Beta-Amyloid Peptides – the Secret Stars behind Lecanemab

The fact that Alzheimer's patients can now benefit from Lecanemab is thanks not only to the hard-working scientists in this research area but also to the beta-amyloid peptides. They played a central role in the development of Lecanemab, as it is a monoclonal antibody that specifically targets soluble oligomers and protofibrils of beta-amyloid (Aβ) – a peptide crucially involved in the progression of Alzheimer’s.

Here’s how peptides were instrumental in the development process:

1. Beta-Amyloid as Target Structure

Beta-amyloid is a peptide derived from the amyloid precursor protein (APP) through enzymatic cleavage. In Alzheimer’s disease, beta-amyloid aggregates into soluble oligomers and insoluble amyloid plaques in the brain. These aggregates are toxic to neurons and play a major role in the disease. The precise identification and characterization of different beta-amyloid species (e.g. Aβ40, Aβ42) were essential for developing therapies like Lecanemab. 

Some of the rarer mutations in the APP gene result in higher levels of soluble amyloid species and earlier onset of Alzheimer’s disease symptoms without plaque deposition. Lecanemab targets the Arctic mutation: this mutation is caused by the APParc/E693G variant of APP. [1] It leads to increased formation of large soluble oligomers, called Aβ protofibrils, while amyloid plaque levels remain low. In patients with the Arctic mutation Alzheimer's disease begins early. Patients with the Osaka mutation are carriers of the APP variant E693Delta, in which the production of Aβ oligomers is also increased and leads to the development of early dementia with minimal plaque pathology. The Icelandic A673T mutation, on the other hand, reduces Aβ monomer production by about 30% and thus decreases the risk of Alzheimer's disease fourfold.

2. Beta-Amyloid Peptides in Preclinical Studies

In preclinical research, synthetic beta-amyloid peptides were used to study the properties and aggregation mechanisms of these molecules. For example, scientists injected the synthetic peptides Aβ1-40 and Aβ1-40-Arc of the Arctic mutation intracerebroventricularly into the hippocampal CA1 subfield of rats. The result: Aβ1-40 Arc inhibited LTP (long-term potentiation, a mechanism of synaptic plasticity) about 100-fold more potently than the wild-type Aβ1-40 peptide. [2]

Synthetic beta-amyloid peptides were employed in various animal models and cell cultures to simulate the neurotoxic effects of beta-amyloid and to test potential therapeutic agents.

3. Antibody Development Through Beta-Amyloid Peptides

Peptides were used as antigen models to develop Lecanemab: Researchers utilized beta-amyloid peptides to generate and screen antibodies that preferentially bind to soluble protofibrils without targeting normal, physiological forms of beta-amyloid. This specificity was crucial to minimize potential side effects associated with the complete removal of beta-amyloid. 

Lecanemab works by binding to soluble beta-amyloid protofibrils, preventing their aggregation, and potentially reducing plaque formation and neurodegeneration. [3] The targeted mechanism was based on a deep understanding of beta-amyloid peptides’ structure and their tendency to aggregate.

4. Peptide Models in Clinical Studies

Beta-amyloid peptides were also used in the biochemical characterization and validation of the drug during preclinical and clinical studies. These models helped demonstrate Lecanemab’s binding affinity and specificity for toxic amyloid forms. [4]

Conclusion

Beta-amyloid peptides were both the target and a tool in the research that led to Lecanemab. They enabled a precise understanding of the pathological processes underlying Alzheimer’s disease and facilitated the development of a drug that selectively targets disease-relevant forms of this peptide.

Literature

1. Tolar, Martin et al. “Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression.” International journal of molecular sciences vol. 22,12 6355. 14 Jun. 2021, doi:10.3390/ijms22126355
2. Ono, Kenjiro, and Mayumi Tsuji. “Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease.” International journal of molecular sciences vol. 21,3 952. 31 Jan. 2020, doi:10.3390/ijms21030952
3. Vitek, Grace E et al. “Lecanemab (BAN2401): an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease.” Expert opinion on investigational drugs vol. 32,2 (2023): 89-94. doi:10.1080/13543784.2023.2178414
4. Söderberg, Linda et al. “Lecanemab, Aducanumab, and Gantenerumab - Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics vol. 20,1 (2023): 195-206. doi:10.1007/s13311-022-01308-6