By Luciano Marinelli
Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease affecting myelinated axons in the central nervous system (CNS). With more than 300,000 patients in the US (Goldenberg, 2012), new treatments are constantly being developed to help symptoms, even though there is still no cure. The use of monoclonal antibodies has been very promising, both for their efficacy and high tolerability (Harrison et al., 2009). This review will provide an overview on the pathology of this disease and outline the mechanisms by which different monoclonal antibody treatments help in slowing the progression of MS.
Firstly, MS can be classified as primary progressive, in which symptoms gradually worsen over time, and relapsing, in which patients have sudden attacks of symptoms. Most patients with relapsing MS develop secondary progressive MS, in which the disability steadily worsens but relapses occur less often (mssociety.org.uk).
Because it is an autoimmune CNS disorder, immune cells must penetrate the blood brain barrier first. The blood brain barrier is severely affected in MS, due to enhanced expression of cell adhesion molecules and a reduced expression of efflux pumps (de Vries et al., 2012), which causes immune cell infiltration and their cytokines into the CNS (Ghasemi et al., 2017). Affected regions include the spinal cord, optic nerve, brain stem and paraventricular regions, causing symptoms including motor, visual and sensory dysfunction, and extreme weakness (Arneth BM, 2019).
The acquired immune system plays a vital role in this condition. Reports from animal models as well as studies on brain lesions in MS patients have confirmed that autoreactive IL17-releasing CD4+ (Th17) cells are heavily involved in the pathology of MS (Zepp et al., 2011; Høglund et al., 2014). Activated antigen presenting cells (APCs) release cytokines such as TGF-β, IL6, IL21 and IL23, which promote the differentiation, hence development, of autoreactive Th17 cells (Guglani et al., 2010). These release IL17, which promotes inflammation by upregulating the expression of various proinflammatory genes, which also promotes infiltration of immune cells into the CNS (Fletcher et al., 2010).
Research has shown that CD20+ B cells are also involved; in particular, these target autoantigens, even though these are not yet identified. A study has shown that in 90% of MS patients oligoclonal immunoglobulin (Ig) is present in cerebrospinal fluid indicating a role of B cells in the pathogenesis of MS. By interaction with T cells, they produce autoantibodies which, coupled by the inflammatory responses mentioned earlier, will cause demyelination and axonal degradation by binding to myelin. A subtype of B cells, B1B cells, has been shown to be able to produce IL6, which aids Th17 cell differentiation, increasing the severity of MS. (Arneth, 2019).
Amongst the various treatment options for MS, monoclonal antibodies (MABs) are often the preferred option because of their efficacy and high target specificity, which means less drug-drug interactions and off target effects. These are usually injected intramuscularly and are made to target specific antigens on immune cells which have a negative impact on the CNS. To prevent the development of anti-drug antibodies, mouse MABs are often partially humanized, containing human constant domains and murine variable domains, or totally humanized. Ocrelizumab and natalizumab are one of the most common prescribed MABs (Voge et al., 2019).
Ocrelizumab is a humanized MAB that targets the CD20 antigens on the surface of circulating B lymphocytes. It is the first anti-CD20 MAB approved by the FDA, even though another anti-CD20 MAB, rituximab, was previously being used off-label (Voge et al., 2019). By binding to CD20, ocrelizumab selectively depletes CD20+ B cells, which, as mentioned earlier, play a crucial role in MS pathogenesis. It has shown efficiency in the treatment of primary progressive MS. A phase III trial showed that the percentage of patients with 24-week progression was significantly lower in those given ocrelizumab compared to those given placebo (29.6% versus 35.7%). The total volume of brain lesions, measured using MRI, decreased by 3.4% with ocrelizumab but increased by 7.4% with placebo; and the percentage of brain volume loss was 0.9% with ocrelizumab versus 1.09% with placebo. Ocrelizumab also showed high efficacy in relapsing MS (Montalban et al., 2017).
On the other hand, natalizumab is a humanized MAB that prevents immune cells to enter the blood brain barrier. It acts by preventing integrin α-4 to form a heterodimer with integrin β-1 (Voge et al., 2019). The α4β1 integrin is found on the surface of activated lymphocytes and monocytes and binds to vascular cell adhesion molecule-1 (VCAM-1) on the vascular endothelium, allowing leukocytes to pass through the BBB. Therefore natalizumab, by preventing the formation of the α4β1 integrin, prevents entry of leukocytes into the CNS (Brandstadter et al., 2017). It is particularly prescribed for relapsing MS. In a placebo-controlled randomized trial, natalizumab reduced the annual relapse rate by 68% compared to the placebo and resulted in an 83% reduction in new or enlarging T2 lesions (Polman et al., 2006).
Overall, monoclonal antibodies are generally well accepted in the medical field because of their efficacy and relatively high tolerability. However, the major limitation of these drugs is their route of administration since they are injected intramuscularly or intravenously. Because of the discomfort of having to self-inject the medication, patients may not adhere to the prescribed therapy (Harrison et al., 2009). Furthermore, with injection there is a risk of experiencing infusion related reactions, which are side effects caused by the injection of the drug and may present themselves as nausea, fever, and rash (McBride A et al., 2010). As a result, an increasing number of oral therapies are currently being developed. Cladribine is an example of an oral drug that has only recently been approved and works by damaging the DNA of T cells (Harrison et al., 2009).
Ultimately, the increasing understanding of the underlying mechanisms of MS will help develop more specific therapies with less side effects in the future, including the potential use of haematopoietic stem cells. Thanks to the ongoing research and the development of an increasing number of therapies, the future of MS seems very promising.
Goldenberg, M. M. (2012). Multiple Sclerosis Review. Pharmacy and Therapeutics, [online] 37(3), pp. 175-184. Available at: https://www.ncbi.nlm.nih.gov/portal/utils/pageresolver.fcgi?recordid=5f4d01750f93c72249894c2e
Harrison, D. M., Calabresi, PA. (2009). Promising treatments of tomorrow for multiple sclerosis. Annals of Indian Academy of Neurology, [online] 12(4), pp. 283-290. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824956/
MS Society. Types of MS. Available at: https://www.mssociety.org.uk/about-ms/types-of-ms
de Vries, H. E., Kooji, G., Frenkel, D., Georgopoulos, S., Monsonego, A., Janigro, D. (2012). Inflammatory events at blood-brain barrier in neuroinflammatory and neurodegenerative disorders: Implications for clinical disease. Epilepsia, [online] 53(6), pp. 45-52. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853914/
Ghasemi, N., Razavi, S., Nikzad, E. (2017). Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell journal, [online] 19(1), pp. 1–10. Available at: https://doi.org/10.22074/cellj.2016.4867
Arneth, B. (2019). Impact of B cells to the pathophysiology of multiple sclerosis. Journal of Neuroinflammation, [online] 16(128), pp. 1-9. Available at: https://jneuroinflammation.biomedcentral.com/track/pdf/10.1186/s12974-019-1517-1
Zepp, J., Wu, L., Li, X. (2011). IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends in immunology, [online] 32(5), pp. 232–239. Available at: https://doi.org/10.1016/j.it.2011.02.007
Høglund, R. A., Maghazachi, A. A. (2014). Multiple sclerosis and the role of immune cells. World journal of experimental medicine, [online] 4(3), pp. 27–37. Available at: https://doi.org/10.5493/wjem.v4.i3.27
Guglani, L., Khader, S. (2010). Th17 cytokines in mucosal immunity and inflammation. Current opinion in HIV and AIDS, [online] 5(2), pp. 120-127. Available at: https://insights.ovid.com/article/01222929-201003000-00004
Fletcher, J. M., Lalor, S. J., Sweeney, C. M., Tubridy, N., and Mills, K. H. (2010). T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clinical and experimental immunology, [online] 162(1), pp. 1–11. Available at: https://doi.org/10.1111/j.1365-2249.2010.04143.x
Voge, N. V., and Alvarez, E. (2019). Monoclonal Antibodies in Multiple Sclerosis: Present and Future. Biomedicines, [online] 7(1), p. 20. Available at: https://doi.org/10.3390/biomedicines7010020
Montalban, X. et al. (2017). Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. The New England journal of medicine, [online] 376(3), pp. 209–220. Available at: https://doi.org/10.1056/NEJMoa1606468
Brandstadter, R., Katz Sand, I. (2017). The use of natalizumab for multiple sclerosis. Neuropsychiatric disease and treatment, [online] 13, pp. 1691–1702. Available at: https://doi.org/10.2147/NDT.S114636
Polman, C. H. et al. (2006). A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. National Library of Medicine, [online] 354(9), pp. 899-910. Available at: https://pubmed.ncbi.nlm.nih.gov/16510744/
McBride, A., Ngo, N., Campen, C. (2010). Infusion-related Reactions. The Oncology Pharmacist, [online] 3(3). Available at: http://theoncologypharmacist.com/top-issues/2010-issues/may-vol-3-no-3/10516-top-10516