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Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases

Bharath Wootla, PhD1,2; Jens O. Watzlawik, PhD1,2; Arthur E. Warrington, PhD1,2; Nathan J. Wittenberg, PhD3,4; Aleksandar Denic, MD, PhD1,2; Xiaohua Xu, MD, PhD1,2; Luke R. Jordan, BA3,4; Louisa M. Papke, BS1,2; Laurie J. Zoecklein, MS1,2; Mabel L. Pierce1,2; Sang-Hyun Oh, PhD3,4; Orhun H. Kantarci, MD1,2; Moses Rodriguez, MD1,2,5
[+] Author Affiliations
1Department of Neurology, Mayo Clinic, Rochester, Minnesota
2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota
3Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis
4Department of Biomedical Engineering, University of Minnesota, Minneapolis
5Department of Immunology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. 2015;72(11):1346-1353. doi:10.1001/jamaneurol.2015.2188.
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Importance  Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.

Objective  To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.

Evidence Review  Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.

Findings  Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.

Conclusions and Relevance  Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.

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Figure 1.
Roles of IgM Naturally Occurring Antibodies (NAbs)

The NAbs are a first line of defense against invading microbes. They also maintain tissue homeostasis and shape subsequent immune responses. NAbs help recognize apoptotic cells; promote their clearance by phagocytic cells, such as dendritic cells (DCs) and macrophages (MΦ); and clear altered or malignant cells and misfolded proteins. NAbs activate complement pathways and help prevent inflammation, autoimmunity, and malignancy. The IgM NAbs confer protection against invading pathogens (ie, bacteria and viruses) either through direct neutralization or via activation of classical complement pathways, opsonization of pathogens, and phagocytosis by DCs and MΦ.

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Figure 2.
Oligodendrocyte- and Neuron-Reactive Antibodies

A, The recombinant human monoclonal IgM (rHIgM22) targets myelin and oligodendrocytes (OLs). B, Isolated OLs were cultured for 7 days and labeled live with rHIgM22 (red channel) and the mouse IgM OL marker antisulfatide, O4 (green channel); rHIgM22 binds near the edges of sulfatide-positive myelin membrane. The top left panel represents a phase contrast image to show that the experiment is being conducted on a morphologically correct and intact cell type. C and D, In demyelinated lesions in animal models of multiple sclerosis (C), rHIgM22 promotes remyelination (D). E, Recombinant HIgM12 targets the surface of neurons. F, Hippocampal neurons were double labeled live with rHIgM12 (red channel) and anti–neural cell adhesion molecule (green channel). Neurons were then fixed and stained with the neuronal marker, anti–β3-tubulin (blue channel). Recombinant HIgM12 and anti–neural cell adhesion molecule colocalized. Scale bar 20 μm for all panels. G and H, Hippocampal neurons were seeded onto polylysine- or rHIgM12-coated substrates. Twelve hours later, neurons were labeled with anti–β3-tubulin (green channel) and anti–F-actin (red channel), and nuclei were stained with 4',6-diamidino-2-phenylindole (blue channel). Recombinant HIgM12 supported robust axon outgrowth. NAb indicates naturally occurring antibody.

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