificity for IL-6 to prevent or treat disease or to improve survivability or quality of life of a patient in need thereof. In preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level, reduced serum albumin level, elevated D-dimer or other coagulation cascade related protein(s), cachexia, fever, weakness and/or fatigue prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, and others. Additional preferred embodiments of the subject invention relate to therapeutic compositions and methods treating or preventing rheumatoid arthritis, especially subcutaneous and intravenous formulations and dosage regimens using IL-6 antagonists according to the invention, as well as methods for preventing or treating GVHD or leukemia relapse in subjects receiving transplanted cells, tissue or organs, use thereof in the treatment or prevention of mucositis, and use thereof to potentiate the cytotoxic, apoptotic, and anti-metastatic or anti-invasive effects of chemotherapeutics and radiation on cancers, especially cancers that have developed a resistance to radiation or chemotherapy, such as an EGFR inhibitor.

Claims

1-271. -271. (canceled)

272. A method of treating rheumatoid arthritis by subcutaneously or intravenously administering an effective dosage of an anti-IL-6 antibody having the same epitopic specificity as an antibody comprising the variable light and heavy sequences in SEQ ID NO:

2 and 3 respectively, or an antibody that competes with said antibody or antibody fragment for binding to IL-6 to a patient in need thereof.

273. The method of claim 272, wherein said antibody or antibody fragment comprises a light chain polypeptide comprising:

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

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

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

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

723; and

a heavy chain polypeptide comprising;

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

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

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

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

700;

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

274. The method of claim 272, wherein the subcutaneous dosage is at least about 50 or 100 mg.

275. The method of claim 272, wherein said subcutaneous administration results at least in one of the following:

(i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control subcutaneous formulation.

276. The method of claim 272, wherein said subcutaneous administration results in a prolonged improvement in disease (observed at least 4, 6, 8, 10, 12, 14 or 16 weeks after antibody administration) as manifested by at least one of the following:

(i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control subcutaneous formulation.

277. The method claim 272, wherein said patient has previously received or is still receiving methotrexate.

279. The method of claim 272, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 95% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

280. The method of claim 272, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 98% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

281. The method of claim 272, wherein said anti-IL-6 antibody contains the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

282. The method of claim 272, which comprises intravenously or subcutaneously administering an anti-IL-6 antibody having the same epitopic specificity as an antibody comprising the variable light and heavy sequences in SEQ ID NO:

2 and 3 respectively by intravenously administering a dosage of about (+/−

20%>

) 80, 160 or 320 mg of said antibody to a patient in need thereof.

283. The method of claim 282, wherein the patient is administered said dosage every 8 weeks or 2 months.

284. The method of claim 282, wherein said dosage is administered at least twice.

285. The method of claim 284, wherein the first dosage is on day one and the second dosage during week 8 (8th week after day 0).

286. The method of claim 282, which results in at least one of the following (i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control intravenous formulation.

287. The method of claim 282, wherein said intravenous administration results in a prolonged improvement in disease (observed at least 4, 6, 8, 10, 12, 14 or 16 weeks after antibody administration) as manifested by at least one of the following (i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control intravenous formulation.

288. The method of claim 282, wherein said patient has previously received or is still receiving methotrexate.

289. The method of claim 282, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 90% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

290. The method of claim 282, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 95% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20 of the applications incorporated by reference herein.

291. The method of claim 282, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 98% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

292. The method of claim 282, wherein said anti-IL-6 antibody contains the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

293. The method of claim 272, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same epitope on an intact IL-6 polypeptide or fragment thereof that is specifically bound by an antibody containing the variable heavy and light sequences in SEQ ID NO:

3 and 2 respectively, and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in each of the IL-6 fragments selected from those respectively consisting of amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72 of SEQ ID NO;

1.

294. The method of claim 282, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same epitope on an intact IL-6 polypeptide or fragment thereof that is specifically bound by an antibody containing the variable heavy and light sequences in SEQ ID NO:

3 and 2 respectively, and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in each of the IL-6 fragments selected from those respectively consisting of amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72 of SEQ ID NO;

1.

295. The method of claim 272, wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.

296. The method of claim 282, wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.

297. A subcutaneous administrable composition for use in the method of claim 272, comprising an effective subcutaneous dosage of an anti-IL-6 antibody containing the variable heavy and light sequences in SEQ ID NO:

19 and 20 respectively.

298. The composition according to claim 297, wherein the subcutaneous dosage is at least about 50 or 100 mg.

299. The composition according to claim 297, wherein subcutaneous administration results in an improvement in disease as manifested by at least one of the following:

(i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control subcutaneous formulation.

300. The composition according to claim 297, wherein said subcutaneous administration results in a prolonged improvement in disease (observed at least 4, 6, 8, 10, 12, 14 or 16 weeks after antibody administration) as manifested by at least one of the following:

(i) improved DAS-28 scores, (ii) improved EULAR scores, (iii) improved LDAS scores (iv) improved ACR scores, (v) an increase in serum albumin, (vi) a decrease in CRP relative to patients not treated with said antibody or patients receiving a placebo or control subcutaneous formulation.

301. The composition of claim 297, further comprising methotrexate.

302. The composition of claim 297, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 90% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

303. The composition of claim 297, wherein said anti-IL-6 antibody contains the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

278. The method of claim 278, wherein said anti-IL-6 antibody contains variable heavy and light sequences which are at least 90% identical has the variable heavy and light sequences contained in SEQ ID NO:

19 or 20.

304. A method of using an anti-IL-6 antibody or antibody fragment having the same epitopic specificity as an antibody or antibody fragment containing the variable heavy and light sequences in SEQ ID NO:

3 and 2 respectively, for preventing or alleviating the onset of graft-versus-host disease (GVHD), or leukemia relapse in a subject receiving transplanted cells, tissues or organs.

305. The method of claim 304, wherein the subject has or is to receive a hematopoietic stem cell transplant (HCT), bone marrow transplantation (BMT).

306. The method of claim 304, wherein the subject has or is to receive transplanted cells, tissues or organs potentially containing dendritic cells.

307. The method of claim 304, wherein the subject has or is to receive transplanted cells, tissues or organs potentially containing BDCAA4+ plasmacytoid dendritic cells.

308. The method of claim 304 wherein the transplanted cells, tissues or organ comprise pancreatic, liver or skin cells.

311. The method of claim 304, wherein said method reduces the risk of leukemia relapse in a leukemia subject who has or is to receive transplanted cells, tissues or organs, especially those potentially containing dendritic cells by administering prior, concurrent or after transplant an amount of at least one anti-IL-6 antibody or antibody fragment having the epitopic specificity sufficient to prevent or reduce the risk of leukemia relapse.

312. The method of claim 311, wherein said leukemia comprises a Chronic Leukemia or an Acute Leukemias.

313. The method of claim 311, wherein said leukemia includes chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), hairy cell leukemia, T cell prolymphcytic leukemia, (T-PLL) and large granular lymphocytic leukemia.

309. A method of pre-treating cells, tissues or organ which are to be used for transplant to reduce the risk of GVHD or leukemia comprising contacting said cells, tissue or organ in vitro with an IL-6 antagonist in order to reduce IL-6 expression.

310. The method of claim 309, wherein the cells, tissues or organ are also contacted with an IL-10 antagonist.

314. A cancer treatment regimen that includes the administration of at least one chemotherapeutic agent and/or radiation, wherein the efficacy of said chemotherapeutic or radiation against the cancer is enhanced by further administering an anti-IL-6 antibody or antibody fragment tumor that is selected from 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, and chimeric or humanized variants thereof and IL-6 binding fragment of any of the foregoing.

316. The method of claim 321, wherein the mucositis is oral or gastrointestinal mucositis.

317. The method of claim 321, wherein the patient treated has one or more symptoms of oral mucositis.

321. The method of claim 314, wherein said combination potentiates the effect of said chemotherapeutic agent or radiation against a treated cancer in a patient and comprises administering an anti-IL-6 antibody or antibody fragment according to the invention in an amount effective to enhance the effect of said chemotherapeutic agent or radiation which is further administered to treat said cancer.

322. The method of claim 321, wherein said anti-IL-6 antibody or antibody fragment is administered prior, concurrent or after administration of said chemotherapeutic or radiation.

323. The method of claim 321, wherein the chemotherapeutic is an EGFR inhibitor.

324. The method of claim 323, wherein said EGFR inhibitor is selected from the group consisting of Cetuximab (Erbitux) available from ImClone, Erlotinib (Tarceva) available from OSI Pharmaceuticals, Gefitinib (Iressa) available from AstraZeneca, Lapatinib (Tykerb) available from Glaxo, Panitimumab (Vectibox) available from Amgen, Sunitinib or Sutent (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) marketed by Pfizer, Gefitinib or N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine marketed by AstraZeneca, and Zalutumumab in clinical development by GenMab.

325. The method of claim 321, wherein the patient has a cancer that has exhibited resistance to said chemotherapeutic or radiation after at least one round of chemotherapy or radiation.

326. The method of claim 321, which reduces or prevents the treated cancer from invading or metastasizing to other sites in the body and/or which results in increased apoptosis of the treated cancer cells.

327. The method of claim 321, wherein the treated cancer is selected from advanced and non-advanced cancers including metastasized cancers such as metastatic and non-metastatic lung cancer, breast cancer, head and neck cancer, pharyngeal cancer, pancreatic cancer, colorectal cancer, anal cancer, glioblastoma multiforme, epithelial cancers, renal cell carcinomas, acute or chronic myelogenous leukemia and other leukemias, non-small cell lung cancer (NSCLC) and acute myelogenous leukemia (AML).

328. The method of claim 321, wherein the chemotherapeutic is erlotinib or sunitinib.

329. The method of claim 321, wherein the subject'"'"'s cancer has developed a resistance to said chemotherapeutic prior to administration of said anti-IL-6 antibody or antibody fragment.

330. The method of claim 321, wherein a biopsy is effected prior to anti-IL-6 antibody therapy which indicates that the treated cancer comprises cells which are expressing IL-6 at elevated levels and/or in vivo imaging is effected using an anti-IL-6 antibody or antibody fragment prior to said treatment which reveals increased IL-6 levels at the site(s) of the treated cancer.

331. The method of claim 321, which includes prior to therapy identifying whether the treated cancer is potentially resistant to the effects of a chemotherapeutic or radiation by assaying for IL-6 using an antibody according to the invention in order to detect whether elevated IL-6 levels are present at the site of the treated cancer and thereby identifying the cancer as one potentially resistant to the effects of a chemotherapeutic or radiation.

315. A method of treating or preventing mucositis in a patient at risk of developing mucositis as a result of chemotherapy or radiotherapy, by administering an amount of an anti-IL-6 antibody in an amount effective to treat or prevent the onset of mucositis.

318. The method of claim 315, wherein the patient treated has one or more symptoms of gastrointestinal mucositis.

319. The method of claim 315, wherein the patient has a cancer selected from head and neck cancer, esophageal cancer, throat cancer, lung cancer, gastrointestinal cancers such as stomach cancer, colorectal cancer, pancreatic cancer, as well as hematological cancers such as multiple myeloma, leukemia, and lymphoma.

320. The method of claim 315, wherein the patient has or is to receive autologous stem cell or bone marrow transplant and/or has multiple myeloma.