Purpose: Induction therapy using anti-lymphocytic antibodies is a potent tool for the prevention of early rejection after kidney transplantation. TOL-101, an IgM monoclonal antibody, with specificity for the ΑΒTCR and absence of mitogenicity, is well suited for this purpose.

Methods: After local IRB approval 13 centers enrolled 28 low-moderate risk kidney recipients (crossmatch negative, ABO compatible with <20% PRA, EBV IgG+, age 21-60 years) in a dose finding study using a maintenance regimen of tacrolimus-mycophenolate-steroids. The six-month trial used GPC/FDA guidelines to evaluate safety parameters, cytokine release syndrome, standard laboratory tests, BPAR, and renal function. The ability of TOL101 to modulate the T-lymphocyte count was used as the pharmacodynamic endpoint, targeting absolute CD3 counts <25/mm3.

Results: Ascending IV doses (delivered days 0-5) ranging from 0.28-42mg of TOL-101 were given to 28 subjects in cohorts of 2-4; demonstrating greater downregulation of T cells. Infusion reactions were rare, and significant cytokine release (IL6, TNF, IFN-Γ) was absent. An unanticipated but transient first dose rash occurred in 10/28 patients, maximal at 42mg, This resulted in defining a best escalating 14-21-28-42-42-42mg daily schedule. There have been no deaths or graft losses at 6 months. There were 35 SAEs in 11 patients (one possibly study drug related-pneumonia) with GI Disorders (8) most reported. No malignancies or serious (opportunistic, etc.) infections have been observed. There were 4 (14%) treated BPAR (Banff 1a=1, Banff 2a=3). The overall mean plasma elimination T½ of TOL-101 was 23 hours (range 15-31) over 4 cohorts. The mean iothalamate GFR at 6 months was 55.7 mL/min/1.73m2.

Conclusions: The initial use of TOL-101 appears to be a safe and well tolerated after 6 months, at doses that have substantial T-cell modulating effects, supporting phase 3 initiation in 2013.

Wiseman, A.: Employee, Tolera. Getts, D.: Employee, Tolera.

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