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. • Quigley, Michael • LEMAR, Hadia • Nayeem, Akbar
Assignees
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Publication Number
US-12091462-B2
Publication Date
2024-09-17
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 provides isolated antibodies that bind specifically to human VISTA (hVISTA). The antibodies comprise a heavy chain variable region (VH) and a light chain variable region (VL), and the VH and VL contain complementarity determining regions (CDRs) corresponding to named antibody variants including P1-070976, P1-070976_H95D, VISTA.4, P1-065333, and P1-070976_E97P, as defined by the listed SEQ ID numbers.
A central aspect is acidic pH selectivity. The antibodies bind hVISTA under acidic conditions and exhibit reduced or absent binding at physiological or neutral pH, with substantially different binding kinetics including KD and koff differences across acidic and neutral conditions. The disclosure also describes inhibition of hVISTA binding to human T cells at pH below 7.0.
The document further states functional consequences of the pH-selective binding, including inhibition of VISTA-mediated T cell activation and inhibition of NF-baB signaling. Additional antibody engineering concepts include Fc engineering to modulate Fcb3RIII-mediated effector functions, glycoengineering approaches such as aglycosylation and altered glycosylation patterns, activatable or masked antibody concepts, and embodiments for nucleic acids encoding antibodies and cells expressing antibodies for therapeutic use.
Claims Coverage
The independent claim set centers on one independent claim that defines an isolated hVISTA-binding antibody by VH and VL CDRs corresponding to specified named variants. Dependent claims further constrain the antibody by acidic-condition binding, substantially different binding kinetics, inhibition of hVISTA binding to human T cells, NF-baB inhibition, specific heavy-chain and light-chain sequence pairings, and isolated nucleic acids encoding the antibody.
Isolated hVISTA-binding antibody defined by CDR sequences for named variants
An isolated antibody that binds specifically to human VISTA (hVISTA), comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL comprise the complementarity determining regions (CDRs) of P1-070976, P1-070976_H95D, VISTA.4, P1-065333, or P1-070976_E97P, as specified by the listed SEQ ID numbers.
Acidic pH-range hVISTA binding
The isolated antibody binds hVISTA under acidic conditions where the pH is between 6.0 and 6.5.
Substantially different binding kinetics across acidic and neutral pH with functional inhibition at pH below 7.0
The isolated antibody binds hVISTA under acidic conditions with substantially different binding kinetics, including KD and koff differences versus neutral conditions, and inhibits hVISTA binding to human T cells at pH below 7.0.
Inhibition of VISTA-mediated T cell activation via NF-baB inhibition
The isolated antibody inhibits VISTA-mediated T cell activation, as assessed by NF-baB inhibition measured with Jurkat NF-baB-luciferase reporter cells.
Specific heavy-chain and light-chain sequence pairings
An isolated antibody comprising a heavy chain and a light chain defined by specific amino acid sequence ID combinations for the heavy chain and light chain pairings.
Isolated nucleic acids encoding the antibody
An isolated nucleic acid, or at least two isolated nucleic acids, that encode the antibody of claim 1.
The claims define isolated hVISTA-binding antibodies through specific VH and VL CDR sets tied to named variants and SEQ ID numbers. The scope is further narrowed by acidic pH binding, altered binding kinetics, inhibition of hVISTA-mediated T cell activation through NF-baB inhibition, specific heavy-chain/light-chain pairing, and nucleic-acid embodiments.
Stated Advantages
Selective hVISTA binding under acidic conditions with reduced or absent binding at physiological or neutral pH.
Inhibition of VISTA-mediated T cell activation, including NF-baB inhibition.
Modulation of Fcb3RIII-mediated effector functions through Fc engineering, including enhanced ADCC and complement-reduced or reduced effectorless variants.
Reduced complement fixation/CDC and effectorless activity are described in relation to Fc variants.
Altered glycosylation, including aglycosylation, hypofucosylation, and bisecting GlcNAc, is described as part of the antibody engineering concepts.
Substantially longer mean residence time than VISTA.4 in non-transgenic cynomolgus macaques when administered intravenously.
Retention of acidic pH selectivity in vivo.
Tumor microenvironment blockade is associated with driving efficacy.
Acidic pH-selective anti-VISTA antibodies block VISTA binding to PSGL-1.
VISTA.4 binding is selective for acidic pH over physiological pH.
Mutant analysis indicates acidic pH binding can be retained while effects on binding and function depend on specific VISTA histidines.
Documented Applications
Therapeutic uses described include cancer and infectious disease, including embodiments for administering a therapeutically effective amount.
Combination uses are described with immune checkpoint modulators such as CTLA-4, PD-1, PD-L1, LAG-3, CD137 (4-1BB), OX40, and CD40.
Infectious pathogen contexts are described, including HIV, hepatitis, influenza, and other infectious pathogens.
Methods and embodiments are described for identifying and generating pH-selective VISTA antibodies.
Intravenous administration of pH-selective anti-VISTA antibodies in non-transgenic cynomolgus macaques to assess residence time and in vivo retention of acidic pH selectivity, associated with tumor microenvironment blockade driving efficacy.
Use of PSGL-1 deletion, ectopic expression, binding assays, and co-crystal structure and mutational analysis to study pH-dependent VISTA-PSGL-1 interaction and acidic pH-selective inhibition of VISTA binding and function, including T-cell suppression.
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