Abstract 1637: A fully human anti-vista antibody as a promising therapy against poorly immunogenic tumors

Abstract

V-domain Immunoglobulin Suppressor of T cell Activation (VISTA/PD-1H) is an immune checkpoint regulator of the B7 family. VISTA can be found on the cell surface of some tumor types, however for the majority of cancers, VISTA is highly expressed in the immunological myeloid cell compartment in the tumor microenvironment (TME). VISTA has been shown, in vitro and in vivo, to inhibit T cell activation and prevent T cell recruitment into tumors. In patients, high VISTA expression is associated with poor prognosis and is also a potential mediator of resistance to anti-CTLA-4 and anti-PD-(L)1 therapies. Therefore, VISTA is a very attractive new target for cancer immunotherapy. Kineta has selected a lead candidate anti-VISTA monoclonal antibody after a deep screen of 107 fully human and highly diverse antibodies directed against the VISTA extracellular domain. The candidate exhibits high potency in the subnanomolar range and is characterized by a long constant of dissociation evaluated by ELISA and Octet binding. It targets human and cynomolgus monkey VISTA on a unique epitope. Cross reactivity against other B7 family members has also been evaluated, and the lead candidate demonstrates high specificity against VISTA. The candidate antibody also efficiently induces T cell activation, proliferation and IFNg secretion on a Staphylococcal EnterotoxinB assay, as well as in a coculture experiment with a cell line overexpressing VISTA. The candidate promotes maturation of Antigen Presenting Cells with an increase of CD80 and HLA-DR surface expression as well as CXCL10 secretion in a monocyte activation assay. The mechanism of action is mediated in part by NK cells. This anti-VISTA antibody also prevents the immunosuppressive function of differentiated MDSCs in vitro against T cells. In Knock-In-human VISTA mice, anti-VISTA antibody treatment mediates single-agent antitumor activity in vivo in multiple syngeneic tumor models and shows enhanced efficacy in combination with either anti-PD-(L)1 or anti-CTLA-4 treatment. Finally, anti-VISTA antibody treatment was well-tolerated in exploratory toxicology studies in cynomolgus monkey and has a half-life consistent with other monoclonal antibodies. Our results strongly support the continued development of our anti-VISTA antibody for the treatment of colder, less immunogenic tumors. Citation Format: Thierry Guillaudeux, Eric Tarcha, Robert Bader, Benjamin Dutzar, Nathan Eyde, Emily Frazier, David Jurchen, Remington Lance, Cristina Loomis, Kurt Lustig, Yulia Ovechkina, David Peckham, Jeff Posakony, Shaarwari Sridhar, Mei Xu, Shawn Iadonato. A fully human anti-vista antibody as a promising therapy against poorly immunogenic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1637.

Distinct immune stimulatory effects of anti-human VISTA antibodies are determined by Fc-receptor interaction

“…This could again be explained by the concept that VISTA needs to be clustered and/or sequestered away to prevent its immune inhibitory effects, probably in trans, as the CD16 expressed on myeloid cells does not enable this effect. This particular aspect of the dependency on IgG1-WT backbone and NK cells has been presented previously for the clinical trial candidates VISTA antibody CI-8993 (formerly JNJ-61610588) ( 49 , 50 ) and KVA12.1 ( 51 ). Another study similarly demonstrated that myeloid cells were activated upon incubation with anti-VISTA antibodies on human IgG1-WT backbone, but not when these clones (KO11-1B1 and VIBE1A) were placed on an IgG1-variant with reduced Fc-effector function (mutations L234A, L235A, P324G) ( 9 ).…”

Development of Inhibitors Targeting the V-Domain Ig Suppressor of T Cell Activation Signal Pathway

“…Onvatilimab has entered a phase I study (NCT04475523), which encompassed the plan for managing CRS and enabled escalation to therapeutic dose levels. Another anti-VISTA antibody (KVA-12.1) from Kineta Inc. demonstrates high specificity against VISTA and exceptional immune-enhancing activity, including prevention of the immunosuppressive function of differentiated myeloid-derived suppressor cells in vitro against T cells . Pre-IND studies revealed that KVA-12.1 is well-tolerated in exploratory toxicology studies in cynomolgus and showed a good half-life, in line with other monoclonal check-point inhibitors, and KVA-12.1 will be advanced into the clinical trials in early 2022 .…”