Highly frequent anti‐idiotype antibody in cynomolgus monkeys developed against mouse‐derived regions of anti‐Fas antibody humanized by complementarity determining region grafting

• Published in: British journal of pharmacology 2009-09, Vol.158 (2), p.548-557
• Main Authors: Saito‐Yabe, M, Yoshigae, Y, Takasaki, W, Kurihara, A, Ikeda, T, Okazaki, O
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Anti-Idiotypic - biosynthesis; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacokinetics; anti‐Fas monoclonal antibody; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Biological and medical sciences; CDR grafting; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epitopes - immunology; Fas; Granulocytes - metabolism; Humans; immunogenicity; Injections, Intravenous; Leukocytes, Mononuclear - metabolism; Macaca fascicularis; Medical sciences; Mice; monkey; pharmacokinetics; Pharmacology. Drug treatments; Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2009.00326.x

Background and purpose:  We investigated the immunogenicity of a humanized anti‐human Fas monoclonal antibody, R‐125224, in cynomolgus monkeys to estimate its efficacy, as well as its toxicity in clinical situations. Experimental approach:  R‐125224 was intravenously administered to cynomolgus monkeys at single doses of 0.4, 1.2, 6 and 30 mg·kg−1, and the plasma concentrations of R‐125224 and anti‐R‐125224 antibody (ARA) were measured. We conducted a competitive enzyme‐linked immunosorbent assay to determine which part of R‐125224 was recognized by ARA. We also examined the retention of radioactivity in mononuclear cells and granulocytes after the injection of [125I]‐R‐125224 to a collagen‐induced arthritis monkey model. Key results:  After i.v. administration of R‐125224, the elimination of the plasma R‐125224 concentrations was accelerated at around 10 days post‐dose, and 10 of 12 monkeys were ARA positive. From an epitope analysis of ARA, the ARA produced in monkeys recognized the mouse‐derived regions located in complementarity determining regions, but could not recognize the human IgG. After the injection of [125I]‐R‐125224 to a collagen‐induced arthritis monkey model, a significantly longer retention of the radioactivity in mononuclear cells compared to granulocytes was observed. Conclusions and implications:  In monkeys, the development of antibodies against R‐125224 is rapid and highly frequent. Our hypothesis is that this highly frequent development of ARA might be due to the binding of R‐125224 to immune cells, and its circulation in monkey blood might contribute to an increase in its chances of being recognized as an immunogen.