Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugates: A Promising Approach for Metastatic Castration-Resistant Prostate Cancer

Abstract

Prostate cancer (PCa), especially metastatic castration-resistant prostate cancer (mCRPC), is a significant cancer characterized by its poor prognosis and limited treatment options. Prostate-specific membrane antigen (PSMA) has emerged as a diagnostic and therapeutic target for PCa due to its restricted expression in malignant prostate tissues. In this case, several PSMA-targeting molecules were developed for radiotherapy and immunotherapy. Antibody-drug conjugates (ADCs) are a novel therapeutic approach for various carcinomas that can selectively target PSMA-positive tumor cells and minimize off-target toxicity. ADCs have made great progress in the treatment of breast and bladder cancers, and some have received FDA approval for target therapy. However, studies on PSMA ADCs are limited, and most clinical trials are at stage I or II. Therefore, this study reviewed trials about PSMA-targeting ADCs for the treatment of PCa. Clinical trials have reported a favorable pharmacokinetic profile and antitumor activity. Toxicity studies have revealed manageable adverse effects, with no significant off-target toxicity in PSMA-negative tissues. This study highlights the therapeutic potential of PSMA ADCs for the treatment of mCRPC. However, it also emphasizes the necessity of further clinical investigation to optimize efficacy, safety, and patient outcomes.

Keywords: chemotherapy; metastasis; prostate neoplasm; systemic therapy; target therapy.

Figure 1

The structure of an ADC is composed of three key components: an antibody (green), a linker (brown), and a cytotoxic payload(red). The antibody is designed to specifically recognize and bind to tumor antigens. The linker is the bridge between the antibody and the cytotoxic pay-load. The cytotoxic payload (such as MMAE) is a potent agent that disrupts cellular processes, leading to cell death. This structure insures the selective delivery of the payload to tumor cells and minimizes the off-target effects.

Figure 2

The mechanism of ADCs involves several sequential steps. First, the antibody component of the ADC specifically binds to the target antigen on the surface of the tumor cell membrane. After binding, the ADC is internalized into the cell through endocytosis, forming an early endo-some (blue membrane). This early endosome then becomes a late endosome, which eventually fuses with a lysosome (red membrane). Inside the lysosome, the ADC is degraded by lysosomal enzymes (red Pac-man), and the cytotoxic payload (red star polygon) is released. The free payload disrupts the formation of microtubules or leads to DNA strand breakage, which eventually induces apoptosis of the tumor cell.

Figure 3

Summary of development of PSMA-targeting ADCs.