ARX-517 (JNJ-95298177): A Next-Generation PSMA-Targeted Antibody-Drug Conjugate for Advanced Prostate Cancer

1. Introduction

ARX-517, now designated JNJ-95298177 following corporate acquisition, represents an investigational, next-generation antibody-drug conjugate (ADC) engineered to target the prostate-specific membrane antigen (PSMA).[1] Developed initially by Ambrx Biopharma utilizing a proprietary expanded genetic code technology platform for precise, site-specific conjugation, ARX-517 embodies a novel approach to treating advanced prostate cancer.[1] The subsequent acquisition of Ambrx by Johnson & Johnson (J&J) in early 2024 underscores the perceived potential of this technology and the ARX-517 program specifically.[3]

The therapeutic rationale for ARX-517 is firmly rooted in the biology of prostate cancer and the validated role of PSMA as a therapeutic target. PSMA, a type II transmembrane glycoprotein, exhibits significantly elevated expression on the surface of prostate cancer cells, particularly in the context of metastatic castration-resistant prostate cancer (mCRPC), while displaying limited expression in most healthy tissues.[1] This differential expression profile makes PSMA an attractive target for directed therapies like ADCs. Furthermore, PSMA internalizes upon antibody binding, a crucial characteristic enabling the intracellular delivery of cytotoxic payloads conjugated to the targeting antibody.[14] The clinical validation of PSMA as a target was solidified by the approval and success of PSMA-targeted radioligand therapies, such as $^{177}$Lu-PSMA-617.[15] However, significant unmet medical need persists, particularly for patients with heavily pretreated mCRPC who have exhausted standard-of-care options, including potent androgen receptor pathway inhibitors (ARPIs) like abiraterone and enzalutamide, and taxane-based chemotherapy.[1] This patient population often faces a poor prognosis with limited survival