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

• Published in: American journal of transplantation Vol. 20; no. 2; pp. 463 - 473
• Main Authors: Espié, Pascal, He, YanLing, Koo, Phillip, Sickert, Denise, Dupuy, Cyrielle, Chokoté, Edwige, Schuler, Roland, Mergentaler, Heidi, Ristov, Jacinda, Milojevic, Julie, Verles, Aurelie, Groenewegen, Andrea, Auger, Anita, Avrameas, Alexandre, Rotte, Michael, Colin, Laurence, Tomek, Charles S., Hernandez‐Illas, Martha, Rush, James S., Gergely, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.02.2020
• Subjects: Adolescent; Adult; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Autoimmune diseases; Case-Control Studies; CD40 antigen; CD40 Antigens - immunology; CD40L protein; CD69 antigen; clinical research/practice; clinical trial; Double-Blind Method; Female; Follow-Up Studies; Humans; immunosuppressant – fusion proteins and monoclonal antibodies: B cell specific; immunosuppression/immune modulation; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Injections, Intravenous; Injections, Subcutaneous; Intravenous administration; Lymphocytes B; Male; Middle Aged; Monoclonal antibodies; Pharmacodynamics; Pharmacokinetics; Rheumatoid arthritis; Safety; Thromboembolism; translational research/science; Transplantation; Young Adult; clinical trial; translational research/science; immunosuppressant - fusion proteins and monoclonal antibodies: B cell specific; immunosuppression/immune modulation; clinical research/practice
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.15661

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. Iscalimab is a promising blocker of the CD40‐CD154 costimulatory pathway with potential use in transplantation and autoimmune diseases.