IP Library › Granted Patent US 12,234,286
Granted Patent B2
US 12,234,286 · App. 17/534,916 · Granted Feb 25, 2025

Anti-TIGIT antibodies and their use as therapeutics and diagnostics

Inventors: Tong Zhang (Beijing, CN); Liu Xue (Beijing, CN); Qi Liu (Beijing, CN); Min Wei (Beijing, CN); Kang Li (Beijing, CN)
Assignee: BEIGENE SWITZERLAND GMBH
C07K16/2803A61K45/06C07K2317/24C07K2317/54C07K2317/55C07K2317/565C07K2317/622
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,234,286
App. No.
17/534,916
Granted
Feb 25, 2025
Kind
B2
Abstract

Provided are antibodies that specifically bind to TIGIT (T cell immunoreceptor with Ig and ITIM domains, WUCAM or Vstm3) and inhibit Tigit-mediated cellular signaling and activities in immune cells. The anti-TIGIT antibodies can be used to treat or diagnose cancer, infectious diseases or other pathological disorders that may be modulated by Tigit-mediated functions.

Claims (27)

1. A method for treating a cancer or a tumor, comprising administrating to a subject in need thereof an antibody, which is capable of binding to human Tigit, or antigen binding fragment thereof comprising:

(a) a heavy chain variable region (VH) comprising heavy chain complementarity determining region (CDR)1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 3, 13, and 5, respectively; and

(b) a light chain variable region (VL) comprising light chain CDR1, CDR2, and CDR3 comprising amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively.

2. The method of claim 1 , wherein the antibody or the antigen-binding fragment is administrated in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is selected from a chemotherapy, a targeted therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.

3. The method of claim 1 , wherein the antibody is a humanized antibody molecule.

4. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 14, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 16.

5. The method of claim 4 , wherein the antibody or antigen binding fragment thereof comprises one or more of:

(a) a heavy chain variable domain with a T to A mutation at position 24 of SEQ ID NO 14;

(b) a heavy chain variable domain with a I to V mutation at position 37 of SEQ ID NO 14;

(c) a light chain variable domain with a V to I mutation at position 58 of SEQ ID NO 16.

6. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 19, and a light chain variable domain having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO 21.

7. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 14, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 16; or

(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 19, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 21.

8. The method of claim 1 , wherein the antigen-binding fragment is a Fab, F(ab′)2, Fv, or a single chain Fv(ScFv).

9. The method of claim 1 , wherein the antibody comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4 or a variant thereof, and a light chain constant region of the type of kappa or lambda or a variant thereof.

10. The method of claim 1 , wherein the cancer or the tumor comprises a lung cancer, a liver cancer, a stomach cancer, a cervical cancer, a breast cancer, a head and neck cancer, lymphoma or a skin cancer.

11. The method of claim 1 , wherein the cancer or the tumor comprises a non-small cell lung cancer.

12. The method of claim 1 , wherein the cancer or the tumor comprises a small-cell lung cancer.

13. The method of claim 1 , wherein the cancer or the tumor comprises a lung cancer.

14. The method of claim 1 , wherein the cancer or the tumor comprises a liver cancer.

15. The method of claim 1 , wherein the cancer or the tumor comprises a stomach cancer.

16. The method of claim 1 , wherein the cancer or the tumor comprises a cervical cancer.

17. The method of claim 1 , wherein the cancer or the tumor comprises a head and neck cancer.

18. The method of claim 1 , wherein the cancer or the tumor comprises a breast cancer.

19. The method of claim 1 , wherein the cancer or the tumor comprises lymphoma.

20. The method of claim 1 , wherein the cancer or the tumor comprises a skin cancer.

Assignments (3)
CHANGE OF NAME Recorded Sep 23, 2025
From: BEIGENE SWITZERLAND GMBH
To: BEONE MEDICINES I GMBH
Reel/Frame 072872/0076 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 15, 2022
From: BEIGENE, LTD.
To: BEIGENE SWITZERLAND GMBH
Reel/Frame 059010/0914 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 24, 2021
From: ZHANG, TONG; XUE, LIU; LIU, QI; WEI, MIN; LI, KANG
To: BEIGENE, LTD.
Reel/Frame 058206/0490 →
Priority Claims (1)
WO PCT/CN2017/120392 · Dec 30, 2017 · international
Continuity (2)
Division 16958262
Related Publication 20220153837A1 · May 19, 2022
References Cited (58)
US 11214616B2 · Zhang et al. · 2022 [cited by applicant]
US 20200255516A1 · Fu et al. · 2020 [cited by applicant]
US 20200331999A1 · Zhang et al. · 2020 [cited by applicant]
JP 2016500251A · 2016 [cited by applicant]
WO 2014089113A1 · 2014 [cited by applicant]
WO WO2015009856A2 · 2015 [cited by applicant]
WO WO2016011264A1 · 2016 [cited by applicant]
WO WO2016028656A1 · 2016 [cited by applicant]
WO WO2016081746A2 · 2016 [cited by applicant]
WO WO2016106302A1 · 2016 [cited by applicant]
WO WO2017030823A2 · 2017 [cited by applicant]
WO WO2017053748A2 · 2017 [cited by applicant]
WO WO2017059095A1 · 2017 [cited by applicant]
WO WO2019129261A1 · 2019 [cited by applicant]
Beum, P. V. et al., “Loss of CD20 and Bound CD20 Antibody from Opsonized B Cells Occurs More Rapidly Because of Trogocytosis Mediated by Fc Receptor-Expressing Effector Cells Than Direct Internalization by the B Cells,”… [cited by applicant]
Boles, K. S. et al., “A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC,” Eur. J. Immunol., 2009, 39:695-703. [cited by applicant]
Bottino, C. et al., “Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule,” J. Exp. Med., vol. 198, No. 4, Aug. 2003, pp. 557-567. [cited by applicant]
Carlsten, M. et al., “Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma,” Clin Cancer Res., Jun. 2016, 22(21):5211-5222. [cited by applicant]
Casado, J. G. et al., “Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines,” Cancer Immunol Immuno… [cited by applicant]
Chan, C. J. et al., “The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions,” Nature Immunology, May 2014, vol. 15, No. 5, pp. 431-438. [cited by applicant]
Chauvin, J-M et al., “TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients,” Clin Invest. 2015;125(5):2046-2058. [cited by applicant]
Chew, G. M. et al., “TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection,” PLoS Pathog., Jan. 2016, 12(1):e1005349. doi:10.1371/jour… [cited by applicant]
Chothia, C. et al., “Canonical structures for the hypervariable regions of immunoglobulins,” J Mol Biol., Aug. 20, 1987;196(4):901-917. [cited by applicant]
Chothia, C. et al., “Conformations of immunoglobulin hypervariable regions”, Nature (1989); 342(6252):877-83. [cited by applicant]
De St. Groth, S. F. et al., “Production of monoclonal antibodies: strategy and tactics,” Journal of Immunological Methods, 35:1-21 (1980). [cited by applicant]
Engels, N. et al., “The signaling tool box for tyrosine-based costimulation of lymphocytes,” Current Opinion in Immunology, 2011,23:324-329. [cited by applicant]
Extended European Search Report for European Application No. 18894270.0, mailed Jul. 29, 2021, 8 pages. [cited by applicant]
Ganesan, L. P. et al., “FcRlIb on liver sinusoidal endothelium clears small immune complexes,” The Journal of Immunology, 2012, 189:4981-4988; Prepublished online Oct. 2012. [cited by applicant]
Gil Del Alcazar, C. R. et al., “Immune escape in breast cancer during in situ to invasive carcinoma transition,” Cancer Discov., 2017, 7(10):1098-1115. [cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/CN2018/125375, mailed Mar. 29, 2019, 12 pages. [cited by applicant]
Johnston, R. J. et al., “The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function,” Cancer Cell, Dec. 2014,26:923-937. [cited by applicant]
Joller, N. et al., “Cutting edge: TIGIT has T cell-intrinsic inhibitory functions,” Journal of Immunology, 2011;186:1338-1342. [cited by applicant]
Joller, N. et al., “Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses,” Immunity, Apr. 2014, 40:569-581. [cited by applicant]
Kabat, E. A. et al., “Sequences of Proteins of Immunological Interest,” vol. I, Fifth Edition, U.S. Department of Health and Human Services, Public Health Service National Institutes of Health (1991), 152 pages. [cited by applicant]
Kabat, E. A. et al., “Unusual distributions of amino acids in complementarity-determining (hypervariable) segments of heavy and light chains of immunoglobulins and their possible roles in specificity of antibody-combini… [cited by applicant]
Kabat, E. A., “The structural basis of antibody complementarity,” Adv. Prot. Chem., 32:1-75 (1978). [cited by applicant]
Kong, Y. et al., “T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8 T-Cell Exhaustion and Poor Clinical Outcome in AML Patients,” Clin. Cancer Res., 2016,22(12):3057-3066. Published Online Jan. 2016. [cited by applicant]
Kurtulus, S. et al., “TIGIT predominantly regulates the immune response via regulatory T cells,” J Clin Invest. 2015;125(11):4053-4062. https://doi.org/10.1172/JCI81187. [cited by applicant]
Lefranc, M-P et al., “IMGT, the international ImMumoGeneTics database,” Nucleic Acids Research, 27(1):209-212 (1999). [cited by applicant]
Levin, S. D. et al., “Vstm3 is a member of the CD28 family and an important modulator of T-cell function,” Eur. J. Immunol., 2011, 41:902-915. [cited by applicant]
Li, M. et al., “T-cell Immunoglobulin and ITIM Domain (TIGIT) Receptor/Poliovirus Receptor (PVR) Ligand Engagement Suppresses Interferon-γ Production of Natural Killer Cells via β-Arrestin 2-mediated Negative Signaling,… [cited by applicant]
Liu, S. et al., “Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells,” Cell Death and Differentiation, (2013), 20:456-464. Published online Nov. 2012. [cited by applicant]
Mechetner, E., “Development and Characterization of Mouse Hybridomas,” Chapter 1 In: Methods in Molecular Biology, vol. 378: Monoclonal Antibodies: Methods and Protocols, Edited by: M. Albitar, Humana Press Inc., Totowa… [cited by applicant]
Mendelsohn, C. L. et al., “Cellular receptor for poliovirus: Molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily,” Cell, vol. 56, pp. 855-865, Mar. 1989. [cited by applicant]
Stanietsky, N. et al., “The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity,” PNAS, Oct. 2009, vol. 106, No. 42, pp. 17858-17863. [cited by applicant]
Stengel, K. F. et al., “Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering,” PNAS, Apr. 2012, vol. 109, No. 14… [cited by applicant]
Tassi, E. et al., “Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non-Small Cell Lung Cancer,” Cancer Research, 2017, 77(4):851-861. Published online: Dec. 2016. [cited by applicant]
Taylor, R. P. et al., “Fc-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments,” Blood, Jan. 2015;125(5):762-766. [cited by applicant]
Wang, F. et al., “TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals,” Eur. J. Immunology., 2015, 45:2886-2897. [cited by applicant]
Wu, T. T. et al., “An analysis of the sequences of the variable regions of bence jones proteins and myeloma light chains and their implications for anti-body complementarity,” J. Exp. Med., 132(2):211-250 (Aug. 1970). [cited by applicant]
Xie, J. et al., “Expression of immune checkpoints in T cells of esophageal cancer patients,” Oncotarget, vol. 7, No. 39, Aug. 2016, pp. 63669-63678. [cited by applicant]
Yu, X. et al., “The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells,” Nature Immunology, Jan. 2009, vol. 10, No. 1, pp. 48-57. [cited by applicant]
Taiwanese Search Report issued in App. No. TW112133818, dated May 29, 2024, 2 pages. [cited by applicant]
Casset, et al., “A peptide mimetic of an anti-CD4 monoclonal antibody by rational design,” Biochemical and Biophysical Research Communications, vol. 307, pp. 198-205 (2003). [cited by applicant]
De Pascalis, et al., “Grafting of ”Abbreviated“ Complementarity-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody,”… [cited by applicant]
Non-Final Office Action issued in U.S. Appl. No. 17/675,515, dated Nov. 21, 2024. [cited by applicant]
Paul, Fundamental Immunology, “Fv Structured and Diversity in Three Dimensions,” 3rd Edition, pp. 292-295 (1993). [cited by applicant]
Rudikoff, et al., “Single Amino Acid Substitution Altering Antigen-Binding Specificity,” Proc. Natl. Acad. Sci., vol. 79, pp. 1979-1983 (Mar. 1982). [cited by applicant]