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

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.