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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.