Antibodies binding to vista at acidic pH
Inventors
Johnston, Robert J. • Rajpal, Arvind • Sheppard, Paul O. • Borges, Luis • Rankin, Andrew • BAHJAT, Keith Sadoon • Korman, Alan J. • Deng, Xiaodi • Su, Lin Hui • RAKESTRAW, Ginger • PINCKNEY, JASON R. • CRITTON, DAVID A. • Chen, Guodong • HUANG, Richard Y. • Deyanova, Ekaterina G.
Assignees
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Publication Number
US-12173069-B2
Publication Date
2024-12-24
Expiration Date
Abstract
The present application relates to antibodies specifically binding to the V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA) at acidic pH and their use in cancer treatment. In some embodiments, the antibodies bind specifically to human VISTA at acidic pH, but do not significantly bind to human VISTA at neutral or physiological pH.
Core Innovation
The invention relates to acidic pH-selective antibodies that bind specifically to human V-domain Ig Suppressor of T cell Activation (hVISTA). The antibodies bind to hVISTA in acidic pH conditions with a K_D at least 10 fold lower than their K_D in neutral or physiological pH conditions, distinguishing acidic pH environments from neutral or physiological pH environments.
The antibodies are characterized by defined heavy chain variable region (VH) complementarity-determining regions CDR1, CDR2 and CDR3, and by a light chain variable region (VL) comprising VL CDR1, CDR2 and CDR3. The VH CDR positions correspond to positions 26-35, 50-66, and 99-112 of specified P1-061029-derived variants, including P1-061029_F100fE_V102D, P1-061029_F100fE, P1-061029_V102D, P1-061029_Y32E, and P1-061029_Y32E_F100fE, and the VL CDR positions correspond to amino acid positions 24-35, 51-57, and 90-98 of SEQ ID NO: 68.
Additional disclosed characteristics include binding selectivity between acidic and physiological or neutral pH conditions, kinetic properties such as k_off and binding kinetics, and functional behaviors under pH conditions. The patent also describes constant-region specifications, including IgG1.3 heavy chain and effector or effectorless options, along with alternative IgG1 allotypes and modified constant regions.
Claims Coverage
The claim coverage centers on one independent claim directed to an isolated hVISTA-specific antibody with pH-dependent binding and specific VH/VL CDR position constraints for defined P1-061029-derived variants, with at least 10-fold lower K_D in acidic pH than in neutral or physiological pH. Three inventive features are identified across the provided claim summaries.
Acidic pH-selective hVISTA binding with at least 10-fold lower K_D
An isolated antibody that binds specifically to hVISTA wherein the antibody binds to hVISTA in acidic pH conditions with a K_D that is at least 10 fold lower than its K_D in neutral or physiological pH conditions.
VH CDR-defined by specific P1-061029-derived VH variants
An antibody comprising heavy chain variable region (VH) complementarity-determining region 1, CDR2 and CDR3 of the VH of P1-061029_F100fE_V102D, P1-061029_F100fE, P1-061029_V102D, P1-061029_Y32E, or P1-061029_Y32E_F100fE, with VH CDR positions corresponding to positions 26-35, 50-66, and 99-112 of SEQ ID NO: 491, 503, 515, 527, or 539.
VL CDR-defined by P1-061029 light chain positions
An antibody comprising a light chain variable region (VL) comprising VL CDR1, CDR2 and CDR3 of the VL of P1-061029, wherein the VL CDR1, CDR2, and CDR3 comprise amino acid positions 24-35, 51-57, and 90-98 of SEQ ID NO: 68.
Overall, the claim coverage focuses on a single isolated hVISTA-specific antibody with stronger binding in acidic pH than in neutral or physiological pH, together with VH and VL CDR position constraints tied to specified P1-061029-derived variants.
Stated Advantages
Acidic pH-selective binding to hVISTA, with at least 10-fold stronger binding in acidic pH than in neutral or physiological pH.
Acidic pH-dependent VISTA-mediated T cell binding and suppression.
Differences in intracellular recycling and ADCD-related activity under pH-selective binding conditions.
Cynomolgus macaques pharmacokinetic and mean residence time advantages for acidic pH-selective antibodies.
Documented Applications
Therapeutic and immune-checkpoint-related context for anti-VISTA antibodies, including tumor therapy and immune checkpoint combinations (e.g., CTLA-4, PD-1/PD-L1, LAG-3).
Tumor-selective binding under acidic pH conditions using activatable pH/cleavable masking concepts.
Inhibition or stimulation of T cell activation and VISTA-mediated cell-cell adhesion or related activities under pH conditions in the context of hVISTA binding and interactions with PSGL-1 and heparan sulfate proteoglycans.
Binding and functional interaction with cynomolgus VISTA, including residence time in cynomolgus monkeys.
Tumor efficacy context is described for a VISTA/PD-1 combination using engineered VISTA antibodies (MC38 tumors).
Receptor engagement under acidic pH is described, including PSGL-1 engagement at acidic pH.
Structural mapping is described via a co-crystal structure of P1-068767 Fab with hVISTA.
Epitope mapping of VISTA is described, including VISTA.4 using HDX-MS to define receptor-binding interface regions and acidic histidine-driven epitope behavior.
Inhibition or stimulation of T-cell and VISTA-mediated activities under pH conditions, including VISTA mediated cell-cell adhesion and T cell activation.
Use in contexts involving human T cells and VISTA biology effects under acidic versus neutral or physiological pH conditions, including cross-competition and downstream T-cell activation/effector effects.
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