Targeting prostate cancer with site-specific antibody-drug conjugates enabled by tandemly fused ADP-ribosyl cyclases

Lei Zhang; Mashael F Aldossari; Arshad J Ansari; Guoyun Kao; Sunny H Kim; Thuc Oanh Hoang; Kaiyu Shen; Zeyu Zhang; Srinivasarao Singireddi; Zekun Li; Yuanteng Zhao; Po-Wen Yu; Fariborz Nasertorabi; Benjamin B Katz; Ling Li; Yong Zhang

doi:10.1016/j.biopha.2025.118274

Targeting prostate cancer with site-specific antibody-drug conjugates enabled by tandemly fused ADP-ribosyl cyclases

Biomed Pharmacother. 2025 Jun 17:189:118274. doi: 10.1016/j.biopha.2025.118274. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
² Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Pharmaceutics, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
³ Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, USC Structure Biology Center, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
⁵ Department of Hematological Malignancies Translational Science, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
⁶ Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: yongz@usc.edu.

PMID: 40532576
DOI: 10.1016/j.biopha.2025.118274

Abstract

Antibody-drug conjugates (ADCs) bring superior efficacy and safety profiles to the clinic by harnessing the power of biologics and chemotherapy. Despite numerous ADCs at different preclinical and clinical stages, homogeneous ADC with increased numbers of payloads conjugated at specific positions are still desired for enhanced pharmacological properties. To generate site-specifically conjugated ADCs with greater drug-to-antibody ratios (DARs), monoclonal antibodies targeting prostate-specific membrane antigens (PSMA) were genetically fused with tandem CD38 enzymes, a member of the ADP-ribosyl cyclase family. The resulting antibody-CD38 fusions coupled with its dinucleotide substrate-derived drug linker facilitate generation of ADP-ribosyl cyclase-enable ADCs (ARC-ADCs) carrying 2, 4, 6, and 8 tubulin inhibitors. In vitro and in vivo studies indicated highly potent and selective cytotoxicity against human PSMA-expressing prostate cancer cells for the anti-PSMA ARC-ADC with a DAR of 6. This proof-of-concept study demonstrates feasibility of producing site-specific ARC-ADCs with increased DARs by tandemly fused CD38 and generates candidate ADCs for targeting prostate tumors.

Keywords: ADP-ribosyl cyclase; Antibody-drug conjugate; Drug delivery; Prostate cancer; Targeted therapy.