Anti-TIGIT antibodies and their use as therapeutics and diagnostics
Inventors
Zhang, Tong • Xue, Liu • Liu, Qi • Wei, Min • Li, Kang
Assignees
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Publication Number
US-11214616-B2
Publication Date
2022-01-04
Expiration Date
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.
Core Innovation
The invention relates to an antibody or an antigen-binding fragment thereof that is capable of binding to human Tigit. The binding antibody comprises a heavy chain variable region (VH) having heavy chain complementarity determining region (CDR)1, CDR2, and CDR3 sequences defined by SEQ ID NOs: 3, 13, and 5, respectively, and a light chain variable region (VL) having light chain CDR1, CDR2, and CDR3 sequences defined by SEQ ID NOs: 6, 7 and 8, respectively. The described antibodies include humanized variants.
The invention addresses TIGIT-mediated signaling by providing anti-TIGIT antibodies that specifically bind human TIGIT and inhibit TIGIT-mediated signaling. Functional effects described include blocking TIGIT-ligand interactions, including interactions with PVR (CD155) and PVR-L2 (CD112/nectin-2), and promoting IFN-gamma secretion by CMV-specific T cells.
Additional functional effects described include enhancing NK-mediated cytotoxicity and inducing FcγR-mediated trogocytosis that reduces Tigit surface expression. The described properties further include evaluation of Fc effector functions, with emphasis that CDC is not detected while ADCC can reduce Tregs for a wild-type IgG1 Fc variant, and binding behavior is described as pH dependent, favoring acidic tumor microenvironment conditions.
Claims Coverage
The independent claim provides a binding-defined antibody or antigen-binding fragment to human Tigit based on specific VH and VL CDR amino-acid sequences corresponding to SEQ ID NOs 3/13/5 and 6/7/8, respectively. The dependent claims identified refine the independent claim by specifying humanization, sequence-identity constraints to additional SEQ ID NOs, selected amino-acid substitutions, particular antigen-binding fragment formats, and a method of stimulating an immune response by administration.
Tigit-binding antibody with defined VH and VL CDR sequences
An antibody or an antigen-binding fragment capable of binding to human Tigit, comprising a VH with CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 3, 13, and 5 respectively, and a VL with CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8 respectively.
Humanized Tigit-binding antibody
The antibody or antigen-binding fragment of the Tigit-binding antibody is a humanized antibody molecule.
High sequence identity to defined VH and VL sequences
The antibody or antigen-binding fragment comprises a heavy chain variable domain and a light chain variable domain having specified sequence identity thresholds relative to SEQ ID NO 14 (heavy chain) and SEQ ID NO 16 (light chain).
Variable domain amino-acid substitutions relative to defined sequences
The antibody or antigen-binding fragment comprises heavy and/or light chain variable domains having specified amino-acid substitutions at particular positions in SEQ ID NO 14 and SEQ ID NO 16.
Antigen-binding fragment format selection
The antibody or antigen-binding fragment comprises an antigen-binding fragment selected from Fab, F(ab′)2, Fv, or a single chain Fv (ScFv).
Administration to stimulate an immune response
A method for stimulating an immune response in a subject by administering an antibody or an antigen-binding fragment in an effective amount to stimulate that immune response.
Across the identified claims, the core coverage is an antibody or antigen-binding fragment binding human Tigit defined by specific VH and VL CDR sequences (SEQ ID NOs 3/13/5 and 6/7/8). Dependent claims further constrain humanization, impose sequence-identity and residue-substitution requirements relative to additional SEQ ID NOs, specify permitted antigen-binding fragment formats, and include a method of stimulating an immune response via administration of an effective amount.
Stated Advantages
Inhibits TIGIT-mediated signaling.
Blocks TIGIT-ligand interactions with PVR (CD155) and PVR-L2 (CD112/nectin-2).
Promotes IFN-gamma secretion by CMV-specific T cells.
Enhances NK-mediated cytotoxicity.
Induces FcγR-mediated trogocytosis that reduces Tigit surface expression.
No CDC is detected, while ADCC can reduce Tregs for a wild-type IgG1 Fc variant.
Binding behavior favors acidic tumor microenvironment conditions.
Documented Applications
Therapeutic and/or diagnostic use in cancer and infectious diseases.
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