Administration of an anti-activin-a compound to a subject

Abstract

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.