Data from Synergistic Treatment of Prostate Cancer and Multiple Myeloma using CD46-Targeted Radioimmunotherapy Antibody–Drug Conjugates
Year: 2026
Type: other
Abstract: 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.
Authors: Anil P. Bidkar, Scott Bidlingmaier, Anju Wadhwa, Ellis Mayne, Athira Raveendran, Shubhankar Naik, Cheng Xue, Megha Basak, Kondapa Naidu Bobba, Bonell Patiño-Escobar, Nancy Greenland, Juan Antonio Camara Serrano, Veronica Steri, Jonathan Chou, Arun Wiita, Jiang He, David M. Wilson, Rahul Aggarwal, Henry F. VanBrocklin, Youngho Seo, Bin Liu, Robert R. Flavell
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7164991760