Methods, systems and products for predicting response of tumor cells to a therapeutic agent and treating a patient according to the predicted response

Abstract

The invention provides methods for treating patients which methods comprise methods for predicting responses of cells, such as tumor cells, to treatment with therapeutic agents. These methods involve measuring, in a sample of the cells, levels of one or more components of a cellular network and then computing a Network Activation State (NAS) or a Network Inhibition State (NIS) for the cells using a computational model of the cellular network. The response of the cells to treatment is then predicted based on the NAS or NIS value that has been computed. The invention also comprises predictive methods for cellular responsiveness in which computation of a NAS or NIS value for the cells (e.g., tumor cells) is combined with use of a statistical classification algorithm. Biomarkers for predicting responsiveness to treatment with a therapeutic agent that targets a component within the ErbB signaling pathway are also provided.

What is claimed is: 
     
         1 . A method of treating a patient selected for treatment with an anti-ErbB3 antibody, said patient having a neoplastic tumor, said method comprising:
 administering an effective amount of an anti-ErbB3 antibody to the patient;   wherein the selection for treatment with the anti-ErbB3 antibody comprises:   (a) obtaining a sample of the tumor,   (b) determining a level of pErbB3 in the sample by indirect measurement that includes:   measuring total protein in the sample and levels of (i) at least one receptor selected from ErbB 1, ErbB2, and ErbB3 and (ii) at least one of heregulin and betacellulin,   (c) subsequently selecting the patient for treatment with the anti-ErbB3 antibody only when the level of pErbB3 determined in the sample is no lower than 0.096 pg/μg total protein, 0.122 pg/μg total protein, 0.128 pg/μg total protein, 0.144 pg/μg total protein, or 0.16 pg/μg total protein.   
     
     
         2 . A method according to  claim 1 , wherein the at least one receptor is ErbB2, which is measured by quantitative fluorescence activated cell sorting, enzyme linked immunosorbent assay, immunohistochemistry, quantitative immunohistochemistry, fluorescence resonance energy transfer, Forster resonance energy transfer, biomolecular fluorescence complementation, mass spectrometry, immunoblot assay or coimmunoprecipitation assay. 
     
     
         3 . The method of  claim 2 , wherein the at least one of heregulin and betacelulin is heregulin, which is measured as RNA. 
     
     
         4 . A method according to  claim 3 , wherein the anti-ErbB3 antibody comprises at least one of:
 (i) an antibody comprising heavy chain variable region (V H ) and light chain variable region (V L ) sequences as shown in SEQ ID NOs: 1 and 2, respectively, or an antibody comprising V H  and V L  CDR sequences as shown in SEQ ID NOs: 7-9 and 10-12, respectively;   (ii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 3 and 4, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 13-15 and 16-18, respectively;   (iii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 5 and 6, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 19-21 and 22-24, respectively;   (iv) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 25 and 26, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 27-29 and 30-32, respectively; and   (v) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 33 and 34, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 35-37 and 38-40, respectively.   
     
     
         5 . A method according to  claim 4 , wherein the anti-ErbB3 antibody comprises MM-121. 
     
     
         6 . A method according to  claim 3 , wherein the tumor is a tumor of a tissue selected from of lung, rectum, gall bladder, brain, spinal cord, breast, kidney, pancreas, stomach, colon, liver, bone, skin, spleen, ovary, testis, prostate and muscle. 
     
     
         7 . A method according to  claim 3 , wherein the sample of the tumor is selected from tumor tissue, fine needle aspirate, nipple aspirate, circulating tumor cells isolated from a blood sample, whole blood, serum, plasma, lymph, saliva and urine, or shed or circulating tumor cells isolated therefrom. 
     
     
         8 . A method of treating a patient selected for treatment with an anti-ErbB3 antibody, said patient having a neoplastic tumor, said method comprising:
 administering an effective amount of an anti-ErbB3 antibody to the patient;   wherein the selection for treatment with the anti-ErbB3 antibody comprises:   (a) obtaining a sample of the tumor,   (b) determining a level of pErbB3 in the sample by indirect measurement that includes:   measuring total protein in the sample and levels of (i) at least one receptor selected from ErbB 1, ErbB2, and ErbB3 and (ii) at least one of heregulin and betacellulin,   (c) subsequently selecting the patient for treatment with the anti-ErbB3 antibody only when the level of pErbB3 determined in the sample is no lower than 0.064 pg/μg total protein.   
     
     
         9 . A method according to  claim 8 , wherein the at least one receptor is ErbB2, which is measured by quantitative fluorescence activated cell sorting, enzyme linked immunosorbent assay, immunohistochemistry, quantitative immunohistochemistry, fluorescence resonance energy transfer, Forster resonance energy transfer, biomolecular fluorescence complementation, mass spectrometry, immunoblot assay or coimmunoprecipitation assay. 
     
     
         10 . The method of  claim 9 , wherein the at least one of heregulin and betacelulin is heregulin, which is measured as RNA. 
     
     
         11 . A method according to  claim 10 , wherein the anti-ErbB3 antibody comprises at least one of:
 (i) an antibody comprising heavy chain variable region (V H ) and light chain variable region (V L ) sequences as shown in SEQ ID NOs: 1 and 2, respectively, or an antibody comprising V H  and V L  CDR sequences as shown in SEQ ID NOs: 7-9 and 10-12, respectively;   (ii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 3 and 4, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 13-15 and 16-18, respectively;   (iii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 5 and 6, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 19-21 and 22-24, respectively;   (iv) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 25 and 26, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 27-29 and 30-32, respectively; and   (v) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 33 and 34, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 35-37 and 38-40, respectively.   
     
     
         12 . A method according to  claim 11 , wherein the anti-ErbB3 antibody comprises MM-121. 
     
     
         13 . A method according to  claim 10 , wherein the tumor is a tumor of a tissue selected from of lung, rectum, gall bladder, brain, spinal cord, breast, kidney, pancreas, stomach, colon, liver, bone, skin, spleen, ovary, testis, prostate and muscle. 
     
     
         14 . A method according to  claim 10 , wherein the sample of the tumor is selected from tumor tissue, fine needle aspirate, nipple aspirate, circulating tumor cells isolated from a blood sample, whole blood, serum, plasma, lymph, saliva and urine, or shed or circulating tumor cells isolated therefrom. 
     
     
         15 . A method of treating a patient selected for treatment with an anti-ErbB3 antibody, said patient having a neoplastic tumor, said method comprising:
 administering an effective amount of an anti-ErbB3 antibody to the patient;   wherein the selection for treatment with the anti-ErbB3 antibody comprises:   (a) obtaining a sample of the tumor,   (b) determining a level of pErbB3 in the sample by indirect measurement that includes:   measuring total protein in the sample and levels of (i) at least one receptor selected from ErbB 1, ErbB2, and ErbB3 and (ii) at least one of heregulin and betacellulin,   (c) subsequently selecting the patient for treatment with the anti-ErbB3 antibody only when the level of pErbB3 determined in the sample is no lower than 0.08 pg/μg total protein.   
     
     
         16 . A method according to  claim 15 , wherein the at least one receptor is ErbB2, which is measured by quantitative fluorescence activated cell sorting, enzyme linked immunosorbent assay, immunohistochemistry, quantitative immunohistochemistry, fluorescence resonance energy transfer, Forster resonance energy transfer, biomolecular fluorescence complementation, mass spectrometry, immunoblot assay or coimmunoprecipitation assay. 
     
     
         17 . The method of  claim 16 , wherein the at least one of heregulin and betacelulin is heregulin, which is measured as RNA. 
     
     
         18 . A method according to  claim 17 , wherein the anti-ErbB3 antibody comprises at least one of:
 (i) an antibody comprising heavy chain variable region (V H ) and light chain variable region (V L ) sequences as shown in SEQ ID NOs: 1 and 2, respectively, or an antibody comprising V H  and V L  CDR sequences as shown in SEQ ID NOs: 7-9 and 10-12, respectively;   (ii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 3 and 4, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 13-15 and 16-18, respectively;   (iii) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 5 and 6, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 19-21 and 22-24, respectively;   (iv) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 25 and 26, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 27-29 and 30-32, respectively; and   (v) an antibody comprising V H  and V L  sequences as shown in SEQ ID NOs: 33 and 34, respectively, or an antibody comprising V H  and V L  CDR sequences shown in SEQ ID NOs: 35-37 and 38-40, respectively.   
     
     
         19 . A method according to  claim 18 , wherein the anti-ErbB3 antibody comprises MM-121. 
     
     
         20 . A method according to  claim 17 , wherein the tumor is a tumor of a tissue selected from of lung, rectum, gall bladder, brain, spinal cord, breast, kidney, pancreas, stomach, colon, liver, bone, skin, spleen, ovary, testis, prostate and muscle. 
     
     
         21 . A method according to  claim 17 , wherein the sample of the tumor is selected from tumor tissue, fine needle aspirate, nipple aspirate, circulating tumor cells isolated from a blood sample, whole blood, serum, plasma, lymph, saliva and urine, or shed or circulating tumor cells isolated therefrom.