Claims for Patent: 8,349,574

Summary for Patent: 8,349,574

Title:	Methods of determining patient response by measurement of Her-3
Abstract:	The invention provides methods of measuring and/or quantifying the presence and/or amount of Her-3 and/or Her-3 in a complex in a sample. The invention also provides antibodies specific for Her-3.
Inventor(s):	Bates; Michael (San Carlos, CA), Mukherjee; Ali (Millbrae, CA), Parry; Gordon (Oakland, CA), Sperinde; Jeff (El Granada, CA), Cook; Jennifer W. (San Mateo, CA), Diedrich; Gundo (Potomac, MD), Goodman; Laurie (El Granada, CA), Williams; Stephen J. (San Carlos, CA)
Assignee:	Laboratory Corporation of America Holdings (Burlington, NC)
Application Number:	12/688,798
Patent Claims:	1. A method for determining whether a subject with a cancer is likely to respond to treatment with a Her family targeted agent, for predicting a time course of disease during treatment with a Her family targeted agent, and/or for predicting the probability of a significant event in the time course of the subject's cancer during treatment with a Her family targeted agent, comprising: (a) obtaining a biological sample from of the subject's cancer; (b) measuring the amount of Her-3 in the biological sample using a Her-3 antibody that specifically binds to a polypeptide sequence set forth in one of SEQ ID NOs 1-8; (c) determining whether the amount of Her-3 in the subject's sample is above a Her-3 cutoff; (d) correlating the amount of Her-3 measured in the biological sample to at least one of determining the relative likelihood of whether a subject with a Her-2 positive cancer will respond to treatment with a Her-family targeted agent, predicting a time course of disease during treatment with a Her family targeted agent, and/or predicting a probability of a significant event in the time course of the subject's cancer during treatment with a Her family targeted agent; and (e) indicating that the subject is more likely to respond to the Her family targeted agent, more likely to have a long time course during treatment with a Her family targeted agent, and/or less likely to have a significant event during treatment with a Her family targeted agent if the amount of Her-3 in the biological sample is below the Her-3 cutoff as compared to if the Her-3 in the biological sample is above the Her-3 cutoff. 2. The method of claim 1, wherein the subject's cancer comprises breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer or gastric cancer. 3. The method of claim 1, wherein the subject's cancer comprises metastatic breast cancer. 4. The method of claim 1, wherein the subject's cancer comprises early stage breast cancer. 5. The method of claim 1, wherein the Her family-targeted agent comprises a multi-target agent. 6. The method of claim 1, wherein the Her family-targeted agent comprises a dual kinase inhibitor or a bispecific antibody. 7. The method of claim 1, wherein the Her family-targeted agent comprises at least one of trastuzumab, lapatinib, pertuzumab, cetuximab, panitumumab, erlotinib or gefitinib. 8. The method of claim 1, wherein likeliness to respond, likeliness to have a long time course and/or likeliness to have a significant event is measured as at least one of overall survival rate, as time to progression, disease-free survival, progression-free survival, time to distant reoccurrence, hazard ratio and/or objective tumor response or clinical benefit using the RECIST criteria. 9. The method of claim 1, wherein measuring the amount of Her-3 in the biological sample comprises measuring at least one of total Her-3 protein, Her-3 homodimers or Her-3 heterodimers. 10. The method of claim 1, wherein the Her-family targeted agent comprises a single-target agent. 11. The method of claim 1, wherein the Her-family targeted agent comprises at least one of a Her-2 targeted agent or a Her-3 targeted agent. 12. The method of claim 1, wherein measuring the amount of Her-3 in the biological sample comprises the steps of: a) contacting the biological sample with the Her-3 antibody; b) contacting the Her-3 antibody with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the Her-3 antibody; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-3 protein in the biological sample. 13. The method of claim 1, wherein measuring the amount of Her-3 in the biological sample comprises using immunohistochemistry to quantitate the amount of Her-3. 14. The method of claim 1, further comprising: (i) measuring the amount of p95 in the biological sample; (ii) determining whether the amount of p95 in the subject's sample is above a p95 cutoff (iii) correlating the amount of p95 measured in the biological sample to at least one of determining the relative likelihood of whether a subject with a Her-2 positive cancer will respond to treatment with a Her-family targeted agent, predicting a time course of disease during treatment with a Her family targeted agent, and/or predicting a probability of a significant event in the time course of the subject's cancer during treatment with a Her family targeted agent; and (iv) indicating that the subject is more likely to respond to the Her family targeted agent, more likely to have a long time course during treatment with a Her family targeted agent, and/or less likely to have a significant event during treatment with a Her family targeted agent if the amount of p95 in the biological sample is below the p95 cutoff than if the amount of Her-3 and/or p95 in the biological sample are above their respective cutoffs. 15. The method of claim 14, wherein measuring the amount of p95 in the biological sample comprises quantitation of p95 gene expression levels. 16. The method of claim 14, wherein measuring the amount of p95 in the biological sample comprises measuring the amount of total p95 protein. 17. The method of claim 14, wherein measuring the amount of p95 in the biological sample comprises the steps of: a) contacting the biological sample with a p95 binding composition that specifically binds to p95 protein; b) contacting the p95 binding composition with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the p95 binding composition; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of p95 protein in the biological sample. 18. The method of claim 1, wherein measuring the amount of Her-3 in the biological sample comprises the steps of: a) contacting the biological sample with a tagged Her-3 binding composition that specifically binds to Her-3 protein, wherein the tagged Her-3 binding composition comprises the Her-3 antibody and a molecular tag attached thereto via a cleavable linkage; b) contacting the biological sample with a cleaving agent; c) cleaving the cleavable linkage of the tagged Her-3 binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-3 protein in the biological sample. 19. The method of claim 18, wherein measuring the amount of Her-2 in the biological sample comprises measuring at least one of total Her-2 protein or Her-2 homodimers. 20. The method of claim 1, wherein the Her 3 antibody is at least one of a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 13, 14 and 15, respectively, and (b) a heavy chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 16, 17 and 18, respectively; or a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 19, 20 and 21, respectively, and (b) a heavy chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 22, 23 and 24, respectively. 21. The method of claim 1, wherein the Her 3 antibody is at least one of an antibody comprising an amino acid sequence set forth in SEQ ID NOs: 9 and 11 for the light and heavy chains, respectively, or SEQ ID NOs: 10 and 12 forth the light and heavy chains, respectively. 22. The method of claim 1, wherein the subject's cancer has been characterized as Her-2 positive based on the level of Her-2 in the biological sample being above a Her-2 cutoff. 23. The method of claim 22, wherein measuring the amount of Her-2 in the biological sample comprises measuring at least one of total Her-2 protein or Her-2 homodimers. 24. The method of claim 22, wherein characterization of the subject's cancer as Her-2 positive comprises the steps of: a) contacting the biological sample with a Her-2 binding composition that specifically binds to Her-2 protein; b) contacting the Her-2 binding composition with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the Her-2 binding composition; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-2 protein in the biological sample. 25. The method of claim 22, wherein the method by which the subject's cancer has been characterized as Her-2 positive comprises quantitation of Her-2 gene expression levels or Her-2 gene copy number. 26. The method of claim 22, wherein the method by which the subject's cancer has been characterized as Her-2 positive comprises using in situ hybridization, immunohistochemistry, quantitative mRNA analysis or a hybridization array to quantitate the amount of Her-2 in the biological sample. 27. The method of claim 22, wherein characterization of the subject's cancer as Her-2 positive comprises the steps of: a) contacting the biological sample with a tagged Her-2 binding composition that specifically binds to Her-2 protein, wherein the tagged Her-2 binding composition comprises a molecular tag attached thereto via a cleavable linkage; b) contacting the biological sample with a cleaving agent; c) cleaving the cleavable linkage of the tagged Her-2 binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-2 protein in the biological sample. 28. A method for determining whether a subject with a cancer is likely to respond to treatment with a Her family targeted agent, for predicting a time course of disease during treatment with a Her family targeted agent, and/or for predicting the probability of a significant event in the time course of the subject's cancer during treatment with a Her family targeted agent, comprising: (a) obtaining a biological sample from the subject's cancer; (b) measuring the amount of Her-3 and p95 in the biological sample, wherein the amount of Her-3 antibody that specifically binds to a polypeptide sequence set forth in one of SEQ ID NOs 1-8; (c) determining whether the amount of Her-3 in the subject's sample is above a Her-3 cutoff and whether the p95 in the subject's sample is above a p95 cutoff; and (d) correlating the amount of Her-3 and p95 measured in the biological sample to at least one of determining the relative likelihood of whether a subject with a Her-2 positive cancer will respond to treatment with a Her-family targeted agent, predicting a time course of disease during treatment with a Her family targeted agent, and/or predicting a probability of a significant event in the time course of the subject's cancer during treatment with a Her family targeted agent; and (e) indicating that the subject is more likely to respond to the Her family targeted agent, more likely to have a long time course during treatment with a Her family targeted agent, and/or less likely to have a significant event during treatment with a Her family targeted agent if the amount of Her-3 in the biological sample is below the Her-3 cutoff than if the Her-3 and/or p95 in the biological sample are above their respective cutoffs. 29. The method of claim 28, wherein measuring the amount of Her-3 in the biological sample comprises measuring at least one of total Her-3 protein, Her-3 homodimers or Her-3 heterodimers. 30. The method of claim 28, wherein measuring the amount of p95 in the biological sample comprises measuring the amount of total p95 protein. 31. The method of claim 28, wherein the subject's cancer comprises breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer or gastric cancer. 32. The method of claim 28, wherein the subject's cancer comprises-metastatic breast cancer. 33. The method of claim 28, wherein the subject's cancer comprises early stage breast cancer. 34. The method of claim 28, wherein the Her-family targeted agent comprises at least one of a Her-2 targeted agent or a Her-3 targeted agent. 35. The method of claim 28, wherein the Her-family targeted agent comprises a single-target agent. 36. The method of claim 28, wherein the Her family-targeted agent comprises a multi-target agent. 37. The method of claim 28, wherein the Her family-targeted agent comprises a dual kinase inhibitor or a bispecific antibody. 38. The method of claim 28, wherein the Her family-targeted agent comprises at least one of trastuzumab, lapatinib, pertuzumab, cetuximab, panitumumab, erlotinib or gefitinib. 39. The method of claim 28, wherein likeliness to respond, likeliness to have a long time course and/or likeliness to have a significant event is measured as at least one of overall survival rate, time to progression, disease-free survival, progression-free survival, time to distant reoccurrence, hazard ratio and/or objective tumor response or clinical benefit using the RECIST criteria. 40. The method of claim 28, wherein measuring the amount of Her-3 in the biological sample comprises the steps of: a) contacting the biological sample with the Her-3 antibody; b) contacting the Her-3 antibody with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the Her-3 antibody; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-3 protein in the biological sample. 41. The method of claim 28, wherein measuring the amount of Her-3 in the biological sample comprises using immunohistochemistry, to quantitate the amount of Her-2 in the biological sample. 42. The method of claim 28, wherein measuring the amount of p95 in the biological sample comprises quantitation of p95 gene expression levels. 43. The method of claim 28, wherein measuring the amount of p95 in the biological sample comprises the steps of: a) contacting the biological sample with p95 binding composition that specifically binds to p95 protein; b) contacting the p95 binding composition with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the p95 binding composition; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of p95 protein in the biological sample. 44. The method of claim 28, wherein measuring the amount of Her-3 in the biological sample comprises the steps of: a) contacting the biological sample with a tagged Her-3 binding composition that specifically binds to Her-3 protein, wherein the tagged Her-3 binding composition comprises the Her-3 antibody and a molecular tag attached thereto via a cleavable linkage; b) contacting the biological sample with a cleaving agent; c) cleaving the cleavable linkage of the tagged Her-3 binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-3 protein in the biological sample. 45. The method of claim 28, wherein the Her 3 antibody is at least one of a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 13, 14 and 15, respectively, and (b) a heavy chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 16, 17 and 18, respectively; or a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 19, 20 and 21, respectively, and (b) a heavy chain variable region comprising CDR1, CDR2 and CDR3 having sequences as set forth in SEQ ID NOs: 22, 23 and 24, respectively. 46. The method of claim 28, wherein the Her 3 antibody is at least one of an antibody comprising an amino acid sequence set forth in SEQ ID NOs: 9 and 11 for the light and heavy chains, respectively, or SEQ ID NOs: 10 and 12 forth the light and heavy chains, respectively. 47. The method of claim 28, wherein the subject's cancer has been characterized as Her-2 positive based on the level of Her-2 in the biological sample being above a Her-2 cutoff. 48. The method of claim 47, wherein characterization of the subject's cancer as Her-2 positive comprises the steps of: a) contacting the biological sample with a Her-2 binding composition that specifically binds to Her-2 protein; b) contacting the Her-2 binding composition with a tagged binding composition, wherein the tagged binding composition comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged binding composition specifically binds to the Her-2 binding composition; c) cleaving the cleavable linker of the tagged binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-2 protein in the biological sample. 49. The method of claim 47, wherein characterization of the subject's cancer as Her-2 positive comprises the steps of: a) contacting the biological sample with a tagged Her-2 binding composition that specifically binds to Her-2 protein, wherein the tagged Her-2 binding composition comprises a molecular tag attached thereto via a cleavable linkage; b) contacting the biological sample with a cleaving agent; c) cleaving the cleavable linkage of the tagged Her-2 binding composition, thereby releasing the molecular tag; and d) quantitating the released molecular tag to determine the amount of Her-2 protein in the biological sample. 50. The method of claim 47, wherein the method by which the subject's cancer has been characterized as Her-2 positive comprises quantitation of Her-2 gene expression levels or Her-2 gene copy number. 51. The method of claim 47, wherein the method by which the subject's cancer has been characterized as Her-2 positive comprises using in situ hybridization, quantitative mRNA analysis, a hybridization array, immunohistochemistry to quantitate the amount of Her-2 in the biological sample.

Details for Patent 8,349,574

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2029-01-15
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2029-01-15
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2029-01-15
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2029-01-15