PMID- 26389734 OWN - NLM STAT- MEDLINE DCOM- 20160311 LR - 20151110 IS - 2168-6157 (Electronic) IS - 2168-6149 (Linking) VI - 72 IP - 11 DP - 2015 Nov TI - Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases. PG - 1346-53 LID - 10.1001/jamaneurol.2015.2188 [doi] AB - 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. FAU - Wootla, Bharath AU - Wootla B AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Watzlawik, Jens O AU - Watzlawik JO AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Warrington, Arthur E AU - Warrington AE AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Wittenberg, Nathan J AU - Wittenberg NJ AD - Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis4Department of Biomedical Engineering, University of Minnesota, Minneapolis. FAU - Denic, Aleksandar AU - Denic A AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Xu, Xiaohua AU - Xu X AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Jordan, Luke R AU - Jordan LR AD - Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis4Department of Biomedical Engineering, University of Minnesota, Minneapolis. FAU - Papke, Louisa M AU - Papke LM AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Zoecklein, Laurie J AU - Zoecklein LJ AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Pierce, Mabel L AU - Pierce ML AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Oh, Sang-Hyun AU - Oh SH AD - Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis4Department of Biomedical Engineering, University of Minnesota, Minneapolis. FAU - Kantarci, Orhun H AU - Kantarci OH AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota. FAU - Rodriguez, Moses AU - Rodriguez M AD - Department of Neurology, Mayo Clinic, Rochester, Minnesota2Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota5Department of Immunology, Mayo Clinic, Rochester, Minnesota. LA - eng GR - R01 GM092993/GM/NIGMS NIH HHS/United States GR - R01 NS048357/NS/NINDS NIH HHS/United States GR - R21 NS073684/NS/NINDS NIH HHS/United States GR - UL1 TR000135/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review PL - United States TA - JAMA Neurol JT - JAMA neurology JID - 101589536 RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunoglobulin Isotypes) RN - 0 (Recombinant Proteins) SB - IM MH - Animals MH - Antibodies, Monoclonal/*therapeutic use MH - Humans MH - Immunoglobulin Isotypes/*immunology MH - Nervous System Diseases/*drug therapy/immunology MH - Recombinant Proteins/*therapeutic use EDAT- 2015/09/22 06:00 MHDA- 2016/03/12 06:00 CRDT- 2015/09/22 06:00 PHST- 2015/09/22 06:00 [entrez] PHST- 2015/09/22 06:00 [pubmed] PHST- 2016/03/12 06:00 [medline] AID - 2442472 [pii] AID - 10.1001/jamaneurol.2015.2188 [doi] PST - ppublish SO - JAMA Neurol. 2015 Nov;72(11):1346-53. doi: 10.1001/jamaneurol.2015.2188.