ANTAGONISTS OF IL-6 TO PREVENT OR TREAT THROMBOSIS

• US 20130101598A1
• Filed: 08/31/2012
• Published: 04/25/2013
• Est. Priority Date: 11/25/2008
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Foundation)
• Inventors: Smith, Jeffrey T.L.
• Granted Patent: US 9,212,223 B2
• Time in Patent Office: Days
• US Class Current: 424/145.1
• 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: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• 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: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat thrombosis in diseases associated with abnormal blood coagulation or fibrinolysis. In preferred embodiments these patients will comprise those exhibiting elevated D-dimer or other coagulation cascade related proteins and optionally will further exhibit elevated C reactive protein prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, et al.

Claims

1-90. -90. (canceled)

91. A method of reducing the risk of hypercoagulation or thrombosis in a subject having an elevated IL-6 level and an elevated D-dimer level by reducing the level of serum D-dimer in said subject, comprising administering to the subject an amount of an IL-6 antagonist, wherein said IL-6 antagonist is an antibody or antibody fragment that specifically binds human IL-6, wherein said antibody or antibody fragment comprises (i) the VL CDRs in SEQ ID NO:

23, 24 and 25 and the VH CDRs in SEQ ID NO;

26-28;

(ii) the VL CDRs in SEQ ID NO;

39, 40 and 41 and the VH CDRs in SEQ ID NO;

42, 43 and 44;

(iii) the VL CDRs in SEQ ID NO;

55, 56 and 57 and the VH CDRs in SEQ ID NO;

58, 59 and 60;

(iv) the VL CDRs in SEQ ID NO;

71, 72 and 73 and the VH CDRs in SEQ ID NO;

74, 75 and 76;

(v) the VL CDRs in SEQ ID NO;

87, 88 and 89 and the VH CDRs in SEQ ID NO;

90, 91 and 92;

(vi) the VL CDRs in SEQ ID NO;

103, 104 and 105 and the VH CDRs in SEQ ID NO;

106, 107 and 108;

(vii) the VL CDRs in SEQ ID NO;

124, 125 and 126 and the VH CDRs in SEQ ID NO;

127, 128 and 129;

(viii) the VL CDRs in SEQ ID NO;

140, 141 and 142 and the VH CDRs in SEQ ID NO;

143, 144 and 145;

(ix) the VL CDRs in SEQ ID NO;

156, 157 and 158 and the VH CDRs in SEQ ID NO;

159, 160 and 161;

(x) the VL CDRs in SEQ ID NO;

172, 173 and 174 and the VH CDRs in SEQ ID NO;

175, 176 and 177;

(xi) the VL CDRs in SEQ ID NO;

188, 189 and 190 and the VH CDRs in SEQ ID NO;

191, 192 and 193;

(xii) the VL CDRs in SEQ ID NO;

204, 205 and 206 and the VH CDRs in SEQ ID NO;

207, 208 and 209;

(xiii) the VL CDRs in SEQ ID NO;

220, 221 and 222 and the VH CDRs in SEQ ID NO;

223, 224 and 225;

(xiv) the VL CDRs in SEQ ID NO;

236, 237 and 238 and the VH CDRs in SEQ ID NO;

239, 240 and 241;

(xv) the VL CDRs in SEQ ID NO;

252, 253 and 254 and the VH CDRs in SEQ ID NO;

255, 256 and 257;

(xvi) the VL CDRs in SEQ ID NO;

268, 269 and 270 and the VH CDRs in SEQ ID NO;

271, 272 and 273;

(xvii) the VL CDRs in SEQ ID NO;

284, 285 and 286 and the VH CDRs in SEQ ID NO;

287, 288 and 289;

(xviii) the VL CDRs in SEQ ID NO;

300, 301 and 302 and the VH CDRs in SEQ ID NO;

303, 304 and 305;

(xix) the VL CDRs in SEQ ID NO;

316, 317 and 318 and the VH CDRs in SEQ ID NO;

319, 320 and 321;

(xx) the VL CDRs in SEQ ID NO;

332, 333 and 334 and the VH CDRs in SEQ ID NO;

335, 336 and 337;

(xxi) the VL CDRs in SEQ ID NO;

348, 349 and 350 and the VH CDRs in SEQ ID NO;

351, 352 and 353;

(xxii) the VL CDRs in SEQ ID NO;

364, 365 and 366 and the VH CDRs in SEQ ID NO;

367, 368 and 369;

(xxiii) the VL CDRs in SEQ ID NO;

380, 381 and 382 and the VH CDRs in SEQ ID NO;

383, 384 and 385;

(xxiv) the VL CDRs in SEQ ID NO;

396, 397, and 398 and the VH CDRs in SEQ ID NO;

399, 400 and 401;

(xxv) the VL CDRs in SEQ ID NO;

412, 413 and 414 and the VH CDRs in SEQ ID NO;

415, 416 and 417;

(xxvi) the VL CDRs in SEQ ID NO;

428, 429 and 430 and the VH CDRs in SEQ ID NO;

431, 432 and 433;

(xxvii) the VL CDRs in SEQ ID NO;

444, 445 and 446 and the VH CDRs in SEQ ID NO;

447, 448 and 449;

(xxviii) the VL CDRs in SEQ ID NO;

460, 461 and 462 and the VH CDRs in SEQ ID NO;

463, 464 and 465;

(xxix) the VL CDRs in SEQ ID NO;

476, 477 and 478 and the VH CDRs in SEQ ID NO;

479, 480 and 481;

(xxx) the VL CDRs in SEQ ID NO;

492, 493 and 494 and the VH CDRs in SEQ ID NO;

495, 496, and 497;

(xxxi) the VL CDRs in SEQ ID NO;

508, 509 and 510 and the VH CDRs in SEQ ID NO;

511, 512 and 513;

(xxxii) the VL CDRs in SEQ ID NO;

524, 525 and 526 and the VH CDRs in SEQ ID NO;

527, 528 and 529;

(xxxiii) the VL CDRs in SEQ ID NO;

540, 541 and 542 and the VH CDRs in SEQ ID NO;

543, 544 and 545;

(xxxiv) the VL CDRs in SEQ ID NO;

556, 557 and 558 and the VH CDRs in SEQ ID NO;

559, 560 and 561;

or (xxxv) the VL CDRs in SEQ ID NO;

572, 573 and 574 and the VH CDRs in SEQ ID NO;

575, 576 and 577, and which antibody or fragment is administered in an amount effective to reduce the level amount of serum D-dimer thereby reducing the risk of hypercoagulation or thrombosis in said subject.

93. The method of claim 91 wherein the antibody or fragment comprises human IgG1 constant regions.

94. The method of claim 91 wherein the D-dimer levels are determined before antibody administration.

95. The method of claim 91 wherein said subject also has an elevated C-reactive protein (CRP) level prior to treatment.

96. The method of claim 91 wherein said method further comprises the administration of at least one statin or anti-coagulant.

97. The method of claim 91, 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.

98. The method of claim 91, wherein the subject'"'"'s coagulation profile is assayed before and/or after treatment.

99. The method of claim 91, further comprising administration of one or more anti-coagulants or statins.

100. The method of claim 91, wherein the subject'"'"'s coagulation profile is assessed before or after treatment by measurement of the subject'"'"'s serum level of one or more of D-dimer, Factor II, Factor V, Factor VIII, Factor IX, Factor XI, Factor XII, F/fibrin degradation products, thrombin-antithrombin III complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor.

101. The method of claim 91, further comprising measuring the subject'"'"'s international normalized ratio (INR) prior to administration of the anti-IL-6 antibody or antibody fragment and administering to the subject said anti-IL-6 antibody if the subject'"'"'s INR is less than about 0.9.

102. The method of claim 91, wherein the subject treated has cancer and/or the subject being treated is undergoing chemotherapy.

103. The method of claim 91, further comprising measuring the level of IL-6 and/or the C-reactive protein in the subject prior to treatment.

104. The method of claim 91, wherein said antibody or fragment inhibits the interaction of IL-6 with gp 130.

105. The method of claim 91, wherein said antibody or fragment inhibits the interaction of IL-6 with IL-R 1.

106. The method of claim 91, wherein said antibody or fragment inhibits the interaction of IL-6 with gp130 and IL-6R1.

107. The method of claim 91, wherein said antibody or fragment neutralizes IL-6 in vivo.

108. The method of claim 91, wherein said antibody or fragment 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>, 5×

10<sup>−

14</sup>, 10<sup>−

14</sup>, 5×

10<sup>−

15</sup> or 10<sup>−

15</sup>.

109. The method of claim 91, wherein said antibody or fragment possesses a K_off value less than or equal to 10⁻

4 S<sup>−

1</sup>.

110. The method of claim 91, wherein said antibody or fragment is administered intravenously or subcutaneously.