KLK2: The New Promising Target for Prostate Cancer

Pasritamig Advanced to Phase 3 Clinical Trials

In September 2025, Johnson & Johnson (J&J) initiated a Phase 3 clinical trial (NCT07164443) of Pasritamig for metastatic castration-resistant prostate cancer (mCRPC). Pasritamig (JNJ-78278343) is a first-in-class bispecific antibody targeting KLK2 and CD3, and is currently the most advanced KLK2-targeting drug in development.

Results from the Phase 1 trial showed that 42.4% of mCRPC patients achieved a ≥50% reduction in prostate-specific antigen (PSA), with a median radiographic progression-free survival (rPFS) of 7.9 months. In terms of safety, 9.8% (17 of 174) Grade 3 treatment-related adverse events (TRAEs) and four cases (4/45) of cytokine release syndrome (CRS), all Grade 1.

Based on these favorable Phase 1 results, Pasritamig advanced directly to Phase 3, skipping Phase 2, and is expected to become a milestone drug in the KLK2 field.

Partial data from the Pasritamig Phase 1 study [1]

Expression and Function of KLK2

KLK2, short for Kallikrein 2 (also known as hK2), is a trypsin-like serine protease. It is primarily expressed in prostate tissue, where it converts pro-prostate-specific antigen (pro-PSA, i.e., pro-KLK3) into its active enzymatic form, which hydrolyzes seminal proteins, contributes to semen liquefaction, and regulates the prostate microenvironment.

Structure of KLK2 [2]

KLK2 is secreted as an inactive zymogen (pro-KLK2), which can be activated by KLK5 (another family member) or through autocatalysis, although the latter occurs more slowly and less efficiently. Studies suggest that serum KLK2 levels can predict PSA relapse after radiotherapy [3]. In addition to its secreted form, KLK2 can also be expressed on the cancer cell surface, challenging the traditional view of KLK2 as purely a secreted protein - a finding that provides a rationale for cell-targeted therapies [4].

Role of KLK2 in Prostate Cancer [5]

Diseases associated with aberrant KLK2 expression are mainly prostate cancer (PCa). Compared with PSMA and STEAP1, KLK2 shows higher tumor-type specificity and greater expression consistency across disease stages in PCa.

Relative expression of KLK2, PSMA, and STEAP1 in normal tissues and cancers [4]

Expression of KLK2 and PSMA across prostate cancer stages [4]

Moreover, KLK2 expression is regulated by androgen receptor (AR) signaling. Increased AR activity correlates with higher KLK2 expression [6][7]. These characteristics make KLK2 an ideal therapeutic target for PCa.

Schematic of functional androgen response elements (AREs) in KLK2 (green) and KLK3 (purple) gene promoters and enhancers [8]

Drug Development Targeting KLK2

Among bispecific antibodies, Pasritamig is joined by EM1031 from Anmai Biotech (China). In May 2025, EM1031 was licensed to Juri Biosciences in a deal worth up to $210 million.

Preclinical studies demonstrated that EM1031 activates T cells only in the presence of KLK2-positive target cells, shows lower cytokine release compared to similar drugs, and maintains comparable in vitro cytotoxicity against KLK2-positive prostate cancer cell lines [9].

KLK2 is also suitable for the development of radioimmunoconjugate drugs, likely due to its high tissue specificity and compact structure (especially compared with STEAP1).
J&J developed the radioimmunotherapy agent 225Ac-labeled JNJ-69086420 (225Ac-DOTA-h11B6), the first radiolabeled therapy targeting KLK2. Although patient deaths in the Phase 1 trial raised serious safety concerns, J&J continues to optimize dosing and administration to mitigate risk.

In cell therapy, J&J’s anti-KLK2 CAR-T candidate JNJ-75229414 (NCT05022849) has been disclosed.

In preclinical prostate cancer mouse models, both 225Ac-labeled KLK2-targeting antibodies and anti-KLK2 CAR-T cells significantly inhibited tumor growth [10].

Summary

J&J’s diverse early-stage investment in KLK2 demonstrates strong confidence in this emerging target. Currently, KLK2 has become a rising star following PSMA and STEAP1, offering several unique advantages and potentially expanding therapeutic options for prostate cancer. KACTUS provides high-quality recombinant KLK2 proteins in their mature forms, suitable for diverse research and drug development applications related to KLK2-targeted therapy.

Product Validation Data

Immobilized Human Kallikrein 2, No Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-Kallikrein 2 Antibody, hFc Tag with the EC50 of 3.3 ng/ml determined by ELISA (QC Test).

Measured by its ability to cleave the fluorogenic peptide substrate: PFR-AMC. The specific activity is >450 pmol/min/µg (QC Test).

Product List

References:

[1] Pasritamig, a First-in-Class, Bispecific T-Cell Engager Targeting Human Kallikrein 2, in Metastatic Castration-Resistant Prostate Cancer: A Phase I Study. doi: 10.1200/JCO-25-00678

[2] Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity. doi: 10.1074/jbc.M114.598201

[3] Androgen receptor upregulation mediates radioresistance after ionizing radiation. doi: 10.1158/0008-5472.CAN-15-0892

[4] Human Kallikrein 2: A Novel Lineage-Specific Surface Target in Prostate Cancer. doi: 10.1158/1078-0432.CCR-25-0950

[5] Mechanism of Semen Liquefaction and Its Potential for a Novel Non-Hormonal Contraception. doi: 10.1093/biolre/ioaa075

[6] Androgen induction of a human prostate-specific kallikrein, hKLK2: characterization of an androgen response element in the 5' promoter region of the gene. doi: 10.1021/bi00076a020

[7] Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation. doi: 10.1007/s13277-013-1253-6

[8] Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus. doi: 10.1210/er.2009-0034

[9] EM1031, a novel KLK2 x CD3 bispecific T-cell engager with highly effective efficacy in preclinical models. doi: 10.1158/1538-7445.AM2025-3520

[10] https://www.jnjmedicalconnect.com/media/attestation/congresses/oncology/2024/gu/preclinical-characterization-of-human-kallikrein-2-hk2-as-a-novel-target-for-the-treatment-of-prosta.pdf

[11] Serine proteases leading to prostate cancer: Structures, functions, and development of anticancer drugs. doi: 10.1016/B978-0-12-818168-3.00008-5