Immunotoxicity profile of natalizumab.
Natalizumab is a monoclonal antibody to human alpha4 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 alpha4 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.
Wehner
Nancy G
NG
Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. ngwehner@gmail.com
Gasper
Carolyn
C
Shopp
George
G
Nelson
Joyce
J
Draper
Ken
K
Parker
Suezanne
S
Clarke
Janet
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000276:immunology* / Q000628:therapy; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D039441:Integrin alpha4 / Q000276:immunology; D020014:K562 Cells; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy; D000069442:Natalizumab; D009929:Organ Size; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D016207:Cytokines; D000069442:Natalizumab; D039441:Integrin alpha4