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Masked Antibody Therapeutics in Genitourinary Malignancies: Expanding the Therapeutic Window Through Tumor-Selective Activation

The development of immunotherapies for genitourinary (GU) malignancies has historically been hindered by the lack of truly tumor-exclusive targets. While antigens such as PSMA, HER2, EGFR, and EpCAM are highly expressed on malignant cells, they are also present in vital healthy tissues, leading to "on-target, off-tumor" toxicities.1 This challenge has driven the development of masked antibody technologies designed to restrict biologic activity to the tumor microenvironment. These agents utilize biochemical "locks" that prevent systemic activation, ensuring that target binding, T-cell recruitment, or payload delivery occurs preferentially within tumors. Masked antibodies, therefore, represent a rational evolution of targeted therapy, shifting from systemic target engagement toward spatially controlled activation. By separating systemic exposure from biologic activation, these platforms aim to preserve efficacy while minimizing toxicity, a balance that has historically limited the development of highly potent immune-engaging therapies in genitourinary malignancies.

The fundamental rationale for masking lies in widening the therapeutic window. In GU cancers, targeting a protein such as PSMA in prostate cancer often results in unintended injury to salivary and lacrimal glands.2 A masked antibody typically consists of the parent antibody or T-cell engager tethered to a masking peptide via a protease-cleavable linker. This mask physically obstructs the antibody’s binding site (the paratope), rendering the molecule functionally inert while circulating in the bloodstream. Activation is triggered by the high concentration of extracellular proteases, such as matrix metalloproteinases or legumain, that are enriched within the tumor microenvironment.3 Once these enzymes cleave the linker, the mask dissociates, allowing the antibody to bind to its intended target.

Among masked antibody platforms currently in clinical development, dual-masked T-cell engager strategies have emerged as a particularly promising approach to mitigate systemic immune activation. In these constructs, both the tumor-targeting domain and the CD3-binding domain are masked, creating two independent safeguards against off-tumor T-cell activation and cytokine release syndrome (CRS).4

The most clinically mature masked antibody data in GU oncology come from VIR-5500, a dual-masked PSMA-directed T-cell engager. At the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, the Phase 1 dose-escalation results in heavily pretreated patients with metastatic castration-resistant prostate cancer received significant attention. Treatment with VIR-5500 demonstrated a favorable safety profile, with CRS limited to grades 1 and 2, and no dose-limiting toxicities across evaluated dose levels.4 Importantly, early signals of antitumor activity were observed in dose-expansion cohorts, including substantial prostate-specific antigen declines and radiographic tumor regressions in a small subset of patients treated at higher dose levels.4 These findings provide proof-of-concept that dual-masked T-cell engager technology can achieve potent immune activation while maintaining an acceptable safety margin, supporting continued clinical development.

A parallel masked antibody platform has been developed using the Tumor Activated T Cell Engager (TRACTr) technology. JANX007, a PSMA-directed masked T-cell engager, has demonstrated early clinical activity in patients with metastatic castration-resistant prostate cancer, including meaningful PSA reductions and a manageable safety profile characterized primarily by low-grade CRS.5 While follow-up remains limited, these findings reinforce the potential of tumor-activated immune engagement to expand the therapeutic window of PSMA-directed therapy.

Masked antibody technology is also being extended into other biologic formats, including antibody-drug conjugates. CX-2051 is a masked EpCAM-directed antibody-drug conjugate designed to reduce off-tumor exposure in epithelial tissues while enabling selective delivery of a cytotoxic payload to tumor sites. While early data have been press released showing activity in advanced colorectal cancer, ongoing clinical trials include patients with other solid tumors.6

Collectively, these data support masked antibodies as an emerging class of precision immunotherapies capable of uncoupling potency from systemic toxicity. As these platforms mature, key questions will center on durability of response, outpatient feasibility, and whether increased dose intensity translates into deeper and more sustained tumor control.
The current clinical landscape of masked antibody therapeutics in genitourinary oncology is defined primarily by early-phase dose-escalation studies, many of which enroll biomarker-selected cohorts within broader solid tumor populations. Please see below for some ongoing clinical trials.

Actively Accruing Clinical Trials of Masked Antibody Platforms that Include Patients with Genitourinary Malignancies

  • VIR-5500: Phase 1 study of a dual-masked PSMA-directed T-cell engager (NCT05997615) for patients with metastatic castration-resistant prostate cancer
  • JANX007: Phase 1 study of a tumor-activated PSMA-directed T-cell engager (NCT05519449) for patients with metastatic castration-resistant prostate cancer (ENGAGER-PSMA-01)
  • JANX008: Phase 1/1b study of a tumor-activated EGFR-directed T-cell engager for patients with advanced or metastatic solid tumors, including patients with renal cell carcinoma (NCT05783622)
  • JANX014: Phase 1 first-in-human study of a next-generation PSMA-directed masked T-cell engager for patients with metastatic castration-resistant prostate cancer (NCT07545811)
  • VIR-5818: Phase 1 study of a dual-masked HER2-directed T-cell engager for patients with HER2-expressing tumors, including patients with urothelial carcinoma (NCT05356741)
  • CX-2051: Phase 1 study of a masked EpCAM-directed antibody-drug conjugate for patients with advanced solid tumors (NCT06265688)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Boixareu C, et al. Targeting the tumour cell surface in advanced prostate cancer. Nat Rev Urol. 2025; 22:569-89.
  2. Muniz M, et al. Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going. Cancer Treat Rev. 2024; 127:102748.
  3. Poreba M. Protease-activated prodrugs: strategies, challenges, and future directions. FEBS J. 2020; 287:1936-69.
  4. de Bono JS, et al. J Clin Oncol. Vol. 44. No. 7_suppl.17.
  5. https://investors.januxrx.com/investor-media/news/news-details/2025/Janux-Announces-Encouraging-Efficacy-and-Safety-Profile-from-Ongoing-Phase-1-Clinical-Trial-for-JANX007-in-mCRPC/default.aspx
  6. https://ir.cytomx.com/news-releases/news-release-details/cytomx-announces-positive-interim-data-phase-1-dose-escalation