Immunotoxicity profile of natalizumab

被引:14
作者
Wehner, Nancy G. [1 ]
Gasper, Carolyn [2 ]
Shopp, George [3 ]
Nelson, Joyce [4 ]
Draper, Ken [4 ]
Parker, Suezanne [5 ]
Clarke, Janet [6 ]
机构
[1] Elan Pharmaceut Inc, San Francisco, CA 94080 USA
[2] XOMA US LLC, Berkeley, CA USA
[3] Shopp Nonclin Consulting LLC, Boulder, CO USA
[4] Preclin Serv Nevada, Charles River Labs, Reno, NV USA
[5] Biogen Idec Inc, San Diego, CA USA
[6] Biogen Idec Inc, Cambridge, MA USA
关键词
Natalizumab; alpha; 4; integrin; monoclonal antibody; immune function; Macaca fascicularis; Macaca mulatta; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RELAPSING MULTIPLE-SCLEROSIS; PLACEBO-CONTROLLED TRIAL; ACTIVE CROHNS-DISEASE; NATURAL-KILLER-CELLS; HEMATOPOIETIC PROGENITORS; ALPHA-4; INTEGRINS; IN-VIVO; THERAPY; SPLEEN;
D O I
10.1080/15476910902977381
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Natalizumab is a monoclonal antibody to human alpha 4 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 alpha 4 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 sub sets (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 pharmaco logic effect on cell trafficking, and showed no adverse effect on immune cell function.
引用
收藏
页码:115 / 129
页数:15
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