Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

doi:10.1517/14712598.2016.1158809

Review

. 2016 Jun;16(6):827-839.

doi: 10.1517/14712598.2016.1158809. Epub 2016 Mar 10.

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

Bharath Wootla^#^{1

2

3}, Jens O Watzlawik^#⁴, Nikolaos Stavropoulos⁵, Nathan J Wittenberg^{6

7}, Harika Dasari^{1

2}, Murtada A Abdelrahim^{1

2}, John R Henley^{8

3

9}, Sang-Hyun Oh^{6

7}, Arthur E Warrington^{1

2}, Moses Rodriguez^{1

2

10}

Affiliations

¹ Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
² Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
³ Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
⁴ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
⁵ Department of General Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, Hradec Kralove 1, 500 38, Czech Republic.
⁶ Department of Electrical and Computer Engineering, University of Minnesota, 200 Union Street SE, 4-174 Keller Hall Minneapolis, MN 55455, USA.
⁷ Department of Biomedical Engineering, University of Minnesota, 200 Union Street SE, 4-174 Keller Hall Minneapolis, MN 55455, USA.
⁸ Department of Neurologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
⁹ Center for Regenerative Medicine, Neuroregeneration, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
¹⁰ Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

^# Contributed equally.

PMID: 26914737
PMCID: PMC4913471
DOI: 10.1517/14712598.2016.1158809

Review

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

Bharath Wootla et al. Expert Opin Biol Ther. 2016 Jun.

. 2016 Jun;16(6):827-839.

doi: 10.1517/14712598.2016.1158809. Epub 2016 Mar 10.

Authors

Affiliations

¹ Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
² Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
³ Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
⁴ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
⁵ Department of General Medicine, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, Hradec Kralove 1, 500 38, Czech Republic.
⁶ Department of Electrical and Computer Engineering, University of Minnesota, 200 Union Street SE, 4-174 Keller Hall Minneapolis, MN 55455, USA.
⁷ Department of Biomedical Engineering, University of Minnesota, 200 Union Street SE, 4-174 Keller Hall Minneapolis, MN 55455, USA.
⁸ Department of Neurologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
⁹ Center for Regenerative Medicine, Neuroregeneration, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
¹⁰ Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

^# Contributed equally.

PMID: 26914737
PMCID: PMC4913471
DOI: 10.1517/14712598.2016.1158809

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.

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Figures

**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.

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References

1. Ehrlich P. Aus Theorie und Praxis der Chemotherapie. W. Klinkhardt; Leipzig: 1911.
1. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495–7. * First described the technology to produce on-demand monoclonal antibodies with desired specificties.
1. Lonberg N. Human antibodies from transgenic animals. Nat Biotechnol. 2005 Sep;23(9):1117–25. - PubMed
1. Rees AR. The antibody molecule : from anti-toxins to therapeutic antibodies. Oxford University Press; New York, NY: 2014.
1. Smith SL. Ten years of Orthoclone OKT3 (muromonab-CD3): a review. J Transpl Coord. 1996 Sep;6(3):109–19. quiz 20-1. - PubMed

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[1] Ehrlich P. Aus Theorie und Praxis der Chemotherapie. W. Klinkhardt; Leipzig: 1911.

[2] Ehrlich P. Aus Theorie und Praxis der Chemotherapie. W. Klinkhardt; Leipzig: 1911.

[3] Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495–7. * First described the technology to produce on-demand monoclonal antibodies with desired specificties.

[4] Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495–7. * First described the technology to produce on-demand monoclonal antibodies with desired specificties.

[5] Lonberg N. Human antibodies from transgenic animals. Nat Biotechnol. 2005 Sep;23(9):1117–25. - PubMed

[6] Lonberg N. Human antibodies from transgenic animals. Nat Biotechnol. 2005 Sep;23(9):1117–25. - PubMed

[7] Rees AR. The antibody molecule : from anti-toxins to therapeutic antibodies. Oxford University Press; New York, NY: 2014.

[8] Rees AR. The antibody molecule : from anti-toxins to therapeutic antibodies. Oxford University Press; New York, NY: 2014.

[9] Smith SL. Ten years of Orthoclone OKT3 (muromonab-CD3): a review. J Transpl Coord. 1996 Sep;6(3):109–19. quiz 20-1. - PubMed

[10] Smith SL. Ten years of Orthoclone OKT3 (muromonab-CD3): a review. J Transpl Coord. 1996 Sep;6(3):109–19. quiz 20-1. - PubMed

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Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

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Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

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