Abstract 5455: TAVO605, a novel CD318 (CDCP1) ADC, for the treatment of solid cancers that are non-responding or resistant to Enhertu treatment

Background: CD318, also known as Cub Domain Containing Protein 1 (CDCP1), is a single span transmembrane receptor containing three Cub domains with low level expression in healthy epithelial tissues. The CD318 expression is significantly upregulated in response to RAS transformation in several major types of solid tumors, including breast, lung, pancreatic, colorectal, bladder and prostate cancers. CD318 is an important mediator of aberrant cancer-associated cascades critical for survival, growth, metastasis, and treatment resistance of tumor. The elevated expression of CD318 is associated with poor prognosis and overall survival of cancer patients. Methods and Results: We discovered several anti-CD318 antibodies with high binding affinities and prepared ADC conjugates with MMAE/MMAF. The CD318-ADC showed potent cytotoxicity to multiple cancer cell lines in in vitro cytotoxicity assays. The cytotoxicity activities correlated with the cell surface receptor densities and the binding affinities of CD318 antibodies. In multiple CDX and PDX solid tumor xenograft models involving pancreatic, colon, triple negative breast and non-small cell lung cancer, CD318-MMAE (DAR=4) showed potent tumor growth inhibition activities with efficacies comparable to or better than Enhertu (DS-8201). By employing an anti-CD318 antibody with cross-reactivity to murine CD318, we confirmed that the CD318-ADC with high drug dosing level was tolerable in a mouse toxicity study. Conclusions: By targeting a novel tumor associated antigen CD318 (CDCP1) with high expression in multiple major solid tumors, our lead CD318-ADC molecule (TAVO605) showed potent cytotoxicity to multiple tumor cell lines as well as in CDX and PDX solid tumor xenograft models. CD318-ADC was tolerable and will be further evaluated in preclinical monkey toxicity studies. Our data supported the further development of TAVO605 as a potent therapy for solid tumors non-responding or resistant to current available treatments, e.g., by Enhertu, especially in tumors with low or no HER2 expression such as triple negative breast cancers. This antibody can also be used in other modalities to control solid tumors. Citation Format: Guangmao Mu, Fulai Zhou, Honglei Bi, Zhengxia Zha, Sheng Huang, Ying Jin, Mingcan Yu, Chao Han, Mark Chiu, Di Zhang. TAVO605, a novel CD318 (CDCP1) ADC, for the treatment of solid cancers that are non-responding or resistant to Enhertu treatment [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 5455.