Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys.

ABSTRACT: ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aβ) protein oligomer. Development of ABT-736 for Alzheimer's disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody r

SUBMITTER: Loberg LI 

PROVIDER: S-EPMC7894423 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature