[O2–14–05]: PRECLINICAL CHARACTERIZATION OF AN ANTIBODY [LY3303560] TARGETING AGGREGATED TAU

Abstract

A humanized antibody engineered to bind and neutralize soluble tau aggregate was characterized to determine its epitope, specificity and pharmacokinetic properties in rats and primates. LY3303560 was tested in surface plasmon resonance binding and ELISA assays to assess its selectivity to tau aggregates over monomer, as well as to determine the antibody epitope. Serum concentrations of LY3303560 in monkey and rats were measured using an antigen capture ELISA. LY3303560 demonstrated very high affinity to soluble tau aggregate in vitro (KD: <220 pM), compared to monomer tau (KD: 235 nM). The antibody recognizes a conformational epitope of tau with primary epitope located in the N-terminal region. The high affinity binding to aggregates was driven by avidity. After IV administration to monkeys, the mean clearance was 0.15 ml/h/kg and mean terminal half-life of 310 hours. After SC administration the mean bioavailability was approximately 79%. Rat CSF concentrations were 0.1% of plasma concentrations at 24 hours after IV administration. LY3303560, engineered to target aggregated tau, was shown to have superior selectivity to aggregated tau over monomer. It also demonstrated acceptable pharmacokinetic properties in rat and monkey.