Engineered Toxin Bodies Targeting Pd-L1 To Alter Tumor Immunophenotypes And Deliver Broad Antigenic Diversity And Patient Coverage.

Abstract Targeting PD-L1 has shown clinical efficacy in multiple solid tumor indications. Currently approved PD-L1 targeted approaches rely on monoclonal antibodies which sterically inhibit PD-L1 and prevent PD-1 mediated checkpoint activity. While these molecules have shown great activity in the clinic, the need for pre-existing tumor specific immunity and immune infiltration precludes responses in some patients and leads to resistance in others. Therefore, there remains a need for new modalities and treatment paradigms in these indications. Molecular Templates has developed MT-6402, an engineered toxin body (ETB) targeting PD-L1, as a single agent immunotoxin designed to overcome the challenges of current PD-L1 targeting approaches by 1) directly depleting PD-L1 positive tumor cells or immunosuppressive immune cells displaying PD-L1 in the tumor microenvironment and 2) delivery of an HLA: A*02 restricted viral peptide to alter the tumor immunophenotype for recruitment of CMV-restricted CTLs to target the tumor for depletion (antigen seeding). MT-6402 is slated for clinical development in 2021. Here we describe the preclinical characterization of several ETB candidates derived from MT-6402 delivering antigenic peptides restricted to the most prevalent MHC haplotypes in the U.S. population to broaden the patient population suitable for antigen seeding. ETBs were engineered with the ability to deliver viral peptides across a range of HLA restriction, including HLA: A*01, HLA: A*03, and HLA: A*24. ETBs were screened and benchmarked against MT-6402 and candidates were identified that retain comparable specificity, selectivity, and potency. Alteration of peptide antigen did not change the specificity or selectivity of ETBs which retained similar PD-L1 binding profiles to MT-6402. Binding profiles correlated to targeted potency and ETBs with varied HLA restricted peptides were found to target tumor and immune cells for depletion with similar potency to MT-6402. ETBs delivered an antigen seeding response in a PD-L1 dependent manner and only in conditions in which tumor cell and CTLs shared a matched HLA to the delivered antigenic peptide specificity. Preclinical assessment of the in vivo efficacy and safety profile of candidates is ongoing and further development is slated for 2021. Citation Format: Joseph D. Dekker, Swati Khanna, Elizabeth Saputra, Wenzhao Dong, Lindsey Aschenbach, Lilia A. Rabia, Garrett L. Cornelison, Michaela Sousares, Jay Zhao, Garrett L. Robinson, Betty Chang, Hilario J. Ramos. Engineered toxin bodies targeting PD-L1 to alter tumor immunophenotypes and deliver broad antigenic diversity and patient coverage [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 1628.