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

Nishant Mehta,Amanda Rabe,Sainiteesh Maddineni,Louai Labanieh,Caitlyn L Miller,John L Silberstein,Robert B Lee,Ryan L Kelly,Jennifer R Cochran,Sean A Hunter,R Andres Parra Sperberg

doi:10.1038/s41598-020-71519-4

Nishant Mehta, Amanda Rabe + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-71519-4

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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.

Highlights

In many cancers, immune cells capable of tumor clearance infiltrate the tissue but are suppressed or directed towards inactivity
A clinical trial involving an anti-human VISTA antibody of the human IgG1 isotype developed by Janssen/ImmuNext (VSTB112; NCT02671955) was terminated, the molecule is being pursued by Curis (CI-8993)
For an initial round of screening, the scFv library was incubated with human VISTA coupled to magnetic beads, and the pool of bead-bound yeast cells was collected

Summary

Introduction

Immune cells capable of tumor clearance infiltrate the tissue but are suppressed or directed towards inactivity. Antibodies known as checkpoint inhibitors can bolster the anti-tumor immune response by blocking immune regulation between T cells, antigen-presenting cells (APCs), and tumors, slowing down progression or even clearing the tumor. These antibody therapeutics have emerged as effective treatments for patients who are refractory to chemotherapy, and as a first-in-line therapy for multiple cancer types. A pH-dependent binding interaction was identified between VISTA and PSGL-115, a receptor expressed on leukocytes that plays a role in immune cell trafficking. Anti-VISTA antibodies from Bristol-Myers Squibb (BMS767) and Hummingbird Biosciences (HMBD-002) are in preclinical development All three of these antibodies have been generated from animal immunization efforts. The strategy outlined here for cross-reactive antibody engineering, along with the elucidation of potential binding epitopes for VISTA antibodies, as well as PSGL-1 and VSIG3, will bolster efforts for continued therapeutic development

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