Preclinical data show potential of CD46-targeted combination therapy in prostate cancer

In the following video, Robert Flavell, MD, PhD, and Anil P. Bidkar, PhD, of the University of California, San Francisco, discuss preclinical data supporting CD46-targeted combination strategies that pair radioimmunotherapy with antibody-drug conjugates (ADCs) for prostate cancer and multiple myeloma. The findings, published in Clinical Cancer Research, highlight the synergistic antitumor activity of the treatment strategy and support further assessment in early phase clinical trials.¹

Flavell and Bidkar explained that the study was built around CD46, a cell-surface antigen broadly overexpressed in multiple malignancies, including prostate cancer. Their team has been developing 2 distinct CD46-directed therapeutic platforms: the ADC YS5-MMAE, which delivers the microtubule inhibitor monomethyl auristatin E (MMAE), and an actinium-225 (²²⁵Ac)-labeled alpha-particle radioimmunotherapy agent. Because the 2 agents work through different mechanisms—MMAE induces mitotic arrest while alpha radiation causes potent DNA damage—they hypothesized that combining them could enhance efficacy while maintaining manageable toxicity. Bidkar noted that MMAE had previously demonstrated radiosensitizing properties with external beam radiation, providing additional rationale for evaluating the combination at lower doses than would be used as monotherapy.

According to the investigators, the first major finding was that co-administration of the ADC and the ²²⁵Ac-labeled antibody produced superior antitumor activity in vivo compared with either agent alone. In prostate cancer xenograft models, each monotherapy generated only modest responses at the low doses selected for combination testing, whereas the dual-treatment approach led to marked tumor growth inhibition and the longest median survival. These findings aligned with in vitro data showing that the combination induced synergistic G2/M cell-cycle arrest, increased γ-H2AX foci as a marker of DNA damage, and enhanced tumor cell death relative to either monotherapy alone.

The second major advance was development of a dual-payload radioconjugate, described as an R-ADC, that incorporates both MMAE and actinium-225 on the same CD46-targeting antibody scaffold. This design enables simultaneous delivery of cytotoxic drug and alpha radiation to the same tumor cell. The investigators reported that the construct outperformed standard ADC therapy and non-drug-loaded radiolabeled antibody controls in cell-based studies and demonstrated promising tumor growth inhibition in multiple in vivo models, including C4-2B, DU145, patient-derived xenografts, and disseminated/metastatic disease models. They emphasized that the favorable tolerability profile and compatibility with CD46 immuno-PET imaging for real-time dosimetry support continued advancement into early-phase clinical trials for both prostate cancer and multiple myeloma.

REFERENCE

1. Bidkar AP, Bidlingmaier S, Wadhwa A, et al. Synergistic Treatment of Prostate Cancer and Multiple Myeloma using CD46-Targeted Radioimmunotherapy Antibody-Drug Conjugates. Clin Cancer Res. 2026;32(8):1540-1556. doi:10.1158/1078-0432.CCR-25-4110