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EP-3985024-B1 - ANTI-ACTIVIN-A ANTIBODY AND CHEMOTHERAPY COMBINATION FOR THE TREATMENT OF OVARIAN CANCER

EP3985024B1EP 3985024 B1EP3985024 B1EP 3985024B1EP-3985024-B1

Inventors

  • HAN, Huiquan
  • HAQQ, Christopher, Michael
  • CIECHANOVER, ISAAC
  • ZHOU, XIAOLAN
  • LU, John, Zhao-nian

Dates

Publication Date
20260506
Application Date
20140203

Claims (14)

  1. A first compound and a second compound, wherein the first compound is an anti-activin-A compound, and wherein the second compound is a chemotherapeutic compound, for use in a method of treating ovarian cancer by preventing tumor neovascularization in a subject, wherein the anti-activin-A compound is an antibody and the antibody comprises: a. a light chain CDR3 comprising a sequence selected from the group consisting of: i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences as follows; ii. X 73 QX 74 X 75 X 76 X 77 X 78 X 79 X 80 (SEQ ID NO: 132); iii. LQHNX 81 YX 82 X 83 T (SEQ ID NO: 131); and iv. QAWDX 84 STX 85 X 86 (SEQ ID NO: 248); wherein X 73 is a methionine residue, a glutamine residue, or an arginine residue, X 74 is an alanine residue, a tyrosine residue, a glutamine residue, or a serine residue, X 75 is a leucine residue, a tyrosine residue, or an asparagine residue, X 76 is a glutamine residue, a serine residue, or a threonine residue, X 77 is a threonine residue, a tyrosine residue, or an isoleucine residue, X 78 is a proline residue or a serine residue, X 79 is a cysteine residue, a tryptophan residue, a leucine residue, or a proline residue, X 80 is a serine residue or a threonine residue, X 81 is a threonine residue or a serine residue, X 82 is a proline residue or a threonine residue, X 83 is a phenylalanine residue or a tryptophan residue, X 84 is an arginine residue or a serine residue, X 85 is a valine residue or an alanine residue, and X 86 is a valine residue or no residue, and said anti-activin-A compound binds specifically to human activin-A; or b. a heavy chain CDR3 comprising a sequence selected from the group consisting of: i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences as follows; ii. X 87 X 88 X 89 X 90 X 91 X 92 X 93 X 94 FDY (SEQ ID NO: 187); iii. X 95 X 96 X 97 YX 98 DX 99 X 100 GWX 101 X 102 X 103 (SEQ ID NO: 188); and iv. X 104 X 105 X 106 X 107 X 108 X 109 YX 110 X 111 X 112 X 113 X 114 X 115 X 116 X 117 X 118 (SEQ ID NO: 249); wherein X 87 is a valine residue or no residue, X 88 is a glutamine residue or no residue, X 89 is an aspartate residue, a tryptophan residue, or no residue, X 90 is a serine residue, a leucine residue, or no residue, X 91 is an isoleucine residue, a glutamate residue, or a glutamine residue, X 92 is an alanine residue, a leucine residue, or a glycine residue, X 93 is an alanine residue or a leucine residue, X 94 is a proline residue, a tyrosine residue, or a glycine residue, X 95 is an aspartate residue or no residue, X 96 is a glutamine residue or no residue, X 97 is an aspartate residue or an alanine residue, X 98 is a tyrosine residue or a glycine residue, X 99 is a serine residue or a tyrosine residue, X 100 is a serine residue or an arginine residue, X 101 is a phenylalanine residue or no residue, X 102 is a glycine residue or an aspartate residue, X 103 is a histidine residue or a proline residue, X 104 is a glycine residue or no residue X 105 is a serine residue, a glutamate residue, or no residue X 106 is an arginine residue, a serine residue, or no residue, X 107 is an aspartate residue, an asparagine residue, a serine residue, or a glutamine residue X 108 is a serine residue, an arginine residue, or a tryptophan residue, X 109 is a glycine residue, an aspartate residue, an asparagine residue, a tyrosine residue, or a leucine residue, X 110 is a serine residue, a glycine residue, an aspartate residue, or no residue, X 111 is a serine residue, a valine residue, an asparagine residue, or a tyrosine residue, X 112 is a serine residue, an asparagine residue, a tyrosine residue, or a histidine residue X 113 is a tryptophan residue, a tyrosine residue, or a glutamine residue, X 114 is a histidine residue, an aspartate residue, a tyrosine residue, or no residue, X 115 is a phenylalanine residue, an alanine residue, or a glycine residue, X 116 is an aspartate residue, a phenylalanine residue, a leucine residue, or a methionine residue, X 117 is a tyrosine residue, or an aspartate residue, X 118 is an isoleucine residue, a valine residue, or no residue, and said anti-activin-A compound binds specifically to human activin-A; or c. the light chain CDR3 sequence of (a) and the heavy chain CDR3 sequence of (b), and said anti-activin-A compound binds specifically to human activin-A.
  2. The first compound and second compound for the use according to claim 1, wherein the anti-activin A compound further comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence disclosed herein; ii. a light chain CDR2 sequence o disclosed herein; and iii. a light chain CDR3 sequence disclosed herein; or b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence disclosed herein; ii. a heavy chain CDR2 sequence disclosed herein; and iii. a heavy chain CDR3 sequence disclosed herein; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
  3. The first compound and second compound for the use according to claim 1 or claim 2, wherein the chemotherapeutic compound is capecitabine or a doxorubicin lipid complex.
  4. The first compound and second compound for the use according to claim 1 to 3, wherein the ovarian cancer is serous ovarian cancer or clear cell ovarian cancer.
  5. An anti-activin-A compound for use in a method for treating serous ovarian cancer by preventing tumor neovascularization in a subject in need thereof, wherein the anti-activin-A compound is an antibody and the antibody comprises: a. a light chain CDR3 comprising a sequence selected from the group consisting of: i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences as follows; ii. X 73 QX 74 X 75 X 76 X 77 X 78 X 79 X 80 (SEQ ID NO: 132); iii. LQHNX 81 YX 82 X 83 T (SEQ ID NO: 131); and iv. QAWDX 84 STX 85 X 86 (SEQ ID NO: 248); wherein X 73 is a methionine residue, a glutamine residue, or an arginine residue, X 74 is an alanine residue, a tyrosine residue, a glutamine residue, or a serine residue, X 75 is a leucine residue, a tyrosine residue, or an asparagine residue, X 76 is a glutamine residue, a serine residue, or a threonine residue, X 77 is a threonine residue, a tyrosine residue, or an isoleucine residue, X 78 is a proline residue or a serine residue, X 79 is a cysteine residue, a tryptophan residue, a leucine residue, or a proline residue, X 80 is a serine residue or a threonine residue, X 81 is a threonine residue or a serine residue, X 82 is a proline residue or a threonine residue, X 83 is a phenylalanine residue or a tryptophan residue, X 84 is an arginine residue or a serine residue, X 85 is a valine residue or an alanine residue, and X 86 is a valine residue or no residue, and said anti-activin-A compound binds specifically to human activin-A; or b. a heavy chain CDR3 comprising a sequence selected from the group consisting of: i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences as followsin; ii. X 87 X 88 X 89 X 90 X 91 X 92 X 93 X 94 FDY (SEQ ID NO: 187); iii. X 95 X 96 X 97 YX 98 DX 99 X 100 GWX 101 X 102 X 103 (SEQ ID NO: 188); and iv. X 104 X 105 X 106 X 107 X 108 X 109 YX 110 X 111 X 112 X 113 X 114 X 115 X 116 X 117 X 118 (SEQ ID NO: 249); wherein X 87 is a valine residue or no residue, X 88 is a glutamine residue or no residue, X 89 is an aspartate residue, a tryptophan residue, or no residue, X 90 is a serine residue, a leucine residue, or no residue, X 91 is an isoleucine residue, a glutamate residue, or a glutamine residue, X 92 is an alanine residue, a leucine residue, or a glycine residue, X 93 is an alanine residue or a leucine residue, X 94 is a proline residue, a tyrosine residue, or a glycine residue, X 95 is an aspartate residue or no residue, X 96 is a glutamine residue or no residue, X 97 is an aspartate residue or an alanine residue, X 98 is a tyrosine residue or a glycine residue, X 99 is a serine residue or a tyrosine residue, X 100 is a serine residue or an arginine residue, X 101 is a phenylalanine residue or no residue, X 102 is a glycine residue or an aspartate residue, X 103 is a histidine residue or a proline residue, X 104 is a glycine residue or no residue X 105 is a serine residue, a glutamate residue, or no residue X 106 is an arginine residue, a serine residue, or no residue, X 107 is an aspartate residue, an asparagine residue, a serine residue, or a glutamine residue X 108 is a serine residue, an arginine residue, or a tryptophan residue, X 109 is a glycine residue, an aspartate residue, an asparagine residue, a tyrosine residue, or a leucine residue, X 110 is a serine residue, a glycine residue, an aspartate residue, or no residue, X 111 is a serine residue, a valine residue, an asparagine residue, or a tyrosine residue, X 112 is a serine residue, an asparagine residue, a tyrosine residue, or a histidine residue X 113 is a tryptophan residue, a tyrosine residue, or a glutamine residue, X 114 is a histidine residue, an aspartate residue, a tyrosine residue, or no residue, X 115 is a phenylalanine residue, an alanine residue, or a glycine residue, X 116 is an aspartate residue, a phenylalanine residue, a leucine residue, or a methionine residue, X 117 is a tyrosine residue, or an aspartate residue, X 118 is an isoleucine residue, a valine residue, or no residue, and said anti-activin-A compound binds specifically to human activin-A; or c. the light chain CDR3 sequence of (a) and the heavy chain CDR3 sequence of (b), and said anti-activin-A compound binds specifically to human activin-A.
  6. The anti-activin A compound for the use according to claim 5, wherein the anti-activin A compound further comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence disclosed herein; ii. a light chain CDR2 sequence o disclosed herein; and iii. a light chain CDR3 sequence disclosed herein; or b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence disclosed herein; ii. a heavy chain CDR2 sequence disclosed herein; and iii. a heavy chain CDR3 sequence disclosed herein; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b)
  7. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for the use according to claim 5 or 6, wherein the subject has a mutated activin gene or a mutated activin counter-regulator gene, optionally wherein the mutation is an Asn386Ser mutation in the beta-A-subunit of inhibin or activin, an Arg60Leu mutation of the alpha prodomain of activin or inhibin, or a Gly280Glu mutation of the alpha prodomain of activin or inhibin.
  8. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for use for use according to claim 5 or 6 wherein the anti-activin-A compound is administered to a subject subcutaneously, intravenously, or intraperitoneally.
  9. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for use for use according to claim 5 or 6, wherein the anti-activin-A compound is administered to a subject at least once a week at a dosage of at least 0.5 mg/kg.
  10. The first compound and second compound for the use according to claim 1 or 2 or the anti-activin-A compound for use according to claim 5 or 6, further comprising: identifying the subject by detecting elevated levels of biomarker CA-125 and/or activin-A in the subject compared to a control.
  11. The first compound and second compound for the use according to claim 1 or 2, further comprising: identifying the subject by detecting elevated levels activin-A, VEGF, and/or Ang-1 factors in the subject compared to a control.
  12. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for use for use according to claim 5 or 6 wherein the anti-activin-A compound comprises: a. a light chain variable domain sequence selected from the group consisting of: i. a sequence of amino acids at least 80% identical to a light chain variable domain sequence of L1-L14 of a light chain variable domain sequence disclosed herein; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding a light chain variable domain sequence of L1-L14 of a light chain variable domain sequence disclosed herein; and iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a light chain variable domain sequence of L1-L14 of a light chain variable domain sequence disclosed herein; or b. a heavy chain variable domain sequence selected from the group consisting of: i. a sequence of amino acids at least 80% identical to a heavy chain variable domain sequence of H1-H14 of a heavy chain variable domain sequence disclosed herein; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding a heavy chain variable domain sequence of H1-H14 of a heavy chain variable domain sequence disclosed herein; and iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a heavy chain variable domain sequence of H1-H14 of a heavy chain variable domain sequence disclosed herein; or c. (c) the light chain variable domain of (a) and the heavy chain variable domain of (b); wherein said antigen binding protein binds to human activin-A.
  13. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for use for use according to claim 5 or 6 wherein the anti-activin-A compound comprises: a. a light chain variable domain sequence selected from the group consisting of L1-L14 of a light chain variable domain sequence disclosed herein; or b. a heavy chain variable domain sequence selected from the group consisting of H1-H14 of a heavy chain variable domain sequence disclosed herein; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
  14. The first compound and second compound for the use according to any one of claims 1-4 or the anti-activin-A compound for use for use according to claim 5 or 6 wherein the anti-activin-A compound comprises a light chain variable domain sequence of SEQ ID NO: 275 and a heavy chain variable domain sequence of SEQ ID NO: 278.

Description

BACKGROUND Activin-A is a member of the TGF-β family that was originally identified in gonadal fluids. It plays an important role in regulating the menstrual cycle by controlling Follicle Stimulating Hormone (FSH) release from the pituitary gland. Activin-A is also known to serve diverse other functions such as in cell growth and differentiation, immune responses, and wound healing. Ovarian cancer is the deadliest of all gynecologic cancers. In the United States, approximately one in every 60 women develops ovarian cancer, and more than 25,000 new cases are diagnosed each year. Less than 25% of ovarian cancer cases are diagnosed before cancer has spread beyond the ovary, and the chance of five-year survival for late stage ovarian cancer is less than 30%. Robertson et al., Endocrine-Related Cancer (2004), vol 11, pages 35-49 reviews the role of activin and inhibin in ovarian cancer. SUMMARY Described herein are methods for treating ovarian cancer in a subject by administering anti-activin-A compounds to the subject, including anti-activin-A antibodies and/or activin receptors. Also described are methods of identifying subjects for treatment of ovarian cancer by evaluating levels of specific proteins in a subject. The embodiments of the invention are set out in the appended claims. Subject matter falling outside the scope of the claims is described herein for reference purposes only and does not form part of the invention. In one embodiment, the invention provides a first compound and a second compound, wherein the first compound is an anti-activin-A compound, and wherein the second compound is a chemotherapeutic compound, for use in a method of treating ovarian cancer by preventing tumor neovascularization in a subject, wherein the anti-activin-A compound is an antibody and the antibody comprises:: (a) a light chain CDR3 comprising a sequence selected from the group consisting of: i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences disclosed herein, and;ii. X73QX74X75X76X77X78X79X80 (SEQ ID NO: 132);iii. LQHNX81YX82X83T (SEQ ID NO: 131); andiv. QAWDX84STX85X86 (SEQ ID NO: 248); wherein X73 is a methionine residue, a glutamine residue, or an arginine residue, X74 is an alanine residue, a tyrosine residue, a glutamine residue, or a serine residue, X75 is a leucine residue, a tyrosine residue, or an asparagine residue, X76 is a glutamine residue, a serine residue, or a threonine residue, X77 is a threonine residue, a tyrosine residue, or an isoleucine residue, X78 is a proline residue or a serine residue, X79 is a cysteine residue, a tryptophan residue, a leucine residue, or a proline residue, X80 is a serine residue or a threonine residue, X81 is a threonine residue or a serine residue, X82 is a proline residue or a threonine residue, X83 is a phenylalanine residue or a tryptophan residue, X84 is an arginine residue or a serine residue, X85 is a valine residue or an alanine residue, and X86 is a valine residue or no residue, and said anti-activin-A compound binds specifically to human activin-A; or(b) a heavy chain CDR3 comprising a sequence selected from the group consisting of: i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences disclosed herein;ii. X87X88X89X90X91X92X93X94FDY (SEQ ID NO: 187);iii. X95X96X97Y X98 D X99 X100 GWX101X102X103 (SEQ ID NO: 188); andiv. X104X105X106 X107X108X109 YX110X111 X112 X13 X114X115X116X117X118 (SEQ ID NO: 249); wherein X87 is a valine residue or no residue, X88 is a glutamine residue or no residue, X89 is an aspartate residue, a tryptophan residue, or no residue, X90 is a serine residue, a leucine residue, or no residue, X91 is an isoleucine residue, a glutamate residue, or a glutamine residue, X92 is an alanine residue, a leucine residue, or a glycine residue, X93 is an alanine residue or a leucine residue, X94 is a proline residue, a tyrosine residue, or a glycine residue, X95 is an aspartate residue or no residue, X96 is a glutamine residue or no residue, X97 is an aspartate residue or an alanine residue, X98 is a tyrosine residue or a glycine residue, X99 is a serine residue or a tyrosine residue, X100 is a serine residue or an arginine residue, X101 is a phenylalanine residue or no residue, X102 is a glycine residue or an aspartate residue, X103 is a histidine residue or a proline residue, X104 is a glycine residue or no residue X105 is a serine residue, a glutamate residue, or no residue X106 is an arginine residue, a serine residue, or no residue, X107 is an aspartate residue, an asparagine residue, a serine residue, or a glutamine residue X108 is a serine residue, an arginine residue, or a tryptophan residue, X109 is a glycine residue,