First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Abstract

Pascal Espié and YanLing He are co-first authors who have contributed equally to the work. James S. Rush and Peter Gergely have contributed equally to the work.Clinical Trial Registration Number: NCT02089087.Abbreviations: AEs, adverse events; AUC last , area under the plasma concentration-time curve from time zero to the last quantifiable concentration; BLQ, below limit of quantification;Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases. K E Y W O R D S clinical research/practice, clinical trial, immunosuppressant -fusion proteins and monoclonal antibodies: B cell specific, immunosuppression/immune modulation, translational research/ science S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20: 463-473. https ://doi.

Experimental modeling of desensitization: What have we learned about preventing AMR?

“…However, we reasoned that there may be additive or synergistic impact when these agents were added to other conventional immunosuppression in sensitized recipients. The current clinical trial with iscalimab (anti‐CD40 mAb) for kidney transplant may yield data on this question in the near future 35 . On the other hand, belatacept had already shown efficacy in reducing posttransplant DSA production, 36,37 similar to what we showed in an NHP model.…”

Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study

“…16,21 In Cohort 1, 3 mg/kg SC resulted in mean trough plasma concentrations less than 10 µg/mL (supplementary figure 1, upper panel), significantly lower than expected based on PK data of healthy volunteers in the first-in-human study. 22 In Cohort 2 (10 mg/kg IV), mean trough plasma concentrations were above levels previously reported to be sufficient for the suppression of GC development and inhibition of T celldependent antigen responses in non-human primates 16 blockade have been observed. While an association between the CD40-CD154 pathway and autoimmune diseases such as pSS has been suggested, no clinical trial has assessed the efficacy and safety of any modality that blocks this pathway in pSS patients.…”

Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients

“…Recent studies also describe the identification of antagonistic anti-CD40 Abs, which can prolong allograft survival in models of transplantation and inhibit T cellinduced B cell responses. Several of these Abs are being evaluated in human trials [27][28][29][30][31].…”