76P Highly potent fully human anti-VISTA antibodies efficiently abrogate the interaction of this new target checkpoint inhibitor to its different putative receptors at different pH

Abstract

In physiological conditions, negative checkpoint molecules control the T cell immune response and limit the development of autoimmunity. However, their function is also used by the tumor environment to limit the activation of anti-tumuor cytotoxic T lymphocytes. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) also known as Programmed death-1 homolog (PD-1H), is a CD28/B7 family molecule highly expressed on circulating and intratumoural myeloid cells as well as Treg and NK cells. Different research groups have demonstrated the ability of VISTA to inhibit T cell activation. In patients, VISTA is also a potential mediator of resistance to anti-CTLA-4 and anti-PD1 or anti-PD-L1 therapies. For this reason, VISTA represents an attractive new immunotherapeutic target for cancer. Different research groups have demonstrated that VISTA can interact with at least 5 receptors: VISTA itself, PSGL-1 in acidic conditions, VSIG3, VSIG 8 and LRIG1. Using ELISA and Octet we demonstrated the interaction of VISTA with its 5 putative receptors, and tested our lead antibodies, selected from 107 fully human ScFv antibodies directed against VISTA, in a binding competition assay. Anti-Vista antibody efficacy against cold tumour was also evaluated in syngenic and human-VISTA KI mouse models. In this study, we first confirmed the ability of VISTA to bind to these 5 receptors at neutral or acidic pH and then compared the binding affinity of VISTA against these different receptors using ELISA and Octet. We next demonstrated the ability of Kineta’s anti-VISTA antibodies to selectively inhibits these interactions with different potencies. Finally, we showed that anti-VISTA antibodies mediate single-agent antitumor effects in syngeneic tumours, in wild type and VISTA Knock-in mice, even in the highly resistant B16F10 model. The efficacy of Kineta’s anti-VISTA antibodies was further enhanced in combination with anti-PDL1. Our results strongly favour further characterization and continued development of selected lead antibodies for their high potential to treat colder, less immunogenic tumours.