Abstract 2888: Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy

Abstract

Abstract Targeting CD28 for systemic T cell activation caused severe cytokine storm and multiorgan failure in an anti-CD28 antibody TGN1412 phase 1 trial. However, tumor specific CD28 targeting in a tumor associated antigen (TAA)×CD28 bispecific format, similar to the clinically validated tumor specific CD3 bispecific T-cell engagers (TCEs), offers an attractive solution to mitigate the serious safety concerns associated with systemic CD28 activation while delivering potent T-cell costimulatory signal. Our goal is to combine tumor specific bispecific TCEs targeting both CD3 and CD28, the two essential pathways in T cell activation for safe and long-lasting T cell-mediated synergistic immunotherapies. Following our success in utilizing the CD3 POWERbody™ TCE platform for tumor targeting with tight safety control, we further applied our suite of antibody technologies to develop tumor specific bispecific CD28 POWERbody TCE programs. Our NEObody™ and SAFEbody® technologies enabled us to discover and engineer species cross-reactive anti-CD28 antibodies targeting a unique and conserved epitope of CD28 as well as precision masking of the antigen binding sites for conditional activation in tumor microenvironment. The engineered tailor-made anti-CD28 arm and the tumor specific antigen targeting arm were then integrated into our proprietary bispecific platform that has robust CMC properties. Toward this end we developed multiple TAA×CD28 bispecific TCEs, including B7-H3×CD28, HER2×CD28, and TROP-2×CD28, etc., which possess fine-tuned specificity and safety profiles to minimize their on-target off-tumor toxicities and to prevent the systemic cytokine release syndrome (CRS). These TAA×CD28 bispecific POWERbodies have no superagonist activities on their own and can be activated for tumor antigen binding by the TAA arm and T cell engagement by the CD28 arm. When combined with TAA×CD3 TCEs and/or checkpoint inhibitors, they show strong synergistic T cell-mediated antitumor responses with robust safety profiles. Taken together, our tumor specific CD28 bispecific POWERbody TCEs exhibit enormous potential to fulfill the promises of safe and durable T cell-mediated immunotherapies when combined with CD3 bispecific POWERbody TCEs and/or checkpoint inhibitors. Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Bin Cai, Aaron N. Nguyen, Songmao Zheng, Jiangchun Xu, Yan Li, Felix Du, Peter Luo. Tumor-targeted CD28 bispecific POWERbody࣪ for safe and synergistic T cell-mediated immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2888.