Focusing on KLK2 Target Research: KACTUS Monkey KLK2 is Now Available

KLK2 has become an important target in the field of innovative drug development for prostate cancer.

In recent years, with the continuous development of precision treatment for prostate cancer, KLK2 (Kallikrein-related peptidase 2) has gradually become an important therapeutic target drawing industry attention, second only to PSMA. Drug development centered around KLK2 continues to achieve new progress: Pasritamig, a KLK2×CD3 bispecific antibody developed by Johnson & Johnson (J&J), has advanced from early clinical stages to global Phase 3 studies, demonstrating the excellent clinical development potential of the KLK2 target^[1]. Simultaneously, KLK2-targeted radiopharmaceuticals and molecular imaging probes, represented by h11B6, have also entered clinical exploration, further expanding the application potential of KLK2 in the field of integrated diagnosis and treatment. 

Expression and Function of KLK2

KLK2 (Kallikrein 2, also known as hK2) is a trypsin-like serine protease primarily expressed in the prostate epithelium and enters the prostatic fluid and semen as a secreted protein. KLK2 can cleave the propeptide of precursor prostate-specific antigen (pro-PSA, i.e., pro-KLK3), promoting the maturation and activation of PSA. The activated PSA further participates in the degradation of semen clot proteins, thereby facilitating semen liquefaction and sperm release. 

Structure of KLK2^[2]

KLK2 is initially synthesized as the inactive zymogen pro-KLK2. Its N-terminus contains a short propeptide, which requires proteolytic cleavage at specific Arg sites. Only after the release of the propeptide can the catalytically active, mature KLK2 be formed. Pro-KLK2 can be autoactivated or activated by other proteases such as KLK5. The propeptide is not only an important structural element for maintaining KLK2 in its zymogen state but also a key regulatory node for its maturation and activation process. Mature KLK2 possesses the typical structure of a trypsin-like serine protease. Within its structure, the 99-loop (E1 region, 105-116), the E2 region (186–197), and the catalytic triad consisting of His65, Asp120, and Ser213 are several particularly crucial structural features. Among them, the 99-loop is an important structure regulating enzyme activity, while the catalytic triad is responsible for the proteolytic reaction. 

Studies have shown that the level of the secreted form of KLK2 in serum can serve as a basis for predicting recurrence after radiotherapy^[3]. Besides the secreted form, KLK2 can also be expressed on the surface of cancer cells. This overturns the previous perception that KLK2 is exclusively a secreted protein, providing an important basis for targeted cell therapy^[4]. 

The role of KLK2 in prostate cancer^[5]

Cell surface expression of KLK2^[4]

Diseases related to KLK2 abnormalities are primarily concentrated in prostate cancer (PCa). Compared to PSMA and STEAP1, the expression of KLK2 in PCa is more specific to the cancer type and more uniform across disease stages. 

Relative expression of KLK2, PSMA, and STEAP1 in normal human tissue types and cancer types^[4]

Expression of KLK2 and PSMA across different stages of PCa^[4]

Furthermore, KLK2 is regulated by signaling from androgens (AR) and their receptors, and enhanced AR signaling activity is closely associated with elevated KLK2 levels^[6][7]. These characteristics make KLK2 an ideal target for PCa treatment. 

Schematic diagram of functional AREs in the KLK2 (green) and KLK3 (purple) gene promoters and enhancers^[8]

In summary, relying on features such as high tissue specificity, restricted distribution in normal tissues, and relatively stable expression across different disease stages, KLK2 has become an important development target for prostate cancer drugs. 

Drug Landscape for KLK2

Pasritamig is the current clinical leader. In the first-in-human Phase 1 study, the PSA50 response rate in the RP2D population (n=33) reached 42.4%, with a median rPFS of 7.85 months. Subsequently, in the Phase Ib study in combination with docetaxel (n=51), the PSA50 and PSA90 response rates reached 64.7% and 35.3%, respectively, and no CRS was observed. Based on single-agent activity, good combined tolerability with standard chemotherapy, and further anti-tumor activity signals, Pasritamig has advanced to Phase 3 to further validate its efficacy and clinical value in mCRPC. 

Kaplan-Meier curve of radiographic progression-free survival in the Pasritamig RP2D study^[1]

Maximum percentage reduction in PSA for mCRPC patients treated with Pasritamig plus Docetaxel^[9]

Besides Pasritamig, there is EM1031 from the domestic company EpimAb Biotherapeutics. In May 2025, EM1031 was licensed to Juri Biosciences for $210 million. Preclinical trials demonstrated that EM1031 can only activate T cells in the presence of KLK2-positive target cells. It exhibits lower cytokine release against KLK2-positive prostate cancer cell lines compared to similar drugs while maintaining comparable in vitro tumor cell killing activity^[10]. 

Mechanism of action for EM1031^[10]

Radiolabeled antibody-drug conjugates are also being developed for KLK2. JNJ-69086420 (i.e., ²²⁵Ac-DOTA-h11B6), deployed by J&J, is the first targeted radioligand therapy for this target. The drug is currently in Phase 1 clinical trials (NCT04644770), exploring the optimal dose and administration schedule to evaluate its clinical therapeutic potential. 
In the field of cell therapy, J&J also took the lead in deploying KLK2-targeted CAR-T therapies, with the representative candidate drug being JNJ-75229414 (NCT05022849), expanding the development pathways for KLK2 in the direction of cell therapy. 

In preclinical PCa mouse models, ²²⁵Ac-labeled KLK2-targeting antibody and anti-KLK2 CAR T-cell therapy significantly inhibited tumor growth^[4]

Examples of KLK2 Drugs

KACTUS KLK2 Research Tools Assist Key Stages of Drug Development

The deepening R&D of KLK2-targeted drugs has raised higher requirements for high-quality recombinant KLK2 protein tools. To this end, KACTUS continues to improve its related recombinant protein product system. Currently, it can provide KLK2 proteins covering human, monkey, and mouse species, supporting various application scenarios such as drug screening, affinity evaluation, cross-species binding analysis, and safety studies. Additionally, KACTUS has also deployed recombinant protein products related to other members of the KLK family, providing more tool options for research on related targets. 

Data Examples

Immobilized Rhesus macaque Kallikrein 2, His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for h11B6, hFc Tag with the EC₅₀ of 5.2 ng/ml determined by ELISA (QC Test).

Immobilized Rhesus macaque Kallikrein 2, His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Pasritamig with the EC₅₀ of 12.5 ng/ml determined by ELISA (QC Test).

h11B6 captured on CM5 Chip via Protein A can bind Rhesus macaque Kallikrein 2, His Tag with an affinity constant of 12.48 nM as determined in SPR assay (QC Test).

Pasritamig captured on CM5 Chip via Protein A can bind Rhesus macaque Kallikrein 2, His Tag with an affinity constant of 34.85 nM as determined in SPR assay (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. Safety and Efficacy of Pasritamig (PAS) + Docetaxel (DOCE) in Participants With Metastatic castration-Resistant Prostate Cancer (mCRPc): Initial Results of : Phase 1b study. Presented by D.R. Wise at ASCO GU 2026; February 26-28, 2026; San Francisco, CA, USA
10. EM1031, a novel KLK2 x CD3 bispecific T-cell engager with highly effective efficacy in preclinical models. doi: 10.1158/1538-7445.AM2025-3520
11. Serine proteases leading to prostate cancer: Structures, functions, and development of anticancer drugs. doi: 10.1016/B978-0-12-818168-3.00008-5