Therefore, an unmet need exists to find a biomarker that can be used as an alternative to PSMA in prostate cancer, with several promising targets now under investigation.
Schematic representation of the mechanism of tumor-specific alpha therapy using CD46 targeted antibody.
CD46 is a cell surface protein that is highly expressed in prostate cancer and demonstrates great promise as a therapeutic target in prostate and other cancers. Prior work from investigators at UCSF and elsewhere demonstrated that a cancer specific epitope on this protein can be targeted using antibodies, resulting in the development of an antibody-drug conjugate, and immunoPET imaging agent ([89Zr]DFO-YS5).1,2 More recently, these agents have been translated into the clinic, with ongoing PET imaging (NCT05245006) and antibody-drug conjugate (NCT03575819 NCT05011188) therapy trials.
Bidkar et al. investigated the anti-tumor effect of CD46-targeted 225Ac alpha particle therapy.3 CD46 protein was overexpressed in the range of PSMA-positive and PSMA-negative patient-derived xenografts. An antibody targeting the cancer-specific epitope on CD46 was established and used to deliver 225Ac to tumor cells.1,2 Biodistribution studies in prostate cancer xenografts confirmed that the 225Ac-labeled anti-CD46 antibody ([225Ac]DOTA-YS5) specifically targeted the tumor tissue with high specificity (11.64±1.37 %ID/g, 28.58±10.88 %ID/g, 29.35±7.76%ID/g, and 31.78±5.89 %ID/g at 24 h, 96 h, 168 h, and 408 h, respectively). The [225Ac]DOTA-YS5 demonstrated improved survival and tumor suppression in cell-derived 22Rv1 (PSMA-positive) and DU145 (PSMA-negative) as well as patient-derived LTL-484 (PSMA-positive) and LTL-545 (PSMA-negative) xenografts.
In addition to therapeutic efficacy, the complete toxicity profile of [225Ac]DOTA-YS5 was studied for short-term (acute) and long-term (chronic) effects. Ex-vivo biodistribution and toxicity studies revealed that kidneys were the dose-limiting organ for [225Ac]DOTA-YS5 therapy. Nephrotoxicity was noted at higher doses (0.5 µCi) of [225Ac]DOTA-YS5, primarily due to the accumulation of daughter isotopes (221Fr and 213Bi) of 225Ac in the kidneys. However, lower doses of 0.125 and 0.25 µCi showed a significant antitumor response without kidney toxicity.
The presented data strongly indicate that [225Ac]DOTA-YS5 has therapeutic efficacy in preclinical models of prostate cancer. When taken together with our prior imaging study supporting the potential clinical translation of CD46-targeted radioligand therapy in the future.
Written by: Anil P. Bidkar, Sinan Wang, Kondapa Naidu Bobba, Emily Chan, Scott Bidlingmaier, Emily A. Egusa, Robin Peter, Umama Ali, Niranjan Meher, Anju Wadhwa, Suchi Dhrona, Chandrashekhar Dasari, Denis Beckford-Vera, Yang Su, Ryan Tang, Li Zhang, Jiang He, David M. Wilson, Rahul Aggarwal, Henry F. VanBrocklin, Youngho Seo, Jonathan Chou, Bin Liu, Robert R. Flavell
University of California, San Francisco, San Francisco, CA, United States., University of California, San Francisco, San Francisco, California, China., University of California, San Francisco, San Franciso, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States., University of California, Berkeley, CA, USA, United States., University of South Florida, Tampa, FL, United States., University of Virginia, Charlottesville, VA, United States.
- Su, Y. et al. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight 3, e121497 (2018).
- Wang, S. et al. Molecular imaging of prostate cancer targeting CD46 using immunoPET. Clinical Cancer Research 27, 1305–1315 (2021).
- Bidkar, A. P. et al. Treatment of prostate cancer with CD46 targeted 225Ac alpha particle radioimmunotherapy. Clinical Cancer Research CCR-22-3291 (2023) doi:10.1158/1078-0432.CCR-22-3291.