Human kallikrein 2: A novel lineage-specific surface target in prostate cancer

Abstract

Purpose: Targeted therapies for metastatic prostate cancer (PCa) are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across PCa disease continuum. However, it was not recognized as a therapeutic target for PCa in the past due to limited evidence of its cell surface expression. Here, we systematically characterized KLK2 expression in PCa, confirmed its cell surface expression, and demonstrated preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

Experimental design: KLK2 expression profile in different stages of PCa and its cell surface expression were confirmed by immunohistochemistry and multiplex immunofluorescent stainings. Preclinical efficacy of three KLK2-targeting therapeutics was characterized using in vitro PCa cell lines, patient-derived material, and in vivo xenograft mouse models.

Results: KLK2 was found to be robustly and homogenously expressed in localized PCa and metastatic hormone-sensitive PCa, while some heterogeneity was observed in the visceral lesions of metastatic castration-resistant PCa. KLK2 expression was more specific than that of other PCa target antigens. Although KLK2 is traditionally described as a secreted protease, our results demonstrated its cell surface expression in both PCa cell lines and patient-derived tumors. Notably, targeting KLK2 with three different MoA, including bispecific T-cell redirector, targeted alpha-radioligand, and autologous CAR T, showed potent in vitro activity and robust in vivo tumor control.

Conclusions: Our study establishes KLK2 as a highly prostate-specific cell surface target. Targeting KLK2 with various MoA represents novel therapeutic approaches for advanced PCa.