Abstract 4256: HY0001a: A novel antibody-drug conjugate (ADC) targeting CUB domain containing protein 1 (CDCP1)

Abstract Introduction: Current ADC development focus on a small number of tumor-associated antigens (TAA). In recognizing heterogeneity of cancers and acquired resistance evolved in response to therapies, we have strategized our ADC development by focusing on discovering and develop novel TAAs. Methods: Integrative mining of large-scale omics databases was carried out to discover TAA. In-house antibody discovery and engineering platforms were employed for antibody discovery. In vitro assays were used to screen antibodies of high affinity, high specificity, efficient internalization and developability. A MMAE based ADC was evaluated in vitro for stability, cytotoxicity and bystander effect and in vivo in CDX models for anti-tumor efficacy. PK/TK and GLP toxicology studies were carried out in monkeys. Results: CDCP1 was identified to be significantly up-regulated in large proportions of cancer cells across many solid tumors, which was comparable to or higher expression than targets of the marketed ADC drugs. It is associated with cancer progression, metastasis and contributed to resistance to cancer therapies. We discovered and humanized a CDCP1-binding antibody (HY0001) which shows high affinity and specificity, and displays high efficiency of internalization and yet no agonist activity. We developed an ADC preclinical candidate (HY0001a) by conjugating HY0001 with vcMMAE at a DAR=4. HY0001a was rapidly internalized upon binding to CDCP1+ cancer cells and colocalized with lysosomes in 1∼2 hours after endocytosis. In vitro cytotoxicity assays with CDCP1+ cancer cell lines, HY0001a showed high cytotoxicity activities (IC50 = 0.05∼10 nM) in a target- and dose-dependent manner with strong bystander effect. HY0001a demonstrated strong anti-tumor efficacy in a target- and dose-dependent (1-5 mg/kg) manner when tested across multiple CDX models, including prostate, breast, pancreatic, colon, ovarian and bladder cancers. Like MMAE, HY0001a, but not HY0001, could arrest proliferative cancer cells in their G2M phase and significantly increase the number of apoptotic cells. HY0001a significant induced the apoptotic pathway in the tumor tissue of MDA-MB-231 CDX model. HY0001a is stable in biomatrix and possesses desired PK profiles (T1/2= 2-4 days in the CDX models and 2-3 days in cynomolgus monkeys). HY0001a showed toxicity profiles, similar to the marketed MMAE-based ADC drugs. We have completed development of the CMC processes and production of lots to enable the IND submission and early clinical trials. Conclusions: We identified CDCP1 as an excellent ADC TAA with great potential against multiple cancers. We discovered an antibody (HY0001) of high affinity, cancer cell-specific and efficiently internalization, and completed development of a preclinical candidate MMAE based ADC (HY0001a), which showed a great rationale for further clinical investigation to provide a novel cancer therapy. Citation Format: Wenjun Yan, Yang Zhang, Mengyun Zhang, Bo An, Yujing Zhang, Qing Xiong, Guifeng Chen, Ao Fu, Dan Sun, Xiaoqiang Cai, Huaqin Chen, Mingxia Geng, Haibo Wang, Chengwei Yan, Yike Yuan, Tao Wei. HY0001a: A novel antibody-drug conjugate (ADC) targeting CUB domain containing protein 1 (CDCP1) [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 4256.