Kallikrein-related peptidase 2 (KLK2) (KLK2)

Kallikrein-related peptidase 2 (KLK2) is a trypsin-like serine protease that is highly and specifically expressed in the prostate gland [1, 4]. It is regulated by the androgen receptor and plays a critical physiological role in semen liquefaction by activating pro-prostate-specific antigen (pro-PSA) and cleaving semenogelins [1, 12]. In the context of prostate cancer, KLK2 is significantly overexpressed across all stages, including metastatic castration-resistant prostate cancer (mCRPC) [1, 4]. While traditionally characterized as a secreted protein, recent research has identified its presence on the cell surface of malignant cells, establishing it as a promising therapeutic target [2, 6]. Current drug development efforts leverage this surface expression through various modalities, including bispecific T-cell engagers like pasritamig and targeted alpha therapies such as JNJ-69086420 [1, 4]. These approaches aim to exploit the high tissue specificity of KLK2 to minimize off-target toxicities commonly associated with other prostate-specific targets like PSMA [4]. Additionally, KLK2 is being explored as a target for chimeric antigen receptor (CAR) T-cell therapy and as a biomarker for predicting disease recurrence [1, 10]. The development of KLK2-targeted agents represents a significant advancement in precision oncology for advanced prostate cancer [4, 8].

Other names

hK2Human glandular kallikrein 1hGK-1KLK2A2

Mechanisms include T-cell redirection via bispecific antibodies to induce tumor lysis [1, 2], targeted alpha therapy using radiolabeled antibodies for localized radiation delivery [1, 4], and chimeric antigen receptor (CAR) T-cell therapy for cellular immunotherapy [1, 2]. Other approaches involve protease inhibition to disrupt cancer progression and prodrug activation where KLK2 enzymatic activity releases cytotoxic agents specifically within the tumor microenvironment [5, 12].