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- Title
Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain.
- Authors
Bai, Jingyi; Li, Xi; Zhao, Jun; Zong, Huifang; Yuan, Yuan; Wang, Lei; Zhang, Xiaoshuai; Ke, Yong; Han, Lei; Xu, Jianrong; Ma, Buyong; Zhang, Baohong; Zhu, Jianwei
- 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.
- Subjects
MONOCLONAL antibodies; PEPTIDES; AMYLOID; CD20 antigen; ALZHEIMER'S disease; AMYLOID beta-protein; CYTOTOXINS
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 3, p1593
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25031593