Immunotoxicity profile of natalizumab

Abstract

Natalizumab is a monoclonal antibody to human α4 integrin indicated for treatment of multiple sclerosis and Crohn’s disease that prevents extravasation of leukocytes into surrounding tissues and their involvement in inflammation. Because α4 integrins and their receptors are involved in hematopoiesis and immune cell trafficking, natalizumab may interfere with these processes. We evaluated the effects of natalizumab on immune function in monkeys using in vitro and in vivo studies. Consistent with the pharmacologic effects of natalizumab, dose-related increases in white blood cell counts and spleen weights were observed. Administration to monkeys did not result in statistically significant alterations in the percentages of circulating B-cells, T-cells, T-cell subsets (CD4, CD8), or stem cells (CD34). A modest and highly variable delay in the primary humoral response to T-cell-dependent antigens was observed. Ex vivo studies using cells from natalizumab-treated monkeys demonstrated that treatment did not alter immune regulatory or effector cell functions in blood lymphocytes or spleen cells. A similar lack of effect on these functions was observed in vitro following treatment of PBMC and monocytes from human donors. Overall, natalizumab was well tolerated in monkeys, demonstrated the expected pharmacologic effect on cell trafficking, and showed no adverse effect on immune cell function.

Keywords::

• Natalizumab
• α4 integrin
• monoclonal antibody
• immune function
• Macaca fascicularis
• Macaca mulatta

Acknowledgments

The authors wish to thank the following for analytical and bioanalytical support: Julie Taylor, Shulah Iflah, Jessica Krakow, and James Chin, of Elan Pharmaceuticals, Inc.; Michaela Lerner, Matthew Cooper, and Meena Subramanyam of Biogen Idec, Inc.; Patricia Giclas of National Jewish Clinical Laboratories; Jerome Moore of Pacific BioDevelopment; and Caudex Medical Inc. for writing and editorial assistance.

Declaration of interest: N. Wehner is a former employee of and current consultant for Elan Pharmaceuticals. S. Parker and J. Clarke are employees of Biogen Idec. C. Gasper, G. Shopp, J. Nelson, and K. Draper, report no conflicts of interest. The authors alone are responsible for the content of the paper.