Search

CA-3059366-C - ANTI-CD137 ANTIBODIES AND METHODS OF USE THEREOF

CA3059366CCA 3059366 CCA3059366 CCA 3059366CCA-3059366-C

Abstract

The instant disclosure provides antibodies that specifically bind to CD137 (e.g., human CD137) and increases CD137 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Inventors

  • Yanping Xiao
  • Olga Ignatovich
  • Nicholas Stuart Wilson
  • Benjamin Maxime Morin
  • Mark Arthur Findeis
  • Cornelia Anne Mundt
  • Marc van Dijk
  • Dhan Sidhartha Chand
  • David Adam Savitsky
  • Dennis John Underwood

Assignees

  • AGENUS INC.

Dates

Publication Date
20260505
Application Date
20180412
Priority Date
20170413

Claims (20)

  1. WHAT IS CLAIMED IS: 1. An isolated antibody that specifically binds to human CD137, the antibody comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) CDRHl, CDRH2, and CDRH3, and a light chain variable region (VL) comprising CDRs CDRLl, CDRL2, and CDRL3, wherein CDRHl, CDRH2, CDRH3, CDRLl, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6; 1, 2, 59, 4, 5, and 6; 1, 2, 3, 4, 5, and 60; 1, 2, 3, 4, 5, and 61; or 1, 2, 3, 4, 5, and 62, respectively.
  2. 2. The isolated antibody of claim 1, wherein the VH comprises an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7.
  3. 3. The isolated antibody of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, 63, 64, or 65.
  4. 4. The isolated antibody of claim 3, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7.
  5. 5. The isolated antibody of claim 1, wherein the VL comprises an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8.
  6. 6. The isolated antibody of claim 1, wherein the VL comprises the amino acid sequence of SEQ ID NO: 8, 66, 67, or 68.
  7. 7. The isolated antibody of claim 6, wherein the VL comprises the amino acid sequence of SEQ ID NO: 8.
  8. 8. The isolated antibody of claim 1, wherein the VH and VL comprise the amino acid sequences of SEQ ID NOs: 7 and 8; 63 and 8; 64 and 66; 7 and 67; or 65 and 68, respectively. 135 Date re~ue/Date received 2024-06-10
  9. 9. The isolated antibody of claim 8, wherein the VH and VL comprise the amino acid sequences of SEQ ID NOs: 7 and 8, respectively.
  10. 10. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
  11. 11. The isolated antibody of claim 10, wherein the antibody comprises an IgG 1 heavy chain constant region.
  12. 12. The isolated antibody of claim 11, wherein the antibody comprises an IgG 1 heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 15.
  13. 13. The isolated antibody of claim 11, wherein the amino acid sequence of the IgGl heavy chain constant region comprises an N297 A mutation, numbered according to the EU numbering system.
  14. 14. The isolated antibody of claim 13, wherein the antibody comprises an IgGl heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 16.
  15. 15. The isolated antibody of claim 11, wherein the amino acid sequence of the IgG 1 heavy chain constant region comprises S267E and L328F mutations, numbered according to the EU numbering system.
  16. 16. The isolated antibody of claim 15, wherein the antibody comprises an IgGl heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 17.
  17. 17. The isolated antibody of claim 10, wherein the antibody comprises an IgG2 heavy chain constant region. 136 Date re~ue/Date received 2024-06-10
  18. 18. The isolated antibody of claim 17, wherein the antibody comprises an IgG2 heavy chain constant region comprising the amino acid sequence of SEQ IDNO: 18.
  19. 19. The isolated antibody of claim 17, wherein the amino acid sequence of the IgG2 heavy chain constant region comprises an N297 A mutation, numbered according to the EU numbering system.
  20. 20. The isolated antibody of claim 17, wherein the antibody comprises an IgG2 heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 19.

Description

ANTI-CD137 ANTIBODIES AND METHODS OF USE THEREOF [0001] 1. FIELD [0002] The instant disclosure relates to antibodies that specifically bind to CD137 (e.g., 5 human CD137) and methods of using the same. 2. BACKGROUND [0003] CD137, also known as TNFRSF9 or 4-lBB, is a transmembrane protein in the Tumor Necrosis Factor (TNF) receptor superfamily. It has an N-terminal extracellular domain containing cysteine-rich motifs, a transmembrane domain, and a short C-terminal cytoplasmic 10 domain containing potential phosphorylation sites. CD137 is expressed on activated CD4+ T lymphocytes, activated CD8+ T lymphocytes, activated natural killer (NK) cells, monocytes, dendritic cells, B cells, neutrophils, and mast cells (Vinay et al. (2011) Cellular & Molecular Immunology 8:281-84). CD137L, also known as TNFSF9 or 4-lBBL, is a ligand of CD 137. Upon CD137L binding, CD137 transduces a co-stimulatory signal that promotes cell survival, 15 proliferation, cytokine production, and activation of effector functions. CD137L binding to CD137 has also been shown to co-stimulate CD8+ T cells to a greater degree than CD4+ T cells. [0004] Studies in animal models have shown that ligation ofCD137, using eitherCD137L or agonistic antibodies, suppresses tumor growth by promoting T cell activity (Vinay et al. 20 (2012) Mol. Cancer. Tuer. 11:1062-70). CD137 has also been shown to enhance T cell immunity against human immunodeficiency virus (HIV) and hepatitis C virus (HCV) following vaccination (Munks et al. (2004) Immunology 112:559-66; Arribillaga et al. (2005) Vaccine 23:3493-99). Additionally, CD137 agonists have been shown to ameliorate autoimmunity in animal models of lupus, collagen-induced arthritis, and experimental autoimmune 25 encephalomyelitis. [0005] Given the apparent role of human CD137 in modulating immune responses, therapeutic agents designed to promote CD137 signaling hold great promise for the treatment of diseases that involve immune suppression. 3. SUMMARY [0006] The instant disclosure provides antibodies that specifically bind to CD137 (e.g., human CD137 or cynomolgus CD137) and increase or promote CD137 function, e.g., 1 Date re<;ue/Date received 2024-06-10 CD 137-mediated immune activation. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies. The antibodies disclosed herein are particularly useful for increasing T cell 5 activation against an antigen (e.g., a tumor antigen or an infectious disease antigen) and/or decreasing Treg-mediated immune suppression, and hence for treating cancer in a subject or treating or preventing an infectious disease in a subject. [0007] Accordingly, in one aspect, the instant disclosure provides an antibody or isolated antibody comprising a heavy chain variable region (VH) comprising complementarity 10 determining regions (CDRs) CDRHl, CDRH2 and CDRH3 and a light chain variable region (VL) comprising complementarity determining regions CDRLI, CDRL2 and CDRL3, wherein: (a) CDRHl comprises the amino acid sequence ofX1X2X3X4H (SEQ ID NO: 82), wherein X1 is G, A, D, E, L, N, Q, R, S, or W; X2 is Y, F, H, N, R, or S; X3 is Y or H; and X4 is M, I, T, or V; (b) CDRH2 comprises the amino acid sequence ofWINPNSGGTNYAQKFQG (SEQ ID NO: 2); 20 (c) CDRH3 comprises the amino acid sequence ofX1PX2YX3GX4GLXsX6 (SEQ ID NO: 83), wherein X1 is E or G; X2 is G, A, R, or S; X3 is Y, F, H, or S; X4 is S, A, or T; Xs is D or G; and X6 is Y orH; (d) CDRLI comprises the amino acid sequence of GGDDIGDKRVH (SEQ ID NO: 4); (e) CDRL2 comprises the amino acid sequence ofEDRYRPS (SEQ ID NO: 5); and/or 30 (f) CDRL3 comprises the amino acid sequence of QX1WX2X3X4XsX6X1PGV (SEQ ID NO: 84), wherein X1 is V or I; X2 isD,A, E, G, H, N, orY; X3 is S, A, E, F, L, P, R, T, W, or Y; 2 WO 2018/191502 X4 is S, A, L, M, or R; Xs is S, A, F, G, L, P, Q, R, or T; X6 is D, E, H, V, or Y; and X7 is H orY. 5 [0008] In certain embodiments, PCT/US2018/027310 (a) CDRHl comprises the amino acid sequence ofX1X2YX3H (SEQ ID NO: 85), wherein X1 is G, A, D, L, R, S, orW; X2 is Y, F, H, orN; and X3 is M orV; 10 (b) CDRH3 comprises the amino acid sequence of EPGYX1GX2GLDX3 (SEQ ID NO: 86), wherein X1 is Y or F; X2 is Sor T; and X3 is Y or H; and/or 15 (c) CDRL3 comprises the amino acid sequence of QVWX1X2X3X4XsX6PGV (SEQ ID NO: 87), wherein X1 is D, A, E, H, N, or Y; X2 is S, A, E, L, R, or T; X3 is S, A, L, or R; 20 X4 is S, A, F, G, L, P, Q, or R; Xs is D, E, or V; and X6 is H orY. [0009] In certain embodiments, (a) CDRHl comprises the amino acid sequence of GYYMH (SEQ ID NO: l); 25 (b) CDRH3 comprises the amino acid sequence of EPGYYGSGLDY (SEQ ID NO: 3) or EPGYYGTGLDY (SEQ ID NO: 59); and/or (c) CDRL3 comprises the amino acid sequence of QVWDSSSDHPGV (SEQ ID NO: 6), QVWNSSSDHPGV (SEQ ID NO: 60), QVWDSSSDYPGV (SEQ ID NO: 61), or QVWYSSPDHPGV (SEQ ID NO: 6