Background and objectives: TOL101 is a highly selective murine anti-αβ T cell receptor (TCR) IgM antibody and has recently completed phase II testing in primary renal transplant patients. This study was undertaken to determine the pharmacokinetic, pharmacodynamic, and immunogenic profile of TOL101.
Methods: Nine cohorts of two to six patients received at least five daily doses (of, or combination of, 0.28, 1.4, 7, 14, 28, or 42 mg) of TOL-101 administered at successively higher doses. Semi-logarithmic graphs of serum TOL101 concentration versus time supported the use of a one-compartment intravenous infusion pharmacokinetic model. The model was parameterized in terms of serum clearance (CL) and volume of distribution (V d).
Results: There was a trend toward a decrease in serum CL as the dose increased from 1.4 to 28 mg. However, the mean values for CL and V d were consistent across the cohorts that received 28, 32, and 42 mg. The mean ± standard deviation half-lives for these five cohorts ranged from 15.1 ± 7.35 to 28.6 ± 8.46 h, with an overall mean of 23.8 h, supporting both daily as well as fixed (i.e., not based on weight) dosing. Using CD3+ ≤25 cells/mm(3) as the primary pharmacodynamic marker, all non-responders were in the 0.28, 1.4, or 7 mg cohorts, suggesting that starting doses above 14 mg are required. Finally, one patient out of 36 was found to have anti-drug antibody.
Conclusions: Together, the data show that while TOL101 is a highly potent anti-TCR antibody, its pharmacological profile is somewhat versatile, allowing for daily dosing without immunogenicity concerns.