title: The pharmacokinetics and pharmacodynamics of TOL101, a murine IgM anti-human αβ T cell receptor antibody, in renal transplant patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Research and Development, Tolera Therapeutics Inc, Kalamazoo, MI, USA, d-getts@northwestern.edu.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: William G
authors.initials: WG
authors.lastname: Kramer
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Wiseman
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Flechner
mesh_terms: D000328:Adult; D000906:Antibodies / Q000032:analysis; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics*; D019540:Area Under Curve; D054316:Biomarkers, Pharmacological / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell
chemical_list: D000906:Antibodies; D058846:Antibodies, Monoclonal, Murine-Derived; D054316:Biomarkers, Pharmacological; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; C000594305:TOL-101