title: Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapy.
abstract: Multiple sclerosis (MS) is an autoimmune-inflammatory disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunologic response, there is a large unmet need for treatments that can promote CNS repair. LINGO-1 (leucine-rich repeat and Ig-containing Nogo receptor interacting protein-1) is a membrane protein selectively expressed in the CNS that suppresses myelination, preventing the repair of damaged axons. We are investigating LINGO-1 antagonist antibodies that lead to remyelination as a new paradigm for treatment of individuals with MS. The anti-LINGO-1 Li81 antibody,BIIB033, is currently in clinical trials and is the first MS treatment targeting CNS repair. Here, to elucidate the mechanism of action of the antibody, we solved the crystal structure of the LINGO-1-Li81 Fab complex and used biochemical and functional studies to investigate structure-function relationships. Li81 binds to the convex surface of the leucine-rich repeat domain of LINGO-1 within repeats 4-8. Fab binding blocks contact points used in the oligomerization of LINGO-1 and produces a stable complex containing two copies each of LINGO-1 and Fab that results from a rearrangement of contacts stabilizing the quaternary structure of LINGO-1. The formation of the LINGO-1-Li81 Fab complex masks functional epitopes within the Ig domain of LINGO-1 that are important for its biologic activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 monoclonal antibody can block its function.
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts blake.pepinsky@biogenidec.com.
authors.forename: R Blake
authors.initials: RB
authors.lastname: Pepinsky
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Arndt
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Chao
authors.initials: C
authors.lastname: Quan
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Omar
authors.initials: O
authors.lastname: Quintero-Monzon
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lee
authors.affiliation: Departments of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Sha
authors.initials: S
authors.lastname: Mi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009836:Oligodendroglia / Q000276:immunology; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins