Targeting the Prostate Cancer Landscape: The Offensive and Defensive Strategies of PSMA, STEAP1, and KLK2

As a highly prevalent malignant tumor in men, prostate cancer progresses in a stepwise manner from early localized lesions to metastatic castration-resistant prostate cancer (mCRPC), increasingly rendering traditional treatments ineffective. Today, research and development (R&D) hotspots have precisely focused on prostate cancer cell surface antigens. The three major specific targets—PSMA, STEAP1, and KLK2—are reshaping the new landscape of prostate cancer treatment through their differentiated and complementary characteristics^[1][2].

PSMA: A Mature Target

PSMA is a type II transmembrane glycoprotein specifically and highly expressed on the surface of prostate cancer cells, making it the core target for targeted prostate cancer therapy. At the micro-histological level, PSMA is primarily localized in the secretory cells of the prostatic luminal epithelium, especially in androgen receptor (AR)-positive luminal epithelial cells, while stromal cells and neuroendocrine cells express almost none^[3]. This antigen has low expression in normal tissues but is significantly overexpressed in mCRPC, and its expression level is positively correlated with tumor malignancy (Gleason score) and metastatic burden, making it a stable and accessible targeted antigen for advanced prostate cancer^[4][5][6]. 

Current drug R&D targeting PSMA has formed a comprehensive landscape centered on radiopharmaceutical drug conjugates (RDCs, including radioligand therapy, RLT), while simultaneously covering multiple technology routes such as rADCs, ADCs, bispecific antibodies/TCEs, and monoclonal antibodies. RDC/RLT drugs represented by Pluvicto (¹⁷⁷Lu-PSMA-617) have achieved commercialization, becoming the standard of care for advanced prostate cancer. Several next-generation RDC/rADC candidates have entered pivotal Phase III clinical trials, showing potential in reducing off-target toxicity and overcoming drug resistance. Furthermore, the concurrent advancement of alpha-emitting radionuclides, T-cell engagers (TCEs), and domestic pipelines is continuously pushing the therapeutic window of the PSMA target forward, reshaping the entire diagnostic and therapeutic journey of prostate cancer. 

Global R&D Progress of Select PSMA-Targeted Drugs

STEAP1: A Potential Target Post-PSMA Resistance

STEAP1 is a transmembrane protein highly enriched in prostate cancer, featuring high expression and broad coverage within prostate tumor tissues. Compared to PSMA, its greatest advantage lies in lower tumor heterogeneity and fewer negative patients. It maintains stable expression especially in prostate cancers where PSMA expression is downregulated, drug-resistant, or undergoing neuroendocrine differentiation, making it an emerging target with immense complementary value^[7]. 

STEAP1 R&D focuses heavily on immunotherapy, with technology routes concentrating on immune-targeted regimens like TCEs, ADCs, and monoclonal antibodies, precisely offsetting the limitations of radiopharmaceutical therapies. Currently, the global pipeline for STEAP1 targets is primarily in the early clinical exploration stage. Several TCEs and novel ADC drugs are in Phase I/II. By virtue of their excellent tumor specificity and broad-spectrum expression capabilities, they have become core alternative options for PSMA-resistant and negative populations, as well as a hot direction for cutting-edge targeted R&D in prostate cancer today. 

Global R&D Progress of Select STEAP1-Targeted Drugs

KLK2: A Highly Specific New Choice

KLK2 is a highly prostate-tissue-specific serine protease. In prostate cancer, KLK2 is regulated by AR signaling. Literature reports indicate that it is highly and more uniformly expressed in tumors across different disease stages^[8]. According to an article published by Johnson & Johnson, KLK2 expression is more specific than other prostate cancer targets. Although KLK2 is traditionally considered a secreted protease, data confirm that cell surface expression of KLK2 exists in prostate cancer cell lines and patient-derived tumors, making it a highly specific surface target for prostate cancer^[9]. In preclinical models, KLK2 can be targeted via multiple strategies, including T-cell engagers, CAR-T cells, and radioligand therapy. Relying on its high specificity and low endogenous toxicity, it has become an important supplementary target for drug-resistant patients. 

Box plot analysis of the KLK2, PSMA, and STEAP1 relative expression in normal human tissue types (n = 43) and cancer types (n = 68).^[9]

Multi-modal targeting of KLK2 in prostate cancer. KLK2-expressing prostate cancer is targetable by multiple methodologies including T-cell engagers, CAR-T cell therapy and radioligand therapy (RLT).

Today, KLK2 targeted therapy has formed a multi-route parallel R&D layout. Among them, Pasritamig has entered Phase III clinical trials, while regimens like CAR-T and RLT are advancing in early stages, expected to provide new therapeutic options for PSMA-resistant or negative prostate cancer patients. 

Global R&D Progress of Select KLK2-Targeted Drugs

The KACTUS Solution

Targeting the three core prostate cancer targets—PSMA, STEAP1, and KLK2—KACTUS has developed a recombinant protein product matrix covering multiple species and formats, providing one-stop tool support for drug R&D and preclinical research. These products undergo rigorous activity and purity validation, seamlessly addressing full-process research needs from target discovery to candidate molecule screening. 

PSMA: As the cornerstone and benchmark target for prostate cancer targeted therapy, KACTUS provides PSMA/FOLH1 active proteins across multiple species, including human, cynomolgus monkey, mouse, and rat. These encompass various specifications such as active dimers, ultra-low endotoxin, and biotinylated labels, comprehensively supporting scenarios ranging from antibody screening to efficacy validation. 

STEAP1: Confronting the challenge of the complex STEAP1 protein structure, KACTUS utilizes VLP technology to provide full-length STEAP1 proteins. These highly simulate the native antigen conformation, offering a reliable tool for developing highly active antibodies and related targeted drugs. 

KLK2: KACTUS has constructed a recombinant protein product matrix covering the entire KLK family, providing various forms including Active Form, Pro Form, and biotinylated labels. Achieving multi-species coverage, it comprehensively supports target validation and drug screening for TCEs, CAR-T, ADCs, and radioligand therapies. 

PSMA Product List

STEAP1 Product List

KLK2 Product List

References

1.    Chen J, He L, Ni Y, Yu F, Zhang A, Wang X, Yan J. Prevalence and associated risk factors of prostate cancer among a large Chinese population. Sci Rep. 2024 Nov 1;14(1):26338. doi: 10.1038/s41598-024-77863-z. PMID: 39487298; PMCID: PMC11530631. 
2.    D Ye. Expert consensus on whole-course management of prostate cancer (2025 edition). Chin J Oncol. 2025;47 (7):533-550. DOI:10.3760/cma.j.cn112152-20250212-00053. 
3.    Bakht, Martin K., and Himisha Beltran. Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer. Nature Reviews Urology (2024): 1-20. 
4.    Horoszewicz, J.S., Kawinski, E. and Murphy, G.P. (1987) Monoclonal Antibodies to a New Antigenic Marker in Epithelial Prostatic Cells and Serum of Prostatic Cancer Patients. Anticancer Research, 7, 927-935. 
5.    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3(1):81-85. 
6.    Chang SS, Reuter VE, Heston WD, et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 2002;59(13):3192-3198. 
7.    Bhatia V, Kamat NV, Pariva TE, Wu LT, Tsao A, Sasaki K, Sun H, Javier G, Nutt S, Coleman I, Hitchcock L, Zhang A, Rudoy D, Gulati R, Patel RA, Roudier MP, True LD, Srivastava S, Morrissey CM, Haffner MC, Nelson PS, Priceman SJ, Ishihara J, Lee JK. Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy. Nat Commun. 2023 Apr 11;14(1):2041. doi: 10.1038/s41467-023-37874-2. PMID: 37041154; PMCID: PMC10090190 
8.    Blinka S, Yu EY. Drug Targets in Prostate Cancer: An Appetite for KLK2-Mediated Destruction. Clin Cancer Res. 2025;31(21):4393-4395. doi:10.1158/1078-0432.CCR-25-2546 
9.    Fei Shen, Ryan Smith, Theresa McDevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer McCann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake; Human Kallikrein 2: A Novel Lineage-Specific Surface Target in Prostate Cancer. Clin Cancer Res 1 November 2025; 31 (21): 4543–4556. https://doi.org/10.1158/1078-0432.CCR-25-0950