There are currently no effective treatments to prevent or reverse neurologic deficits in MS. All available drugs target the immune system. Long term CNS repair may require a paradigm shift to focus on drugs that target the nervous system. We have identified a human monoclonal IgM that binds to the surface of living neurons, including those of human origin. The IgM promotes neurite extension even in the presence of normally inhibitory CNS myelin and protects neurons in culture from cell death. The IgM was isolated from the serum of an individual who carried it at high levels for many years without adverse effects and has shown no signs of toxicity to cells or animals. In vivo the IgM improves spinal cord axon health in a virus (Theiler's murine encephalomyelitis virus, TMEV) mediated mouse model of chronic progressive MS. A recombinant form of the IgM, called rHIgM12, was constructed, a research production cell line established, certified for GMP production and banked at a vendor. We have manufactured and purified over 200 mg of rHIgM12 using a procedure appropriate for GLP and GMP production. The efficacy of a single i.v. dose of rHIgM12 (25 mg/kg) has been demonstrated to protect axons and preserve neurologic deficits in the TMEV model of MS. Over the time frame of functional improvement, the number of myelinated axons in the spinal cord are preserved, and N-acetyl aspartate (NAA) concentrations in the brain stem increase, as measured by magnetic resonance spectroscopy (MRS). We have validated the use of NAA in the brain stem as a surrogate marker of axon preservation throughout the spinal cord (37). This MRS based assay is easily applicable to human studies and may become a valid clinical trial endpoint. After peripheral administration rHIgM12 accumulates within spinal cord lesions, co-localized with the axon marker, neurofilament. Our data supports a mechanism of action in which the IgM clusters neuron membrane domains by binding to gangliosides, activating tubulin and initiating signals that result in axon protection and process extension. This project is designed to generate sufficient safety and dose response data for rHIgM12 to support a larger translational program. 1) Efficacy and safety studies in an autoimmune mediated model of MS (EAE) will address concerns that administering a CNS binding Ab in the face of active autoimmunity may exacerbate disease. 2) There is clear efficacy in protecting axons in the TMEV model. A rigorous dose response study in this model will further define the minimum effective dose and guide safety studies. 3) Studies to measure the ability of rHIgM12 to cross the blood brain barrier will strengthen the data supporting direct signaling within the CNS and tissue binding studies across species using rHIgM12 will justify species selection in safety studies.
We identified a natural human antibody that binds to the surface of neurons. The antibody protects neurons from death in culture, and preserves spinal cord axons and improves neurologic function in an animal model of multiple sclerosis. We constructed a recombinant form of this therapeutic antibody which mimics the character of the natural one, including binding to neurons from humans. We can now manufacture large amounts of the antibody necessary for safety testing in animals and clinical trials in humans. This research proposal is designed to test whether this recombinant antibody is effective in a second model of multiple sclerosis, one mediated autoimmunity. We will also determine whether the antibody crosses the blood brain barrier to enter the brain and spinal cord in disease models.
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|Wittenberg, Nathan J; Johnson, Timothy W; Jordan, Luke R et al. (2014) Formation of biomembrane microarrays with a squeegee-based assembly method. J Vis Exp :|
|Wootla, Bharath; Denic, Aleksandar; Rodriguez, Moses (2014) Polyclonal and monoclonal antibodies in clinic. Methods Mol Biol 1060:79-110|
|Denic, Aleksandar; Wootla, Bharath; Zoecklein, Laurie et al. (2014) Deletion of Virus-specific T-cells Enhances Remyelination in a Model of Multiple Sclerosis. J Neurol Transl Neurosci 2:|
|Tutuncu, Melih; Tang, Junger; Zeid, Nuhad Abou et al. (2013) Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 19:188-98|
|Xu, Xiaohua; Denic, Aleksandar; Warrington, Arthur E et al. (2013) Therapeutics to promote CNS repair: a natural human neuron-binding IgM regulates membrane-raft dynamics and improves motility in a mouse model of multiple sclerosis. J Clin Immunol 33 Suppl 1:S50-6|
|Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses (2013) PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLoS One 8:e55149|
|Xu, Xiaohua; Wittenberg, Nathan J; Jordan, Luke R et al. (2013) A patterned recombinant human IgM guides neurite outgrowth of CNS neurons. Sci Rep 3:2267|
|Denic, Aleksandar; Wootla, Bharath; Rodriguez, Moses (2013) CD8(+) T cells in multiple sclerosis. Expert Opin Ther Targets 17:1053-66|
|Watzlawik, Jens O; Wootla, Bharath; Painter, Meghan M et al. (2013) Cellular targets and mechanistic strategies of remyelination-promoting IgMs as part of the naturally occurring autoantibody repertoire. Expert Rev Neurother 13:1017-29|
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