Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives

Abstract

Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.

Keywords: Aducanumab; Alzheimer’s disease; Amyloid-related imaging abnormalities; Donanemab; Gantenerumab; Lecanemab.

Fig. 1

Second-generation anti-amyloid monoclonal antibodies (MABs) target different forms of Aβ. Aducanumab targets Aβ fibrils and plaques. Lecanemab binds to soluble Aβ oligomers, protofibrils, fibrils, and plaques. Gantenerumab targets soluble Aβ oligomers, protofibrils, fibrils and plaques. Donanemab specifically targets the N-terminus of pyroglutamate present in Aβ plaques

Fig. 2

The putative mechanisms by which second-generation anti-amyloid monoclonal antibodies (MABs) reduce the accumulation of Aβ in Alzheimer’s disease (AD). Donanemab-Aβ and lecanemab-Aβ complexes inhibit Aβ accumulation by blocking nucleation and aggregation, and clear Aβ by glial cell-mediated phagocytosis and peripheral sink mechanisms. In addition, gantenerumab-Aβ and aducanumab-Aβ complexes degrade Aβ into sub-aggregates, inducing phagocytosis and peripheral sink mechanisms. Second-generation anti-amyloid MABs have been humanized to the IgG1 subclass

Fig. 3

The putative pathophysiological mechanisms leading to the incidence of amyloid-related imaging abnormalities (ARIAs) in the brains of patients with Alzheimer’s disease (AD). a The schematic diagram shows the occurrence of ARIA by the classical complement cascade in the vasculature. Anti-amyloid monoclonal antibodies (MABs) induce the formation of C1 complex. The C1 complex disrupts the blood brain barrier (BBB) by forming the membrane attack complex (MAC) C5b-9 through multiple complement signaling pathways. b The schematic diagram shows the incidence of ARIA by the FcR-mediated signaling pathways in the brain. During the removal process of Aβ aggregates by antibodies, detritus, such as soluble Aβ, is transported towards the BBB by ApoE. This transported Aβ contributes to the formation of cerebral amyloid angiopathy (CAA). The antibody-mediated clearance of formed CAA not only damages the BBB but also activates macrophages through the FcR-mediated signaling pathway. The activated macrophages induce inflammatory signaling, such as tissue inhibitor of metalloproteinases-1 (TIMP1) and matrix metallopeptidase 9 (MMP9), leading to an increased recruitment of monocytes around the BBB. The BBB is damaged by this inflammatory response