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Objective：SMMU-16, a biosimilar of adalimumab, is developed for the treatment of rheumatoid arthritis clinically in the future.The purpose of this study was to evaluate the pre-clinical safety of SMMU-16 in Cynomolgus monkeys and to elucidate the underlying immunotoxicological mechanisms.
Methods：Thirty healthy Cynomolgus monkeys (15 male and 15 female, aged 3-4 years,)were divided into 5 groups according to the body weight: control group, SMMU-16 10, 33,200 mg kg-1 and adalimumab 33 mg kg-1 dose groups with 6 animals in each group.The drugs were administrated subcutaneously once a week for successive 4 weeks with a4-week recovery. The control animals received saline solution of the same volume as those given to the administrative group animals. At the end of treatment (day28) and end of recovery (day56), half of the monkeys in each group were anesthetized and sacrificed to perform clinical observations,clinical pathological evaluations histopathological examination, TUNEL examination and T cell development analysis. Cell proliferation and cell cycle were examined in vitro by using thymic cells isolated from thymuses in controlanimals at day56.
Results:There were no treatment-related changes in clinical observations,clinical pathological evaluations, electrocardiographic and body weight examinations except for a slight anemia in adalimumab 33 mg kg-1 and SMMU-16 33, 200 mg kg-1 groups at the end of treatment (day28). The most serious treatment-related changes were thymic atrophy and splenic atrophy in animals of these three groups at day28, which wasnot induced by apoptosis. Further studies indicated that adalimumab and SMMU-16 inhibited thymic cell proliferation by arresting cell cycle at GO/G1 phase, which might contribute to the treatment-related thymic atrophy. Splenic atrophy might share same mechanisms with thymic atrophy.
Conclusions:These findings will provide experimental supports for the further development of SMMU-16 and partly reveal the mechanisms involved in the clinicaladverse effects of TNFa antagonists, including adalimumab.