Targeting CD40 with Antibody CHIR-12.12: A Therapeutic Approach to Human B Cell Lymphoma

Anti-tumor antibodies are emerging as a viable treatment for lymphoma, with potential to target specific receptors or activate immune responses through antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated pathways. The CD40 antigen, found on most non-Hodgkin's B cell lymphomas, is a promising target due to its role in B cell lymphoma survival and proliferation. An antagonistic antibody against CD40 could have therapeutic benefits by disrupting the CD40/CD40L interaction.

The study introduces CHIR-12.12, a fully human anti-CD40 antagonistic IgG1 monoclonal antibody derived from mice with a human immunoglobulin gene loci. The CD40 expression on primary lymphoma cells was compared to CD20, the target of rituximab, and found to be significantly lower. CHIR-12.12 was observed to bind effectively to lymphoma cells without inducing proliferation, unlike an agonist anti-CD40 antibody which did stimulate cell growth.

Experiments were conducted to test CHIR-12.12's ability to interfere with the CD40-CD40L interaction, demonstrating that it could inhibit the proliferation of follicular lymphoma and CLL/SLL cells in a dose-dependent manner, with up to 90% inhibition at higher concentrations.

While CHIR-12.12 did not induce complement-mediated cytotoxicity like rituximab, both antibodies were capable of inducing effective ADCC using NK cells from a healthy donor. Notably, CHIR-12.12 induced a similar level of ADCC killing as rituximab, despite the lower expression of CD40 on tumor cells.

The findings suggest that CHIR-12.12 has potential as a therapeutic agent for B cell lymphoma by blocking the CD40/CD40L interaction and mediating ADCC, even with a lower antigen density. This supports the further development of CHIR-12.12 for treating patients with this condition.