KLK2: From a Peripheral Target to a Strategic Opportunity in Prostate Cancer Drug Development

Why Is KLK2 Re-emerging After the PSMA-Centric Era?

Prostate cancer drug development has been largely shaped by the rapid rise of PSMA as a dominant therapeutic target. Multiple modalities---including T-cell engagers (TCEs), antibody-drug conjugates (ADCs), radioligand therapies, and CAR-T platforms---have converged on PSMA, accelerating innovation but also creating increasing target saturation.

As the field matures, several limitations of a PSMA-centered strategy are becoming more apparent, including heterogeneous antigen expression, treatment resistance, and overlapping safety constraints across modalities. These challenges are prompting a gradual shift in interest toward alternative or complementary targets that can expand therapeutic coverage beyond PSMA-defined patient populations.

Within this context, KLK2 (kallikrein-related peptidase 2) is gaining renewed attention. Its emergence reflects a broader evolution in target selection strategy---from prioritizing the most established antigen to designing more diversified and biologically complementary target portfolios.

KLK2: Re-evaluating a Historically Underexplored Target

KLK2 is a prostate-enriched serine protease with relatively restricted expression in normal tissues compared with many solid tumor-associated antigens. This expression pattern has long suggested potential therapeutic relevance, but KLK2 has historically received limited drug development focus due to its classification as a secreted protein, which was considered less tractable for conventional antibody-based approaches.

This perception is now being revisited. Emerging biological and translational evidence suggests that KLK2 can be effectively engaged through tumor-associated or pericellular contexts, enabling antibody recognition and supporting multiple biologic modalities.

Importantly, KLK2 expression has also been reported to persist in subsets of tumors with low or heterogeneous PSMA expression, as well as in disease states that may exhibit reduced sensitivity to PSMA-directed therapies. This raises the possibility that KLK2 could serve as a biologically distinct entry point for patient populations not fully addressed by current standard targets.

Together, these observations reposition KLK2 from a largely exploratory biomarker to a potentially actionable therapeutic target.

Figure 1. Structural overview of KLK2 and its catalytic domains.
Adapted from J Biol Chem. DOI: 10.1074/jbc.M114.598201

Early Clinical Validation: Pasritamig as a First Translational Signal

The most clinically advanced KLK2-directed program to date is Pasritamig, a KLK2 × CD3 bispecific T-cell engager developed by Johnson & Johnson.

Its design incorporates a high-affinity KLK2-binding arm paired with a lower-affinity CD3-binding domain, a strategy intended to balance tumor engagement with controlled T-cell activation and mitigate excessive immune-related toxicity.

Figure 2. Proposed mechanism of action of Pasritamig (KLK2 × CD3 bispecific T-cell engager)
Source: Johnson & Johnson corporate materials / pipeline presentation.

Early clinical observations, although still limited in size and follow-up, provide an initial proof-of-concept for both activity and tolerability:

- Cytokine release syndrome (CRS) events have been reported predominantly as low grade in early cohorts

- Preliminary combination studies with docetaxel have not indicated an unexpected CRS signal in the available datasets

- In later-line metastatic castration-resistant prostate cancer (mCRPC), PSA50 and PSA90 response rates of approximately 65% and 39%, respectively, have been reported

- In earlier treatment settings, PSA responses appear higher, with PSA50 around 75% and PSA90 approximately 54%

While these findings remain early and require validation in larger, controlled studies, they collectively suggest that KLK2-directed T-cell engagement can achieve clinically meaningful activity with a potentially manageable safety profile.

Figure 3. Preliminary Phase I clinical activity of Pasritamig ± docetaxel in mCRPC.
Data presented at ASCO GU 2026.

KLK2 vs PSMA and STEAP1: A Question of Complementarity, Not Competition

KLK2 should not be viewed as a replacement for PSMA or STEAP1, but rather as a potential complement within a broader prostate cancer targeting landscape.

1. Tissue Distribution and Safety Considerations

PSMA is expressed not only in prostate tumors but also in normal tissues such as salivary glands and kidneys, contributing to known modality-specific toxicities. STEAP1 also exhibits broader expression across tissues. In contrast, KLK2's more prostate-restricted pattern may offer a relatively narrower on-target/off-tumor exposure profile, although this remains to be fully validated clinically.

2. Coverage of PSMA-Low or Resistant Disease

A growing clinical challenge in prostate cancer is the emergence of PSMA-low or PSMA-negative disease states following targeted therapy. KLK2 may provide an orthogonal antigen axis that could help address this emerging resistance space.

3. Competitive Landscape Maturity

Compared with PSMA, which is already highly competitive across multiple modalities, KLK2 remains at an earlier stage of clinical and commercial development. This creates greater space for mechanistic exploration and modality diversification.

Figure 4. Tissue-enriched expression profile of KLK2 with predominant prostate association.
Source: ASCO GU 2026 presentation.

Expanding Modality Space Around KLK2

A notable feature of the KLK2 landscape is the diversity of therapeutic modalities now being explored. Development programs are no longer limited to bispecific antibodies but are extending into multiple platforms, including:

- T-cell engagers (TCEs)

- Radiopharmaceutical approaches, including alpha-emitting isotopes

- ADC strategies, including novel payload classes

- Combination approaches, particularly with PSMA-targeted or cytotoxic regimens

This multi-modality exploration is an important indicator of target robustness. In modern oncology drug development, a clinically relevant target is increasingly defined not only by single-agent activity but by its ability to support diverse therapeutic engineering strategies.

KLK2 is beginning to demonstrate this characteristic.

Beyond KLK2: Implications for the Kallikrein Family

The renewed interest in KLK2 also raises broader questions about the druggability of the kallikrein family (KLK1--KLK15).

KLK3 (PSA) has already played a central role in prostate cancer diagnostics and has been selectively explored in therapeutic contexts. Other kallikreins, such as KLK6, have been investigated in oncology but remain largely early-stage.

If KLK2 continues to show clinical validity, it may provide broader biological rationale for reconsidering kallikreins as a functional target class rather than isolated biomarkers. This could potentially expand the target space beyond prostate cancer into other disease contexts where kallikrein biology is relevant.

Strategic Perspective: KLK2 as Portfolio Diversification, Not Target Replacement

The resurgence of KLK2 reflects a broader shift in prostate cancer drug development toward more diversified and adaptive target strategies.

Rather than relying on a single dominant antigen, future therapeutic success is increasingly likely to depend on:

- Multi-target portfolio design

- Biology-driven patient stratification

- Sequencing strategies across resistance states

- Balanced optimization of efficacy and tolerability across modalities

Within this framework, KLK2 is best understood not as a competitor to PSMA, but as a complementary node that may help address the limitations of a PSMA-centric treatment paradigm.

For drug developers, KLK2 represents a target class worth close attention---not because it replaces established biology, but because it expands the strategic flexibility of prostate cancer therapy design.

Spotlight: Accelerating KLK2 Discovery with Validated Research Tools

As KLK2 advances from emerging biology to actionable target class, robust preclinical tools become increasingly important for rapid validation and candidate screening.

ACROBiosystems offers a focused KLK2 tool portfolio to support early-stage discovery workflows:

- Recombinant KLK2 Protein for binder screening, functional assays, and assay development

- KLK2 Stable Cell Line for potency, specificity, and cell-based characterization studies

- Bispecific Human KLK2 & CD3 Bridging ELISA Kit for streamlined dual-binding evaluation of TCE candidates

Designed to reduce assay variability, improve decision confidence, and accelerate KLK2 therapeutic development.

As KLK2 moves from emerging biology to translational opportunity, the right tools may help determine who moves first.

Learn More About KLK Family Molecules