Abstract 2656: DB-1329: A novel antibody-drug conjugate targeting CDCP1 demonstrates potent preclinical anti-tumor activity across multiple solid tumors

Abstract Background: Antibody-drug conjugates (ADCs) are designed to eradicate cancer cells while minimizing damage to healthy tissues. The identification and prioritization of viable tumor-associated antigen (TAA) targets are crucial for ADC development. To address this, we employed an integrative multi-omics approach to systematically discover and prioritize cell surface targets suitable for ADC development. Methods: We established an integrative framework for the identification and prioritization of tumor-associated antigen (TAA) targets. Following target identification and validation, ADCs were developed and evaluated for anti-tumor efficacy and toxicology. Results: Our AI-driven multi-omics-based platform identified CUB Domain-Containing Protein 1 (CDCP1), as a cell surface protein that is significantly upregulated in a large proportion of cancer cells across many solid tumors (notably lung, pancreatic, ovarian, and colorectal cancers) with limited expression in normal tissues. Given its role in promoting metastasis and therapy resistance, CDCP1 represents an attractive therapeutic target. We developed a novel antibody-drug conjugate, DB-1329, which consists of a fully human anti-CDCP1 monoclonal antibody with high affinity and specificity, conjugated via a protease-cleavable linker to a potent camptothecin-based TOP1 inhibitor payload. DB-1329 exhibited rapid and efficient internalization upon binding to CDCP1 and demonstrated potent and specific cytotoxicity in CDCP1-positive cancer cell lines. In vivo, DB-1329 induced profound and durable tumor regression across multiple patient-derived (PDX) and cell line-derived xenograft (CDX) models of lung, pancreatic, and colon cancers, demonstrating superior antitumor efficacy compared to benchmark ADC-treated animals. DB-1329 also displayed a favorable pharmacokinetic profile, was well-tolerated in toxicology studies, and exhibited a manageable safety profile. Conclusion: These compelling preclinical results establish CDCP1-ADC DB-1329 as a promising therapeutic candidate, with potent and targeted anti-tumor efficacy against multiple CDCP1-positive solid malignancies. Our findings strongly support the continued development and clinical translation of CDCP1-ADC. Citation Format: Hui Yang, Yujie Liu, Yang Qiu, Haiqing Hua. DB-1329: A novel antibody-drug conjugate targeting CDCP1 demonstrates potent preclinical anti-tumor activity across multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2656.