Her-2 binding antagonists

Abstract

There is disclosed a a pharmaceutical composition for treating solid tumors that overexpress HER-2, comprising an agent selected from the group consisting of (a) an isolated polypeptide having from about 50 to 79 amino acids taken from the sequence of SEQ ID NO:1, wherein the polypeptide binds to the extracellular domain ECD of HER-2 with an affinity binding constant of at least 10 8 M −1 , (b) an isolated and glycosylated polypeptide having from about 300 to 419 amino acids taken from the sequence of SEQ ID NO:2, wherein the C terminal 79 amino acids are present, and wherein at least three N-linked glycosylation sites are present, (c) a monoclonal antibody that binds to the ECD of HER-2, and (d) combinations thereof, with the proviso that the agent cannot be the monoclonal antibody alone, and pharmaceutically acceptable carrier. Also disclosed are prognostic and diagnostic assays.

1 .- 23 . (canceled) 
     
     
         24 . A method for determining the prognosis of tumor treatment in a patient for a tumor that overexpresses HER-2, comprising: (a) obtaining a bodily fluid sample from a patient, wherein the bodily fluid is selected from the group consisting blood, serum, urine, lymph, saliva, tumor tissue, placental tissue, umbilical cord tissue, amniotic fluid, chorionic villi tissue and combinations thereof; and (b) measuring the amount of p68HER-2 expressed using an anti-p68HER-2 antibody-based assay, wherein a method for determining the prognosis of tumor treatment in a patient is provided. 
     
     
         25 . The method for determining the prognosis of tumor treatment for a tumor that overexpresses HER-2 of  claim 24 , further comprising measuring the amount of p185HER-2 ECD in the bodily fluid. 
     
     
         26 . The method for determining the prognosis of tumor treatment for a tumor that overexpresses HER-2 of  claim 24 , further comprising determining a ratio between the amount of p68HER-2 and p185HER-2, whereby the higher the p68HER-2 to p185HER-2 ratio, the better the prognosis of the patient. 
     
     
         27 . An assay for cancer treatment, prognosis or diagnosis in a patient comprising:
 (a) obtaining a bodily fluid sample from the patient, wherein the bodily fluid is selected from the group consisting of blood, serum, urine, lymph, saliva, tumor tissue, placental tissue, umbilical cord tissue, amniotic fluid, chorionic villi tissue and combinations thereof;   (b) determining whether an ECDIIIa variant sequence is present in the bodily fluid sample using a sequence identity assay; and   (c) correlating the presence of the ECDIIIa variant sequence to cancer treatment and diagnosis using an historical database, wherein an assay for cancer treatment, prognosis or diagnosis in a patient is provided.   
     
     
         28 . The diagnostic assay of  claim 27 , wherein the sequence identity assay is selected from the group consisting of DNA sequencing, PCR assays, ELISA immunologic assays, immunoassays, hybridization assays, and combinations thereof. 
     
     
         29 . The diagnostic assay of  claim 27 , further comprising measuring the amount of p185HER-2 ECD in the bodily fluid. 
     
     
         30 . An assay for cancer treatment, prognosis or diagnosis in a patient comprising:
 (a) obtaining a bodily fluid sample from the patient, wherein the bodily fluid is selected from the group consisting of blood, serum, urine, lymph, saliva, tumor tissue, placental tissue, umbilical cord tissue, amniotic fluid, chorionic villi tissue and combinations thereof;   (b) determining whether an amount of an p68HER-2 ECDIIIa variant is present in the bodily fluid sample using an anti-p68HER-2 antibody-based assay; and   (c) correlating the presence or amount of the p68HER-2 ECDIIIa variant to cancer treatment and diagnosis using an historical database, wherein an assay for cancer treatment, prognosis or diagnosis in a patient is provided.   
     
     
         31 . The diagnostic assay of  claim 30 , wherein the sequence identity assay is selected from the group consisting of DNA sequencing, PCR assays, ELISA immunologic assays, hybridization assays, and combinations thereof. 
     
     
         32 . The diagnostic assay of  claim 30 , further comprising measuring the amount of p185HER-2 ECD in the bodily fluid. 
     
     
         33 . The diagnostic assay of  claim 32 , further comprising determining a ratio between the amount of p68HER-2 and p185HER-2 ECD. 
     
     
         34 .- 37 . (canceled) 
     
     
         38 . The method of  claim 24 , wherein measuring the amount of p68HER-2 expressed using an anti-p68HER-2 antibody-based assay, comprises use of at least one assay selected from the group consisting of ELISA, immunoprecipitation, immunohistocytochemistry, and Western analysis. 
     
     
         39 . The method of  claim 27 , wherein the ECDIIIa variant sequence comprises an ECDIIIa variant sequence according to SEQ ID NO:1. 
     
     
         40 . The method of  claim 30 , wherein determining whether an amount of the p68HER-2 ECDIIIa variant is present comprises determining an amount of a p68HER-2 polypeptide according to SEQ ID NO:2. 
     
     
         41 . The method of  claim 41 , wherein and wherein p68HER-2 polypeptide comprises at least three N-linked glycosylation sites. 
     
     
         42 . The method of  claim 30 , wherein measuring the amount of p68HER-2 expressed using an anti-p68HER-2 antibody-based assay, comprises use of at least one assay selected from the group consisting of ELISA, immunoprecipitation, immunohistocytochemistry, and Western analysis.