Innovative Antagonistic Anti-CD40 mAb: Preclinical Insights and Therapeutic Potential

The CD40-CD40L interaction is crucial for immune and non-immune cell activation, with targeting this pathway showing promise for treating autoimmune diseases. However, previous attempts to target CD40L were hindered by thrombotic issues, and developing a potent CD40 antagonistic antibody has been difficult. BI 655064, a modified human IgG1 monoclonal antibody against CD40 designed to eliminate effector functions, is being developed for autoimmune disorder treatment.

In vitro studies have shown BI 655064's binding affinity to CD40 on B cells and its capacity to inhibit CD40L-induced B cell proliferation and cytokine release in dendritic cells. A pharmacokinetic/pharmacodynamic study in cynomolgus monkeys indicated that doses exceeding 1 mg/kg resulted in complete target engagement and biological effects. In vivo testing in a human peripheral blood lymphocyte-induced SCID mouse model of graft-versus-host disease and in immunized monkeys demonstrated BI 655064's impact on B cell function and immune response inhibition.

Furthermore, BI 655064 did not affect platelet activation in vitro and showed no impact on platelet function in treated monkeys. The study suggests that BI 655064 is a humanized anti-CD40 monoclonal antibody with potential for clinical trials in autoimmune disorders, exhibiting pharmacological activity at doses of >1 mg/kg in animal models. The authors are affiliated with Boehringer Ingelheim Pharmaceuticals, with one author declaring no conflict of interest.