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P1‐081: Optimization of the Pharmacokinetic (PK) and Pharmacodynamic (PD) Properties of an Anti‐Abeta Antibody M266 FAB Fragment Variant by Site‐Specific Pegylation
Author(s) -
Racke Margaret M.,
Day Theresa A.,
Hole Justin T.,
Chow Chi-Kin,
Lu Jirong,
DeMattos Ronald B.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.829
Subject(s) - pegylation , chemistry , peg ratio , antibody , pharmacokinetics , pharmacodynamics , pharmacology , monoclonal antibody , in vivo , biophysics , biochemistry , immunology , polyethylene glycol , medicine , biology , microbiology and biotechnology , finance , economics
neuronal culture assay with an EC50of approximately 250 pM. Following acute oral treatment with 0, 0.3, 1.0, or 3.0 mg/kg LY3202626, dose-dependent reductions in Ab, sAPPb, and C99 were observed in cortex and hippocampus of PDAPPmice. In beagle dog, acute oral dosing of 1.5 mg/kg LY3202626 resulted in lowering of plasma and CSF Ab 1-x by approximately 80% at the nadir; the CSF Ab 1-x was still reduced by approximately 75% at 24 hours post-dosing. Exposure of LY3202626 in plasma and CSF correlated significantly with pharmacodynamic effects upon Ab in both PDAPP mice and beagle dogs. Conclusions:LY3202626 is a potent and selective inhibitor of the BACE1 and BACE2 enzymes. The robust in vivo effects of LY3202626 are consistent with its in vitro potency and exposure in target compartments. These data support further clinical development of LY3202626 for the treatment of AD.