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.
Legal entity responsible for the study
S. Iadonato: Officer/Board of Directors: Kineta Inc. E. Tarcha, R. Bader, B. Dutzar, N. Eyde, E. Frazier, D. Jurchen, R. Lance, C. Loomis, K. Lustig, Y. Ovechkina, D. Peckham, J. Posakony, S. Sridhar, M. Xu, T. Guillaudeux: Full/Part-time employment: Kineta Inc.