Building IP: BMY Patent Application re "TREATMENT OF CANCER WITH ANTI-GITR AGONIST ANTIBODIES" | BMY Message Board Posts

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Msg  4162 of 4337  at  9/17/2020 1:23:13 AM  by

JBWIN


Building IP: BMY Patent Application re "TREATMENT OF CANCER WITH ANTI-GITR AGONIST ANTIBODIES"

 
United States Patent Application20200291122
Kind CodeA1
KRISHNAN; Suba ; et al.September 17, 2020

TREATMENT OF CANCER WITH ANTI-GITR AGONIST ANTIBODIES

Abstract

Provided herein are methods for treating cancer, comprising administering to a subject having cancer a therapeutically effective amount of an anti-GITR antibody alone or together with an anti-PD-1 or anti-PD-L1 antibody.


Inventors:KRISHNAN; Suba; (New York, NY) ; PHILLIPS; Penny E.; (Morristown, NJ) ; YANG; Zheng; (Plainsboro, NJ) ; WANG; Haiqing; (Princeton, NJ)
Applicant:
NameCityStateCountryType

BRISTOL-MYERS SQUIBB COMPANY

Princeton

NJ

US
Family ID:1000004887077
Appl. No.:16/612956
Filed:May 15, 2018
PCT Filed:May 15, 2018
PCT NO:PCT/US2018/032750
371 Date:November 12, 2019

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62507071May 16, 2017
62514245Jun 2, 2017
62514312Jun 2, 2017
62573494Oct 17, 2017

Current U.S. Class:1/1
Current CPC Class:C07K 16/2878 20130101; A61K 2039/507 20130101; C07K 16/2827 20130101; C07K 2317/76 20130101; C07K 16/2818 20130101; A61P 35/00 20180101; C07K 2317/75 20130101; A61K 2039/545 20130101
International Class:C07K 16/28 20060101 C07K016/28; A61P 35/00 20060101 A61P035/00

Claims



1. A method of treating a subject having an advanced solid cancer, comprising administering to the subject a combination regimen comprising (1) a GITR agonist agent, and (2) a PD-1 or PD-L1 antagonist agent, wherein the GITR agonist agent and the PD-1 or PD-L1 antagonist agent are administered on the same day and for at least one cycle, wherein each cycle comprises 4 administrations of the combination regimen.

2. (canceled)

3. The method of claim 1, wherein the combination regimen increases the level of one or more of the following cell populations in the peripheral blood of the subject: proliferating (Ki67+) CD8 cells; proliferating CD4 effector memory T cells; activated CD4 effector memory T cells; proliferating CD4 central memory T cells; activated CD4 central memory T cells; proliferating CD8 effector memory T cells; activated CD8 effector memory T cells; proliferating CD8 central memory T cells; and/or activated CD8 central memory T cells, wherein proliferating (Ki67+) CD8 cells are CD45+CD3+CD4-CD8+Ki67+; proliferating CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-Ki67+cells (CD197 is CCR7); activated CD4 effector memory cells are CD45+CD3+CD4+CD8-CD197-CD45RA-HLA-DR+; proliferating CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-Ki67+; and activated CD4 central memory cells are CD45+CD3+CD4+CD8-CD197+CD45RA-HLA-DR+; proliferating CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-Ki67+cells; activated CD8 effector memory cells are CD45+CD3+CD4-CD8+CD197-CD45RA-HLA-DR+; proliferating CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-Ki67+; and activated CD8 central memory cells are CD45+CD3+CD4-CD8+CD197+CD45RA-HLA-DR+.

4-11. (canceled)

12. The method of claim 1, wherein administration of a second or subsequent dose of the combination regimen occurs on a day when one or more of the following cell populations in the peripheral blood of the subject is at or close to its level immediately prior to administration of a first or previous dose of the combination regimen: (a) proliferating (Ki67+) CD8 cells; (b) proliferating (Ki67+) and/or activated (HLA-DR+) memory CD4 and/or CD8 cells; (c) proliferating (Ki67+) NK cells, (d) proliferating CD8 effector memory T cells; (e) activated CD8 effector memory T cells; (f) proliferating CD8 central memory T cells; (g) activated CD8 central memory T cells; (h) proliferating CD4 effector memory T cells; (i) activated CD4 effector memory T cells; (j) proliferating CD4 central memory T cells; (k) activated CD4 central memory T cells, (1) proliferating CD8 effector memory T cells; and (m) activated CD8 effector memory T cells.

13-16. (canceled)

17. The method of claim 12, wherein administration of the second or subsequent dose of the combination regimen occurs on a day when the one or more cell populations that are increased are within 2 fold of their baseline level wherein the baseline level is the level immediately prior to administration of the combination regimen.

18. (canceled)

19. The method of claim 1, wherein the treatment comprises a. measuring the level of (a) proliferating CD8 cells; (b) proliferating (Ki67+) and/or activated (HLA-DR+) memory T cells and/or (c) proliferating (Ki67+) NK cells in the circulating blood of the subject prior to, and within 3-10 days, after administration of a dose, e.g., the first dose, of the combination regimen; and b. administering a second for subsequent dose of the combination regimen when the level of (a) proliferating CD8 cells; (b) proliferating (Ki67+) and/or activated (HLA-DR+) memory T cells and/or (c) proliferating (Ki67+) NK cells, respectively, are close to their baseline level, e.g., within 2 fold.

20-21. (canceled)

22. The method of claim 1, wherein the combination regimen is administered to the subject every 2, 3 or 4 weeks, for at least one cycle, wherein each cycle comprises 4 administrations of the combination regimen.

23-27. (canceled)

28. The method of claim 22, wherein the combination regimen comprises a GITR agonist agent at a flat dose ranging from 30-800 mg and a PD-1 or PD-L1 antagonist agent at a flat dose of 30-800 mg, and the combination regimen is administered every 2, 3 or 4 weeks for at least one cycle, wherein each cycle comprises 4 administrations of the GITR agonist agent and 4 administrations of PD-1 or PD-L1 antagonist agent.

29-32. (canceled)

33. The method of claim 1, wherein the cancer is a tumor type comprising: (a) tumors expressing high levels of GITR, e.g., higher levels of GITR than most tumor types; (b) tumors having high levels of GITR positive Treg and/or Teff cells; (c) tumors having high levels of GITR positive Treg cells; and/or (d) tumors which are PD-L1 positive.

34-38. (canceled)

39. The method of claim 1, wherein: (a) the cancer is not typically responsive to immunotherapy, e.g., responsive to an anti-PD-1 or anti-PD-L1 antagonist; (b) the subject has not been previously treated with an immuno-oncology agent; (c) the subject has progressed on or after prior cancer therapy, e.g., chemotherapy, a BRAF inhibitor, MEK inhibitor, PI3K inhibitor, FGFR inhibitor, or VEGF inhibitor; and/or (d) the subject had progressed on or after a previous immunotherapy, e.g., a PD-1 or PD-L1 antagonist therapy.

40-45. (canceled)

46. The method of claim 1, wherein the cancer is lung cancer (e.g., NSCLC), SCCHN, cervical cancer (e.g., metastatic cervical cancer), melanoma, colon, breast, bladder, ovarian, HCC, nasopharyngeal cancer or adenocarcinoma of the ampulla of Vater.

47-52. (canceled)

53. The method of claim 1, wherein the PD-1 or PD-Ll antagonist agent is an anti-PD-1 or anti-PD-L1 antagonist antibody, e.g., nivolumab, pembrolizumab, atelozilumab, durvalumab, avelumab, REGN2810, PDR001, AMP-514 (MEDI0608), AMP-224, BGB-A317 or a PD-1 or PD-Ll antagonist described in any one of the following publications: WO 2009/014708, WO 03/099196, WO 2009/114335 and WO 2011/161699.

54-55. (canceled)

56. The method of claim 53, wherein the PD-1 or PD-L1 antagonist antibody is: (a) an antibody that comprises the VH CDR1, CDR2, CDR3 and VL CDR1, CDR2 and CDR3 of nivolumab or that competes with nivolumab for binding to human PD-1; (b) an antibody that comprises VH and VL regions that are least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence of the VH and VL regions, respectively, of nivolumab; (c) an antibody that comprises VH and VL regions of nivolumab; (d) an antibody that comprises a heavy chain that comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence the heavy chain of nivolumab, and a light chain that comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence the light chain of nivolumab; or (e) an antibody that comprises the heavy and light chains of nivolumab.

57-65. (canceled)

66. The method of claim 1, wherein the GITR agonist agent is: (a) an anti-GITR agonist antibody (including multivalent antibody); (b) GITRL or a fusion protein or multivalent form thereof; (c) TRX518; MK-4166; MK-1248; Medi 1873; AMG 228; LKZ-145; GWN-323; INCAGN01876; iNBRX-110 (FPA-154); CK-302; OMP-336B11; Regeneron/Sanofi anti-GITR antibody; HERA-GITR-ligands; or a GITR agonist agent described in any one of the following publications: WO06/105021; WO2011/028683; JP2008278814; US20140072566; US20140072565; US20140065152; WO2015/031667; WO/2015/116178; WO2015/184099; WO/2016/054638; WO2016/057841; WO2016/057846; CN 105669867; WO/2016/126781; WO/2017/015623; WO/2017/025610; WO/2017/068185; and WO/2017/06818 ; (d) an antibody which binds to human GITR comprising VH CDR1, CDR2, CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 20, 21 and 22, respectively, and VL CDR1, CDR2, CDR3 comprising amino acid sequences set forth in SEQ ID NOs: 23, 24 and 25, or competes with 28F3.IgG1 for binding to human GITR; (e) an antibody which binds to human GITR comprising a variable heavy domain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 13, and a variable light domain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 14; (f) an antibody which binds to human GITR comprising a variable heavy domain comprising the amino acid sequence set forth in SEQ ID NO: 13 and a variable light domain comprising the amino acid sequence set forth in SEQ ID NO: 14; (g) an antibody which binds to human GITR comprising a heavy chain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 17 and a light chain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 19; or (h) an antibody which binds to human GITR comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 19.

67-71. (canceled)

72. The method of claim 66, wherein the anti-GITR agonist antibody comprises an IgG heavy chain constant region.

73-78. (canceled)

79. The method of claim 66, comprising administering to a subject having an advanced solid cancer an anti-GITR agonist antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 17 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 19, at a flat dose ranging from 30-800 mg every 2 weeks, and 240 mg of nivolumab every 2 weeks on the same days as the anti-GITR agonist antibody, for at least 3 or 4 cycles, wherein each cycle comprises 4 administrations of the anti-GITR agonist antibody and 4 administrations of nivolumab.

80. The method of claim 1, wherein, after 8 days of treatment (with, e.g., 30-240 mg, of anti-GITR agonist agent and 240 mg nivolumab), (a) the number of proliferating (Ki67+) NK cells in peripheral blood is at least 2 fold higher (e.g., on average in a population of subjects that are being treated) relative to baseline level (level prior to the first dose), (b) the number of proliferating (Ki67+) CD8+ T cells or a subset thereof, such as memory CD8+ T cells (e.g., Teff memory cells and central memory T cells), in peripheral blood is at least 1.5 fold higher (e.g., on average in a population of subjects that are being treated) relative to baseline level (level prior to the first dose), (c) the number of activated (HLA-DR +) CD8+ T cells or a subset thereof, such as memory CD8+ T cells (e.g., Teff memory cells and central memory T cells), in peripheral blood is at least 1.5 fold higher (e.g., on average in a population of subjects that are being treated) relative to baseline level (level prior to the first dose), and/or (d) the number of activated (HLA-DR+) CD4+ T cells or a subset thereof, such as memory CD4+ T cells (e.g., Teff memory cells and central memory T cells), in peripheral blood is at least 1.5 fold higher (e.g., on average in a population of subjects that are being treated) relative to baseline level (level prior to the first dose).

81-85. (canceled)

86. A method of treating a subject having cancer with an immunotherapy, comprising administering to the subject a first dose and at least a second dose, wherein a first dose of the immunotherapy is administered and a second dose of immunotherapy is administered at a time when the proliferation or activation of peripheral effector memory T cells and/or central memory T cells are at or close to their respective baseline level that was present in the subject immediately prior to administration of the first dose of the immunotherapy.

87. The method of claim 86, further comprising determining the level of proliferation and/or activation of peripheral effector memory T cells and/or central memory T cells (e.g., CD8+ or CD4+ effector memory or central memory T cells) before the start of the immunotherapy (base level) and after administration of the first dose of immunotherapy, wherein the second and optionally subsequent, doses of immunotherapy are administered at a time when the proliferation and/or activation of peripheral effector memory T cells and/or central memory T cells is close to their respective base level.

88-89. (canceled)

90. A method of predicting whether a subject having cancer will respond to an immunotherapy treatment, comprising determining the level of proliferation or activation of peripheral effector memory T cells and/or central memory T cells (e.g., CD8+ effector memory or central memory T cells) before the start of an immunotherapy (base level) and after administration of the first and/or subsequent dose of the immunotherapy, wherein the presence of enhanced proliferation or activation of peripheral effector memory T cells and/or central memory T cells after administration of the first or subsequent dose of the immunotherapy relative to their respective base level, indicates that the subject is responding to the immunotherapy.

91. (canceled)

92. The method of claim 90, wherein the immunotherapy comprises a PD-1 or PD-L1 antagonist, and/or a GITR agonist.

93-98. (canceled)
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2018/032750, filed on May 15, 2018, which claims priority to U.S. Provisional Application Nos. 62/507,071, filed on May 16, 2017; 62/514,245, filed on Jun; 2, 2017; 62/514,312, filed on Jun. 2, 2017; and 62/573,494, filed on Oct. 17, 2017, respectively. The contents of the aforementioned applications are hereby incorporated by reference.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 12, 2019, is named MXI_559US_Sequence_Listing.txt and is 651,606 bytes in size.

BACKGROUND

[0003] The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.

[0004] Recently, several immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of an antibody (Ab), ipilimumab (YERVOY.RTM.), that binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) for the treatment of patients with advanced melanoma and the development of Abs such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013) that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway.

SUMMARY

[0005] Provided herein are methods of treatment of a subject having cancer, e.g., advanced solid tumors, by administering an anti-GITR agonist Ab in combination with an anti-PD-1 or anti-PD-L1 Ab.


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