CDCP1-targeted antibody-drug conjugates and immunocytokines for cancer therapy.

PURPOSE: CUB domain-containing protein 1 (CDCP1) is an emerging tumor-associated surface antigen broadly expressed in solid tumors and linked to poor prognosis, making it an attractive target for selective therapeutic delivery. We evaluated CDCP1 as a platform for two distinct therapeutic modalities: an antibody-drug conjugate (ADC) for cytotoxic payload delivery and an immunocytokine for targeted delivery of interferon-α2b (IFNα2b). METHODS: Novel humanized anti-CDCP1 monoclonal antibodies were generated and characterized for binding to recombinant and cell-surface CDCP1. CDCP1 expression in tumor cells and xenografts was assessed by flow cytometry and immunohistochemistry. CDCP1-targeted ADCs and CDCP1-targeted IFNα2b fusion proteins, including attenuated IFNα2b variants, were evaluated for in vitro cytotoxicity and in vivo antitumor activity in multiple solid tumor xenograft models. A murine cross-reactive anti-CDCP1 ADC was further assessed in an acute mouse toxicity study. RESULTS: CDCP1 was broadly expressed across multiple solid tumor cell lines and xenografts. CDCP1-targeted ADCs mediated potent, target-dependent cytotoxicity in vitro, and MMAE-conjugated ADCs showed robust antitumor activity in pancreatic, lung, breast, and colon xenograft models, with tumor growth inhibition up to 90%. Antibodies recognizing the proteolyzed amino-terminal region of CDCP1 also retained in vivo activity. The murine cross-reactive ADC was well tolerated in an acute toxicity study. CDCP1-targeted IFNα2b fusion proteins displayed markedly enhanced potency against CDCP1-positive tumor cells versus a non-targeted control, and IFNα2b attenuation enabled tunable cytokine activity. In a human PBMC-supported BxPC-3 model, a CDCP1-targeted IFNα2b immunocytokine achieved significant tumor growth inhibition. CONCLUSION: These findings established CDCP1 as a versatile therapeutic target and supported further development of parallel CDCP1-targeted ADC and immunocytokine strategies for solid tumors.