Preclinical development of keliximab, a Primatized (TM) anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model andsafety studies

The preclinical safety assessment of biopharmaceuticals necessitates that s tudies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals f or many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Ke liximab is a human-cynomolgus monkey chimeric (Primatized(R)) monoclonal an tibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support ch ronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genot oxic studies. In addition, immunotoxicity studies were conducted in these m ice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to a ssess the effects of keliximab on host resistance to infection and immunosu rveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmac ologic activity on CD4(+) T lymphocytes. The use of transgenic mice express ing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.