ADMINISTRATION OF AN ANTI-ACTIVIN-A COMPOUND TO A SUBJECT
The present invention relates to methods of treating ovarian cancer in a subject by administering to the subject by evaluating the subject's expression levels of specific biomarkers or angiogenic an anti-activin-A compound, such as an anti-activin-A antibody or an activin-A-binding receptor. In some embodiments, at least two compounds are administered to the subject, where the first compound is an anti-activin A compound, and the second compound is a chemotherapeutic compound, for example capecitabine. The invention further relates to methods of identifying subjects for treatment factors.
1 . A method of treating ovarian cancer in a subject, comprising:
administering a therapeutically effective amount of at least two compounds:
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.
2 .- 38 . (canceled)
39 . A method for treating serous ovarian cancer in a subject in need thereof comprising administering a therapeutically effective amount of an anti-activin-A compound to the subject.
40 - 59 . (canceled)
60 . The method of claim 1 , wherein the anti-activin-A compound is an ActRIIB-Fc fusion protein or an anti-activin antibody or an antigen binding fragment thereof.
61 . The method of claim 1 , wherein the anti-activin-A compound comprises the sequence set forth in SEQ ID NO: 10.
62 . The method of claim 1 , wherein the anti-activin-A compound comprises a stabilized activin IIB receptor polypeptide (svActRIIB), wherein the polypeptide is selected from the group consisting of:
(a) a polypeptide consisting of the sequence set forth in the group consisting of SEQ ID NO: 4, 6, 12 and 14;
(b) a polypeptide having at least 90% sequence identity to (a), wherein the polypeptide has a W or a Y at the position corresponding to position 28 of SEQ ID NO:2 and a T at the position corresponding to position 44 of SEQ ID NO:2, wherein the polypeptide is capable of binding myostatin, activin-A, or GDF-11; and
(c) a polypeptide having at least 95% sequence identity to (a), wherein the polypeptide has a W or a Y at the position corresponding to position 28 of SEQ ID NO:2 and a T at the position corresponding to position 44 of SEQ ID NO:2, wherein the polypeptide is capable of binding myostatin, activin-A, or GDF-11.
63 . The method of claim 62 , wherein the svActRIIB polypeptide is operably linked to at least one heterologous polypeptide, optionally wherein the heterologous polypeptide is an Fc.
64 . The method of claim 1 , wherein the anti-activin-A compound comprises an anti-activin antibody or an antigen binding fragment thereof comprising a light chain variable region and a heavy chain variable region, and wherein the light chain variable region comprises the sequence set forth in SEQ ID NO:275 (SYEVTQAPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPE RFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSTAVFGGGTKLTVL) and the heavy chain variable region comprises the sequence set forth in SEQ ID NO:278 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGLSWVRQAPGQGLEWMGWIIPYNG NTNSAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYFCARDRDYGVNYDAFDIWG QGTMVTVSS).
65 . The method of claim 1 , wherein the chemotherapeutic compound is capecitabine or a doxorubicin lipid complex.
66 . The method of claim 1 , further comprising: identifying the subject by detecting elevated levels of biomarker CA-125 and/or activin-A in the subject compared to a control, or compared to a previous level of biomarker CA-125 and/or activin-A in the subject; or identifying the subject by detecting elevated levels of activin-A, VEGF, and/or Ang-1 factors in the subject compared to a control.
67 . The method of claim 1 , wherein the ovarian cancer is serous ovarian cancer, clear cell ovarian cancer, Granulosa cell ovarian cancer, a Leydig cell tumor, or a sex cord stromal tumor.
68 . The method of claim 1 , wherein the anti-activin-A compound and/or the chemotherapeutic compound is administered to a subject subcutaneously, intravenously, or intraperitoneally.
69 . The method of claim 1 , 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.
70 . The method of claim 39 , wherein the subject has a mutated activin gene or a mutated activin counter-regulator gene, optionally wherein the mutation is an Asn386Ser mutation, an Arg60Leu mutation, or a Gly280Glu mutation.
71 . The method of claim 39 , wherein the anti-activin-A compound is an ActRIIB-Fc fusion protein or an anti-activin antibody or an antigen binding fragment thereof.
72 . The method of claim 39 , wherein the anti-activin-A compound comprises the sequence set forth in SEQ ID NO: 10.
73 . The method of claim 39 , wherein the anti-activin-A compound comprises an anti-activin antibody or an antigen binding fragment thereof comprising a light chain variable region and a heavy chain variable region, and wherein the light chain variable region comprises the sequence set forth in SEQ ID NO:275 (SYEVTQAPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPE RFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSTAVFGGGTKLTVL) and the heavy chain variable region comprises the sequence set forth in SEQ ID NO:278 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGLSWVRQAPGQGLEWMGWIIPYNG NTNSAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYFCARDRDYGVNYDAFDIWG QGTMVTVSS).
74 . The method of claim 39 , wherein the anti-activin-A compound comprises a stabilized activin IIB receptor polypeptide (svActRIIB), wherein the polypeptide is selected from the group consisting of:
(d) a polypeptide consisting of the sequence set forth in the group consisting of SEQ ID NO: 4, 6, 12 and 14;
(e) a polypeptide having at least 90% sequence identity to (a), wherein the polypeptide has a W or a Y at the position corresponding to position 28 of SEQ ID NO:2 and a T at the position corresponding to position 44 of SEQ ID NO:2, wherein the polypeptide is capable of binding myostatin, activin-A, or GDF-11; and
(f) a polypeptide having at least 95% sequence identity to (a), wherein the polypeptide has a W or a Y at the position corresponding to position 28 of SEQ ID NO:2 and a T at the position corresponding to position 44 of SEQ ID NO:2, wherein the polypeptide is capable of binding myostatin, activin-A, or GDF-11.
75 . The method of claim 39 , wherein the anti-activin-A compound is administered to a subject subcutaneously, intravenously, or intraperitoneally.
76 . The method of claim 39 , 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.
77 . The method of claim 39 , further comprising: identifying the subject by detecting elevated levels of biomarker CA-125 and/or activin-A in the subject compared to a control, or compared to a previous level of biomarker CA-125 and/or activin-A in the subject; or identifying the subject by detecting elevated levels of activin-A, VEGF, and/or Ang-1 factors in the subject compared to a control.