Table 2.
Examples of MAB therapies that have been discontinued from further clinical trials due to lack of efficacy or serious adverse events in the treatment of multiple sclerosis.
| MAB | Composition | Target/Mechanism | Withdrawn |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. |
Abbreviations: transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI), B-lymphocyte stimulator, also known as TNFSF20 (BLyS), a proliferation-inducing ligand, also known as TNFSF13 (APRIL), monoclonal antibody (MAB), T activation (Tac), cluster of differentiation (CD), interleukin (IL-), B-cell activating factor (BAFF), relapsing multiple sclerosis (RMS), gadolinium (Gd), T helper (Th), very late antigen-2 (VLA-2; also known as integrin α2β1).