Laquinimod in Relapsing–Remitting Multiple Sclerosis
pericarditis, pleuritis, pancreatitis, and vasculitis of the coronary arteries, resulting in several myocardial infarctions.3 subsequently stopped.
Its development was
Research on the structure and activity relationships of the parent compound led to the development of laquinimod. Laquinimod is a quinoline 3-carboxamide derivative that was selected from over 60 quinoline carboxamide derivatives on the basis of structure and activity relationships that were maximized to achieve superior safety and efficacy in EAE.4
Numerous compounds from this class were
systematically evaluated to obtain a compound with maximal efficacy in EAE and an absence of proinflammatory effects in beagle dogs. The type and position of the quinoline ring was the major determinant of efficacy, whereas the N-carboxyamide substitution appeared to be the major factor determining safety. Laquinimod proved to have the best safety and efficacy profile of all the compounds tested.
In acute EAE in SJL/N mice, disease severity was decreased in a dose-dependent fashion and laquinimod was 20 times more potent than roquinimex.8
Laquinimod ameliorated neurologic deficits in both acute and chronic EAE.5–7
In a Lewis rat model of EAE, laquinimod was
more potent at inhibiting disease than roquinmex and was again dose-dependent, suggesting that it affected a biologically relevant target in inflammatory disease of the CNS. Its administration resulted in a decrease in the infiltration of CD+ T cells and macrophages into CNS tissue, and this effect was more robust than that seen with the parent compound, roquinimex.6
There was an associated downregulation of
tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12) and an upregulation of transforming growth factor-beta (TGF-β), IL-4, and IL-10, consistent with the hypothesis that an effect on cytokine profiles in an inflammatory environment could be partly responsible for the anti-inflammatory effects of laquinimod.
In myelin oligodendrocyte (MOG)-protein-induced EAE in C57BL/6 mice, laquinimod reduced macrophage and T-cell infiltration into spinal cord tissue and significantly reduced demyelination and axonal loss. These effects were apparent when laquinimod was given both as pre-treatment and after the start of clinical disease.9
These effects were accompanied by a downregulation of pro-inflammatory cytokines.
Laquinimod was also effective in other forms of EAE. In EAE induced with myelin basic protein (MBP) fragment 89–101, there was a reduction in EAE disease severity. This effect was also dose-dependent.6 Once again, there was a marked reduction of macrophage and T-cell infiltration into the CNS and a decrease in demyelination and axonal loss compared with vehicle-treated animals. Of interest is that laquinimod had potent effects on reducing disease severity in animal models of other autoimmune disease, including experimental allergic neuritis (EAN).10
Mechanism of Action
Our understanding of the mechanism of action of laquinimod is far from complete, but some information has been derived from its evaluation in EAE and from other basic immunologic investigation. Laquinimod appears to act as a broad-spectrum immunomodulatory agent with varied effects on the immune system. The administration of laquinimod
US NEUROLOGY
to C57BL/6 mice with MOG-induced EAE and with depleted CD4+ and CD25+ T cells inhibited disease severity. This indicated that laquinimod does not require this regulatory pathway for the inhibition of MOG-induced EAE.11
Moreover, there was no effect on cardiac allograft
rejection in rats, suggesting that laquinimod has no effect on the ability of an animal to mount a cellular or humoral immune response. In other words, it is not immunosuppressive, which has important implications for safety in human use.
In the Lewis rat model of EAE, laquinimod induced a shift in the cytokine profile from a Th1 to a Th2 pattern.6
Following the administration of
laquinimod there was an upregulation of MBP-specific IL-4-, IL-10-, and TGF-β-expressing cells. Similar results have been obtained in other types of EAE. In MBP-induced EAE there was an upregulation of Th2/Th3 cells and a downregulation of MBP Th1 cells consistent with a shift in the cytokine profile to an anti-inflammatory milieu.6
In another
EAE study in mice, laquinimod produced a profound effect on the steady-state distribution of monocyte subsets that the authors thought might be due to its impact on the myeloid precursor compartment.12
In addition to the downregulation of inflammatory cytokines, laquinimod brought about a decrease in the expression of major histocompatibility complex (MHC) class II antigens required for antigen presentation.13
This
will also contribute to the downregulation of CNS inflammation. In EAE, laquinimod decreased the production of TNF-α and IFN-γ and increased IL-4 mRNA expression.6
It also brought about a reduction in
the disease-specific T-cell response. Since laquinimod has effects in both EAE and EAN, it may affect a pivotal pathway involved in autoimmunity. While little is known about its mechanism of action at this point in time, it appears to be a broad-spectrum immunomodulator that has no immunosuppressive effects.
In studies on peripheral blood mononuclear cells from patients with RRMS and from healthy controls, laquinimod reduced the expression of MHC class II antigen-presenting molecules, chemokine signaling molecules, integrin, and adhesion-related molecules.14
Laquinimod
also brought about a profound downregulation of the dendritic cell compartment in murine EAE, suggesting that it could also be acting through this mechanism.15
These effects are also consistent with a suppression of inflammatory disease activity.
In purified human B cells derived from healthy controls stimulated with CpG oligonucleotid, culture of cells with 1µM laquinimod decreased the percentages of CD5+ and CD27+ cells (p<0.004 and p<0.03, respectively compared with no laquinimod). CD86+ and CD25+ cells, however, were increased (p<0.04 and p<0.0, respectively) and the subpopulation overexpressing IL-10 was significantly increased by laquinimod.16
In studies on cell cultures from patients with RRMS, laquinimod affected CD4+ cells by activating the IL-4 gene, suppressing the ALOX5 gene and there was an over-expression of TNFRSF4 receptor genes consistent with anti-inflammatory Th2 response.17
In CD8+ cells, laquinimod
suppressed cell proliferation, which the study authors suggested could be explained by suppression of the cell cycle transcription factor genes E2F3 and CDK3 and may reverse the autoimmune pathogenic effects of CD8+ T cells in MS. Similar effects were noted in B cells. This study also
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