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
| Autor: | Werner Meier, Ellen Garber, Zhaohui Shao, Lee Walus, R. Blake Pepinsky, Christilyn Graff, Benxiu Ji, Yinghui Hu, Qin Wang, Gym Meng, Sha Mi, Xinhua Lee |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Encephalomyelitis Autoimmune Experimental Central nervous system Drug Evaluation Preclinical Nerve Tissue Proteins Pharmacology Rats Sprague-Dawley Myelin medicine Animals Regeneration Rats Long-Evans Remyelination Cerebrospinal Fluid biology Dose-Response Relationship Drug Chemistry Multiple sclerosis Experimental autoimmune encephalomyelitis Antibodies Monoclonal Brain Lysophosphatidylcholines Membrane Proteins medicine.disease Spinal cord Rats Disease Models Animal medicine.anatomical_structure Spinal Cord Blood-Brain Barrier Immunology Systemic administration biology.protein Molecular Medicine Female Antibody |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 339(2) |
| ISSN: | 1521-0103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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