Site-Specific Antibody-Drug Conjugates with Various Drug-to-Antibody-Rations for Prostate Cancer Therapy

Abstract

Prostate cancer (PC) is one of the most common cancers affecting men and is among the primary causes of mortality. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein found on the surface of PC. It is often targeted in PC diagnosis and treatment because it is frequently overexpressed in PC cells. Antibody-drug conjugates (ADCs) are a promising category of cancer therapeutics and offer targeted therapy for cancer treatment by selectively damaging cancer cells while sparing healthy cells. Most marketed ADCs depend on lysine and cysteine residues in conjugation processes, resulting in heterogeneous mixtures. Recently, we developed a new approach using the catalytic domain of human CD38 with an NAD+ analog to generate ADP-ribosyl cyclase-enabled ADCs (ARC-ADCs). In this study, we generated ARC-ADCs with various drug-to-antibody ratios (DARs) that target prostate-specific membrane antigens (PSMA) in prostate cancer. Through a one-step process, various anti-PSMA antibodies with different numbers and positions of CD38 on both light and/or heavy chains were attached to a cytotoxic payload. Anti-PSMA IgG CD38 fusions display a high affinity to recombinant PSMA antigen and excellent efficacy against PSMA-positive prostate cancer cells. These results show promising in vitro cytotoxicity of ADCs, which could help develop targeted drug therapy for prostate cancer.