Abstract 1882: DXC024, a novel anti-TROP2/EGFR bispecific antibody and tubulysin conjugate, for targeted treatment of highly TROP2- or EGFR-expressing tumors
Authors: Jingjing Zhu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Lingli Zhang, Yongxiang Chen, Lu Bai, Yunxia Zheng, Wei Zheng, Jun Zheng, Juan Wang, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Fang Du, Miaomiao Chen, Zhixiang Guo, Qingliang Yang, Robert Y. Zhao
Journal: Cancer Research (2024)

Abstract Antibody drug conjugates (ADCs) which combine the precision of targeted therapy with the cytotoxic effects of chemotherapy have become a promising drug class in cancer therapy. Epidermal growth factor receptor (EGFR) is overexpressed in a wide diversity of epithelial tumors, promoting cell proliferation and survival pathways. Tumor-associated calcium signal transducer 2 (Trop2) is also expressed in a wide range of solid tumors and has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate constructions for clinic applications. However, the approved Trop2 ADC, sacituzumab govitecan, only showed an objective response rate (ORR) of 17% and median OS of 9.5 months for lung cancers. In addition, both EGFR-ADC and Trop2-ADC had exhibited strong side effects in clinical trials due to their expression on some normal tissues, such as skin, mouth, eyes, etc. We generated bispecific Fab/scFv antibodies targeting both TROP2 and EGFR using the knob-into-hole technology, which presumably have wider efficacy, less on-target toxicity in comparison to the ADCs constructed based on the fully individual EGFR and Trop2 IgG antibodies having strong affinity to either EGFR or Trop2 antigens. Indeed, many of generated anti-TROP2/EGFR BsAbs showed strong binding activity in TROP2highEGFRhigh cells and demonstrated over 60% internalization rate within 60 min in vitro. The selected BsAbs were subsequently conjugated with tubulysin B analogs with varieties of peptidyl linkers to generate bispecific ADC (DXC024) candidates, two of which exhibited strong killing activity in A431, MDA-MB-468, Calu3, MCF-7 cells with IC50 of single to ten digital pM. In vivo, they showed very good durable antitumor response at dose as low as 4.6 mg/Kg for one injection in Calu3 (TROP2highEGFRmoderate) xenograft model, and demonstrated enhanced anti-tumor efficacy in comparison to those of the same payload conjugated to the monoclonal TROP2 or EGFR ADCs. These results indicated that DXC024 would be a promising ADC candidate for targeted treatment of highly either TROP2- or EGFR-expressing tumors. Citation Format: Jingjing Zhu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Lingli Zhang, Yongxiang Chen, Lu Bai, Yunxia Zheng, Wei Zheng, Jun Zheng, Juan Wang, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Fang Du, Miaomiao Chen, Zhixiang Guo, Qingliang Yang, Robert Y. Zhao. DXC024, a novel anti-TROP2/EGFR bispecific antibody and tubulysin conjugate, for targeted treatment of highly TROP2- or EGFR-expressing tumors [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(6_Suppl):Abstract nr 1882.