Lars G. Lannfelt (Sweden)
Uppsala University
Public Health/Geriatrics
Lars Lannfelt, MD, PhD, Senior Professor, Uppsala University, Sweden A major scientific achievement was the detection of the “Swedish” mutation. This genetic mutation causes Alzheimer’s disease in a large family and leads to 3-5 times increased production of amyloid β (Aβ). Another major scientific breakthrough was the detection of the “Arctic” mutation, found in a family from northern Sweden. The pathogenic effect of the mutation was the propensity to generate soluble aggregated Aβ, protofibrils. These species of Aβ are likely to be harmful, and not only in the Arctic mutation family, but in all Alzheimer’s disease cases. This inspired me to target these toxic Aβ protofibrils with immunotherapy and we developed an antibody selective for Aβ protofibrils, mAb158. The antibody was humanized and named lecanemab (BAN2401). It is now in phase 3 clinical development. In 2003, I co-founded BioArctic, based on the discovery of the Arctic mutation. BioArctic has succeeded in signing a long-term license agreement with Eisai Pharmaceuticals of Japan on the clinical development of lecanemab. Selected Honors 2021 Rudbeck Medal for scientific discoveries 2019 Khalid Iqbql Lifetime Achievement Award in Alzheimer’s Disease Research by Alzheimer’s Association and Swedish Alzheimer’s Foundation Grand Research Prize

Presenter of 1 Presentation

 Conference Calendar

SCIENCE OF THE AMYLOID CASCADE AND DISTINCT MECHANISM OF ACTION OF LECANEMAB

Session Name
1290 - ABETA TARGETING THERAPIES IN AD 2 (ID 186)
Session Type
SYMPOSIUM
Date
Fri, 18.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE PLENARY: 115-117
Lecture Time
05:15 PM - 05:40 PM
Presenter

Abstract

Aims

Alzheimer disease (AD) is characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of tau protein. Genetic and biochemical studies point to Aβ as the starting point in the disease. There is a spectrum of aggregated Aβ species, ranging from dimers, oligomers, protofibrils and insoluble fibrillar Aβ, which exist in a complex equilibrium in the AD brain. The most toxic forms of Aβ are not the fibrils found in plaques, but rather the lower molecular weight species known as Aβ oligomers and protofibrils. The bulk of Aβ in the AD cortex is thus far less pathogenic than the smaller soluble oligomers and protofibrils. Immunotherapy against Aβ has emerged as a promising treatment for AD. mAb158, the mouse precursor antibody to lecanemab, was generated based on the Arctic mutation which causes AD due to an enhanced propensity to form protofibrils.

Methods

We review current understanding of the amyloid pathway and where lecanemab, an emerging Aβ therapy, fits into the pathway. We have examined the binding characteristics to Aβ of three antibodies, lecanemab, aducanumab and gantenerumab, by three different methods: inhibition ELISA, immunodepletion and Surface Plasmon Resonance.

Results

Data will be presented comparing the different antibodies and their affinities to different Aβ species.

Conclusions

Several clinical trials in AD with monoclonal antibodies against Aβ have failed due to lack of efficacy and/or adverse events. One explanation for these failures might be that these antibodies have been targeting non harmful forms of Aβ.

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