Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice.

Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.

Rizoska B ，Zachrisson O ，Appelkvist P ，Boström E ，Björklund M ，Rachalski A ，Gkanatsiou E ，Kylefjord H ，Söderberg L ，Nygren P ，Eriksson F ，Ishikawa Y ，Fukushima T ，Koyama A ，Osswald G ，Lannfelt L ，Möller C ... -  《-》

The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice.

Tucker S ，Möller C ，Tegerstedt K ，Lord A ，Laudon H ，Sjödahl J ，Söderberg L ，Spens E ，Sahlin C ，Waara ER ，Satlin A ，Gellerfors P ，Osswald G ，Lannfelt L ... -  《-》

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 (Aβ) 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 Aβ protofibril conformation. The present study prepared extracts of post mortem brain samples from AD patients and non-demented elderly controls, characterized the forms of Aβ present, and investigated their interactions with lecanemab. Brain tissue samples were homogenized and extracted using tris-buffered saline. Aβ 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 Aβ (98 %) was in the insoluble extract. Aβ42 was the most abundant form present, particularly in AD subjects, and most soluble Aβ42 was in soluble aggregated protofibrillar structures. Aβ protofibril levels were much higher in AD subjects than in controls. Protofibrils captured by lecanemab-IP contained high levels of Aβ42 and lecanemab bound to large, medium, and small Aβ42 protofibrils in a concentration-dependent manner. Competitive IP showed that neither Aβ40 monomers nor Aβ40-enriched fibrils isolated from cerebral amyloid angiopathy reduced lecanemab's binding to Aβ42 protofibrils. Immunohistochemistry showed that lecanemab bound readily to Aβ plaques (diffuse and compact) and to intraneuronal Aβ in AD temporal cortex. Taken together, these findings indicate that while lecanemab binds to Aβ plaques, it preferentially targets soluble aggregated Aβ protofibrils. These are largely composed of Aβ42, and lecanemab binds less readily to the Aβ40-enriched fibrils found in the cerebral vasculature. This is a promising binding profile because Aβ42 protofibrils represent a key therapeutic target in AD, while a lack of binding to monomeric Aβ and cerebral amyloid deposits should reduce peripheral antibody sequestration and minimize risk for adverse events.

Johannesson M ，Söderberg L ，Zachrisson O ，Fritz N ，Kylefjord H ，Gkanatsiou E ，Button E ，Svensson AS ，Rachalski A ，Nygren P ，Osswald G ，Lannfelt L ，Möller C ... -  《-》

An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease.

Lord A ，Gumucio A ，Englund H ，Sehlin D ，Sundquist VS ，Söderberg L ，Möller C ，Gellerfors P ，Lannfelt L ，Pettersson FE ，Nilsson LN ... -  《-》

Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody.

Syvänen S ，Hultqvist G ，Gustavsson T ，Gumucio A ，Laudon H ，Söderberg L ，Ingelsson M ，Lannfelt L ，Sehlin D ... -  《Alzheimers Research & Therapy》