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KLK2 Is an Extremely Promising Prostate Cancer Drug Target

Prostate cancer has entered a new era of cell surface targeted biomarkers and therapies with the introduction of prostate-specific membrane antigen (PSMA) PET imaging and treatment with 177Lutetium-PSMA-617.1 Now that radioligand therapy against PSMA has become standard, other therapeutic approaches, including antibody drug conjugate, bispecific antibody, and cellular immunotherapy, are all being tested in clinical trials. However, PSMA is expressed in many normal tissues, including the salivary and lacrimal glands and renal tubules, which can lead to on-target, off-tumor toxicities.

The urgent need for more specific biomarkers and therapeutic targets has drawn attention to members of the kallikrein family, particularly Kallikrein-related peptidase 2 (KLK2). KLK2 is a trypsin-like serine protease encoded by the KLK2 gene located on chromosome 19q13.4, within a cluster that includes KLK3, more commonly noted as prostate-specific antigen (PSA). It is predominantly expressed in the prostate, and like PSA, KLK2 is regulated by androgens via androgen receptor (AR) signaling.2 Its normal physiological function includes the activation of pro-PSA and involvement in seminal clot liquefaction through the cleavage of semenogelins.3 Functionally, KLK2 can also activate other proteases and cleave extracellular matrix proteins, facilitating tumor invasion and metastasis.4

Elevated KLK2 expression has been observed in prostate cancer tissues, with increased levels associated with high-grade tumors, metastatic potential, and biochemical recurrence after treatment.5,6 KLK2 also has restricted expression in prostate tissues, offering a promising profile for targeted therapy. However, KLK2 has been traditionally thought to be secreted into the extracellular environment, making it inaccessible for therapeutic targeting due to the perceived lack of cell surface expression. A recent publication has shown high level KLK2 expression from localized prostate cancer through heavily treated metastatic castration-resistant prostate cancer, with even higher levels, homogenous immunostaining compared to PSMA.7 Importantly, in this publication, KLK2 is expressed on the surface of prostate cancer cells, rendering it accessible for targeting. An 111In-labeled anti-KLK2 monoclonal antibody has also shown selective identification of metastatic castration resistant prostate cancer lesions, with little uptake in normal organs.8

Recent nonclinical studies have successfully shown prostate cancer cell targeting using various therapeutic modalities. Both a KLK2xCD3 bispecific antibody, redirecting T cells to KLK2-expressing prostate cancer cells, and KLK2-targeted CAR-T cells have shown direct interaction, T cell activation, and cytotoxicity in vitro.7 Additionally, experiments in xenograft mouse models showed both of these agents to induce CD4+ and CD8+ T-cell tumor infiltration with associated antineoplastic activity.

Most recently at ASCO 2025, we saw data with Pasritamig, a bispecific T-cell engager targeting KLK2, to demonstrate early efficacy in a metastatic castration-resistant prostate cancer population, with incredibly low rates of treatment related adverse events.9 The recommended phase 2 efficacy population revealed 50% PSA decline or greater in 14 of 33 (42.4%), with confirmation in 36.4%. Radiographic progression-free survival was 7.9 months, which is fairly impressive, given that 4 median lines of prior systemic therapy were administered in this patient population. Impressively, there was an 8.9% incidence of Grade 1 cytokine release syndrome only. This data makes future phase 3 clinical development conducive to outpatient dosing and a once every 6-week dosing schedule.

KLK2 represents a promising drug target in prostate cancer. With its tissue-specific expression, functional relevance to cancer progression, and accessibility to therapeutic agents, KLK2 offers a unique opportunity to advance precision oncology. In addition to the above immunologic agents used in nonclinical and early clinical studies, there are also opportunities for novel protein-based and targeted radioligand therapies for clinical use. Continued clinical research into KLK2-targeted therapies is warranted, and below, I highlight key ongoing relevant clinical trials that are actively accruing patients.

Highlighted KLK2-directed prostate cancer trials:

  • JNJ-78278343, a T-Cell-Redirecting agent against KLK2 (NCT0489634)
  • JNJ-87189401 (PSMA-CD28 bispecific antibody) plus JNJ-78278343 (NCT06095089)
  • JNJ-78278343 in combination with cetrelimab, taxane chemotherapy, or androgen receptor pathway inhibitors (NCT05818683)
  • MDPK67b, a recombinant protein-based KLK2 inhibitor (NCT05580107)
  • JNJ-69086420, an actinium-225-labeled antibody targeting KLK2 (NCT04644770)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Sartor O., de Bono J., Chi K. N., et al. (2021). Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. New England Journal of Medicine, 385(12), 1091-1103.
  2. Petraki, C. D., Gregorakis, A. K., Papanastasiou, P. A., et al. (2006). Immunohistochemical localization of human kallikreins 2, 5, 6, and 10 in benign and malignant prostate tissues. Prostate Cancer and Prostatic Diseases, 9(2), 122–128.
  3. Yousef, G. M., Obiezu, C. V., Luo, L. Y., et al. (2001). Human tissue kallikreins: From gene structure to function and clinical applications. Advances in Clinical Chemistry, 37, 99–141.
  4. Borgoño, C. A., & Diamandis, E. P. (2004). The emerging roles of human tissue kallikreins in cancer. Nature Reviews Cancer, 4(11), 876–890.
  5. Magklara, A., Mellati, A. A., Wasney, G. A., et al. (2003). Characterization of the enzymatic activity of human kallikrein 14: Autoactivation, substrate specificity, and regulation by physiological inhibitors. Biochemistry, 42(27), 792–800.
  6. Black, M. H., Magklara, A., Obiezu, C. V., & Diamandis, E. P. (2009). Expression of kallikrein genes in the human vagina. Reproductive Biology and Endocrinology, 7, 48.
  7. Fei, S., Smith, R., McDevitt, T., et al. (2025). Human kallikrein 2: A novel lineage-specific surface target in prostate cancer. Clinical Cancer Research, epub July 8, 2025.
  8. Pandit-Taskar, N., O’Donoghue J.A., Chetty D., et al. (2024). A phase 0 study to assess the biodistribution and pharmacokinetics of a radiolabeled antibody targeting human kallikrein 2 in participants with metastatic castration-resistant prostate cancer. Journal of Nuclear Medicine, 65(7), 1051-1056.
  9. Baldini, C., Vinceneux A, Robbrecht D, et al. (2025). Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, Volume 43, Number 16_suppl, 5017.

Related Content:

ASCO 2025: Molecular and Clinical Characterization of KLK2 mRNA Expression in Prostate Cancer