Develop novel bispecific antibody-drug conjugates against metastatic lethal prostate cancer across subtype

Abstract Antibody-drug conjugates (ADCs) have shown promise as targeted therapeutics for treating cancer, including solid tumors. However, no ADC has gained FDA approval for treatment of prostate cancer. Multiple factors including target selection and heterogeneity, as well as insufficient tumor uptake and intracellular delivery,

could have contributed to the limited success of current ADCs. To overcome these limitations and improve treatment outcomes, we propose to develop novel bispecific ADCs (bisADCs) that target emerging tumor cell surface antigens (CD46, B7-H3, and DLL3) with clinical validations. Bispecific targeting, which engages two

distinct tumor antigens simultaneously, holds promise for overcoming target heterogeneity, improving internalization and tumor penetration. Unlike a combination of monoclonal ADCs, bisADCs possess the unique ability to exploit synergistic interactions between targets and influence their intracellular fate. This concept

provides a compelling rationale for exploring bisADCs in prostate cancer treatment. We discovered CD46 as a novel prostate cancer cell surface antigen that is persistently expressed across differentiation patterns. We developed and translated a CD46-targeted ADC (FOR46) to phases I (NCT03575819) & II (NCT05011188)

trials. This CD46 ADC showed good tolerability and promising early efficacy signals in mCRPC patients. B7- H3, another emerging target widely expressed in prostate cancer, has been targeted with ADCs like MGC018 and DS-7300, showing acceptable safety and encouraging efficacy in early-phase trials. B7-H3 negativity is

rare in adenocarcinomas but more common in CRPC with neuroendocrine features. DLL3 is overexpressed in several neuroendocrine tumors, and a DLL3-targeted ADC (Rova-T) has been tested in neuroendocrine prostate cancer in a phase I trial, making DLL3 a credentialed target for this subtype. We propose to develop

bisADCs based on those emerging novel targets to address both adenocarcinoma (B7-H3 x CD46) and small cell neuroendocrine (DLL3 x CD46) prostate cancer. In Aim 1, we will determine target co-expression patterns in mCRPC patient samples, generate novel human monoclonal antibodies and nanobodies against the targets

of interest, and construct bispecific antibodies (bisAbs) using robust Ig-like architectures, and generate bisADCs carrying diverse drug payloads with clinical validation. In Aim 2, we will investigate the therapeutic efficacy of B7-H3 x CD46 and DLL3 x CD46 bisADCs in animal models representing adenocarcinoma and

small cell neuroendocrine prostate cancer, respectively. We will benchmark the bisADCs against current ADCs being tested in clinical trials, and identify lead bisADCs that demonstrate improved efficacy against heterogeneous tumors, including target-low tumors, and enhanced survival in animal models of prostate

cancer. The proposed study presents a novel approach to next-generation ADC development and has a clear path of translation to the clinic in prostate cancer patients who have progressed beyond current therapies.