Abstract 2777: Antigen Seeding Technology by Engineered Toxin Bodies provides a targeted immuno-oncology approach for treatment of cancers
Authors: Brieschke Brigitte , Rajagopalan Sangeetha , Robinson Garrett L. , Higgins Jack P. , Willert Erin K. , Ramos Hilario J. 
Published: August 2018

Abstract
Engineered Toxin Bodies (ETBs) are a distinct class of targeted immunotoxins in development by Molecular Templates as anti-cancer therapeutics. ETBs drive a potent and targeted response mediated by antibody-like binding, cellular internalization, and enzymatic ribosomal inhibition via the delivery of a Shiga-like toxin subunit A (SLTA) that has been proprietarily modified to avoid innate and adaptive immune recognition. In addition to this primary mechanism of action (MOA), the intrinsic ability of ETBs to induce internalization in a targeted fashion, present a unique delivery platform for next generation MOAs in the immuno-oncological (IO) space. Recent advances in IO such as checkpoint inhibitors, bi-specific T cell engagers, and CAR-T cells now provide direct clinical evidence that restoration of T cell functionality or re-direction of fully functional T cells drive significant clinical benefit to patients that have failed traditional standard of care. Molecular Templates has developed the Antigen Seeding Technology (AST) platform, rendering next generation ETBs with the unique ability to deliver foreign protein antigen to the cytoplasm of targeted populations of tumor cells. This MOA allows for the intracellular processing of antigen and subsequent surface MHC-I presentation required for activation of a re-directed T lymphocyte response and the capacity to restore a functional immune clearance program against the tumor. Our first generation AST molecule has been engineered as a PD-L1 targeted ETB carrying the immunodominant HLA:A02 restricted peptide (NLVPMVATV) from the Cytomegalovirus (CMV) tegument protein-pp65. This design takes advantage of targeting of PD-L1 expressing tumor cells, which are components of multiple cancers responsive to current IO modalities. Furthermore, the incorporation of an immunodominant CMV-peptide allows for the appropriation of a highly functional and non-exhausted CMV-specific lymphocyte response that is highly prevalent in the human population. Pre-clinical data demonstrate a potent ability for AST to trigger ETB-mediated T cell responses and tumor cell clearance of multiple PD-L1+ tumor targets. This response is highly specific, as treatment of PD-L1+ positive but not negative cell lines leads to detectable surface expression of NLVPMVATV in an HLA:A02 dependent manner. Furthermore, this result correlates with activation of effector T cells and subsequent eradication of multiple PD-L1/A02+ tumor targets after co-culture with healthy T cells from A02/CMV+ donors. Together, our POC data shows that using our AST-platform, we can deliver a targeted antigenic response to re-direct CMV-T cell responses to various tumor cell lines, trigger a T cell-mediated response and targeted-tumor cell clearance. Molecular Templates intends on extending the AST platform to clinical lead programs in 2018.
Citation Format: Brigitte Brieschke, Sangeetha Rajagopalan, Garrett L. Robinson, Jack P. Higgins, Erin K. Willert, Hilario J. Ramos. Antigen Seeding Technology by Engineered Toxin Bodies provides a targeted immuno-oncology approach for treatment of cancers [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 2777.