A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.
BACKGROUND
Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology.


RESULTS
(1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12.


CONCLUSIONS
This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.
Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Wootla.Bharath@mayo.edu.
Bharath
B
Wootla
Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Denic.Aleksandar@mayo.edu.
Aleksandar
A
Denic
Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Watzlawik.Jens@mayo.edu.
Jens O
JO
Watzlawik
Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Warrington.Arthur@mayo.edu.
Arthur E
AE
Warrington
Department of Neurology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Rodriguez.Moses@mayo.edu.|Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA. Rodriguez.Moses@mayo.edu.
Moses
M
Rodriguez
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001369:Axons / Q000187:drug effects; D001921:Brain / Q000473:pathology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric; D017945:Theilovirus / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; C084778:M12 protein, Mouse mammary tumor virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D001224:Aspartic Acid; C000179:N-acetylaspartate