Abstract 2727: The discovery and characterization of PTZ-201, a fully-human, high affinity, antagonistic anti-TIGIT monoclonal antibody

Abstract

Abstract The costimulatory molecule CD226 and the coinhibitory receptor TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif (ITIM) domains) function as a checkpoint pathway regulating immune function with similarity to the CD28-CTLA4 pathway. CD226 and TIGIT bind to the same ligands, PVR (poliovirus receptor, also known as CD155) and PVRL2 (poliovirus receptor-related 2, also known as CD112). CD226 is a positive regulator of T cell responses, while TIGIT is an inhibitor of these signals. TIGIT is highly expressed on memory T cells and Tregs and is co-expressed with other immune checkpoint molecules on exhausted T cells. TIGIT activation has been demonstrated to regulate CD4+ and CD8+ T cell activity, regulatory T cell function, and NK cell activity. Blocking the binding of TIGIT to its ligands has been demonstrated to activate immune function in the tumor microenvironment, and TIGIT antagonists have anti-tumor activity in murine syngeneic tumor models. TIGIT's function suggests it may be a promising target for clinical development of antagonistic monoclonal antibodies to increase the anti-tumor immune response. PTZ-201, developed by Potenza Therapeutics, is a fully human monoclonal IgG4 anti-human TIGIT antagonistic antibody which blocks the binding of TIGIT to its ligands PVR and PVRL2. PTZ-201 binds to human TIGIT with high affinity, binds to Jurkat cells engineered to express TIGIT, and binds to human primary lymphocytes. PTZ-201 increases interleukin (IL)-2 production in functional cell assays using an engineered Jurkat cell assay. In addition, PTZ-201 increases IFNγ and TNF production in cultured peripheral blood mononuclear cells and CD4+ T cells sub-optimally stimulated with anti-CD3/anti-CD28 antibodies. In a cytomegalovirus (CMV)-specific immune recall assay, PTZ-201 increases the activation PBMCs (increased TNF production) and increases the frequency of cytokine producing CD4+ and CD8+ T cells, compared to an isotype control. In this CMV recall assay, the combination of PTZ-201 with an anti-programmed death (PD-1) antibody results in a statistically significant increase in TNF production when compared to either agent alone. Finally, tumor infiltrating lymphocytes (TILs) isolated from multiple human tumor types express high levels of TIGIT, with a majority of CD8+ and Tregs co-expressing PD-1 and TIGIT. These data support the continued development of PTZ-201 as a novel checkpoint inhibitor for the treatment of cancer. Citation Format: Sandra Abbott, Ana C. Anderson, Heather Brodkin, Daniel J. Hicklin, Nesreen Ismail, Nels Nielson, Christopher Nirschl, Andres Salmeron, Cynthia Seidel-Dugan, Philipp Steiner, William Winston. The discovery and characterization of PTZ-201, a fully-human, high affinity, antagonistic anti-TIGIT monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2727.