Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024
MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Lloyd Christopher, Freskgård Per-Ola, Newton Philip, Lowne David, Nickson Adrian, Bogstedt Anna, Eketjäll Susanna, Höglund Kina, Gustavsson Susanne, Welsh Fraser, Chessell Tharani, McFarlane Mary, Bhat Ratan V, Turner Richard, Perkinton Michael S, Santisteban Valencia Zulma, Lindqvist Eva, Pomfret Michael, Dudley Amanda D, Vaughan Tristan J, Groves Maria T, Natanegara Fanni, Feng Yingdong, Sims John R, Proctor Nicholas Kyle, Dage Jeffrey L, Shering Craig, Tan Keith, Ostenfeld Thor, Billinton Andy, Chessell Iain P
Аннотация
INTRODUCTION: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.
METHODS: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ42, the pathogenic self-aggregating species of Aβ.
RESULTS: MEDI1814 reduces free Aβ42 without impacting Aβ40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ42, increases in total (bound and free) Aβ42, but no change in total Aβ40 in CSF across doses.
DISCUSSION: MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ42.
METHODS: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ42, the pathogenic self-aggregating species of Aβ.
RESULTS: MEDI1814 reduces free Aβ42 without impacting Aβ40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ42, increases in total (bound and free) Aβ42, but no change in total Aβ40 in CSF across doses.
DISCUSSION: MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ42.