Use of human epididymis protein 4 (he4) for assessing responsiveness of muc 16-positive cancer treatment

Abstract

The present invention relates to methods and kits or articles of manufacture related thereto that may find use, inter alia, in assessing responsiveness of cancers to MUC16 antagonists by monitoring HE4 expression. In some embodiments, the methods include measuring the level of expression of HE4 in a sample from a subject; comparing the level of expression of HE4 in the sample with the level of expression of HE4 in a sample previously obtained from the subject; and, optionally, administering to the subject a therapeutically effective amount of a MUC16 antagonist.

1 . A method for treating or delaying progression of a cancer in a subject in need thereof, the method comprising:
 (a) measuring the expression level of human epididymis protein 4 (HE4) in a sample obtained from the subject at a first time point, wherein the first time point is prior to administering to the subject an anti-cancer therapy;   (b) administering to the subject a therapeutically effective amount of the anti-cancer therapy; and   (c) measuring the expression level of HE4 in a sample obtained from the subject at a second time point, wherein the second time point is after administration of the anti-cancer therapy, and   wherein the subject is administered one or more additional therapeutically effective amounts of the anti-cancer therapy if the expression level of HE4 at the second time point is at least 25% lower than the expression level of HE4 at the first time point.   
     
     
         2 . The method of  claim 1 , further comprising step (d): administering to the subject the one or more additional therapeutically effective amounts of the anti-cancer therapy when the expression level of HE4 at the second time point is at least 25% lower than the expression level of HE4 at the first time point. 
     
     
         3 . The method of  claim 1 , wherein the subject has never received the anti-cancer therapy. 
     
     
         4 . The method of  claim 1 , wherein the subject is undergoing treatment with the anti-cancer therapy. 
     
     
         5 . A method for treating or delaying progression of a cancer in a subject in need thereof, the method comprising administering to the subject one or more therapeutically effective amounts of an anti-cancer therapy, wherein an initial therapeutically effective amount of the anti-cancer therapy is administered prior to administration of the one or more additional therapeutically effective amounts of the anti-cancer therapy, and:
 wherein a sample obtained from the subject after administration of the initial therapeutically effective amount of the anti-cancer therapy was determined to have a human epididymis protein 4 (HE4) expression level that is at least 25% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the anti-cancer therapy; or   wherein the subject was selected for treatment based on a determination that a sample obtained from the subject after administration of the initial therapeutically effective amount of the anti-cancer therapy has an HE4 expression level that is at least 25% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the anti-cancer therapy; or   wherein treatment is based upon the subject having a sample that expresses HE4 at a level that is at least 25% lower after administration of the initial therapeutically effective amount of the anti-cancer therapy than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the anti-cancer therapy; or   provided that the subject has been found to have a sample that expresses HE4 at a level that is at least 25% lower after administration of the initial therapeutically effective amount of the anti-cancer therapy than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the anti-cancer therapy.   
     
     
         6 . The method of  claim 1 , further comprising administering a second treatment therapy to the subject. 
     
     
         7 . The method of  claim 6 , wherein the second treatment therapy is a maintenance therapy, a chemotherapy, an antibody therapy, or bevacizumab antibody therapy. 
     
     
         8 . The method of  claim 1 , wherein:
 the first time point occurs at least 3 days before, at least 1 day before, at least 12 hours before, at least 4 hours before, at least 1 hour before, less than 1 hour before, or immediately before administering the therapeutically effective amount of the anti-cancer therapy; and/or   the second time point occurs at least 1 hour after, at least 4 hours after, at least 12 hours after, at least 1 day after, at least 3 days after, at least 5 days after, at least 1 week after, at least 2 weeks after, or at least 3 weeks after administering the therapeutically effective amount of the anti-cancer therapy.   
     
     
         9 . The method of  claim 1 , wherein the sample is a blood sample, a serum sample, or a cell sample. 
     
     
         10 . The method of  claim 1 , wherein the expression level of HE4 is circulating level of HE4 protein, protein expression level of HE4, or RNA transcript level of HE4. 
     
     
         11 . The method of  claim 1 , wherein the subject is administered one or more additional therapeutically effective amounts of the anti-cancer therapy if the expression level of HE4 at the second time point is at least 40% lower than the expression level of HE4 at the first time point. 
     
     
         12 . The method of  claim 1 , wherein the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, triple-negative breast cancer, pancreatic cancer, and non-small cell lung cancer. 
     
     
         13 . The method of  claim 1 , wherein the cancer is unresectable pancreatic cancer or an ovarian cancer selected from the group consisting of primary peritoneal carcinoma, epithelial ovarian carcinoma, metastatic ovarian cancer, fallopian tube carcinoma, and platinum-resistant ovarian cancer. 
     
     
         14 . The method of  claim 1 , wherein the cancer is a MUC16-positive cancer. 
     
     
         15 . The method of  claim 1 , wherein the anti-cancer therapy is selected from the group consisting of an antibody or an antibody fragment selected from a Fab, Fab′-SH, Fv, scFv, or F(ab′) 2 , a small molecule inhibitor, a protein, a peptide, a fusion protein, and an immunoadhesin. 
     
     
         16 . The method of  claim 15 , wherein the antibody or antibody fragment is covalently attached to a cytotoxic agent. 
     
     
         17 . The method of  claim 16 , wherein the antibody or antibody fragment is covalently attached to the cytotoxic agent through a linker and the linker comprises one or more of 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2-pyridylthio) pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate (SMCC), N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB), and 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB). 
     
     
         18 . The method of  claim 17 , wherein the linker is attached to the antibody or antibody fragment through a thiol group on the antibody or antibody fragment, and the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). 
     
     
         19 . The method of  claim 1 , wherein the anti-cancer therapy is a NaPi2b antagonist therapy. 
     
     
         20 . The method of  claim 1 , wherein:
 the subject is administered one or more additional therapeutically effective amounts of the anti-cancer therapy if the expression level of HE4 at the second time point is at least 25% to up to 45% lower than the expression level of HE4 at the first time point;   a decrease of at least 25% in the expression level of HE4 from the first time point to the second time point indicates the anti-cancer therapy increases progression-free survival in the subject; or   a decrease of less than 25% in the expression level of HE4 from the first time point to the second time point indicates the cancer in the subject is likely to progress.