TY - JOUR
T1 - Monoclonal remyelination-promoting natural autoantibody SCH 94.03
T2 - Pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis
AU - Hunter, Samuel F.
AU - Miller, David J.
AU - Rodriguez, Moses
N1 - Funding Information:
This research was supported by the National Institutes of Health (NS24180); S.F.H. is supported by a Clinician Investigator Award from Mayo Foundation. We appreciate the constructive comments of J.L. Valentine regarding the pharmacokinetic findings.
PY - 1997/9/10
Y1 - 1997/9/10
N2 - 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 IgMκ 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.
AB - 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 IgMκ 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.
KW - Demyelination
KW - Multiple sclerosis
KW - Myelin
KW - Natural autoantibody
KW - Oligodendrocyte
KW - Pharmacokinetics
KW - Remyelination
KW - Theiler's virus
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U2 - 10.1016/S0022-510X(97)00080-4
DO - 10.1016/S0022-510X(97)00080-4
M3 - Article
C2 - 9268236
AN - SCOPUS:0030752967
SN - 0022-510X
VL - 150
SP - 103
EP - 113
JO - Journal of the neurological sciences
JF - Journal of the neurological sciences
IS - 2
ER -