An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

Sci Rep. 2020 Sep 16;10(1):15171. doi: 10.1038/s41598-020-71519-4.

Abstract

V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint that maintains peripheral T cell quiescence and inhibits anti-tumor immune responses. VISTA functions by dampening the interaction between myeloid cells and T cells, orthogonal to PD-1 and other checkpoints of the tumor-T cell signaling axis. Here, we report the use of yeast surface display to engineer an anti-VISTA antibody that binds with high affinity to mouse, human, and cynomolgus monkey VISTA. Our anti-VISTA antibody (SG7) inhibits VISTA function and blocks purported interactions with both PSGL-1 and VSIG3 proteins. SG7 binds a unique epitope on the surface of VISTA, which partially overlaps with other clinically relevant antibodies. As a monotherapy, and to a greater extent as a combination with anti-PD1, SG7 slows tumor growth in multiple syngeneic mouse models. SG7 is a promising clinical candidate that can be tested in fully immunocompetent mouse models and its binding epitope can be used for future campaigns to develop species cross-reactive inhibitors of VISTA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / metabolism*
  • Antigen-Antibody Reactions
  • B7 Antigens / antagonists & inhibitors*
  • B7 Antigens / genetics
  • B7 Antigens / immunology
  • Binding Sites
  • Cell Adhesion Molecules / metabolism
  • Cell Surface Display Techniques
  • Cross Reactions
  • Epitopes / genetics
  • Epitopes / metabolism*
  • Female
  • Humans
  • Immunoglobulins / metabolism
  • Macaca fascicularis
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Molecular
  • Protein Binding
  • Protein Engineering

Substances

  • Antibodies
  • B7 Antigens
  • Cell Adhesion Molecules
  • Epitopes
  • IGSF11 protein, human
  • Immunoglobulins
  • Membrane Glycoproteins
  • Membrane Proteins
  • P-selectin ligand protein
  • VSIR protein, human
  • Vsir protein, mouse