title: Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys.
abstract: Monoclonal antibody (Mab) 5D12 is a potent antagonist of the CD40-CD40L pathway. This cellular interaction has been validated in a large number of experimental animal models where dys-regulation of the immune system plays a role. Chimeric 5D12 (ch5D12) was constructed to reduce the potential immunogenicity and enhance the in vivo half-life when used in humans. ch5D12 is a molecularly engineered human IgG(4) antibody containing the variable domains of the heavy and light chains of the murine version of 5D12 (mu5D12). This new chimeric Mab was tested in a marmoset experimental autoimmune encephalomyelitis model and was shown to effectively prevent disease symptoms. The results of this in vivo evaluation supported clinical use of ch5D12 for immune targeted diseases. Therefore GMP material was prepared and a GLP-compliant tissue cross-reactivity study on human tissues (3 donors/37 tissues) and cynomolgus tissues (2 donors/37 tissues) was performed. ch5D12 stained on the surface of B cells and selected dendritic cells and no unexpected cross-reactivity was observed. The identical staining patterns in human and cynomolgus tissues justified the use of cynomolgus monkeys as a relevant model for humans. A GLP-compliant safety and tolerability evaluation for ch5D12 in cynomolgus monkeys was performed using the GMP produced material. Weekly administration of ch5D12 at two dose levels for 4 weeks was shown to be safe and without any side effects in all monkeys.
authors.affiliation: Tanox Pharma B.V., Sandinostraat 9, 1069 NJ, Amsterdam, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Antonio
authors.initials: A
authors.lastname: Ortiz-Buijsse
authors.forename: Marcel T
authors.initials: MT
authors.lastname: den Hartog
authors.forename: Simon
authors.initials: S
authors.lastname: Hoffenberg
authors.forename: Patrick
authors.initials: P
authors.lastname: Liu
authors.forename: Fred
authors.initials: F
authors.lastname: Shiau
authors.forename: Mark
authors.initials: M
authors.lastname: de Boer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000633:toxicity*; D015551:Autoimmunity / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D019013:CD40 Antigens / Q000276:immunology*; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D011993:Recombinant Fusion Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins