title: CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome.
abstract: 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.
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
authors.forename: Xiying
authors.initials: X
authors.lastname: Fan
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Upadhyaya
authors.forename: Liming
authors.initials: L
authors.lastname: Wu
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.forename: Mónica
authors.initials: M
authors.lastname: Santín-Durán
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: David
authors.initials: D
authors.lastname: Kleiner
authors.forename: Ester
authors.initials: E
authors.lastname: Williams
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Aaron
authors.initials: A
authors.lastname: Bodansky
authors.forename: Joao B
authors.initials: JB
authors.lastname: Oliveira
authors.forename: Pamela
authors.initials: P
authors.lastname: Edmonds
authors.forename: Ronald
authors.initials: R
authors.lastname: Hornung
authors.forename: Duane W
authors.initials: DW
authors.lastname: Wong
authors.forename: Ronald
authors.initials: R
authors.lastname: Fayer
authors.forename: Tom
authors.initials: T
authors.lastname: Fleisher
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Calman
authors.initials: C
authors.lastname: Prussin
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D023201:CD40 Ligand / Q000819:agonists* / Q000276:immunology; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D003458:Cryptosporidium / Q000302:isolation & purification / Q000502:physiology; D016207:Cytokines / Q000276:immunology; D005243:Feces / Q000382:microbiology; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C518149:selicrelumab; D023201:CD40 Ligand