Document Type

Article

Publication Date

11-3-2025

Comments

This article is the author’s final published version in Clinical cancer research : an official journal of the American Association for Cancer Research, Volume 31, Issue 21, 2025, Pages 4543-4556.

The published version is available at https://doi.org/10.1158/1078-0432.CCR-25-0950. Copyright © 2025 The Authors.

Abstract

PURPOSE: Targeted therapies for metastatic prostate cancer 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 the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer and its cell surface expression were confirmed by IHC and multiplex immunofluorescent staining. The preclinical efficacy of three KLK2-targeting therapeutics was characterized using in vitro prostate cancer cell lines, patient-derived material, and in vivo xenograft mouse models.

RESULTS: KLK2 was found to be robustly and homogeneously expressed in localized prostate cancer and metastatic hormone-sensitive prostate cancer, whereas some heterogeneity was observed in the visceral lesions of metastatic castration-resistant prostate cancer. KLK2 expression was more specific than that of other prostate cancer target antigens. Although KLK2 is traditionally described as a secreted protease, our results demonstrated its cell surface expression in both prostate cancer cell lines and patient-derived tumors. Notably, targeting KLK2 with three different MoAs, including bispecific T-cell redirector, targeted α-radioligand, and autologous chimeric antigen receptor T cells, 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 MoAs represents novel therapeutic approaches for advanced prostate cancer. See related commentary by Blinka and Yu, p. 4393.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

40627156

Language

English

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