1. Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain.
- Author
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Bai, Jingyi, Li, Xi, Zhao, Jun, Zong, Huifang, Yuan, Yuan, Wang, Lei, Zhang, Xiaoshuai, Ke, Yong, Han, Lei, Xu, Jianrong, Ma, Buyong, Zhang, Baohong, and Zhu, Jianwei
- Subjects
MONOCLONAL antibodies ,PEPTIDES ,AMYLOID ,CD20 antigen ,ALZHEIMER'S disease ,AMYLOID beta-protein ,CYTOTOXINS - Abstract
Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and β-amyloid peptide (Aβ) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aβ antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aβ42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aβ42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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