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. Multi–parametric 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.

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