Double-Masked PSMA-TCE JANX014 Enters Phase 1 for mCRPC

A novel double-masked T-cell engager targeting prostate-specific membrane antigen (PSMA), called JANX014, has entered phase 1 testing in patients with metastatic castration-resistant prostate cancer (mCRPC). The first-in-human, open-label, multicenter trial, which dosed its initial participant in mid-April 2026, evaluates safety, tolerability, pharmacokinetics, pharmacodynamics, and early antitumor activity through ascending intravenous doses administered as monotherapy to adults with advanced disease.

JANX014 employs dual masking on both its PSMA-binding and CD3 T-cell recruiting domains, a design engineered to restrict activation to the protease-rich tumor microenvironment where PSMA is overexpressed on cancer cells. By cleaving masks only at the tumor site, JANX014 redirects cytotoxic T cells against PSMA-positive cells while minimizing systemic T-cell engagement that drives cytokine release syndrome (CRS), a frequent barrier to T-cell engagers in solid tumors. This double-masking parallels VIR-5500 (AMX-500), another PSMA-TCE using protease-cleavable masks on both arms, which showed deep PSA declines (to 0.03 ng/mL) and only grade 1 CRS in phase 1 dose-expansion without steroids or IL-6 blockade.

JANX014 builds on phase 1 data from the related PSMA-directed engager JANX007, which demonstrated no grade 3 CRS at active doses (PSA50 declines in 83% at step doses ≥0.2 mg) and radiographic progression-free survival of 7-9 months in pretreated mCRPC. It leverages PSMA’s validation as a therapeutic target, but delivers MHC-independent T-cell killing suited to heterogeneous tumors. The masking strategy widens the safety window for potential outpatient use, longer dosing intervals, or combinations with AR inhibitors and taxanes in late-line settings.

Source.