title: Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration.
abstract: LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.
authors.affiliation: Department of Drug and Molecular Discovery, Biogen Idec, Inc., Cambridge, MA 02142, USA. blake.pepinsky@biogenidec.com
authors.forename: R Blake
authors.initials: RB
authors.lastname: Pepinsky
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Shao
authors.forename: Benxiu
authors.initials: B
authors.lastname: Ji
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Gym
authors.initials: G
authors.lastname: Meng
authors.forename: Lee
authors.initials: L
authors.lastname: Walus
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lee
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Hu
authors.forename: Christilyn
authors.initials: C
authors.lastname: Graff
authors.forename: Ellen
authors.initials: E
authors.lastname: Garber
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.forename: Sha
authors.initials: S
authors.lastname: Mi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D008244:Lysophosphatidylcholines; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C525164:LINGO1 protein, rat; D008244:Lysophosphatidylcholines; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins