A Brain-Targeting Bispecific-Multivalent Antibody Clears Soluble Amyloid-Beta Aggregates in Alzheimer's Disease Mice

Abstract

Amyloid-β (Aβ) oligomers and protofibrils are suggested to be the most neurotoxic Aβ species in Alzheimer’s disease (AD). Hence, antibodies with strong and selective binding to these soluble Aβ aggregates are of therapeutic potential. We have recently introduced HexaRmAb158, a multivalent antibody with additional Aβ-binding sites in the form of single-chain fragment variables (scFv) on the N-terminal ends of Aβ protofibril selective antibody (RmAb158). Due to the additional binding sites and the short distance between them, HexaRmAb158 displayed a slow dissociation from protofibrils and strong binding to oligomers in vitro. In the current study, we aimed at investigating the therapeutic potential of this antibody format in vivo using mouse models of AD. To enhance BBB delivery, the transferrin receptor (TfR) binding moiety (scFv8D3) was added, forming the bispecific-multivalent antibody (HexaRmAb158-scFv8D3). The new antibody displayed a weaker TfR binding compared to the previously developed RmAb158-scFv8D3 and was less efficiently transcytosed in a cell-based BBB model. HexaRmAb158 detected soluble Aβ aggregates derived from brains of tg-ArcSwe and AppNL−G−F mice more efficiently compared to RmAb158. When intravenously injected, HexaRmAb158-scFv8D3 was actively transported over the BBB into the brain in vivo. Brain uptake was marginally lower than that of RmAb158-scFv8D3, but significantly higher than observed for conventional IgG antibodies. Both antibody formats displayed similar brain retention (72 h post injection) and equal capacity in clearing soluble Aβ aggregates in tg-ArcSwe mice. In conclusion, we demonstrate a bispecific-multivalent antibody format capable of passing the BBB and targeting a wide-range of sizes of soluble Aβ aggregates.

The neuroimmune axis of Alzheimer’s disease

“…This anti-amyloid monoclonal antibody, called lecanemab, showed 27% slower progress in cognitive decline in people with early-stage AD compared to placebo, which might likely be due to its mechanism of action in targeting “protofibrils” strands at earlier stages of the disease before they consolidate into β-amyloid plaques and the length of the trial (i.e., 18 months) that allowed showing a meaningful impact on cognition. Moreover, development of bispecific antibodies by linking them to a BBB transporter moiety may facilitate BBB passing into the brain and improve antibody design, which enables targeting soluble Aβ aggregates with a wide range of sizes in a mouse model [ 313 ]. Even though the beneficial effects of Aβ immunotherapy on AD are still uncertain, increasing delivery through the BBB and enhancing antibody binding as well as selectivity to the toxic Aβ aggregates could potentially pave the way to promising therapeutic applications [ 313 ].…”

“…Moreover, development of bispecific antibodies by linking them to a BBB transporter moiety may facilitate BBB passing into the brain and improve antibody design, which enables targeting soluble Aβ aggregates with a wide range of sizes in a mouse model [ 313 ]. Even though the beneficial effects of Aβ immunotherapy on AD are still uncertain, increasing delivery through the BBB and enhancing antibody binding as well as selectivity to the toxic Aβ aggregates could potentially pave the way to promising therapeutic applications [ 313 ].…”

Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer’s disease

“…Unlike our previous results in tg-ArcSwe mice, a single injection of RmAb158-scFv8D3 did not lower soluble Aβ in App NL−G−F mice. The lack of acute treatment effect in this mouse model is likely due to the fact that, compared with tg-ArcSwe mice, the App NL−G−F brain contains low concentrations of soluble Aβ aggregates [ 41 ], which is the main target of RmAb158 and its bispecific variant. Next, we explored if acute RmAb158-scFv8D3 therapy at an early stage of Aβ deposition could remove Aβ seeds and thus postpone Aβ build-up in the brain.…”

Distinct Effects of Aducanumab and Lecanemab on Intraneuronal Endogenous Aβ42 and Phosphorylated Tau in Alzheimer’s Disease Treatment

“…While it effectively diminishes the extracellular fibrillar Aβ42 load in the brain, its impact on clinical symptoms remains limited 9 . In contrast, Lecanemab (LCN) is a subsequent FDA-approved monoclonal antibody, initially formulated to target soluble Aβ42 protofibrils [11][12][13][14] . Uniquely designed as a bispecific antibody, LCN also enhances blood-brain barrier (BBB) permeability by recognizing the transferrin receptor 14 .…”