Monoclonal Antibodies in Multiple Sclerosis: Present and Future
Abstract
:1. Introduction
1.1. Natalizumab (Tysabri™)
1.2. Ocrelizumab (Ocrevus™)
1.3. Rituximab (Rituxan™)
1.4. Ofatumumab
1.5. Ublituximab
1.6. Alemtuzumab (Lemtrada™)
1.7. Opicinumab
2. New Horizons and Future Trends for Therapeutic Monoclonal Antibodies
Author Contributions
Funding
Conflicts of Interest
References
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Therapeutic Monoclonal Antibodies | |||||
---|---|---|---|---|---|
MAB | Composition | Target | Mechanism of Action | Administration | FDA Approval Date for MS |
Alemtuzumab | Humanized MAB IgGk | CD52 | ADCC | Intravenous | November 2014 |
Elezanumab [11] | Fully human MAB | RGMa | Binds and neutralizes RGMa which modulates T cell responses and dendritic cells in CNS lesions | Intravenous | N/A |
GNbAC1 [12] | Humanized IgG4 MAB | Envelope protein of HERV-W MSRV | Targets the envelope protein of HERV-W MSRV, which may play a critical role in multiple sclerosis | Intravenous | N/A |
Natalizumab | Humanized monoclonal IgG1 | Cell adhesion molecule α4-integrin | Preventing lymphocyte transport across the blood brain barrier | Intravenous | November 2004 and reapproved on June 2006 |
Ocrelizumab | Humanized IgG1 | Phosphorylated glycoprotein CD20 on B lymphocytes | ADCC > CDC | Intravenous | March 2017 |
Ofatumumab | Fully humanized IgG1 | CD20 | CDC > ADCC | Subcutaneous | N/A |
Opicinumab | Humanized MAB | Targets LINGO-1 | Allows OPCs to differentiate into mature OLG for remyelination | Intravenous | N/A |
Ublituximab | Chimeric IgG1 MAB | CD20 | CDC and ADCC | Intravenous | N/A |
Rituximab | Chimeric (murine/human) MAB | CD20 | CDC and ADCC | Intravenous | N/A |
VAY736 [13] | Defucosylated, human IgG1 MAB | Targets the receptor for BAFF-R | ADCC and blockade of BAFF:BAFF-R signaling that drives B cell differentiation, proliferation and survival | Intravenous | N/A |
MAB | Composition | Target/Mechanism | Withdrawn |
---|---|---|---|
Atacicept [14] | Fully humanized recombinant fusion protein containing the extracellular ligand-binding portion of the human TACI receptor | Binds to the cytokines BLyS and APRIL, involved in B-cell differentiation, maturation, and survival. | Increases relapse rates in multiple sclerosis reflected on an increase in annualized relapse rates. |
Daclizumab [15] | Humanized IgG1 MAB | CD25, which is attached to the Tac epitope on the alpha chain of CD25 (IL-2 receptor) on activated lymphocytes | Post-marketing vigilance helped to detect secondary autoimmune events, including inflammatory encephalitis in 12 patients worldwide leading to at least 3 deaths where an interaction with the drug could not be ruled out. |
Muromonab [16] | Chimeric MAB, first MAB to ever be approved | Inhibition of CD3 receptor | High toxicity made it unlikely to be a preferred treatment for MS. |
Secukinumab [17] | Humanized IgG1kappa MAB | IL-17 receptor, inhibits proinflammatory IL-17A | Discontinued due to the development of a fully-human anti IL-17 MAB with better potential |
Tabalumab [18] | Selective and fully human IgG4 MAB | Neutralization of membrane-bound and soluble B-cell activating factor (BAFF) | Results from phase 2 clinical trials in patients with RMS, showed no evidence of reduction Gd-enhancing lesions versus placebo, further analysis were discontinued. |
Ustekinumab [19] | Fully humanized IgG1 MAB | Targets subunit P40 on cytokines IL-12 and IL-23 preventing them from differentiating and activating Th1 cells | Discontinued after phase 2 trials for low/lack of efficacy. |
Vatelizumab [20] | Fully humanized MAB that targets VLA-2, a collagen binding integrin expressed on activated lymphocytes | Preventing the crossing of inflammatory cells into the brain, reducing inflammation and tested on RMS | Primary efficacy endpoint was not met after phase 2a and 2b studies halting further development for MS. |
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Voge, N.V.; Alvarez, E. Monoclonal Antibodies in Multiple Sclerosis: Present and Future. Biomedicines 2019, 7, 20. https://doi.org/10.3390/biomedicines7010020
Voge NV, Alvarez E. Monoclonal Antibodies in Multiple Sclerosis: Present and Future. Biomedicines. 2019; 7(1):20. https://doi.org/10.3390/biomedicines7010020
Chicago/Turabian StyleVoge, Natalia V., and Enrique Alvarez. 2019. "Monoclonal Antibodies in Multiple Sclerosis: Present and Future" Biomedicines 7, no. 1: 20. https://doi.org/10.3390/biomedicines7010020
APA StyleVoge, N. V., & Alvarez, E. (2019). Monoclonal Antibodies in Multiple Sclerosis: Present and Future. Biomedicines, 7(1), 20. https://doi.org/10.3390/biomedicines7010020