Immunotoxicity profile of natalizumab

Abstract

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.

Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

“…Natalizumab exhibited a mean concentration producing 50% maximal binding (EC 50 ) of 18.6 6 11.4 ng/ml and IC 50 of 70.4 6 37.2 ng/ml for binding to rhesus monkey memory helper T lymphocytes, which is consistent with a human EC 50 of 11.4 ng/ml and IC 50 of 37.2 ng/ml (Table I) and with a previous investigation (26). Vedolizumab exhibited a mean EC 50 of 27.6 6 21.3 ng/ml and IC 50 of 12.2 6 8.4 ng/ml for binding to rhesus monkey memory helper T lymphocytes, which is consistent with a human EC 50 of 21.3 ng/ml and IC 50 of 8.4 ng/ml (Table I).…”

“…7), despite expression of both a 4 b 1 and a 4 b 7 (4,22,29). Similar overall results have been observed in healthy cynomolgus and rhesus monkeys exposed to natalizumab (26). These data illustrate that the expression pattern of these integrins is not an accurate predictor of potential functional effects of corresponding antagonists (1)(2)(3).…”

“…This is unlike the marmoset EAE model, in which demyelination can be found in animals without clinical EAE (42, 43). Dose-dependent increases in the level of mature lymphocytes in the vasculature upon exposure to natalizumab, without concomitant elevations of more immature forms, has been attributed to inhibiting extravasation of lymphocytes from the circulation into parenchymal tissues (26,44). The blockade of CNS infiltration in monkeys exposed to natalizumab (Fig.…”

“…Therefore, we assessed the effects of antagonizing the a 4 integrins in the rhesus monkey EAE model because this is the only established EAE model (28) in which both vedolizumab and natalizumab are pharmacologically active (Table I). This specific rhMOG protocol was chosen because all animals develop EAE (27) and generally do so prior to the development of strong neutralizing anti-drug Ab responses (23,26). It is characterized by an unpredictable time of onset, extremely rapid development, and deterioration of neurological functions (i.e., within a few days).…”

Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica

“…27 Total peripheral lymphocyte counts are increased as well, [27][28][29] but only the relative frequencies of B cells increase, whereas frequencies of CD4 ϩ T cells, CD8 ϩ T cells, and CD16 ϩ CD56 ϩ natural killer cells remain unaltered. 28,29 In recent years it has become clear that NMO is an antibody-mediated disease characterized by the occurrence of pathogenic AQP4-Abs, perivascular deposition of complement and immunoglobulin, and a subsequent astrocytopathy. 3,30,31 Therefore, one might speculate that persisting or even enhanced disease activity in our patients is a direct cause of a natalizumab-induced increase in the number of peripheral CD138 ϩ plasma cells, which in turn might have caused an increase of circulating AQP4-Abs.…”