Human Kallikrein 2: A Novel Lineage-Specific Surface Target in Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Metastatic prostate cancer (PCa) lacks effective targeted therapies, necessitating new drug targets and mechanisms of action (MoA).
• Human kallikrein 2 (KLK2), a prostate-specific antigen, has been underexplored as a therapeutic target due to prior assumptions about its expression.
• Limited evidence of cell surface expression historically hindered KLK2's recognition as a viable target in PCa.

Purpose of the Study:

• To systematically characterize KLK2 expression across the PCa disease continuum.
• To confirm the cell surface expression of KLK2 in prostate cancer.
• To evaluate the preclinical efficacy of KLK2-targeting therapeutics with distinct MoA.

Main Methods:

• Immunohistochemistry and multiplex immunofluorescent stainings to assess KLK2 expression profiles.
• In vitro studies using PCa cell lines and patient-derived material.
• In vivo xenograft mouse models to evaluate therapeutic efficacy.

Main Results:

• KLK2 demonstrated robust and homogeneous expression in localized and hormone-sensitive PCa, with some heterogeneity in metastatic castration-resistant PCa.
• KLK2 exhibits higher specificity compared to other PCa target antigens and is confirmed to be expressed on the cell surface.
• Three distinct KLK2-targeting therapeutics (bispecific T-cell redirector, targeted alpha-radioligand, CAR T) showed potent in vitro activity and significant in vivo tumor control.

Conclusions:

• KLK2 is validated as a highly prostate-specific cell surface target for PCa.
• Targeting KLK2 presents promising novel therapeutic strategies for advanced prostate cancer.
• The diverse MoA evaluated offer multiple avenues for developing effective KLK2-based therapies.