title: A Fab fragment directed against the neural cell adhesion molecule L1 enhances functional recovery after injury of the adult mouse spinal cord.
abstract: Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery, which leads to severe disabilities in motor functions or pain. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration. In the present study, we describe the cloning, functional expression in Escherichia coli cells and purification of a recombinant αL1 Fab fragment that binds to L1 with comparable activity as the function-triggering monoclonal antibody 557.B6 and induces neurite outgrowth and neuronal survival in cultured neurons, despite its monovalent function. Infusion of αL1 Fab into the lesioned spinal cord of mice enhanced functional recovery after thoracic spinal cord compression injury. αL1 Fab treatment resulted in reduced scar volume, enhanced number of tyrosine hydroxylase-positive axons and increased linear density of VGLUT1 (vesicular glutamate transporter 1) on motoneurons. Furthermore, the number and soma size of ChAT (choline acetyltransferase)-positive motoneurons and the linear density of ChAT-positive boutons on motoneurons as well as parvalbumin-positive interneurons in the lumbar spinal cord were elevated. Stimulation of endogenous L1 by application of the αL1 Fab opens new avenues for recombinant antibody technology, offering prospects for therapeutic applications after traumatic nervous system lesions.
authors.affiliation: *Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.affiliation: *Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Cui
authors.affiliation: †Munich Center for Integrated Protein Science (CiPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Neumaier
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: †Munich Center for Integrated Protein Science (CiPS-M) and Lehrstuhl für Biologische Chemie, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Skerra
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D009416:Nerve Regeneration; D039842:Neural Cell Adhesion Molecule L1 / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*; D050598:Vesicular Glutamate Transport Protein 1 / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D039842:Neural Cell Adhesion Molecule L1; D011994:Recombinant Proteins; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D002795:Choline O-Acetyltransferase