Abstract 2880: TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers

Background: Transmembrane-4-L-six-family member-1 (TM4SF1) is a tetraspanin superfamily member that is overexpressed in cancers such as breast, colon, lung, liver, and prostate. A contributor to tumor development and progression, TM4SF1 participates in microdomains that regulate cancer cell migration and invasion via induction of the epithelial-mesenchymal transition, and angiogenesis. The overexpression of TM4SF1 makes it an attractive target for the developing novel treatments of GI tract cancers. Methods and Results: We have engineered an anti-TM4SF1 antibody that binds with nM affinity to TM4SF1-expressing cells. The mAb has anti-tumor growth inhibition in gastric, ovarian cancer cell lines. This mAb can serve as an efficacious targeting carrier for toxins in an ADC and for siRNA in an ARC. To broaden the scope of cancer cell engagement, we prepared constructed a TM4SF1-cMET bispecific ADC which showed potent cytotoxicity in multiple GI, lung, ovarian, breast, TNBC, and pancreatic cancer cell lines in in vitro cell cytotoxicity assays. The bispecific TM4SF1-cMET MMAE (DAR=4) treatment led to potent tumor growth inhibition (70% to 95% TGI) in CDX pancreatic and gastric cancer xenograft models. The mice in the TM4SF1-cMET MMAE treatment group maintained normal body weight throughout the treatment course without observed toxicity. The TM4SF1 - MYC siRNA conjugates were stable. Treatment of MYC-dependent cancer lines led to MYC protein knockdown and cell growth inhibition. Conclusions: A bispecific TM4SF1 ADC had activity in multiple cancer cell lines. Notably, the TM4SF1-MMAE molecule showed potent in vivo tumor growth inhibition in ovarian, pancreatic, and gastric cell lines. The TM4SF1 - siRNA ARC had tumor cell proliferation inhibition in lung, pancreatic, and gastric cancer cell lines. Preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal of developing TM4SF1 as the “best-in-class” ADC molecule for the treatment of lung, gastric, breast, and pancreatic cancers with significant unmet medical needs. This antibody can be applied to alternative targeting modalities. Citation Format: Mingquan Xie, Peter Li, Han Lu, ShuTing Dong, Nicole Wilski, Poonam Pandey, Nishida Motohiko, Peter Haytko, Mark Chiu, Maria P. MacWilliams. TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2880.