ANTI-IL-6 ANTIBODIES FOR THE TREATMENT OF ORAL MUCOSITIS

• US 20120189629A1
• Filed: 11/23/2011
• Published: 07/26/2012
• Est. Priority Date: 11/23/2010
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Alder Biopharmaceuticals, Inc. (Lundbeck Foundation)
• Inventors: SMITH, Jeffery T. L.
• Granted Patent: US 8,992,908 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/204 IL-6
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• 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 2317/565 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
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57407 : Specifically defined cancers
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as anti-IL-6 antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat mucositis (e.g., oral mucositis) including persons on a treatment regimen with a drug or chemotherapy and/or radiation for cancer (e.g., head and neck cancer) that is associated with increased risk of mucositis, including oral mucositis.

Claims

1. A method of treating or preventing mucositis comprising administration of a composition comprising an effective amount of an IL-6 antagonist.

2. The method of claim 1, wherein said mucositis is oral mucositis.

3. The method of claim 1, wherein said mucositis is alimentary tract mucositis.

4. The method of claim 1, wherein said mucositis is gastrointestinal tract mucositis.

5. The method of claim 1, wherein said mucositis is mucositis associated with chemotherapy.

9. The method of claim 1, wherein said mucositis is mucositis associated with radiotherapy.

13. The method of claim 1, wherein said mucositis is mucositis associated with cancer.

17. The method of claim 1, wherein said mucositis is mucositis associated with hematopoietic stem cell transplant (HSCT).

61. The method of claim 1, wherein said IL-6 antagonist is an anti-IL-6 antibody or antibody fragment.

62. The method of claim 61, wherein said anti-IL-6 antibody or antibody fragment thereof is 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, or Ab36 antibody, or an antibody fragment thereof, to a subject in need thereof, wherein the antibody, or antibody fragment thereof, specifically binds to IL-6.

63. The method of claim 61, wherein said anti-IL-6 antibody or antibody fragment thereof comprises at least one light chain selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence 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, 570, 647, 648, 649, 650, 651, 655, 660, 666, 667, 671, 675, 679, 683, 687, 693, 699, 702, 706, or 709.

65. The method of claim 61, wherein said anti-IL-6 antibody or antibody fragment thereof comprises at least one heavy chain selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence 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, 571, 652, 653, 654, 655, 656, 657, 658, 661, 664, 665, 668, 672, 676, 680, 684, 688, 691, 692, 704, or 708.

67. The method of claim 61, wherein said anti-IL-6 antibody or antibody fragment thereof comprises at least two CDR sequences selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence of SEQ ID NO:

4, 7, 23, 26, 39, 42, 55, 58, 71, 74, 87, 90, 103, 106, 124, 127, 140, 143, 156, 159, 172, 175, 188, 191, 204, 207, 220, 223, 236, 239, 252, 255, 268, 271, 284, 287, 300, 303, 316, 319, 332, 335, 348, 351, 364, 367, 380, 383, 396, 399, 412, 415, 428, 431, 444, 447, 460, 463, 476, 479, 492, 495, 508, 511, 524, 527, 540, 543, 556, 559, 572, 575, 710, 711, 712, 716, 5, 8, 24, 27, 40, 43, 56, 59, 72, 75, 88, 91, 104, 107, 120, 121, 125, 128, 141, 144, 157, 160, 173, 176, 189, 192, 205, 208, 221, 224, 237, 240, 253, 256, 269, 272, 285, 288, 301, 304, 317, 320, 333, 336, 349, 352, 365, 368, 381, 384, 397, 400, 413, 416, 429, 432, 445, 448, 461, 464, 477, 480, 493, 496, 509, 512, 525, 528, 541, 544, 557, 560, 573, 576, 659, 713, 714, 715, 717, 718, 6, 9, 25, 28, 41, 44, 57, 60, 73, 76, 89, 92, 105, 108, 126, 129, 142, 145, 158, 161, 174, 177, 190, 193, 206, 209, 222, 225, 238, 241, 254, 257, 270, 273, 286, 289, 302, 305, 318, 321, 334, 337, 350, 353, 366, 369, 382, 385, 398, 401, 414, 417, 430, 433, 446, 449, 462, 465, 478, 481, 494, 497, 510, 513, 526, 529, 542, 545, 558, 561, 574, or 577.

69. The method of claim 61, wherein the antibody or antibody fragment thereof comprises at least two light chain CDR polypeptide sequences selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence of SEQ ID NO:

4, 23, 39, 55, 71, 74, 87, 103, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, 710, 711, 712, 5, 24, 40, 56, 72, 88, 104, 125, 141, 157, 173, 189, 205, 221, 237, 253, 269, 285, 301, 317, 333, 349, 365, 381, 397, 413, 429, 445, 461, 477, 493, 509, 525, 541, 557, 573, 713, 714, 715, 718, 25, 41, 57, 73, 89, 105, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, or 574.

74. The method of claim 61, wherein the antibody or antibody fragment thereof comprises at least two heavy chain CDR polypeptide sequences selected from the group consisting of an amino acid sequence with at least about 90% sequence identity to an amino acid sequence of SEQ ID NO:

7, 26, 42, 58, 74, 90, 106, 127, 143, 159, 175, 191, 207, 223, 239, 255, 271, 287, 303, 319, 335, 351, 367, 383, 399, 415, 431, 447, 463, 479, 495, 511, 527, 543, 559, 575, 716, 8, 27, 43, 59, 75, 91, 107, 120, 121, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, 659, 717, 718, 9, 28, 44, 60, 76, 92, 108, 129, 145, 161, 177, 193, 209, 225, 241, 257, 273, 289, 305, 321, 337, 353, 369, 385, 401, 417, 433, 449, 465, 481, 497, 513, 529, 545, 561, or 577.

86. The method of claim 61, wherein said antibody is an Ab1 antibody.

87. The method of claim 86, wherein said antibody or antibody fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:

2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709.

88. The method of claim 86, wherein said antibody or antibody fragment thereof comprises a humanized light chain comprising the amino acid sequence of SEQ ID NO:

648, 649, and 650.

89. The method of claim 86, wherein said antibody or antibody fragment thereof comprises at least one light chain CDR comprising the amino acid sequence selected from the group consisting of SEQ ID NO:

4, 5, 6, 710, 711, 712, 713, 714, and 715.

90. The method of claim 86, wherein said antibody or antibody fragment thereof comprises at least one humanized light chain CDR comprising the amino acid sequence selected from the group consisting of SEQ ID NO:

710, 711, 712, 713, 714, and 715.

91. The method of claim 86, wherein said antibody or antibody fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

3, 18, 19, 652, 653, 654, 655, 656, 657, 658, 661, 664, 665, 704, 708.

92. The method of claim 86, wherein said antibody or antibody fragment thereof comprises a humanized heavy chain comprising the amino acid sequence of SEQ ID NO:

653, 654, and 655.

93. The method of claim 86, wherein said antibody or antibody fragment thereof comprises at least one heavy chain CDR comprising the amino acid sequence selected from the group consisting of SEQ ID NO:

7, 9, 74, 716, 8, 120, 659, 717, and 718.

94. The method of claim 86, wherein said antibody or antibody fragment thereof comprises at least one humanized heavy chain CDR comprising the amino acid sequence selected from the group consisting of SEQ ID NO:

74, 716, 717, and 718.

111. The method of claim 61, wherein antibody, or antibody fragment thereof, is expressed from a recombinant cell.

112. The method of claim 111, wherein the cell is a mammalian, yeast, bacterial, and insect cell.

113. The method of claim 112, wherein the cell is a yeast cell.

114. The method of claim 113, wherein the cell is a diploidal yeast cell.

115. The method of claim 114, wherein the yeast cell is a Pichia yeast.

116. The method of claim 61, wherein said antibody is asialated.

118. The method of claim 61, wherein antibody fragment is a Fab, Fab′

, F(ab′

)₂, Fv, scFv, IgNAR, SMIP, camelbody, or nanobody.

119. The method of claim 61, wherein said antibody, or antibody fragment thereof, that has an in vivo half-life of at least about 30 days.

123. The method of claim 61, wherein the antibody or antibody fragment thereof, that is aglycosylated.

124. The method of claim 61, wherein the antibody or antibody fragment thereof, that contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

125. The method of claim 61, wherein the antibody or antibody fragment thereof, is a human, humanized, single chain, or chimeric antibody.

126. The method of claim 61, wherein the antibody or antibody fragment thereof, further comprises a human F_c.

128. The method of claim 5, wherein said chemotherapy comprises administration of a chemotherapy agent selected from the group consisting of Alemtuzumab (Campath®

), Asparaginase (Elspar®

), Bleomycin (Blenoxane®

), Busulfan (Myleran®

, Busulfex®

), Capecitabine (Xeloda®

), Carboplatin (Paraplatin®

), Cisplatin (PLATINOL®

), Cyclophosphamide (Cytoxan®

), Cytarabine (Cytosar-U®

), Daunorubicin (Cerubidine®

), Docetaxel (Taxotere®

), Doxorubicin (Adriamycin®

), Epirubicin (Ellence®

), Etoposide (VePesid®

), Fluorouracil (5-FU®

), Gemcitabine (Gemzar®

), Gemtuzumab ozogamicin (Mylotarg®

), Hydroxyurea (Hydrea®

), Idarubicin (Idamycin®

), Interleukin 2 (Proleukin®

), Irinotecan (Camptosar®

), Lomustine (CeeNU®

), Mechlorethamine (Mustargen®

), Melphalan (Alkeran®

), Methotrexate (Rheumatrex®

), Mitomycin (Mutamycin®

), Mitoxantrone (Novantrone®

), Oxaliplatin (Eloxatin®

), Paclitaxel (Taxol®

), Pemetrexed (Alimta®

), Pentostatin (Nipent®

), Procarbazine (Matulane®

), Thiotepa (Thioplex®

), Topotecan (Hycamtin®

), Trastuzumab (Herceptin®

), Tretinoin (Vesanoid®

), Vinblastine (Velban®

), or Vincristine (Oncovin®

).

147. The method claim 1, wherein said IL-6 antagonist, optionally an anti-IL-6 antibody or antibody fragment, is administered prior, concurrent or after chemotherapy or radiotherapy.

175. The method claim 1, wherein said subject is receiving concomitant chemotherapy.

176. The method claim 1, wherein said subject is receiving concomitant radiotherapy.

187. The method claim 1, wherein said oral and oropharyngeal mucositis is induced by chemoradiation (CRT) regimens or HSCT used for the treatment of cancers of the head and neck.

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21. A method of treating or preventing diarrhea comprising administration of a composition comprising an effective amount of an IL-6 antagonist.

22. The method of claim 21, wherein said diarrhea is diarrhea associated with chemotherapy.

23. The method of claim 21, wherein said diarrhea is diarrhea associated with radiotherapy.

24. The method of claim 21, wherein said diarrhea is diarrhea associated with hematopoietic stem cell transplant (HSCT).

25. A method of treating or preventing emesis comprising administration of a composition comprising an effective amount of an IL-6 antagonist.

26. The method of claim 25, wherein said emesis is emesis associated with chemotherapy.

27. The method of claim 25, wherein said emesis is emesis associated with radiotherapy.

28. The method of claim 25, wherein said emesis is emesis associated with hematopoietic stem cell transplant (HSCT).

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193. A method for the treating oral mucositis in a subject with head and neck cancer receiving concomitant chemotherapy comprising administering an effective amount of a humanized monoclonal antibody that selectively binds IL-6, wherein said antibody is Ab1.

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