Naturally Occurring Antibodies as Therapeutics for Neurologic Disease

Can Human Monoclonal IgMs Replace the Limited Resource IVIG?
  • Arthur E. WarringtonEmail author
  • Virginia Van Keulen
  • Larry R. Pease
  • Moses Rodriguez
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 750)


Naturally occurring autoantibodies (NAbs) are common in normal humans. The majority of NAbs are IgMs, but a small proportion are IgGs. Therefore a certain portion of pooled whole human IgG (IVIG) can be considered NAbs. While the applications of IVIG to modulate human disease have increased dramatically, the use of IgMs as drugs has lagged. In fact, much of the contaminating IgM component of IVIG is disposed of as waste. However, a number of model studies, including those targeting Alzheimer and multiple sclerosis (MS) suggest that IgMs may better modulate disease at much lower doses than IVIG. Our own studies in a model of MS show that polyclonal human IgM promotes better remyelination than IVIG and that monoclonal IgMs promote greater remyelination than monoclonal IgGs containing identical variable region sequences. We propose that this difference is due to the ability of IgM to cross link cell surface antigens better than IgGs and induce signals in nervous system cells. Monoclonal antibodies (mAbs) that promote remyelination induce a transient Ca2+ influx in myelin forming cells, whereas IgGs with identical variable sequences do not. MAbs that promote remyelination were identified in human serum and in EBV-immortalized human B-cell lines obtained from normal adults, fetal cord blood, and rheumatoid arthritis and MS patients. Therefore therapeutic mAbs are present and common in normal circulation. All therapeutic mAbs were IgMs and bound to nervous system cells, however, the tissue binding patterns suggest that binding any one of multiple antigens induces repair. An expression vector was constructed that can manufacture gram quantities of recombinant monoclonal human IgM. Therefore the technology exists to determine whether human monoclonal NAbs can modulate human disease. IVIG can modulate neurologic disease, but using IVIG to treat these chronic diseases is unsustainable. A long-term solution is to identify the functional component of IVIG and test whether a recombinant human monoclonal can replicate its efficacy.


Multiple Sclerosis Optic Neuritis Neurologic Disease Myelin Repair Therapeutic mAbs 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Lacroix-Desmazes S, Kaveri SV, Mouthon L et al. Self-reactive antibodies (natural autoantibodies) in healthy individuals. J ImmunolMethods 1998; 216:117–37. PMID:9760219 doi:10.1016/S0022-1759(98)00074-XGoogle Scholar
  2. 2.
    Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol 1995; 7:812–8. PMID:8679125 doi:10.1016/0952-7915(95)80053-0PubMedCrossRefGoogle Scholar
  3. 3.
    Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology-therapeutic considerations and practical issues. Nat Clin Pract Neurol 2007; 3:36–44. PMID: 17205073 doi:10.1038/ncpneuro0376PubMedCrossRefGoogle Scholar
  4. 4.
    Noseworthy JH, Lucchinetti C, Rodriguez M et al. Multiple sclerosis. N Engl J Med 2000; 343:938–52. PMID: 11006371 doi:10.1056/NEJM200009283431307PubMedCrossRefGoogle Scholar
  5. 5.
    Fazekas F, Deisenhammer F, Strasser-Fuchs S et al. Randomisedplacebo-controlledtrial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet 1997; 349:589–93. PMID:9057729 doi:10.1016/S0140-6736(96)09377-4PubMedCrossRefGoogle Scholar
  6. 6.
    Sorensen PS, Wanscher B, Jensen CV et al. Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998; 50:1273–81. PMID:9595974PubMedCrossRefGoogle Scholar
  7. 7.
    Haas J, Maas-Enriquez M, Hartung HP. Intravenous immunoglobulins in the treatment of relapsing remitting multiple sclerosis-results of a retrospective multicenter observational study over five years. Mult Scler 2005; 11:562–7. PMID:16193894 doi:10.1191/1352458505ms 1224oaPubMedCrossRefGoogle Scholar
  8. 8.
    Fazekas F, Lublin FD, Li D et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology 2008; 71:265–71. PMID: 18645164 doi: 10.1212/01.wnl.0000318281.98220.6fPubMedCrossRefGoogle Scholar
  9. 9.
    Hommes OR, Sorensen PS, Fazekas F et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004; 364:1149–56. PMID:15451222 doi:10.1016/S0140-6736(04)17101-8PubMedCrossRefGoogle Scholar
  10. 10.
    McDonald WI, Barnes D. The ocular manifestations of multiple sclerosis. 1. Abnormalities of the afferent visual system. J Neurol Neurosurg Psychiatry 1992; 55:747–52. PMID:1402963 doi:10.1136/jnnp.55.9.747PubMedCrossRefGoogle Scholar
  11. 11.
    Noseworthy JH, O’Brien PC, Petterson TM et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001; 56:1514–22. PMID: 11402108PubMedCrossRefGoogle Scholar
  12. 12.
    Roed HG, Langkilde A, Sellebjerg F et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 2005; 64:804–10. PMID:15753413 doi:10.1212/01. WNL.0000152873.82631.B3PubMedCrossRefGoogle Scholar
  13. 13.
    Noseworthy JH, O’Brien PC, Weinshenker BG et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000; 55:1135–43. PMID:11071491PubMedCrossRefGoogle Scholar
  14. 14.
    Tselis A, Perumal J, Caon C et al. Treatment of corticosteroid refractory optic neuritis in multiple sclerosis patients with intravenous immunoglobulin. Eur J Neurol 2008; 15:1163–7. PMID:18727675 doi:10.1111/j.1468-1331.2008.02258.xPubMedCrossRefGoogle Scholar
  15. 15.
    Rodriguez M, Oleszak E, Leibowitz J. Theiler’s murine encephalomyelitis: a model of demyelination and persistence of virus. Crit Rev Immunol 1987; 7:325–65. PMID:2827957PubMedGoogle Scholar
  16. 16.
    McGavern DB, Murray PD, Rivera-Quinones C et al. Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 2000; 123:519–31. PMID:10686175 doi:10.1093/brain/123.3.519PubMedCrossRefGoogle Scholar
  17. 17.
    McGavern DB, Murray PD, Rodriguez M. Quantitation of spinal cord demyelination, remyelination, atrophy, and axonal loss in a model of progressive neurologic injury. J Neurosci Res 1999; 58:492–504. PMID:10533042 doi:10.1002/(SICI)1097-4547(19991115)58:4<492::AID-JNR3>3.0.CO;2-PPubMedCrossRefGoogle Scholar
  18. 18.
    McGavern DB, Zoecklein L, Drescher KM et al. Quantitative assessment of neurologic deficits in a chronic progressive murine model of CNS demyelination. Exp Neurol 1999; 158:171–81. PMID:10448429 doi:10.1006/exnr.1999.7082PubMedCrossRefGoogle Scholar
  19. 19.
    Rodriguez M, Lennon VA, Benveniste EN et al. Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 1987; 46:84–95. PMID:2432195 doi: 10.1097/00005072-198701000-00008PubMedCrossRefGoogle Scholar
  20. 20.
    Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 1990; 27:12–7. PMID:2301922 doi:10.1002/ana.410270104PubMedCrossRefGoogle Scholar
  21. 21.
    Huang DW, McKerracher L, Braun PE et al. A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 1999; 24:639–47. PMID: 10595515 doi:10.1016/S0896-6273(00)81118-6PubMedCrossRefGoogle Scholar
  22. 22.
    Ellezam B, Bertrand J, Dergham P et al. Vaccination stimulates retinal ganglion cell regeneration in the adult optic nerve. Neurobiol Dis 2003; 12:1–10. PMID:12609484 doi:10.1016/S0969-9961(02)00013-XPubMedCrossRefGoogle Scholar
  23. 23.
    Miller DJ, Sanborn KS, Katzmann JA et al. Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. J Neurosci 1994; 14:6230–8. PMID:7931575PubMedGoogle Scholar
  24. 24.
    Asakura K, Miller DJ, Murray K et al. Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 1996; 43:273–81. PMID:8714516 doi:10.1002/(SICI)1097-4547(19960201)43:3<273::AID-JNR2>3.0.CO;2-GPubMedCrossRefGoogle Scholar
  25. 25.
    Warrington AE, Pfeiffer SE. Proliferation and differentiation of O4+ oligodendrocytes in postnatal rat cerebellum: analysis in unfixed tissue slices using anti-glycolipid antibodies. J Neurosci Res 1992; 33:338–53. PMID:1453495 doi:10.1002/jnr.490330218PubMedCrossRefGoogle Scholar
  26. 26.
    Asakura K, Miller DJ, Pease LR et al. Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination. JNeurosci 1998; 18:7700–8. PMID:9742140Google Scholar
  27. 27.
    Asakura K, Miller DJ, Pogulis RJ et al. Oligodendrocyte-reactive O1, O4, and HNK-1 monoclonal antibodies are encoded by germline immunoglobulin genes. Brain Res Mol Brain Res 1995; 34:283–93. PMID:8750831 doi:10.1016/0169-328X(95)00190-4PubMedCrossRefGoogle Scholar
  28. 28.
    Avrameas S, Ternynck T, Tsonis IA et al. Naturally occurring B-cell autoreactivity: a critical overview. J Autoimmun 2007; 29:213–8. PMID:17888629 doi:10.1016/j.jaut.2007.07.010PubMedCrossRefGoogle Scholar
  29. 29.
    Warrington AE, Asakura K, Bieber AJ et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci USA 2000; 97:6820–5. PMID: 10841576 doi:10.1073/pnas.97.12.6820PubMedCrossRefGoogle Scholar
  30. 30.
    Brown NA, Miller G. Immunoglobulin expression by human B lymphocytes clonally transformed by Epstein Barr virus. J Immunol 1982; 128:24–9. PMID:6274955PubMedGoogle Scholar
  31. 31.
    Mitsunaga Y, Ciric B, Van Keulen V et al. Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 2002; 16:1325–7. PMID:12154009PubMedGoogle Scholar
  32. 32.
    Bieber AJ, Warrington A, Asakura K et al. Human antibodies accelerate the rate of remyelination following lysolecithin-induceddemyelinationin mice. Glia 2002; 37:241–9. PMID:1 1857682 doi:10.1002/glia.10033PubMedCrossRefGoogle Scholar
  33. 33.
    Warrington AE, Bieber AJ, Ciric B et al. A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 2007; 85:967–76. PMID:17304578 doi:10.1002/jnr.21217PubMedCrossRefGoogle Scholar
  34. 34.
    Pirko I, Ciric B, Gamez J et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004; 18:1577–9. PMID:15319372PubMedGoogle Scholar
  35. 35.
    Hunter SF, Miller DJ, Rodriguez M. Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis. J Neurol Sci 1997; 150:103–13. PMID:9268236 doi:10.1016/S0022-510X(97)00080-4PubMedCrossRefGoogle Scholar
  36. 36.
    Banks WA, Farr SA, Morley JE et al. Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer’s disease: an age-related selective uptake with reversal of learningimpairment. Exp Neurol 2007; 206:248–56. PMID:17582399 doi:10.1016/j.expneurol.2007.05.005PubMedCrossRefGoogle Scholar
  37. 37.
    Paz Soldán MM, Warrington AE, Bieber AJ et al. Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol Cell Neurosci 2003; 22:14–24. PMID:12595235 doi:10.1016/S1044-7431(02)00018-0CrossRefGoogle Scholar
  38. 38.
    Watzlawik J, Holicky E, Edberg DD et al. Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lynkinase in primary rat oligodendrocytes. Glia 2010; 58:1782–93. PMID:20645409 doi:10.1002/glia.21048PubMedCrossRefGoogle Scholar
  39. 39.
    Ciric B, Howe CL, Paz Soldan M et al. Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function. Brain Pathol 2003; 13:608–16. PMID:14655764 doi:10.1111/j.1750-3639.2003. tb00489.xPubMedCrossRefGoogle Scholar
  40. 40.
    Schroeder HW Jr., Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol 2010; 125(Suppl 2):S41–52. PMID:20176268 doi:10.1016/j.jaci.2009.09.046PubMedCrossRefGoogle Scholar
  41. 41.
    Howe CL, Bieber AJ, Warrington AE et al. Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 2004; 15:120–31. PMID:14751777 doi:10.1016/j.nbd.2003.09.002PubMedCrossRefGoogle Scholar
  42. 42.
    Dodel R, Hampel H, Depboylu C et al. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 2002; 52:253–6. PMID: 12210803 doi:10.1002/ana.10253PubMedCrossRefGoogle Scholar
  43. 43.
    Dodel RC, Du Y, Depboylu C et al. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004; 75:1472–4. PMID:15377700 doi:10.1136/jnnp.2003.033399PubMedCrossRefGoogle Scholar
  44. 44.
    Geylis V, Kourilov V, Meiner Z et al. Human monoclonal antibodies against amyloid-beta from healthy adults. Neurobiol Aging 2005; 26:597–606. PMID:15708434 doi:10.1016/j.neurobiolaging.2004.06.008PubMedCrossRefGoogle Scholar
  45. 45.
    Szabo P, Relkin N, Weksler ME. Natural human antibodies to amyloid beta peptide. Autoimmun Rev 2008; 7:415–20. PMID:18558354 doi:10.1016/j.autrev.2008.03.007PubMedCrossRefGoogle Scholar
  46. 46.
    Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400:173–7. PMID:10408445 doi:10.1038/22124PubMedCrossRefGoogle Scholar
  47. 47.
    Bard F, Cannon C, Barbour R et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000; 6:916–9. PMID:10932230 doi:10.1038/78682PubMedCrossRefGoogle Scholar
  48. 48.
    Lindhagen-Persson M, Brannstrom K, Vestling M et al. Amyloid-beta oligomer specificity mediated by the IgM isotype-implications for a specific protective mechanism exerted by endogenous auto-antibodies. PLoS ONE 2010; 5:e13928. PMID:21085663 doi:10.1371/journal.pone.0013928PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Arthur E. Warrington
    • 1
    Email author
  • Virginia Van Keulen
    • 1
  • Larry R. Pease
    • 1
  • Moses Rodriguez
    • 1
  1. 1.Departments of Neurology and ImmunologyMayo ClinicRochesterUSA

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