TNX-1500, an Fc-Modified Anti-CD154 Antibody, Prolongs Nonhuman Primate Cardiac Allograft Survival

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<h3>Purpose</h3> Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to replace current clinical immunosuppression. TNX-1500 (TNX) is a novel humanized anti-CD154 mAb that contains the hu5c8 Fab region and an Fc region engineered to modulate FcγR2 binding to reduce the risk of pro-thrombotic platelet activation and aggregation, and thus potentially prevent the thromboembolic events seen with hu5c8 IgG1 in preclinical models and clinical trials. <h3>Methods</h3> Cynomolgus monkey heterotopic cardiac allograft recipients were treated with TNX either using a ‘standard' regimen (sTNX; 30 mg/kg iv twice weekly x4, then 20 mg/kg weekly from d21, n=5), using a reduced-dose TNX maintenance regimen (loTNX; 30 mg/kg iv twice weekly x4, 10 mg/kg weekly x6, then 20 mg/kg monthly; n=4), or loTNX with mycophenolate mofetil (loTNX+MMF, 200mg/d po, n=4); results were compared to historical data using hu5c8 (n=5). Graft function was monitored by telemetry and ultrasound until graft failure or elective experimental termination at 6 months. Protocol biopsy and explanted graft histology and anti-donor antibody (alloAb) were evaluated. <h3>Results</h3> Four of five grafts treated with sTNX maintained good graft function (MST >154d, range 114-180, 4 of 5 ongoing); one graft rejected at 114d. All grafts treated with loTNX, alone or with MMF, experienced acute cellular rejection and/or antibody-mediated rejection; 7 of 8 grafts failed before 6 months. Relative to hu5c8 alone (MST 123d), loTNX (MST 99d) and sTNX (MST>154d) showed a statistically similar prolongation of cardiac allograft survival. Although loTNX+MMF attenuated IgG alloAb production during treatment (4/4 animals) more consistently than loTNX alone (2/4), cardiac allograft vasculopathy (CAV) tended to be more prominent with loTNX+MMF; alloAb and CAV in the sTNX group after study completion will be presented. Neither sustained thrombocytopenia nor micro- or macrovascular thrombosis were observed in TNX-treated animals. <h3>Conclusion</h3> Blockade of CD154 with TNX monotherapy consistently and safely prevents pathologic alloimmunity in this stringent preclinical model, similar to hu5c8 monotherapy. Lower maintenance dosing with TNX, with or without MMF, was less effective.