Abstract 147P
Background
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune checkpoint regulator that is highly expressed in myeloid cells in the tumor microenvironment (TME). VISTA has been shown to maintain immunosuppressive conditions in the TME. Its expression is associated with poor prognosis in several cancers and with resistance to immune checkpoints inhibitors which makes it a very attractive target for cancer immunotherapy. K01401-020 is a humanized IgG antibody targeting monkey and human VISTA with a high affinity.
Methods
In vitro assays were performed using human recombinant proteins and peripheral blood mononuclear cells (PBMC) from healthy donors. Human VISTA knock-in (KI) mice were generated, engrafted with MC38 cells, and used for the assessment of anti-tumor activity. Non-Human Primate (NHP) were used in GLP 6- and 13-week repeat-dose toxicity studies.
Results
K01401-020 blocks VISTA binding to its main partners (PSGL-1, VSIG3 and VSIG8) independently of pH. In in vitro assay with PBMCs, K01401-020 stimulates monocytes’ activation and proliferation of NK cells and induces release of cytokines contributing to T cell activation. In vivo, K01401-020 treatment mediates single-agent antitumor activity in a syngeneic tumor model by activating the immune response in the tumors. Moreover, K01401-020 shows an enhanced antitumor response when combined with anti-PD-1 antibody. In the NHP 13-week toxicity study, minimal and reversible clinical observations and microscopic findings have only been observed at the highest dose (100 mg/kg/inj). Among the various cytokines tested, transient increases in IL-6, MCP-1 and IP-10 levels have been observed, in a dose-independent manner. At safe lower doses in NHP, exposures were 10-fold above those necessary in mice to observe antitumor activity, suggesting a favorable safety profile.
Conclusions
K01401-020 is a non-pH-sensitive antibody targeting VISTA, inducing immune cell activation and anti-tumor response, as single agent and in combination with anti PD-1 which is well tolerated in NHPs. A First-in-Human dose escalation study as single agent and in combination with pembrolizumab is currently ongoing in advanced solid tumors (NCT04564417).
Legal entity responsible for the study
Pierre Fabre Laboratories.
Funding
Pierre Fabre Laboratories.
Disclosure
G. Gueguen Dorbes, N. Loukili, A. Petain, J. Labbe, N. Boute, B. Akla, M. Broussas, P. Ferre, F. Hofmann: Financial Interests, Personal, Full or part-time Employment: Pierre Fabre.
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