Targeting Autoimmune Disorders: The Preclinical Profile of a Selective Anti-CD40 Monoclonal Antibody

The CD40-CD40L interaction is crucial in immune responses, making it a potential therapeutic target for autoimmune diseases. However, previous attempts to target this pathway have been hindered by thrombotic complications, and developing a potent CD40 antagonistic antibody has been challenging.

BI 655064 is a humanized anti-human CD40 monoclonal antibody (mAb) being developed to address autoimmune disorders. It is designed with a modified Fc region to eliminate effector functions. The antibody's binding affinity to CD40 on primary B cells was assessed using flow cytometry, and its ability to inhibit CD40L-induced B cell proliferation was measured in vitro.

BI 655064 effectively blocked CD40L-induced B cell proliferation and cytokine release in dendritic cells (DCs). It did not induce or augment platelet activation in vitro, which is a critical safety consideration given the thrombotic issues encountered in previous studies.

Pharmacokinetic and pharmacodynamic studies in cynomolgus monkeys showed complete blockade of ex vivo CD54 upregulation at doses above 1 mg/kg, corresponding to full target coverage on B cells. BI 655064 significantly impacted B cell function in a graft-versus-host disease (GvHD) model, where it abrogated human IgM and IgG responses. Furthermore, it inhibited immune responses in monkeys immunized with keyhole limpet hemocyanin (KLH), reducing germinal center size in various lymphoid tissues at doses of 5 mg/kg and above.

Importantly, BI 655064 showed no effects on platelet activation or aggregation in the monkeys. These findings indicate that BI 655064 is a promising antagonistic anti-CD40 mAb with potential for treating autoimmune disorders, demonstrating both in vitro and in vivo activity at clinically relevant doses without inducing thrombotic complications. It is now being prepared for human clinical trials to evaluate its safety and efficacy.