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rHIgM22 stimulates remyelination in chronically demyelinated spinal cord lesions through a single minimal doseJ.O. Watzlawik, A.E. Warrington, M. Rodriguez (Rochester, US)
Introduction: Our group seeks to develop novel potential therapeutics to treat demyelinating diseases like MS. We isolated several human and mouse monoclonal antibodies (mAbs) directed against oligodendrocyte (OL) surface antigens that promote substantial remyelination of chronically demyelinated lesions in in the Theiler's murine encephalomyelitis virus (TMEV) model and the lysolecithin model of MS. The recombinant human antibody rHIgM22 recently entered phase I clinical trials for MS patients.
Objective: (i) To determine the IgMs ability to cross the blood brain barrier (BBB) in infected and uninfected animals; (ii) to evaluate the minimal dose of rHIgM22 required to stimulate remyelination in TMEV-infected animals, (iii) to test the importance of the pentameric IgM structure to promote remyelination
Methods: Blood-brain-barrier crossover of 35S-labeled human antibodies in mice was monitored by autoradiography. The extent of spinal cord demyelination and remyelination was quantified by plastic-embedded cross sections stained with 4% paraphenylenediamine (PPD). Cross sections of 1-mm thickness were cut from every third serial 1-mm block, generating 10-12 cross sections representing the whole spinal cord. From each cross section, we calculated the area of white matter, OL remyelination and demyelination using a Zeiss interactive digital analysis system (ZIDAS).
Results: Approximately 0.1 % of the administered antibody crosses the BBB with twice as much antibody detected in brain and spinal cord of TMEV-infected animals compared to uninfected controls. rHIgM22 stimulated extensive spinal cord remyelination in chronically demyelinated animals after a single low dose of 500 ng per mouse. Doses higher than 500 ng were not more effective in stimulating remyelination. The integrity of the pentameric IgM molecule of rHIgM22 is crucial for its effect on remyelination compared to a tetrameric isoform or PBS.
Conclusions: rHIgM22 crosses the BBB in TMEV-infected and control animals. The low dose of rHIgM22 required to stimulate remyelination corresponds to the amount of antibody crossing the BBB and suggests a non-stoichiometric ratio between antibody and effector cells. Clustering of multiple cells or multiple antigens on a single cell is important for IgM-stimulated remyelination.
All listed authors have nothing to disclose.
This work was supported by grants from the NIH (R01 GM092993, R01 NS048357 and R21 NS073684) and the National Multiple Sclerosis Society (CA 1060A). This work was also supported by a High-Impact Pilot and Feasibility Award (HIPFA) and Novel Methodology Award (NMDA) from the Mayo Clinic Center for Translational Science Activities (CTSA) and Mayo Clinic CTSA grant number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). We also acknowledge with thanks support from the Applebaum, Hilton, Peterson and Sanford Foundations, the Minnesota Partnership Award for Biotechnology and Medical Genomics and the McNeilus family.