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US-12624108-B2 - Anti-galectin-9 antibodies and uses thereof

US12624108B2US 12624108 B2US12624108 B2US 12624108B2US-12624108-B2

Abstract

Disclosed herein are anti-Galectin-9 antibodies and methods of using such for inhibiting a signaling pathway mediated by Galectin-9 or eliminating pathologic cells expressing Galectin-9. Such anti-Galectin-9 antibodies may also be used to diagnose and/or to treat diseases associated with Galectin-9, such as autoimmune diseases and solid tumors.

Inventors

  • Shohei Koide
  • George Miller
  • Akiko Koide
  • Linxiao Chen
  • Eric Elenko
  • Aleksandra Filipovic
  • Joseph Bolen

Assignees

  • NEW YORK UNIVERSITY
  • PURETECH LYT, INC.

Dates

Publication Date
20260512
Application Date
20220628

Claims (20)

  1. 1 . An isolated antibody, which binds human galectin-9, wherein the antibody comprises: (a) a heavy chain that comprises a heavy chain variable region (VH), which comprises a heavy chain complementarity determining region 1 (CDR1) comprising FTVSSSSIH (SEQ ID NO: 361), a heavy chain complementary determining region 2 (CDR2) comprising YISSSSGYTYYADSVKG (SEQ ID NO: 388), and a heavy chain complementary determining region 3 (CDR3) comprising YWSYPSWWPYRGMDY (SEQ ID NO: 406); and (b) a light chain that comprises a light chain variable region, which comprises a light chain complementarity determining region 1 (CDR1) comprising RASQSVSSAVA (SEQ ID NO: 328), a light chain complementary determining region 2 (CDR2) comprising SASSLYS (SEQ ID NO: 329), and a light chain complementary determining region 3 (CDR3) comprising QQSSTDPIT (SEQ ID NO: 352).
  2. 2 . The isolated antibody of claim 1 , which is a full-length antibody or an antigen-binding fragment thereof.
  3. 3 . The isolated antibody of claim 1 , which is a single chain antibody.
  4. 4 . The isolated antibody of claim 1 , which is a human antibody.
  5. 5 . The isolated antibody of claim 1 , which is an IgG molecule.
  6. 6 . The isolated antibody of claim 5 , wherein the antibody is an IgG1 or IgG4 molecule.
  7. 7 . The isolated antibody of claim 6 , wherein the antibody is an IgG4 molecule.
  8. 8 . The isolated antibody of claim 7 , wherein the IgG molecule has a S228P mutation.
  9. 9 . The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO: 108.
  10. 10 . The isolated antibody of claim 9 , wherein the heavy chain consists of the amino acid sequence of SEQ ID NO: 316 and the light chain consists of the amino acid sequence of SEQ ID NO: 108.
  11. 11 . A pharmaceutical composition, comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
  12. 12 . The pharmaceutical composition of claim 11 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO: 108.
  13. 13 . The pharmaceutical composition of claim 12 , wherein the heavy chain consists of the amino acid sequence of SEQ ID NO: 316 and the light chain consists of the amino acid sequence of SEQ ID NO: 108.
  14. 14 . The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable carrier comprises a buffer, a preservative, an amino acid, a chelating agent, a non-ionic surfactant, or a combination thereof.
  15. 15 . The pharmaceutical composition of claim 12 , wherein the pharmaceutically acceptable carrier comprises a buffer, a preservative, an amino acid, a chelating agent, a non-ionic surfactant, or a combination thereof.
  16. 16 . The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable carrier comprises a buffer, a preservative, an amino acid, a chelating agent, a non-ionic surfactant, or a combination thereof.
  17. 17 . A method for inhibiting the activity of galectin-9 or treating a solid tumor in a subject, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 11 .
  18. 18 . The method of claim 17 , wherein the pharmaceutical composition comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO: 108.
  19. 19 . The method of claim 18 , wherein the heavy chain consists of the amino acid sequence of SEQ ID NO: 316 and the light chain consists of the amino acid sequence of SEQ ID NO: 108.
  20. 20 . The method of claim 19 , wherein the pharmaceutical composition comprises a pharmaceutical acceptable carrier, which comprises a buffer, a preservative, an amino acid, a chelating agent, a non-ionic surfactant, or a combination thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application in a continuation of U.S. patent application Ser. No. 16/576,719, filed on Sep. 19, 2019, which is a continuation of Ser. No. 16/406,713, filed on May 8, 2019, now U.S. Pat. No. 10,450,374, which is a continuation of U.S. patent application Ser. No. 16/173,970, filed on Oct. 29, 2018, now U.S. Pat. No. 10,344,091, issued on Jul. 9, 2019, which claims priority to U.S. Provisional patent application No. 62/736,317, filed on Sep. 25, 2018, to U.S. Provisional patent application No. 62/665,175, filed on May 1, 2018, and to U.S. Provisional patent application No. 62/578,111, filed on Oct. 27, 2017, the disclosures of each of which are incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under CA215471 awarded by the National Institutes of Health. The government has certain rights in the invention. 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 Jun. 6, 2022, is named 112174-0077_SUBSEQ.txt, and is 1,052,403 bytes in size. BACKGROUND OF INVENTION Immune checkpoint blockade has demonstrated unprecedented success in the past few years as cancer treatment. Often antibodies are used to block immune inhibitory pathways, such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) pathways. While therapies targeting those two pathways have shown success in treating several cancer types, anti-CTLA-4 and anti-PD-1 therapies have a response rate of 10 to 60% of treated patients, depending on cancer type, and have not yet shown the ability to exceed a response rate of 60%, even when used in combination (Kyvistborg et al., Enhancing responses to cancer immunotherapy; Science. 2018 Feb. 2; 359(6375):516-517). Additionally, a large number of cancer types are refractory to these therapies. As part of efforts to improve existing immunotherapies in the clinic, the field has started to focus on the role of abnormalities in interferon signaling and upregulation of alternative checkpoints as potential causes for the limitation of current therapies. One such potential alternate checkpoint is T-cell immunoglobulin mucin-3 (Tim-3)/Galectin-9 (e.g., reviewed in Yang and Hung; The role of T-cell immunoglobulin mucin-3 and its ligand galectin-9 in antitumor immunity and cancer immunotherapy; Cancer biology and cancer treatment; October 2017, Vol. 60 No. 10: 1058-1064, and references therein). Galectin-9 is a tandem-repeat lectin consisting of two carbohydrate recognition domains (CRDs) and was discovered and described for the first time in 1997 in patients suffering from Hodgkin's lymphoma (HL) (Tureci et al., J. Biol. Chem. 1997, 272, 6416-6422). Three isoforms exist, and can be located within the cell or extracellularly. Elevated Galectin-9 levels have been in observed a wide range of cancers, including melanoma, Hodgkin's lymphoma, hepatocellular, pancreatic, gastric, colon and clear cell renal cell cancers (Wdowiak et al. Int. J. Mol. Sci. 2018, 19, 210). In renal cancer, patients with high Galectin-9 expression showed more advanced progression of the disease with larger tumor size and necrosis (Kawashima et al.; BJU Int. 2014; 113:320-332). In melanoma—a cancer considered as one of the most lethal cancers due to its aggressive metastasis and resistance to therapy—Galectin-9 was expressed in 57% of tumors and was significantly increased in the plasma of patients with advanced melanoma compared to healthy controls (Enninga et al., Melanoma Res. 2016 October; 26(5): 429-441). A number of studies have shown utility for Gal-9 as a prognostic marker, and more recently as a potential new drug target (Enninga et al., 2016; Kawashima et al. BJU Int 2014; 113: 320-332; Kageshita et al., Int J Cancer. 2002 Jun. 20; 99(6):809-16, and references therein). Galectin-9 has been described to play an important role in in a number of cellular processes such as adhesion, cancer cell aggregation, apoptosis, and chemotaxis. Recent studies have shown a role for Galectin-9 in immune modulation in support of the tumor, e.g., through negative regulation of Th1 type responses, Th2 polarization and polarization of macrophages to the M2 phenotype. This work also includes studies that have shown that Galectin-9 participates in direct inactivation of T cells through interactions with the T-cell immunoglobulin and mucin protein 3 (TIM-3) receptor (Dardalhon et al., J Immunol., 2010, 185, 1383-1392; Sanchez-Fueyo et al., Nat Immunol., 2003, 4, 1093-1101). Galectin-9 has also been found to play a role in polarizing T cell differentiation into tumor suppressive phenotypes), as well as promoting tolerogenic macrophage programming and adaptive immune suppression (Daley et al., Nat Med., 2017, 23, 556-567). In mouse models of panc