Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

Abstract

Introduction: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients.

Areas covered: Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells.

Expert opinion: Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.

Keywords: Multiple sclerosis; clinical studies; immunogenicity; mAbs; monoclonal antibodies; safety.

Figure 1. Schematic of the proposed mechanisms of action of existing and emerging therapies for MS

Massive activation of the immune system is followed by the migration of activated immune cells (T and B lymphocytes as well as macrophages) across the disrupted blood-brain barrier (BBB). APC’s would then present CNS antigens to the activated T lymphocytes, which leads to to further differentiation of the naïve T lymphocytes to other groups such as Th1, Th2 and Th17 lymphocytes. Antibodies such as alemtuzumab, daclizumab, natalizumab, rituximab, ocrelizumab, ofatumumab, MOR103, tabalumab, secukinumab, ustekinumab, MED-551 and GNbAC1work mostly on immune cells, cytokines or their receptors at the periphery. rHIgM22 and anti-LINGO-1 antibodies work at the level of CNS and affect OPC’s and OL’s to enhance the process of CNS repair (remyelination). rHIgM22 binds astrocytes in culture and induces a Ca²⁺-influx in astrocytes. rHIgM12 is a poly-specific antibody that binds to either gangliosides or PSA_NCAM and works at the level of neurons and promotes neurite extension. OL: oligodendrocyte, OPC: oligodendrocyte progenitor cell, MP: macrophage, APC: antigen presenting cell, Th1: Type 1 helper T cells, Th2: Type 2 helper T cells, Th17: Type 17 helper T cells (produce IL-17), T: T cell, NKT: natural killer T cell, B: B cell, M: monocyte, VCAM-1: vascular cell adhesion protein, VLA-4: very late antigen-4 (Integrin α4β1), CD19: B-lymphocyte antigen cluster of differentiation 19, CD20: B-lymphocyte antigen cluster of differentiation 20, CD52: cluster of differentiation 52 (CAMPATH-1 antigen), TLR-4: Toll like receptor 4, MSRV-Env: Multiple Sclerosis-Associated Retrovirus-Envelope protein, BAFF: B-cell activating factor, PSA-NCAM: Polysialylated-neural cell adhesion molecule, Gagliosides: GD1a, GT1b.