Methods of determining patient response by measurement of HER-3

• US 10,775,382 B2
• Filed: 08/21/2017
• Issued: 09/15/2020
• Est. Priority Date: 01/15/2009
• Status: Active Grant

• Current Assignee: Laboratory Corporation Of America Holdings
• Original Assignee: Laboratory Corporation Of America Holdings
• Inventors: Bates, Michael, Cook, Jennifer W., Diedrich, Gundo, Goodman, Laurie, Mukherjee, Ali, Parry, Gordon, Sperinde, Jeff, Williams, Stephen J.
• Primary Examiner(s): Sang, Hong
• Application Number:
  US15/681,895
• Publication Number:
  US 20180164319A1
• Time in Patent Office: 1,121 Days
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: G01N 2333/47 Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2333/71 for growth factors; for growth regulators
• CPC Class Codes: G01N 2800/00 Detection or diagnosis of diseases
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/54 Determining the risk of relapse
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/57415 of breast

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.

Claims

1. A method for determining whether a subject with a HER2 positive cancer is likely to respond to treatment with a HER2 acting agent, more likely to have a long time course for unfavorable significant events related to HER2 positive cancer to occur, and/or less likely to have an unfavorable significant event in the time course of disease-during the treatment with the HER2 acting agent, wherein the HER2 acting agent is a HER2 antibody or a small molecule kinase inhibitor, comprising:

(a) providing a biological sample from the subject'"'"'s cancer;

(b) measuring the amount of HER3 in the biological sample using a HER3 antibody that is at least one of;

(i) a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having the 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 the sequences as set forth in SEQ ID NOs;

16, 17 and 18, respectively;

or

(ii) a monoclonal antibody comprising (a) a light chain variable region comprising CDR1, CDR2 and CDR3 having the 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 the sequences as set forth in SEQ ID NOs;

22, 23 and 24, respectively;

(c) determining that the subject is more likely to respond to the HER2 acting agent, more likely to have a long time course for unfavorable significant events to occur, and/or less likely to have an unfavorable significant event in the time course of disease during the treatment with the HER2 acting agent if the amount of HER3 in the biological sample is below a HER3 cutoff than if the amount of HER3 in the biological sample is above the HER3 cutoff, the HER3 cutoff having been determined by positional scanning analysis of a cohort of subjects having HER2 positive cancer of the same kind as the subject.

2. The method of claim 1, wherein the cutoff is a median of HER3 levels in the cohort of subjects having HER2 positive cancer of the same kind as the subject.

3. The method of claim 1, wherein measuring the amount of HER3 in the biological sample comprises measuring at least one of total HER3 protein, HER3 homodimers, or HER3 heterodimers.

4. The method of claim 1, wherein measuring the amount of HER3 in the biological sample comprises using immunohistochemistry to quantitate the amount of HER3.

5. The method of claim 1, wherein measuring the amount of HER3 in the biological sample comprises the steps of:

a) contacting the biological sample with the HER3 antibody;

b) contacting the HER3 antibody with a tagged antibody, wherein the tagged antibody comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged antibody is capable of specifically binding to the HER3 antibody;

c) cleaving the cleavable linker of the tagged antibody, thereby releasing the molecular tag; and

d) quantitating the released molecular tag to determine the amount of HER3 protein in the biological sample.

6. The method of claim 1, wherein the HER3 antibody is at least one of an antibody comprising the 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.

7. The method of claim 1, further comprising:

(i) measuring the amount of a p95 protein in the biological sample;

(ii) determining whether the amount of p95 in the biological sample is above a p95 cutoff; and

(iii) determining that the subject is more likely to respond to the HER2 acting agent, more likely to have a long time course for unfavorable significant events to occur during treatment with the HER2 acting agent, and/or less likely to have an unfavorable significant event during treatment with the HER2 acting agent if the amount of p95 in the biological sample is below the p95 cutoff than if the amount of HER3, the amount of p95, or both, in the biological sample are above their respective cutoffs.

8. The method of claim 7, wherein measuring the amount of p95 in the biological sample comprises measuring the amount of total p95 protein.

9. The method of claim 7, wherein measuring the amount of p95 in the biological sample comprises the steps of:

a) contacting the biological sample with a p95 antibody that specifically binds to p95 protein;

b) contacting the p95 antibody with a tagged antibody, wherein the tagged antibody comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged antibody specifically binds to the p95 antibody;

c) cleaving the cleavable linker of the tagged antibody, thereby releasing the molecular tag; and

d) quantitating the released molecular tag to determine the amount of p95 protein in the biological sample.

10. The method of claim 1, wherein the subject'"'"'s cancer has been characterized as HER2 positive based on the amount of HER2 in the biological sample being above a HER2 cutoff.

11. The method of claim 10, wherein the amount of HER2 in the biological sample is measured by measuring at least one of total HER2 protein or HER2 homodimers.

12. The method of claim 10, wherein the subject'"'"'s cancer has been characterized as HER2 positive by a method comprising quantitation of HER2 gene expression levels or HER2 gene copy number.

13. The method of claim 10, wherein the subject'"'"'s cancer has been characterized as HER2 positive by quantitating the amount of HER2 in the biological sample by in situ hybridization, immunohistochemistry, quantitative mRNA analysis, a hybridization array, or a combination of any thereof.

14. The method of claim 10, wherein characterization of the subject'"'"'s cancer as HER2 positive comprises the steps of:

a) contacting the biological sample with a HER2 antibody;

b) contacting the HER2 antibody with a tagged antibody, wherein the tagged antibody comprises a molecular tag attached thereto via a cleavable linkage, and wherein the tagged antibody specifically binds to the HER2 antibody;

c) cleaving the cleavable linker of the tagged antibody, thereby releasing the molecular tag; and

d) quantitating the released molecular tag to determine the amount of HER2 protein in the biological sample.

15. The method of claim 1, wherein likeliness to respond to the HER2 acting agent is measured by at least one of overall survival, time to progression, disease-free survival, progression-free survival (PFS), time to distant reoccurrence (TTDR), hazard ratio, or objective tumor response or clinical benefit using the RECIST criteria.

16. 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.

17. The method of claim 1, wherein the subject'"'"'s cancer comprises metastatic breast cancer.

18. The method of claim 1, wherein the subject'"'"'s cancer comprises early stage breast cancer.

19. The method of claim 1, wherein the HER2 acting agent comprises a single-target agent.

20. The method of claim 1, wherein the HER2 acting agent comprises a multi-target agent.

21. The method of claim 1, wherein the HER2 acting agent comprises a dual kinase inhibitor or a bispecific antibody.

22. The method of claim 1, wherein the HER2 acting agent comprises at least one of trastuzumab, lapatinib, pertuzumab, erlotinib, or gefitinib.