Claims for Patent: 8,691,231

Summary for Patent: 8,691,231

Title:	Methods of treatment of tumors expressing predominantly high affinity EGFR ligands or tumors expressing predominantly low affinity EGFR ligands with monoclonal and oligoclonal anti-EGFR antibodies
Abstract:	Disclosed are pharmaceutical preparations for, and methods for determining, appropriate and effective treatment with therapeutic agents comprising a single species of anti-EGFR monoclonal antibody or therapeutic agents comprising a plurality of species of such antibodies, as well as kits useful for making such determinations.
Inventor(s):	Bukhalid; Raghida (Melrose, MA), Nielsen; Ulrik (Quincy, MA), Werner; Shannon (Belmont, MA), Kearns; Jeffrey David (Arlington, MA)
Assignee:	Merrimack Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	13/488,270
Patent Claims:	1. A method for determining whether a patient having a tumor is predicted to have an unfavorable outcome as a result of treatment #1 with a monoclonal anti-EGFR antibody preparation comprising a single species of monoclonal antibody, and a favorable outcome as a result of treatment #2 with an oligoclonal anti-EGFR antibody preparation comprising a plurality of species of monoclonal anti-EGFR antibodies, one against each of at least two extracellular epitopes of EGFR, or, whether the patient is predicted to have the favorable outcome as a result of treatment #2 and as a result of treatment #1; the method comprising: obtaining a biopsy sample of the tumor and: a) measuring levels of protein of, or of RNAs coding for, at least two low affinity EGFR ligands selected from amphiregulin, epigen, or epiregulin in the biopsy sample, b) measuring levels of protein of, or of RNAs coding for, at least two high affinity EGFR ligands selected from betacellulin, EGF, HB-EGF or TGF.alpha. in the biopsy sample, wherein all of the levels measured in a) and b) are protein levels or all of the levels measured in a) and b) are RNA levels, and c) comparing the average level of protein of, or of RNAs coding for, each of the high affinity EGFR ligands measured in a) to the average level of protein of, or of RNAs coding for, each of the low affinity EGFR ligands measured in b); and wherein, if the average level of protein of, or of RNAs coding for, low affinity EGFR ligands measured in a) is greater than the average level of protein of, or of RNAs coding for, high affinity EGFR ligands measured in b), the patient is predicted to have the favorable outcome as a result of treatment #1 and the patient is also predicted to have the favorable outcome as a result of treatment #2, and if the average level of protein of, or of RNAs coding for, low affinity EGFR ligands measured in a) is less than or equal to the average level of protein of, or of RNAs coding for, high affinity EGFR ligands measured in b), the patient is predicted to have an unfavorable outcome from treatment #1 and is predicted to have a favorable outcome from treatment #2. 2. The method of claim 1, wherein: the at least two low affinity EGFR ligands is low affinity ligands. 3. The method of claim 1, wherein the at least two high affinity EGFR ligands is at least three high affinity ligands. 4. The method of claim 1, wherein the favorable outcome comprises reduction of growth of the tumor. 5. The method of claim 1, wherein the tumor is malignant. 6. The method of claim 1, wherein the method comprises measuring levels of mRNA. 7. The method of claim 1, wherein the monoclonal anti-EGFR antibody preparation comprises cetuximab, zalutumumab, matuzumab, or nimotuzumab. 8. The method of claim 1, wherein members of the plurality of anti-EGFR antibody species separately and uniquely bind to more than two different extracellular epitopes of EGFR. 9. The method of claim 8, wherein the members of the plurality of anti-EGFR antibody species separately and uniquely bind to no more than three extracellular epitopes of EGFR. 10. The method of claim 8, wherein the oligoclonal anti-EGFR antibody preparation comprises no more than three different species of monoclonal anti-EGFR antibodies. 11. The method of claim 10, wherein the oligoclonal anti-EGFR antibody preparation comprises a first monoclonal antibody comprising heavy and light chain variable regions comprising SEQ ID NOs: 1 and 2, respectively, a second monoclonal antibody comprising heavy and light chain variable regions comprising SEQ ID NOs:3 and 4, respectively, and a third monoclonal antibody comprising heavy and light chain variable regions comprising SEQ ID NOs:5 and 6, respectively. 12. The method of claim 1, wherein the tumor is a tumor of the skin, central nervous system, head, neck, esophagus, stomach, colon, rectum, anus, liver, pancreas, bile duct, gallbladder, lung, breast, ovary, uterus, cervix, vagina, testis, germ cells, prostate, kidney, ureter, urinary bladder, adrenal, pituitary, thyroid, bone, muscle or connective tissue. 13. A method of treating a patient having a tumor, the method comprising: determining, according to the method of claim 1 that the patient is predicted to have the favorable outcome as a result of treatment #2 and as a result of treatment #1, wherein the patient is treated with treatment #1. 14. The method of claim 13, wherein the tumor is a malignant tumor. 15. A method of treating a patient having a tumor, the method comprising: determining, according to the method of claim 1 that the patient is predicted to have the unfavorable outcome as a result of treatment #1 and the favorable outcome as a result of treatment #2, wherein the patient is treated with treatment #2. 16. The method of claim 1, wherein the oligoclonal anti-EGFR antibody preparation comprises one or more of cetuximab, zalutumumab, nimotuzumab and panitumumab. 17. A method for determining whether or not a monoclonal anti-EGFR antibody preparation comprising only a single species of anti-EGFR antibody should be used to treat a malignant tumor, the method comprisingobtaining a biopsy sample of the tumor and: a) measuring levels of protein of, or of RNAs coding for, at least two low affinity EGFR ligands selected from amphiregulin, epigen, or epiregulin in the biopsy sample, b) measuring levels of protein of, or of RNAs coding for, at least two high affinity EGFR ligands selected from betacellulin, EGF, HB-EGF or TGF.alpha. in the biopsy sample, wherein, all of the levels measured in a) and b) are protein levels or all of the levels measured in a) and b) are RNA levels, and c) comparing the average level of protein of, or of RNAs coding for, each of the low affinity EGFR ligands measured in a) to the average level of protein of, or of RNAs coding for, each of the high affinity EGFR ligands measured in b); wherein, if the average level of protein of, or of RNAs coding for, low affinity EGFR ligands measured in a) is greater than the average level of protein of, or of RNAs coding for, high affinity EGFR ligands measured in b), the monoclonal anti-EGFR antibody preparation should be used to treat the tumor, and if the average level of protein of, or of RNAs coding for, low affinity EGFR ligands measured in a) is less than or equal to the average level of protein of, or of RNAs coding for, high affinity EGFR ligands measured in b), the monoclonal anti-EGFR antibody preparation should not be used to treat the tumor.

Details for Patent 8,691,231

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2031-06-03
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2031-06-03
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2031-06-03