Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Synergistic Treatment of Prostate Cancer and Multiple Myeloma using CD46-Targeted Radioimmunotherapy Antibody-Drug Conjugates.
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Bidkar Anil P, Bidlingmaier Scott, Wadhwa Anju, Mayne Ellis, Raveendran Athira, Naik Shubhankar, Xue Cheng, Basak Megha, Bobba Kondapa Naidu, Patiño-Escobar Bonell, Greenland Nancy, Camara Serrano Juan Antonio, Steri Veronica, Chou Jonathan, Wiita Arun, He Jiang, Wilson David M, Aggarwal Rahul, VanBrocklin Henry F, Seo Youngho, Liu Bin, Flavell Robert R
Аннотация
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.
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.