Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis
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Abstract
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.