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Abstract Colorectal cancer (CRC) ranks as one of the most lethal cancers worldwide. Given the advances in immunotherapy and targeted therapy, the survival time in CRC has been improving recently. However, the development of novel and effective therapies for CRC still remains an unmet medical need. Guanylyl cyclase C (GUCY2C) is a transmembrane receptor expressed on the surface of intestinal epithelial cells. Recent studies have demonstrated that GUCY2C is causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. To this end, GUCY2C has emerged as a promising target for immunotherapy and a diagnostic marker of primary and metastatic cancer. Here we describe the discovery and optimization of a novel panel of GUCY2C-targeting T cell engagers (TCEs) developed via our streamlined AI-guided TCE development platform. We have identified a number of anti-GUCY2C antibodies with various binding epitopes on GUCY2C, and subsequently generated a panel of novel GUCY2C-targeting multispecific antibodies with favorable developability and functionalities via our AI-driven engineering technology. Our data demonstrate that a biparatopic GUCY2C x CD3 TCE engineered as an asymmetric ‘1+2’ format can recognize two distinct epitopes on GUCY2C. This biparatopic GUCY2C x CD3 TCE shows enhanced tumor cell binding affinity and superior T cell-mediated cytotoxicity compared to the ‘1+1’ GUCY2C x CD3 TCE and ‘1+2’ bivalent GUCY2C x CD3 TCE where the two GUCY2C targeting arms can only bind to an identical epitope on GUCY2C. In addition, we have engineered a novel GUCY2C × CD3 x CD28 trispecific TCE, in which the CD3-targeting arm in tandem with the co-stimulating CD28-targeting arm mediate the interaction with T cells. This anti-GUCY2C trispecific TCE induces favorable synergistic T cell activation and tumor cell killing in vitro compared to the bispecific counterparts. In vivo anti-tumor activity assessments of these multispecific TCE molecules in various tumor xenograft mouse models are currently ongoing. Citation Format: Liang Tian, Jinxiu Hou, Chenpeng Su, Xiaoou Xu, Xiaoqian Chen, Dandan Liu, Jiyuan Tian, Rui Shen, Yi Pan, Yuan Yuan, Lisha Dong, Tingting Gu, Jian Peng. AI-guided generation of novel GUCY2C-targeting T-cell engagers for the treatment of colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6721.
Tian et al. (Fri,) studied this question.