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The accumulation of amyloid-β (Aβ) in plaques within the brain is a major driver of Alzheimer disease. Several anti-Aβ antibodies with therapeutic intent have been tested in clinical trials but, despite promising efficacy, they have a low ability to penetrate the blood-brain barrier and cerebrospinal fluid. Another concern is amyloid-related imaging abnormality (ARIA), an adverse event with a poorly understood aetiology. ATV:Aβ, a next-generation anti-Aβ antibody, has now been tested in a preclinical study, demonstrating a favourable distribution profile and mitigation of ARIA.
ATV:Aβ was designed to promote active transport into the blood-brain barrier through a transferrin receptor (TfR) binding domain inserted into the human IgG1 Fc domain. TfR-based antibodies generally harbour symmetrical mutations in the Fc domain to prevent immune cell engagement and mitigate haematological toxicities; however, this approach can limit Fab-mediated anti-Aβ activity. Researchers engineered L234A/L235A (LALA) mutations into the human IgG1 Fc symmetrically (ATV) or asymmetrically in cis or trans (ATV and ATV, respectively); they used an ATV with a wild-type Fc (ATV) as a control. In cultured cells, ATV was the only variant that selectively elicited Fab-mediated antibody-dependent cell cytotoxicity and complement-dependent cytotoxicity but no TfR-mediated antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity. In TfR-knock-in mice, ATV:Aβ and ATV:Aβ did not deplete circulating or bone marrow reticulocytes, whereas ATV:Aβ had a deleterious effect in these populations.