A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?

ABSTRACT

Introduction: Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions.

Areas covered: We discuss the history and development of natural human IgM-isotype immunoglobulins (HIgMs) and recently-identified aptamer-conjugates that have been shown to enhance endogenous myelin repair in animal models of demyelination by acting on myelin-producing oligodendrocytes (OLs) or oligodendrocyte progenitor cells (OPCs) within CNS lesions. We also discuss future development aims and applications for these important novel technologies.

Expert opinion: Aptamer conjugate Myaptavin-3064 and recombinant human IgM-isotype antibody rHIgM22 regenerate CNS myelin, thereby reducing axonal degeneration and offering the potential of recovery from MS relapses, reversal of disability and prevention of disease progression. Advancement of these technologies into the clinic for MS treatment is therefore a top priority. It remains unclear to what extent the therapeutic modalities of remyelinating antibodies and aptamers may synergize with other currently-approved therapies to yield enhanced therapeutic effects.

KEYWORDS:

• Antibodies
• aptamers
• humoral immunity
• LJM-3064
• monoclonal antibodies
• multiple sclerosis
• Myaptavin-3064
• natural antibodies
• remyelination
• rHIgM22

Article highlights

• Our historical work in studying the role of CNS autoimmunity in the pathogenesis of MS lead to the hypothesis of CNS autoreactive antibodies having a beneficial role in promoting remyelination.

• Follow-up of these initial observations led to the development of natural human CNS-reactive IgM antibodies and recombinant forms that are now being investigated in clinical trials.

• Through performing in vitro selection against myelin using randomized nucleic acid libraries, we identified aptamers (Myaptavin-3064) capable of inducing remyelination.

• Remyelinating IgM antibodies and nucleic acid aptamers are promising reagents for promoting remyelination in demyelinating disorders such as MS and may especially in combinatory approaches along with FDA-approved MS-drugs be more effective than any current monotherapy.

• rHIgM22 showed an excellent safety profile in a clinical phase I trial and Myaptavin-3064 shows promising results in preclinical animal studies.

This box summarizes key points contained in the article.

Declaration of interest

M Rodriguez, L Maher and A Warrington are inventors on issued patents for antibodies and aptamers discussed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the Mayo Foundation, Minnesota Partnership for Biotechnology and Medical Genomics [15.01], Mayo Clinic Medical Scientist Training Program [1F30 CA220660-01], Applebaum Foundation, Hilton Foundation, and the Peterson Foundation.