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 May 6, 2021.
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