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

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.

Improvement of drug tolerance in immunogenicity testing by acid treatment on Biacore.

Detection of anti-drug antibodies (ADA) can be difficult, if not impossible, in the presence of drug in the sample. This is a particular concern with therapeutic monoclonal antibodies (mAbs), which have typically longer half-lives than other proteins. For detection of ADA in presence of high drug concentrations, assay choice is limited to ELISA-like methods, capable of incorporating acid dissociation procedures to separate drug-ADA immune complexes. To our knowledge, Biacore assays have not been shown to be directly compatible with acid dissociation procedures, until now. As a consequence, steps to ensure adequate clearance of the drug are prerequisite to enable sensitive detection of ADA. Here we describe the development of a novel, rapid and highly drug tolerant Biacore method that uses an acid dissociation step to detect ADA in the presence of excess drug in human serum. Removal of drug after acid treatment is not required.