Synergistic Treatment of Prostate Cancer and Multiple Myeloma using CD46-Targeted Radioimmunotherapy Antibody–Drug Conjugates

PURPOSE: CD46 is highly expressed across multiple cancer types, including prostate cancer and multiple myeloma. We have developed CD46-targeting antibody-drug conjugate (ADC) and actinium-225 (225Ac)-based α particle therapy agents that demonstrated a tumor-selective therapeutic effect. We hypothesized that a treatment strategy targeting CD46 using simultaneous ADC and radioimmunotherapy methods would have synergistic therapeutic efficacy with acceptable toxicity. EXPERIMENTAL DESIGN: Two CD46-targeted combination treatment strategies were evaluated: (i) co-administration of the ADC (YS5-MMAE) and 225Ac-labeled antibody ([225Ac]Macropa-PEG4-YS5) and (ii) a dual-payload radioconjugate ([225Ac]Macropa-PEG4-YS5-MMAE; R-ADC). The in vitro synergy was studied using cell viability, DNA damage, and apoptosis assays. In vivo studies were performed for biodistribution, toxicity, and therapeutic evaluation in subcutaneous, disseminated, and patient-derived xenograft models of prostate cancer and multiple myeloma. RESULTS: Combination therapy induced synergistic G2-M arrest, increased γ-H2AX foci, and enhanced cell death compared with monotherapies. R-ADC and co-administration strategies resulted in improved tumor control and survival benefit. CONCLUSIONS: By integrating orthogonal microtubule inhibition and high-linear energy transfer α irradiation on a single CD46 scaffold, potent, well-tolerated tumor control was achieved across diverse models. The dual-payload construct's compatibility with CD46 immuno-PET for real-time dosimetry further supports progression to early-phase clinical trials in prostate cancer and multiple myeloma.