First-in-Human, Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of TNX-1500, an Fc-Modified anti-CD154 Monoclonal Antibody, Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses in Healthy Adults.

Blocking CD154 (CD40L) has the potential to prolong transplanted solid organ graft survival and treat autoimmune diseases. However, first-generation anti-CD154 IgG1 monoclonal antibodies (mAbs) were associated with an increased risk of thrombosis linked to Fc binding to FcγRIIa (CD32A). Here, we describe a first-in-human, phase 1 clinical trial of TNX-1500, a novel Fc-modified IgG4 anti-CD154 mAb designed to decrease binding to FcγRIIa. Healthy volunteers (N = 26) were enrolled into single-ascending dose (3, 10, and 30 mg/kg) cohorts and received TNX-1500 intravenously. TNX-1500 was generally well tolerated. Among participants receiving TNX-1500 3, 10, and 30 mg/kg, 1 (25%), 3 (38%), and 3 (38%) participants, respectively, reported ≥ 1 treatment-emergent adverse event; all were mild or moderate in severity, and none resulted in study discontinuation. There were no thromboembolic events. Pharmacokinetic analyses of TNX-1500 demonstrated a mean half-life of 37.8 and 33.8 days for 10 and 30 mg/kg, respectively, supportive of monthly dosing; dose-proportional exposure was suggested over the 3 to 30 mg/kg range. TNX-1500 blocked the primary T cell-dependent antibody response to keyhole limpet hemocyanin (KLH) at all doses and blocked the secondary response at the 10 and 30 mg/kg doses. At 3 mg/kg, TNX-1500 reduced peak secondary response to KLH by ~ 70% relative to placebo. TNX-1500 administration was associated with immediate and sustained reduction in soluble CD154. Overall, TNX-1500 demonstrated a safety profile and pharmacologic properties that support further development as an agent with potential for prevention of organ transplant rejection and treatment for autoimmune conditions.