Janux Therapeutics, the San Diego-based NASDAQ-listed biopharmaceutical company (ticker: JANX), has initiated a first-in-human Phase I clinical trial of JANX014, a double-masked bispecific T cell engager targeting prostate-specific membrane antigen (PSMA) and CD3ε, in men with metastatic castration-resistant prostate cancer (mCRPC). The JANX014 clinical trial, registered as NCT07545811, entered active recruitment in April 2026 and represents the company's second PSMA-directed program to reach the clinic, following the earlier single-masked candidate JANX007.
Where conventional T cell engagers have faced dose-limiting cytokine release syndrome by engaging CD3 on circulating T cells systemically, JANX014 applies protease-cleavable masks to both its tumor-binding and T cell-binding domains — a design intended to confine immune activation to the tumor microenvironment. The open-label, multicenter Phase I study will enroll approximately 43 men with histologically confirmed prostate adenocarcinoma who have progressed on at least one novel anti-androgen therapy. The trial follows a sequential dose-escalation and dose-expansion design, with JANX014 administered intravenously. The primary endpoints assess the incidence of dose-limiting toxicities and adverse events over a two-year observation window. Secondary measures include radiographic progression-free survival, PSA response rate, overall response rate, duration of response, pharmacokinetic parameters, and immunogenicity. Primary completion is estimated for Q2 2028, with full study completion projected for Q1 2029.
PSMA is overexpressed on prostate cancer cells and upregulated further in castration-resistant disease, making it a validated target across modalities including radioligand therapy and bispecific antibodies. JANX014 engages PSMA on tumor cells and CD3ε on cytotoxic T lymphocytes simultaneously, physically bridging the two cell types to trigger T cell-mediated lysis independent of MHC-I presentation. The molecule's double-masking architecture — in which both binding domains are sterically occluded by tumor protease-cleavable peptide linkers in circulation — distinguishes it from its predecessor JANX007, which masks only the CD3-binding domain. Janux appears to have developed the TRACTr platform entirely internally, with no publicly disclosed licensing agreement from an academic institution or third party.
Within the PSMA-targeted T cell engager class, acapatamab (Amgen/UCB) has generated Phase I data in mCRPC, as reported by Dorff et al. in Clinical Cancer Research in 2024, demonstrating proof of concept for the CD3-redirecting approach at this target. JANX014 is differentiated from acapatamab by its dual-domain masking strategy, which Janux has designed to reduce systemic T cell activation relative to unmasked or single-masked engagers; whether this translates to a wider therapeutic index in humans remains to be established in the current trial.
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