Lecanemab demonstrates highly selective binding to Aβ protofibrils isolated from Alzheimer's disease brains

Recent advances in immunotherapeutic approaches to the treatment of Alzheimer's disease (AD) have increased the importance of understanding the exact binding preference of each amyloid-beta (A(3) antibody employed, since this determines both efficacy and risk for potentially serious adverse events known as amyloid-related imaging abnormalities. Lecanemab is a humanized IgG1 antibody that was developed to target the soluble A(3 protofibril conformation. The present study prepared extracts of post mortem brain samples from AD patients and non-demented elderly controls, characterized the forms of A(3 present, and investigated their interactions with lecanemab. Brain tissue samples were homogenized and extracted using tris-buffered saline. A(3 levels and aggregation states in soluble and insoluble extracts, and in fractions prepared using size-exclusion chromatography or density gradient ultracentrifugation, were analyzed using combinations of immunoassay, immunoprecipitation (IP), and mass spectrometry. Lecanemab immunohistochemistry was also conducted in temporal cortex. The majority of temporal cortex A(3 (98 %) was in the insoluble extract. A(342 was the most abundant form present, particularly in AD subjects, and most soluble A(342 was in soluble aggregated protofibrillar structures. A(3 protofibril levels were much higher in AD subjects than in controls. Protofibrils captured by lecanemab-IP contained high levels of A(342 and lecanemab bound to large, medium, and small A(342 protofibrils in a concentration-dependent manner. Competitive IP showed that neither A(340 monomers nor A(340-enriched fibrils isolated from cerebral amyloid angiopathy reduced lecanemab's binding to A(342 protofibrils. Immunohistochemistry showed that lecanemab bound readily to A(3 plaques (diffuse and compact) and to intraneuronal A(3 in AD temporal cortex. Taken together, these findings indicate that while lecanemab binds to A(3 plaques, it preferentially targets soluble aggregated A(3 protofibrils. These are largely composed of A(342, and lecanemab binds less readily to the A(340-enriched fibrils found in the cerebral vasculature. This is a promising binding profile because A(342 protofibrils represent a key therapeutic target in AD, while a lack of binding to monomeric A(3 and cerebral amyloid deposits should reduce peripheral antibody sequestration and minimize risk for adverse events.