Pharmacodynamic and Immunomodulatory Effects of TOL-101: An IgM Anti-αβ TCR Monoclonal Antibody Used for Induction Therapy in Kidney Transplantation, The
Cleveland Clinic Foundation, Cleveland
Barnabas Health, West Orange
Dallas Transplant Nephrologists, Dallas
University of Virginia, Charlottesville
University of Michigan, Ann Arbor
University of Utah, Salt Lake City
Tolera Therapeutics Inc, Kalamazoo
Northwestern University, Chicago
University of Kentucky, Lexington
University of Colorado, Denve
Meeting: 2013 American Transplant Congress
Abstract number: C1337
Purpose: TOL-101 is a novel IgM monoclonal antibody that specifically targets the ΑΒ TCR. Results from a Phase 2 dose finding efficacy study in 28 recipients of renal transplants has revealed some unique features of this agent.
Methods: Eight cohorts (2-6 patients) (ranging from 0.28, 1.4, 7, 14, 28, and 42 mg) received 6 daily doses of TOL-101 at successively higher administered doses. Maintenance therapy was tacrolimus, mycophenolate, and steroids. Multiparametric flow cytometry was performed on blood samples, for the presence of pro-inflammatory cytokines IFN-Γ, TNF, IL-1Β, IL-6, and IL-10 (Luminex), as well as Pharmacokinetics at baseline, end infusion, and hours 4-8-24. The target pharmacodynamic marker absolute CD3/mm3 was tracked daily and at day 7 and 14.
Results: TOL-101 in a dose related fashion, downmodulated the CD3 receptor complex on ΑΒ-TCR+ T cells. A transient presumably steroid-induced reduction in ΓΔ-TCR+ T cells, B cells, NK cells, granulocytes, monocytes, and CD2 cells was observed in the first 24 hours after transplant, returning and remaining at or slightly above baseline levels. TOL-101 appears to act by binding reversibly to the ΑΒ-TCR receptor, resulting in downmodulation but not depletion of T cells, which is further confirmed with the recovery of baseline CD3 numbers by day 14 in all patients. The pharmacokinetic profile of TOL-101 correlated with the kinetics of the CD3+ pharmacodynamic marker with maximal CD3 suppression at 4-5,000ng/mL of TOL-101. Inflammatory cytokine production was minimal following TOL101 infusion at all of the dose levels tested. HAMA was detected in only 1/28 (3%) patients at a 1/100 dilution.
Conclusions: Clinically relevant doses of TOL-101 do not cause cytokine release or HAMA formation. TOL-101 specifically down modulates ΑΒ-TCR+ T cells, with little effect on other circulating immune cell subsets.
To cite this abstract in AMA style:
Wiseman A, Mulgaonkar S, Melton L, Waid T, Agarwal A, Sung R, Shihab F, Getts D, Flechner S. Pharmacodynamic and Immunomodulatory Effects of TOL-101: An IgM Anti-αβ TCR Monoclonal Antibody Used for Induction Therapy in Kidney Transplantation, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/pharmacodynamic-and-immunomodulatory-effects-of-tol-101-an-igm-anti-tcr-monoclonal-antibody-used-for-induction-therapy-in-kidney-transplantation-the/. Accessed November 4, 2024.« Back to 2013 American Transplant Congress