Activated her3 as a marker for predicting therapeutic efficacy

Abstract

The present invention provides methods for the determination of the activation level of Receptor Tyrosine kinases, e.g. phosporylated HER3, for the selection of patients for disease treatment. Methods are also provided for the evaluation of the biological and pharmacodynamic effects of an active substance and/or its efficacy in disease treatment, utilizing a tissue sample from a test subject, for example tumor material or normal tissue such as skin or hair follicle. Further, methods for the treatment of HER receptor-associated diseases are disclosed.

1 - 32 . (canceled) 
   
   
       33 . A method of identifying the responsiveness of a disease to treatment with a HER3 modulator comprising
 (a) obtaining at least one sample from a subject at risk of or having said disease,   (b) examining the expression and/or activity of at least one HER3 receptor in said sample, and   (c) identifying a disease as responsive if expression and/or activity of the at least one HER3 receptor is detected.   
   
   
       34 . The method of  claim 33  wherein the disease is a hyperproliferative disease. 
   
   
       35 . The method of  claim 34  wherein the hyperproliferative disease is a tumor disease or psoriasis. 
   
   
       36 . The method of  claim 35  wherein the tumor disease is selected from the group consisting of NSCLC, breast, colon, gastric, melanoma, pancreas or prostate cancer. 
   
   
       37 . The method of  claim 33  wherein the detection of HER3 receptor activity comprises a determination of the HER3 receptor phosphorylation level. 
   
   
       38 . The method of  claim 37  wherein a phospho-specific antibody is employed. 
   
   
       39 . The method of  claim 38  wherein the phospho-specific antibody is an antibody that recognizes a phosphorylated tyrosine residue in a HER3 receptor. 
   
   
       40 . The method of  claim 39  wherein the phospho-specific antibody is directed against at least one of the tyrosine residues Y1289 or Y1222 in the HER3 protein. 
   
   
       41 . The method of  claim 40  wherein the phospho-specific antibody is the phospho-specific HER3 antibody 21D3 or 50C2. 
   
   
       42 . The method of  claim 33  wherein step (b) comprises an immunohistochemical assay, flow cytometry, ELISA or a Western Blot. 
   
   
       43 . The method of  claim 33  wherein the sample is a tissue sample. 
   
   
       44 . The method of  claim 42  wherein the tissue sample is selected from the group of solid tissues as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate. 
   
   
       45 . The method of  claim 33  wherein the subject is a mammal. 
   
   
       46 . The method of  claim 45  wherein the mammal is a human. 
   
   
       47 . A method of determining the therapeutic efficacy of a HER3 modulator comprising
 (a) exposing a subject to at least one HER3 modulator,   (b) obtaining at least one sample from the subject,   (c) detecting the activation level of at least one HER3 receptor in said sample wherein a difference in the activation level of the at least one HER3receptor is observed as a result of the exposure of the pharmaceutical composition as compared to the absence of the exposure to the at least one HER3 modulator.   
   
   
       48 . The method of  claim 47  wherein the HER3 modulator is an inhibitor directed against at least one HER3 receptor. 
   
   
       49 . The method of  claim 47  wherein the detection of activity of a HER3 receptor is achieved by assessing the phosphorylation level. 
   
   
       50 . The method of  claim 47  wherein a phospho-specific antibody is employed. 
   
   
       51 . The method of  claim 47  wherein the phospho-specific antibody is an antibody that recognizes a phosphorylated tyrosine residue in a HER3 receptor. 
   
   
       52 . The method of  claim 50  wherein the phospho-specific antibody is directed against at least on one of the tyrosine residues Y1289 or Y1222 in the HER3 protein. 
   
   
       53 . The method of  claim 50  wherein the phospho-specific antibody is at least one of the phospho-specific HER3 antibodies 21D3 or 50C2. 
   
   
       54 . The method of  claim 47  wherein the detection step (c) comprises an immunohistochemical assay, flow cytometry, ELISA or a Western Blot. 
   
   
       55 . The method of  claim 47  wherein the sample is a tissue sample. 
   
   
       56 . The method of  claim 47  wherein the sample is a normal tissue sample, e.g. hair follicle sample. 
   
   
       57 . The method of  claim 47  wherein the subject is a mammal, particularly a human. 
   
   
       58 . An antibody that detects an activated HER3 receptor. 
   
   
       59 . The antibody of  claim 58  wherein the antibody binds to an epitope that comprises at least one of the tyrosine residues Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 of HER3. 
   
   
       60 . Use of an antibody of  claim 58  for identifying the responsiveness of a disease to treatment with a HER3 modulator. 
   
   
       61 . A kit for evaluating the activation level of an activated HER3 family member comprising
 (a) an antibody that detects expression of a HER3 receptor protein,   (b) an antibody that detects activation of a HER3 receptor member.   
   
   
       62 . Use of a HER3 modulator for the manufacture of a medicament for the treatment of a disease which is associated with HER3 receptor expression, overexpression and/or activity. 
   
   
       63 . The use of  claim 62  wherein the expression, overexpression and/or activity has been determined before administration of the HER3 modulator. 
   
   
       64 . The use of  claim 62  wherein the responsiveness of the disease is tested during the course of the treatment