Abstract 1627: Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion

Abstract

Abstract Regulatory T cell (Treg) depletion enhances the anti-tumor efficacy of CTLA-4 targeted mAbs in preclinical models, and is a mechanism supported by retrospective clinical data analysis. In response to these findings, many next-generation CTLA-4 targeting therapeutics have been designed to increase Fc-mediated Treg depletion in the tumor microenvironment. CTLA-4-targeted engineered toxin bodies (ETBs) are designed to deplete Tregs in the tumor microenvironment (TME) directly and in a manner independent of Fc-mediated effector functions, offering a unique approach to CTLA-4 targeted therapy. ETBs, or engineered toxin bodies, are large molecule proteins consisting of an antibody fragment genetically fused to a proprietary de-immunized (DI) form of the Shiga-like toxin A subunit (SLTA). Once engaged to the specific cell surface target of interest, in this case CTLA-4, ETBs internalize, route to the cytosol, and permanently inactivate ribosomes through an irreversible enzymatic process. This results in cell death via apoptotic mechanisms.Here we describe the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing mAb. We predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery. Utilizing human CTLA-4 knock in mouse syngeneic tumor models, we show that CTLA-4-ETB-A can reduce the % Tregs and increase the CD8/Treg ratio in the TME. Preclinical assessment of safety and pharmacodynamic signals are underway in cynomolgus studies. Citation Format: Swati Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Betty Chang, Hilario J. Ramos, Aimee Iberg. Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion [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 1627.