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US-12624106-B2 - Combination of LILRB1/2 pathway inhibitors and PD-1 pathway inhibitors

US12624106B2US 12624106 B2US12624106 B2US 12624106B2US-12624106-B2

Abstract

This invention relates to combination therapies comprising a Programmed Death 1 receptor (PD-1) pathway inhibitor, and a Leukocyte Immunoglobulin Like Receptor B (LILRB) signaling inhibitor, and the use of the combination therapies for the treatment of cancer. The invention also relates to the treatment of cancer patients who are refractory to monotherapy with a PD-1 pathway inhibitor.

Inventors

  • Xin Yu
  • Wenjun Ouyang
  • Chi-Ming Kevin LI
  • Jackson Graeme EGEN
  • Oh Kyu YOON
  • Ian Halsey DRIVER
  • Shunsuke Takenaka
  • Christy Ann THOMSON
  • Hongyu Wang

Assignees

  • AMGEN INC.

Dates

Publication Date
20260512
Application Date
20190717

Claims (20)

  1. 1 . A method for increasing Interferon-gamma (IFN-γ) expression level in a subject that has cancer, as compared to a control, comprising administering to the subject a therapeutically effective amount of (i) a first antibody, or antigen-binding fragment thereof, that binds Programmed death-1 (PD-1) or Programmed death-ligand 1 (PD-L1); and (ii) a second antibody, or antigen-binding fragment thereof, that binds leukocyte immunoglobulin-like receptor B1 (LILRB1), wherein said first antibody, or antigen-binding fragment thereof is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, anti-PD1 antibody clone 20C1, and an antigen-binding fragment of any of the foregoing; and wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 39, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 40; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 41; or (ii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 48, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 49; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 50; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 52; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 53; or (iii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 58, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 59; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 61, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 62; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 63.
  2. 2 . The method of claim 1 , wherein said first antibody, or antigen-binding fragment thereof, binds PD-1 and comprises: a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and a light chain variable region (VL) that comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24.
  3. 3 . A method for increasing CD8+ T-cell mediated cytotoxicity in a subject that has cancer, as compared to a control, comprising administering to the subject a therapeutically effective amount of (i) a first antibody, or antigen-binding fragment thereof, that binds PD-1 or PD-L1; and (ii) a second antibody, or antigen-binding fragment thereof, that binds LILRB1, wherein said first antibody, or antigen-binding fragment thereof is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, anti-PD1 antibody clone 20C1, and an antigen-binding fragment of any of the foregoing; and wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 39, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 40; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 41; or (ii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 48, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 49; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 50; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 52; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 53; or (iii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 58, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 59; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 61, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 62; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 63.
  4. 4 . The method of claim 3 , wherein said first antibody, or antigen-binding fragment thereof, binds PD-1 and comprises: a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and a light chain variable region (VL) that comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24.
  5. 5 . A method for treating a subject that has a tumor, wherein said subject is refractory to treatment with an anti-PD-1 antibody or antigen-binding fragment thereof, or an anti-PD-L1 antibody or antigen-binding fragment thereof, comprising: administering to the subject a therapeutically effective amount of (i) a first antibody, or antigen-binding fragment thereof, that binds PD-1 or PD-L1; and (ii) a second antibody, or antigen-binding fragment thereof, that binds LILRB1, wherein said first antibody, or antigen-binding fragment thereof is selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, anti-PD1 antibody clone 20C1, and an antigen-binding fragment of any of the foregoing; and wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 39, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 40; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 41; or (ii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 48, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 49; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 50; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 52; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 53; or (iii) a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 58, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 59; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) that comprises: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 61, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 62; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 63.
  6. 6 . The method of claim 5 , wherein said first antibody, or antigen-binding fragment thereof, binds PD-1 and comprises: a heavy chain variable region (VH) that comprises: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 20; and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and a light chain variable region (VL) that comprises: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 23; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 24.
  7. 7 . The method of claim 1 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 42; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 43; or (ii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 54; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 55; or (iii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 64; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 65.
  8. 8 . The method of claim 1 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin G (IgG) heavy chain constant region.
  9. 9 . The method of claim 8 , wherein said human IgG is IgG1, IgG2, or IgG4.
  10. 10 . The method of claim 1 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin kappa or lambda constant domain region.
  11. 11 . The method of claim 1 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a heavy chain constant domain comprising the amino acid sequence of any of SEQ ID NOs: 46 and 68-70, and a light chain constant domain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 47.
  12. 12 . The method of claim 3 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 42; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 43; or (ii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 54; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 55; or (iii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 64; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 65.
  13. 13 . The method of claim 3 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin G (IgG) heavy chain constant region.
  14. 14 . The method of claim 13 , wherein said human IgG is IgG1, IgG2, or IgG4.
  15. 15 . The method of claim 3 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin kappa or lambda constant domain region.
  16. 16 . The method of claim 3 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a heavy chain constant domain comprising the amino acid sequence of any of SEQ ID NOs: 46 and 68-70, and a light chain constant domain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 47.
  17. 17 . The method of claim 5 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and comprises: (i) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 42; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 43; or (ii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 54; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 55; or (iii) a heavy chain variable region (VH) that comprises the amino acid sequence of SEQ ID NO: 64; and a light chain variable region (VL) that comprises the amino acid sequence of SEQ ID NO: 65.
  18. 18 . The method of claim 5 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin G (IgG) heavy chain constant region.
  19. 19 . The method of claim 18 , wherein said human IgG is IgG1, IgG2, or IgG4.
  20. 20 . The method of claim 5 , wherein said second antibody, or antigen-binding fragment thereof, binds LILRB1 and further comprises a human immunoglobulin kappa or lambda constant domain region.

Description

RELATED APPLICATIONS This application is the U.S. National Phase of International Application No. PCT/US2019/042234, filed Jul. 17, 2019 and published in English, which claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/702,493, filed Jul. 24, 2018, and U.S. Provisional Application No. 62/872,431, filed Jul. 10, 2019. The complete contents of the aforementioned applications are incorporated herein by reference for all purposes. SEQUENCE LISTING 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 Jan. 21, 2021, is named A-2271-US-PCT_SL.txt and is 122,949 bytes in size. FIELD OF THE INVENTION The present invention relates to combination therapies useful for the treatment of cancer. BACKGROUND OF THE INVENTION In the two-signal model T-cell activation is regulated by both positive and negative secondary co-stimulatory signals that function to maximize the host's protective immune responses, while maintaining immune tolerance and preventing autoimmunity. While the two-signal model was originally developed to describe the regulation of naive lymphocyte activation, a host's immune response is a multi-step and dynamic process and a similar paradigm of regulation by co-stimulatory signals applies to antigen-experienced T-cells. The positive and negative co-stimulatory signals regulating both naive and antigen-experienced T cell activation are of therapeutic interest as manipulation of these signals provides a means to either enhance or terminate cell-based immune response. For example, the inhibitory receptor programmed cell death 1 (PD-1) is upregulated on chronically stimulated T cells and its sustained expression correlates with T cell dysfunction or anergy. As a result, therapeutics aimed at enhancing T cell activation by targeting of PD-1 or other molecules which signal through interactions with PD-1, such as programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), have generated great interest. PD-L1 is overexpressed in many cancers and is often associated with poor prognosis (Okazaki T et al., Intern. Immun. 2007 19(7):813; Thompson R H et al., Cancer Res 2006, 66(7):3381). Interestingly, the majority of tumor infiltrating T lymphocytes predominantly express PD-1, in contrast to T lymphocytes in normal tissues and peripheral blood T lymphocytes, indicating that up-regulation of PD-1 on tumor-reactive T cells can contribute to impaired antitumor immune responses (Blood 2009 114(8):1537). This may be due to exploitation of PD-L1 signaling, mediated by PD-L1 expressing tumor cells interacting with PD-1 expressing T cells, resulting in attenuation of T cell activation and evasion of immune surveillance (Sharpe et al., Nat Rev 2002, Keir M E et al., 2008 Annu. Rev. Immunol. 26:677). Therefore, inhibition of the PD-L1/PD-1 interaction may enhance CD8+ T cell-mediated killing of tumors. Therapeutic approach of blocking the PD-1/PD-L1 immune checkpoint proteins as anticancer agents has been successful in treating melanoma and NSCLC patients. However, overall more than 70% of cancer patients do not respond to PD-1 blockade. This may be because additional inhibitory mechanisms function to inhibit the activity of CD8+ T cells within the tumor microenvironment. For instance, CD8+ T cells can express other inhibitory receptors in addition to PD-1. Therefore, combination of therapeutic drugs that target different immune regulatory pathways may increase efficacy in cancer treatment. For example, clinical trial data of anti-PD-1 combined with anti-CTLA4, another checkpoint receptor on T cells, has shown improved efficacy in melanoma patients. There is a need for improved therapies for the treatment of cancer, in particular in patients who are poor responders to anti-PD-1/anti-PD-L1 treatment. SUMMARY OF THE INVENTION Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E). E1. A method for increasing IFN-γ expression level in a subject that has cancer, comprising administering to the subject a therapeutically effective amount of (i) a first antibody, or antigen-binding fragment thereof, that binds PD-1, PD-L1, or PD-L2; and (ii) a second antibody, or antigen-binding fragment thereof, that binds LILRB1, LILRB2, or HLA-G. E2. The method of E1, wherein said first antibody, or antigen-binding fragment thereof, binds PD-1. E3. The method of E1 or E2, wherein said first antibody, or antigen-binding fragment thereof, binds human PD-1. E4. The method of any one of E1-E3, wherein said first antibody is nivolumab, pembrolizumab, pidilizumab, or an antigen binding fragment thereof. E5. The meth