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Many T-cell engagers (TCE) and immuno-oncology biologics have limited efficacy in the clinic due to narrow therapeutic windows, checkpoint upregulation, and emergence of resistance mechanisms over time. The PROTECTTM (PROgrammed Tumor Engagement & Checkpoint/Costimulation Targeting) platform is designed to tackle these challenges by combining a masking domain that, when cleaved, provides additional immune-modulatory properties. The PROTECTTM mask consists of a PD1-PDL1 protein pair that sterically hinders CD3 binding in the periphery. The PD-L1 moiety is fused to the anti-CD3 antibody via a linker sequence containing a protease cleavage site. Once cleaved, the resultant molecule is a trispecific antibody providing TCE activity, checkpoint inhibition, and additional differentiated functionality. Previous studies employing pan T cell cytotoxicity assays showed the PROTECTTM mask increased the therapeutic window by 400-fold. We have now expanded our in vitro evaluation to include more relevant PBMC systems showing a greater expansion of the therapeutic window. In vivo treatment of established tumours with the unmasked trispecific results in complete and durable anti-tumour responses. Here we extend those in vivo studies (in context of established tumour models) to evaluate unmasking and pharmacokinetic properties. We further evaluated the unique and differentiated mechanism of action of the cleaved trispecific to not only enhance engagement of effector T-cells with tumor cells through avidity driven cis-engagement of a tumor associated antigen (TAA) and PD-L1 co-expressed on tumor cells, but to also enhance co-engagement of a TAA with effector T cells co-expressing PD-L1. In addition, the ability of the cleaved trispecific to bridge autologous T cells with DCs results in enhanced T cell activation and proliferation. Finally, TCR dependent signaling assays confirmed the ability of the cleaved trispecific to overcome PD1/PDL1 checkpoint activity. Taken together, the PROTECTTM platform integrates a masking and immune-modulatory technology that has the potential to widen the therapeutic window of CD3 engagers. Citation Format: Anna von Rossum, Genevieve Desjardins, Nichole Escalante, Wingkie Wong, Bryant Harbourne, Janessa Li, Begonia Silva Moreno, Prajwal Raghunatha, Richard Kunze, Madeline Fung, Florian Heinkel, Harsh Pratap, Kevin Haworth, Eric Escobar-Cabrera, Brandon Clavette, Surjit Dixit, Nina Weisser, Thomas Spreter von Kreudenstein. PROTECTTM, a novel trispecific antibody masking platform with integrated immune modulation displays unique activity and differentiated modes of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2926. |
