Prostate cancer is the second most common cancer in men. According to the recently released American Cancer Annual Report, the estimated number of new cases of prostate cancer in 2023 is still the highest among male cancers, accounting for about one third of all men, with 120,000 new cases every year in China. Antibody-drug conjugates (ADCs) combine the advantages of high specific targeting ability and strong killing effect to achieve precise and efficient killing of cancer cells, and have become one of the hot spots in the development of anticancer drugs. Since the first ADC drug Mylotarg was approved by the FDA in 2000, a total of 15 ADC drugs have been approved for hematological malignancies and solid tumors worldwide till now. In addition, there are currently more than 100 ADC candidates are in various stages of clinical trials. Let's review the targets and clinical trials of ADC in prostate cancer.
ADC Targets Targeting Prostate Cancer
Androgen deprivation therapy (ADT) is an important treatment for prostate cancer (PCa). However, particularly for castration-resistant disease, treatment options also include chemotherapy, antiandrogen therapy, radioisotope therapy, gene-targeted therapy, immune checkpoint inhibitors, and autologous cellular immunotherapy.
Important targets targeting prostate cancer (PCa) include: prostate-specific membrane antigen (PSMA), six-transmembrane epithelial antigen of prostate 1 (STEAP1), solute carrier family 44 member 4 (SLC44A4), trophoblast cell-surface antigen 2 (TROP2) and B7-H3, the situation of these targets and ADC drugs in the clinical stage are introduced respectively below.
The mechanism of action of ADCs in prostate cancer
(Source: https://www.mdpi.com/1422-0067/22/4/1551)
Table 1 ADCs currently studied in uromalignancy in clinical trials
Recently, Ambrx Biopharma announced that its antibody-drug conjugate (ADC) ARX517 targeting prostate-specific membrane antigen (PSMA) has shown positive preliminary data in a Phase 1 clinical trial (APEX-01 NCT04662580).
ARX517 is an ADC drug composed of Ambrx's proprietary potent microtubule inhibitor AS269 and a fully humanized monoclonal antibody targeting PSMA. As early as August 2021, ARX517 completed the first patient administration, and this data release also represents the latest progress of the pipeline.
PSMA is highly expressed (>89%) in metastatic castration-resistant prostate cancer (mCRPC) and is a validated therapeutic target, and ARX517 is a potential "first in class" ADC drug targeting PSMA.
Clinical Progress of ADC Drugs For Prostate Cancer
As mentioned above, the current major targets targeting prostate cancer are: prostate-specific membrane antigen (PSMA), six-transmembrane epithelial antigen of prostate 1 (STEAP1), solute carrier family 44 member 4 (SLC44A4), trophoblast cell-surface antigen 2 (TROP2) and B7-H3.
PSMA
PSMA is a cell membrane protein specifically expressed in prostate cells, and its expression in prostate cancer and metastatic cells is significantly higher than that in normal prostate tissue.
At present, the most commonly used PSMA antibody radiotherapy drug is 177Lu. A phase II clinical trial showed that among 47 patients treated with 177Lu targeted therapy for metastatic castration-resistant prostate cancer, 60% of the patients showed a decrease in PSA level, and 10.6% of the patients showed a decrease in PSA level of >50% . MLN2704 is an ADC drug conjugated with anti-microtubule drug DM1 and 177Lu. A phase I clinical trial conducted on 23 patients showed that the PSA level of 2 patients decreased by >50%, and grade 3 toxicity occurred in 3 patients. New compounds are currently being designed to reduce the associated cytotoxicity.
STEAP-1
STEAP-1, an ion/protein transporter, is also six-transmembrane epithelial antigen of prostate 1, which is an ideal target for ADC treatment of prostate cancer because it is highly expressed in prostate cancer cells but very poorly expressed in normal tissues.
STEAP-1 expression was observed in every clinical stage of PCa. In non-prostate tissues, STEAP-1 is moderately expressed in bladder cells and overexpressed in cancers other than PCa, such as Ewing's sarcoma, bladder, colon, and ovarian cancer. STEAP regulates tumor growth by regulating intracellular communication between the tumor and the stroma. STEAP-1 expression profile makes it a promising drug target. In addition, STEAP is used in peptide-based vaccines. A preclinical study of PCa and BCa xenografts showed that anti-STEAP antibodies inhibited tumor growth.
For advanced prostate cancer: The new drug DSTP3086S is an ADC drug targeting STEAP1. 62 patients received effective dose treatment (>2mg/kg, once every 3 weeks), and tumor markers in 11 patients decreased by more than half. Among the 36 patients available for imaging evaluation, 2 patients had tumor shrinkage of more than 30%; 27 patients with high circulating tumor cells could be detected in the blood before treatment, and 16 patients had circulating tumor cells in the blood after treatment reduced to an unfathomable level.
SLC44A4
The protein encoded by SLC44A4 has been proved to be a sodium-dependent transmembrane transporter of thiamine pyrophosphate, which is related to temperature, energy and pH. Thereafter it known as thiamine pyrophosphate transporter(TPPT), and was shown to have high expression in the gut, prostate, lung and trachea.
ASG-5ME, an SLC44A4-targeted antibody-carrying monomethyl auristatin E (MMAE, a microtubule inhibitor) ADC drug, was studied in men with metastatic desmoresistant prostate cancer in a phase I study, the primary objective of which was to determine the maximum tolerated dose (MTD) and the recommended phase II dose. A total of 46 patients participated, and 52% of those evaluable had stable or partial remission with >50% reduction in PSA levels.
TROP-2
TROP-2 is a single transmembrane surface glycoprotein encoded and expressed by the TACSTD2 gene. Studies have shown that TROP-2 is expressed in a variety of human epithelial cancers, with the highest expression rate in uroepithelial cancer, cervical cancer and triple-negative breast cancer. And Trop-2 also has a relatively high expression rate (about 90%) in papillary thyroid carcinoma, lung cancer, endometrial cancer, prostate cancer, and colorectal cancer.
NCT03725761 is an ongoing Phase II study to determine the safety and efficacy of SG in mCRPC patients progressing on next-generation anti-androgens (enzalutamide, apalutamide or abiraterone acetate). A total of 55 patients were enrolled. The primary endpoint was to assess the reduction in PSA levels of ≥50% after 9 weeks of treatment. Secondary endpoints included PFS, OS, and toxicity rate.
B7-H3
B7-H3, also known as CD276, is a membrane protein member of the B7-CD28 family of immunomodulatory proteins. It is a type I membrane protein with similar sequence to the extracellular domain of programmed death receptor-1 (PD-L1). B7-H3 expression is low in normal human tissues, but is abnormally high in a variety of tumors, and in prostate cancer, its expression is associated with Gleason score, tumor staging, lymph node metastasis, and castration-resistant disease.
At the 2021 ASCO annual meeting, the biopharmaceutical company MacroGenics announced the preliminary safety and anti-tumor activity data of an ongoing phase I dose-escalation clinical trial of an ADC drug MGC018 targeting B7-H3. Results showed preliminary evidence of antitumor activity of ADCs targeting B7-H3, particularly in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), where a reduction in prostate-specific antigen (PSA) levels of ≥50% was observed in 5 out of 9 mCRPC patients on dose escalation therapy.
With 15 ADC drugs on the market, ADC has made great progress in the field of cancer treatment. However, there are still some limitations and challenges in the development of ADC, such as toxicity and side effects, tumor targeting and payload release, immunogenicity, drug resistance and other problems. It is believed that more ADC drugs will be applied in the treatment of various solid tumors in the near future.
PEG Linker is one of the most widely used linkers in ADCs, Huateng Pharma is dedicated to providing high-quality PEG linkers such as NH2-PEG24-COOH, 2-((Azido-PEG8-carbamoyl)methoxy)acetic acid, Mal-NH-PEG8-COOH, N3-PEG3-SPA etc. to promote the progress of ADC R&D. As a pharmaceutical intermediates supplier, Huateng Pharma also supplies some key intermediates of Enzalutamide which is is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer (mCSPC).
References:
[1] Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduction and Targeted Therapy (2022) 7:93
[2] Current status and future prospects of antibody–drug conjugates in urological malignancies. doi: 10.1111/iju.14925
[3] Antibody–Drug Conjugates in Uro‑Oncology. doi.org/10.1007/s11523-022-00872-3
Related articles:
[1] Challenges of Immunotherapy For Prostate Cancer
[2] Approved Antibody–Drug Conjugates (ADCs) and In Clinical Trials
[3] Directions for Next Generation Antibody-Drug Conjugates