PMID- 22903665
OWN - NLM
STAT- MEDLINE
DCOM- 20121001
LR  - 20161109
IS  - 0065-2598 (Print)
IS  - 0065-2598 (Linking)
VI  - 750
DP  - 2012
TI  - Naturally occurring antibodies as therapeutics for neurologic disease: can human 
      monoclonal IgMs replace the limited resource IVIG?
PG  - 44-55
LID - 10.1007/978-1-4614-3461-0_4 [doi]
AB  - 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 Ca(2+) 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.
FAU - Warrington, Arthur E
AU  - Warrington AE
AD  - Department of Neurology and Immunology, Mayo Clinic, Rochester, Minnesota, USA. 
      warrington.arthur@mayo.edu
FAU - Van Keulen, Virginia
AU  - Van Keulen V
FAU - Pease, Larry R
AU  - Pease LR
FAU - Rodriguez, Moses
AU  - Rodriguez M
LA  - eng
GR  - CA1060A11/CA/NCI NIH HHS/United States
GR  - NS024180/NS/NINDS NIH HHS/United States
GR  - NS032129/NS/NINDS NIH HHS/United States
GR  - NS048357/NS/NINDS NIH HHS/United States
GR  - R01SGM092993/PHS HHS/United States
GR  - R21 NS073684/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Adv Exp Med Biol
JT  - Advances in experimental medicine and biology
JID - 0121103
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Autoantibodies)
RN  - 0 (Immunoglobulin M)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 0 (Recombinant Proteins)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Alzheimer Disease/immunology/*therapy
MH  - Antibodies, Monoclonal/immunology/therapeutic use
MH  - Autoantibodies/*immunology
MH  - B-Lymphocytes/immunology
MH  - Calcium/immunology/metabolism
MH  - Humans
MH  - Immunization, Passive
MH  - Immunoglobulin M/immunology/*therapeutic use
MH  - Immunoglobulins, Intravenous/immunology/*therapeutic use
MH  - Multiple Sclerosis/immunology/*therapy
MH  - Recombinant Proteins/immunology/therapeutic use
EDAT- 2012/08/21 06:00
MHDA- 2012/10/02 06:00
CRDT- 2012/08/21 06:00
PHST- 2012/08/21 06:00 [entrez]
PHST- 2012/08/21 06:00 [pubmed]
PHST- 2012/10/02 06:00 [medline]
AID - 10.1007/978-1-4614-3461-0_4 [doi]
PST - ppublish
SO  - Adv Exp Med Biol. 2012;750:44-55. doi: 10.1007/978-1-4614-3461-0_4.