Main content area

CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome

Fan, Xiying, Upadhyaya, Bhaskar, Wu, Liming, Koh, Christopher, Santín-Durán, Mónica, Pittaluga, Stefania, Uzel, Gulbu, Kleiner, David, Williams, Ester, Ma, Chi A., Bodansky, Aaron, Oliveira, Joao B., Edmonds, Pamela, Hornung, Ronald, Wong, Duane W., Fayer, Ronald, Fleisher, Tom, Heller, Theo, Prussin, Calman, Jain, Ashish
Clinical Immunology 2012 v.143 no.2 pp. 152
Cryptosporidium, T-lymphocytes, agonists, cryptosporidiosis, cytokines, deficiency diseases, immune response, immunoglobulin M, immunosuppression (physiological), monoclonal antibodies, mutation, oocysts, patients, receptors, relapse, secretion, shedding, therapeutics
X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted.