Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis.
Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230-6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3-4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5-2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMkappa antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.
Hunter
S F
SF
Department of Neurology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Miller
D J
DJ
Rodriguez
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D001323:Autoantibodies / Q000494:pharmacology*; D001369:Axons / Q000276:immunology; D001921:Brain / Q000378:metabolism; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D009186:Myelin Sheath / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D009836:Oligodendroglia / Q000276:immunology; D011051:Poliomyelitis / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D017945:Theilovirus; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D001323:Autoantibodies