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.
BackgroundV-domain Immunoglobulin Suppressor of T cell Activation (VISTA/PD-1H) is a B7 family ligand expressed on circulating and intratumoural myeloid cells as well as Treg and NK cells. It has been shown to inhibit T cell responses in vitro and in preclinical models. In patients, VISTA is also a potential mediator of resistance to anti-CTLA-4 and anti-PD1 therapies and therefore is a valuable new target for cancer immunotherapy.MethodsKineta has analyzed 107 fully human ScFv antibodies directed against VISTA.ResultsOur lead candidates exhibit high potencies in the subnanomolar range and are also characterized by a long kDis. They specifically target human and cynomolgus monkey VISTA on a singular unique epitope. In a Staphylococcus Enterotoxin B T-cell activation assay, Kineta’s anti-VISTA antibodies efficiently induce IFNg secretion. They also promote strong maturation of Antigen Presenting Cells with an increase of CD80 and HLA-DR surface expression as well as CXCL10 secretion. The mechanism of action is mediated in part by NK cells. We demonstrated that myeloid cells acquire a high level of VISTA expression during MDSC or M2 differentiation in vitro and that Kineta’s anti-VISTA antibodies prevent the differentiation of MDSC as well as their immunosuppressive activity against T cells. Anti-VISTA antibodies mediate single-agent antitumor effects in syngeneic tumor models in wild-type mice and show enhanced activity in combination with anti-PD1 and anti-CTLA-4 treatment. Candidate anti-VISTA antibodies have also been evaluated in exploratory tolerability and PK studies in cynomolgus monkey. These studies demonstrated that multiple weekly doses of antibodies are well-tolerated with appropriate PK for lead selection and optimization.ConclusionsOur results strongly favor further characterization and continued development of selected lead antibodies for the potential treatment of colder, less immunogenic tumors.Ethics ApprovalStudy approved by the Institutional Animal Care and Use Committee PHS Assurance # D16-00885 and D16-00114
CD27 is a member of the TNF-Receptor superfamily expressed on CD4+ and CD8+ T cells, on NK and NKT cells and on B cells. It promotes T cell co-activation, proliferation, clonal expansion and differentiation into antigen specific cytotoxic and memory T cells after stimulation with its ligand CD70. Its stimulatory signal is mediated via the NFkB pathway, but also via the phosphatidylinositol 3 kinase and the protein kinase B. Moreover, CD27 signaling influences the innate immune response via a direct activation of NK cells and a subsequent secretion of interferon-gamma (IFN-γ). CD27 plays a central role in immunological responses and by promoting T cell and NK cell activation it contributes to anti-tumor immunity. Previous studies have demonstrated tumor growth inhibition with anti-CD27 agonistic monoclonal antibodies in different mice models for solid and hematological tumors. This mechanism of action can be partly explained by the recruitment of IFN-γ producing CD8+ T cells within the tumor. CD27 is a promising target for antitumor therapy. Kineta has generated a library of 147 fully human anti-CD27 monoclonal antibodies after immunization of Trianni mice. From this library, a lead candidate with strong agonistic proprieties has been selected. This anti-CD27 antibody originates from a unique clade after alignment of the variable heavy chains. Kineta’s lead candidate demonstrates selectivity and cross-reactivity with Non-Human Primate (NHP)-CD27 but not with the mouse-CD27. It also induces strong NFkB signaling in a Jurkat T cell-reporter, either soluble or cross-linked. It also induces T cell proliferation and secretion of pro-inflammatory cytokines in vitro. This T cell activation occurs only in the presence of a TCR engagement preventing future risks of spontaneous activation of naïve T cells in vivo. Our lead antibody also induces direct activation of NK cells demonstrated by the expression of CD69 on their surface. We have evaluated the anti-tumor properties of our lead antibody as a single agent in vivo in human CD27 Knock-In (KI) mice. Our anti-CD27 candidate induces a significant anti-tumor activity in the EG7 thymoma model. We have also demonstrated the anti-tumor efficacy of this lead candidate in Raji cells implanted in Scid mice. Preliminary experiments performed in human CD27 KI mice have demonstrated a long half-life of our antibody at different concentrations. Epitope characterization, NHP pharmacokinetic analysis and additional in vivo studies of our lead anti-CD27 antibody in different tumor models use as a single agent and in combination with different check-point inhibitors are on-going. Citation Format: Shawn Iadonato, Jessica Cross, Nathan Eyde, Emily Frazier, Neda Kabi, Chen Katz, Remington Lance, Kurt Lustig, Yulia Ovechkina, David Peckham, Shaarwari Sridhar, Carla Talbaux, Isabelle Tihista, Mei Xu, Thierry Guillaudeux. CD27 an emerging immuno-oncology target at the cross-roads of innate and adaptive anti-tumor immune responses [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A60.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.