Phase 1 Trial: JANX007 Plus JANX013 Combo in mCRPC / mAPMR

A newly registered phase 1 trial is taking an interesting approach to one of the limitations of T-cell engagers in prostate cancer: rather than simply trying to make them more powerful, it will test whether a second immune signal can make their activity more durable. The trial will evaluate JANX007 together with the new drug JANX013 in up to 110 men with metastatic castration-resistant prostate cancer (mCRPC).

JANX007 is a tumour-activated PSMA×CD3 T-cell engager already being studied in mCRPC. Its CD3-binding component is masked and designed to become activated preferentially in the tumour microenvironment, where it can recruit T cells against PSMA-expressing prostate cancer cells. Previous clinical results have shown considerable activity: in updated data from patients receiving active doses, 73% achieved a PSA50 response and 26% achieved PSA90, while median radiographic progression-free survival approached eight months in some expansion groups. JANX007 is currently also being investigated in taxane-naïve mCRPC, including in combination with darolutamide.

JANX013 approaches the immune response from another direction. Instead of targeting CD3, it is a PSMA×CD28 tumour-activated immunomodulator designed to provide the co-stimulatory signal that T cells normally require for strong and sustained activation. Both its PSMA- and CD28-binding components are masked, with the intention of concentrating CD28 stimulation inside the tumour while limiting potentially dangerous systemic immune activation.

The biological logic is essentially a two-signal strategy: JANX007 provides CD3-mediated Signal 1 telling the T cell to attack, while JANX013 provides CD28-mediated Signal 2 intended to enhance T-cell proliferation, function and persistence. Preclinical experiments support this idea. JANX013 markedly increased tumour-cell killing when combined with a PSMA×CD3 engager, while repeated-challenge experiments suggested that CD28 co-stimulation could maintain tumour killing after T cells exposed only to the CD3 engager began losing effectiveness. The activated form of JANX013 also showed a greater than 7,000-fold shift in functional activity compared with its masked state.

The crucial question may not be whether JANX013 produces more initial responses. JANX007 already produces substantial PSA responses on its own. The more interesting possibility is whether adding tumour-restricted CD28 stimulation can keep T cells functional for longer and translate those deep responses into longer disease control.

Clinical trial.