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, Andy X. • Su, Lin Hui • RAKESTRAW, Ginger
Assignees
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Publication Number
US-12195535-B2
Publication Date
2025-01-14
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 nucleic acids encoding antibodies that specifically bind human V-domain Ig Suppressor of T cell Activation (hVISTA). The antibody comprises a heavy chain and a light chain, and the heavy chain variable region (VH) and light chain variable region (VL) include CDR1, CDR2 and CDR3 defined by amino-acid positions on specified SEQ ID NOs. The disclosed compositions include defined VH and VL sequence embodiments and sequence-identity variants for anti-hVISTA monoclonal antibody heavy/light chain sequences.
Binding behavior is described in relation to the VISTA extracellular domain under acidic pH conditions and may differ from binding under neutral or physiological pH. The disclosure includes antibodies that bind hVISTA under acidic pH with high affinity and embodiments that show little or no binding at physiological pH, together with pH-selective, pan-binding, and pH-sensitive binding profiles and binding affinity metrics and kinetic parameters. The rationale links acidic-pH binding to VISTA histidine content and histidine protonation.
The embodiments further specify constant-region options, including human IgG1 heavy-chain constant-region choices and an IgG4 heavy chain constant region containing an S228P substitution. Functional characterization links the antibodies to cross-competition with named antibodies, inhibition of hVISTA–T cell interaction and PSGL-1 binding at acidic pH, inhibition of VISTA-mediated cell:cell adhesion, and in vivo characterization indicated by mean residence time in cynomolgus monkeys.
The document further connects acidic-pH binding to improved functional behavior for cancer therapy. Stated concepts include reduced off-target binding in blood and normal tissues, potential for improved PK via endosomal recycling, and enhanced efficacy or effector activity in tumor microenvironments.
Claims Coverage
The claim coverage centers on nucleic acids encoding anti-hVISTA antibodies with tightly defined VH and VL variable-region CDR composition by amino-acid position ranges tied to specified SEQ ID NOs. Across the independent claim and the dependent refinements reflected in the provided claim context, the inventive features include the VH/VL CDR-position framework, selected SEQ ID NO embodiments, sequence-identity thresholds, constant-region options, and functional binding constraints under acidic versus physiological conditions.
Nucleic acid encoding hVISTA-binding antibody with defined VH CDR positions
A nucleic acid comprising a polynucleotide sequence that encodes an antibody that specifically binds to hVISTA, wherein the heavy chain comprises a VH comprising VH CDR1, CDR2 and CDR3, which comprise amino acid positions 26-35, 50-66, and 99-112, respectively, of specified SEQ ID NOs.
Nucleic acid encoding hVISTA-binding antibody with defined VL CDR positions
A nucleic acid comprising a polynucleotide sequence that encodes an antibody that specifically binds to hVISTA, wherein the light chain comprises a VL comprising VL CDR1, CDR2 and CDR3, which comprise amino acid positions 24-35, 51-57, and 90-98, respectively, of a specified SEQ ID NO.
Fixed VH sequence with sequence-identity threshold
A nucleic acid encoding an antibody where a specified VH CDR-positioned embodiment has a VH amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51 while maintaining the CDR-position constraints.
Acidic pH hVISTA binding affinity threshold
A nucleic acid encoding an antibody that binds hVISTA under acidic pH (pH 6.0 to 6.5) with a Kp of 10^-8 M or less.
No detectable binding at physiological pH measured by SPR
A nucleic acid encoding an antibody that does not detectably bind to hVISTA under physiological conditions as measured by surface plasmon resonance (SPR), where physiological conditions are pH 7.4.
IgG4 heavy chain constant region with S228P substitution
A nucleic acid encoding an antibody whose heavy chain comprises a human IgG4 heavy chain constant region containing an S228P substitution.
Specific VH and VL sequences defined by SEQ ID NO
A nucleic acid encoding an antibody whose VH and VL comprise amino acid sequences SEQ ID NO: 39 and SEQ ID NO: 68, respectively.
Overall claim coverage ties hVISTA-binding to nucleic acids encoding antibodies whose VH and VL CDRs are defined by specific amino-acid position ranges mapped onto multiple enumerated SEQ ID NOs, with further dependent refinements that can fix particular VH/VL sequences, add sequence-identity constraints, and impose binding-behavior constraints under defined conditions as well as specify constant-region elements.
Stated Advantages
Acidic pH preference for hVISTA binding and lack of significant binding at physiological or neutral pH.
Cross-competition with named antibodies.
Inhibition of hVISTA–T cell interaction and PSGL-1 binding at acidic pH.
Inhibition of VISTA-mediated cell:cell adhesion.
Mean residence time in cynomolgus monkeys.
Improved binding of VISTA-ECD to hVISTA under acidic pH conditions.
Acidic-pH-selective binding behavior, including reduced or no detectable binding under physiological conditions as measured by SPR.
Superior anti-tumor efficacy.
Reduced off-target binding in blood and normal tissues.
Potential for improved PK via endosomal recycling.
Enhanced efficacy/effector activity in tumor microenvironments.
Documented Applications
Inhibition of hVISTA–T cell interaction and inhibition of VISTA-mediated cell:cell adhesion, including effects associated with PSGL-1 binding at acidic pH.
Use of antibodies with hVISTA binding behavior characterized by acidic pH preference and lack of significant binding at physiological or neutral pH.
In vivo characterization indicated by mean residence time in cynomolgus monkeys.
Therapeutic compositions employing the disclosed antibodies for anti-tumor efficacy and T-cell activity.
Acidic pH-dependent antibody binding to cell types or leukocytes, with functional blockade and related cell binding behavior.
In vivo or preclinical efficacy in tumor models and associated anti-tumor activity.
Cancer therapy, including enhanced efficacy or effector activity in tumor microenvironments and reduced off-target binding in blood and normal tissues.
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