Exploration of The Application of ADC In Prostate Cancer

Currently, ADC has played a significant role in the treatment of some malignant tumors, such as trastuzumab in the treatment of breast cancer, but its therapeutic application in prostate cancer (PCa) has progressed slowly. In recent years, ADC has made rapid progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC). STEAP1, TROP2, PSMA, CD46, and B7-H3 are currently being focused on as optimal antigens, and studies suggest that these antigens may be targeted by ADCs.

1 ADC for the treatment of PCa

PSMA-based ADCs

PSMA (prostate-specific membrane antigen) is a cell membrane protein specifically expressed by prostate cells, and its expression in PCa and metastatic cells is significantly higher than that in normal prostate tissue. Three PSMA-targeted ADCs are currently in clinical studies (MLN2704, PSMA-MMAE and MEDI3726).

2. Other ADCs

STEAP1 (six-segment transmembrane epithelial antigen of the prostate), an ion/protein transporter, is an ideal target for ADCs because it is highly expressed in PCa cells but very low in normal tissues. DSTP3086S, an MMAE-associated humanized IgG1 anti-STEAP1 monoclonal antibody, demonstrated safety and significant antitumor activity in a phase I trial in 77 mCRPC patients. 18% of patients had a 50% decrease in PSA, 6% of patients had local radiation reactions, and 60% of patients transformed into benign circulating tumor cells <5.

TROP2 (human trophoblastic surface antigen 2) is a membrane-bound glycoprotein commonly expressed in several tissues including the prostate. This antigen is also overexpressed in some cancer cells, including aggressive PCa. Following approval for the treatment of metastatic triple-negative breast cancer, a TROP-2-based ADC is in a phase II trial (NCT03725761), enrolling patients with mCRPC who had progressed on abiraterone or enzalutamide.

Other targets being investigated in mCRPC patients are CD46 (NCT03575819) and B7-H3 or CD276 (NCT003729596). FOR46, a novel ADC that binds to MMAE and targets CD46, is thought to be highly expressed in mCRPC.

3. Limitations of ADC in PCa

It is reported that the therapeutic effect of ADC on PCa in clinical research has not achieved the expected effectiveness and the safety data are not satisfactory. The limiting factors are as follows:

The first challenge is that the tumor antigens targeted by ADCs lack optimal specificity and can be found in other normal tissues.

A second challenge is linker instability, which allows ADCs to release toxins in circulation, contributing to their toxic profile.

The third challenge is the DAR (drug-to-antibody ratio) of ADC drugs. DAR is an important parameter of ADC. High DAR may affect ADC stability, structure and antigen binding, but low DAR will reduce the effectiveness. Therefore, in ADC preparation, it is very important to control DAR.

Additional challenges include resistance mechanisms, altered intracellular processing, recycling, and trafficking pathways of ADCs, cell surface recycling of targeted tumor antigens, and impaired cytoplasmic release of toxic payloads and impaired lysosomal function.

4. Prospect of ADC in PCa field

Advances in biotechnology have improved the antibody specificity, linker stability and cytotoxic efficacy of novel ADCs, and ongoing clinical trials will evaluate the safety and efficacy of these novel ADCs in mCRPC. Although most ongoing trials are focused on mCRPC, it would be interesting to explore the role of ADCs in the early stages of the disease in the coming years if ADCs proves efficacy. In addition, the combination of ADC with other treatments, such as immunotherapy, may improve prognosis and provide new treatment options for PCa.

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