Engineered Toxin Bodies (ETBs) are comprised of a deimmunized Shiga-like toxin subunit A (SLTA) genetically fused to an antibody-like targeting domain. The antibody targeting domain allows for specific targeting of cancer cells while the SLTA component promotes self-internalization of ETBs, an activity that allows for the delivery of an enzymatic and permanent ribosomal destruction against targeted cells even in the context of non-or-poorly internalizing receptor targets. Molecular Templates has developed PD-L1-targeting ETBs as an approach to directly target tumor cells and overcome resistance mechanisms against PD-1 and PD-L1 antibodies. The cytotoxicity delivered by PD-L1-specific ETBs is engineered to be independent of a requirement for tumor infiltrating lymphocytes (TILs), high tumor mutational burden, or modulatory effects of the tumor microenvironment. Further, the activity is not dependent on blockade of the PD-1/PD-L1 checkpoint axis. Thus, PD-L1 targeting ETBs represent a distinct class of therapeutics with direct cell-kill mechanism of action and ability for activity in patients who have progressed on current standard of care or checkpoint therapy. In this study, we highlight the efficacy and safety profile of MT-6020, a human and cynomolgus cross-reactive, PD-L1 targeted, ETB. MT-6020 retains potent catalytic activity and mediates enzymatic destruction of ribosomes at comparable levels to wild-type SLTA in a cell free model. In addition, MT-6020 binds to human NSCLC, Melanoma, and TNBC tumor cell lines with nM affinity and mediates cellular cytotoxicity via ribosomal destruction at low nM to sub-nM potency. MT-6020 binds to cell lines expressing non-human primate (NHP)-PD-L1 and elicits cytotoxic responses comparable to those observed on human tumor target cells. MT-6020 demonstrated pharmacodynamic and pharmacokinetic effects and displayed a favorable tolerability profile in a repeat dose NHP study at doses that are above the presumed therapeutically active concentration. Further our lead PD-L1 ETB, MT-6035, is built upon the MT-6020 scaffold and can deliver a viral peptide for cell surface presentation to and targeting by a specific antiviral CTL population (antigen seeding technology (AST)) for a second and complementary mechanism for tumor cell destruction. MT-6020 and MT-6035 represent a novel approach to targeting and destroying tumors expressing PD-L1 that is unlikely to be inhibited by resistance mechanisms to current checkpoint inhibitors, is well tolerated in relevant toxicity models, and has the capacity for activity in indications where standard of care has failed. Molecular Templates is poised to initiate clinical development of the PD-L1 targeted-ETB (AST), MT-6035, in 2H - 2019. Citation Format: Hilario J. Ramos, Asis K. Sarkar, Sara Le Mar, Brigitte Brieschke, Joseph D. Dekker, Veronica R. Partridge, Pablo A. Maceda, Michaela M. Sousares, Garrett L. Robinson, Aimee Iberg, Shaoyou Chu, Jensing Liu, Jack P. Higgins, Erin K. Willert. The Safety and efficacy profile of a PD-L1 directed, Engineered Toxin Body, as a novel targeted direct-cell kill approach for the treatment of PD-L1 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3900.

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