Dominant CD40 Receptor (CD40R) Antagonist Antibodies as Novel Approach to Treating Autoimmune Diseases

Abstract The CD40R-CD40 ligand pathway is a key co-stimulatory pathway for driving T cell-dependent B cell activation and humoral immune responses. This pathway has been implicated in the pathogenesis of several autoimmune diseases including autoimmune thyroiditis, type 1 diabetes, Crohn’s disease, inflammatory bowel disease, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and Sjogren’s syndrome. Although the use of anti-CD40 ligand antibodies have shown benefits in patients, their use has been linked to the development of thromboembolic events, ADCC issues and low efficacy with poor antagonism in vivo. Two novel IgG2 CD40R antagonists developed by BITT have differentiated mechanisms of action including the formation of inhibitory anti-parallel dimers of the surface receptor. Several unique features include: ligand independence, Fc receptor independence, potency with ligand present and selectivity to rapidly proliferating cells. Multiple BITT antibodies showed strong antagonist activity in B-cell proliferation assays. Two BITT CD40 antagonists were selected for testing in a humanized NSG Mouse Model of graft verse host disease. The BITT CD40R antagonists were compared to isotype control and a known IgG1 CD40R antagonist. The BITT antibodies showed better B cell depletion and better inhibition of IgG levels – including a unique ability to selectively deplete activated (CD86+ cells) and younger B cells making early IgM antibodies. This selective action could result in more potent immune-suppressive function at the site of inflammation and a reduced possibility of developing side effects.