Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain
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. Am...
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/3/1593 |
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| author | Jingyi Bai Xi Li Jun Zhao Huifang Zong Yuan Yuan Lei Wang Xiaoshuai Zhang Yong Ke Lei Han Jianrong Xu Buyong Ma Baohong Zhang Jianwei Zhu |
| author_facet | Jingyi Bai Xi Li Jun Zhao Huifang Zong Yuan Yuan Lei Wang Xiaoshuai Zhang Yong Ke Lei Han Jianrong Xu Buyong Ma Baohong Zhang Jianwei Zhu |
| author_sort | Jingyi Bai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T03:55:55Z |
| format | Article |
| id | doaj.art-bca050be09ea4cb1a19f27d75f3ab83a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T03:55:55Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bca050be09ea4cb1a19f27d75f3ab83a2024-02-09T15:13:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01253159310.3390/ijms25031593Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light ChainJingyi Bai0Xi Li1Jun Zhao2Huifang Zong3Yuan Yuan4Lei Wang5Xiaoshuai Zhang6Yong Ke7Lei Han8Jianrong Xu9Buyong Ma10Baohong Zhang11Jianwei Zhu12Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaCancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USAEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaJecho Biopharmaceutical Institute, Shanghai 200240, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai 200025, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaAmyloidosis 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.https://www.mdpi.com/1422-0067/25/3/1593β-amyloidamyloid light chainamyloidosismAbantibody design |
| spellingShingle | Jingyi Bai Xi Li Jun Zhao Huifang Zong Yuan Yuan Lei Wang Xiaoshuai Zhang Yong Ke Lei Han Jianrong Xu Buyong Ma Baohong Zhang Jianwei Zhu Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain International Journal of Molecular Sciences β-amyloid amyloid light chain amyloidosis mAb antibody design |
| title | Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain |
| title_full | Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain |
| title_fullStr | Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain |
| title_full_unstemmed | Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain |
| title_short | Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain |
| title_sort | re engineering therapeutic anti aβ monoclonal antibody to target amyloid light chain |
| topic | β-amyloid amyloid light chain amyloidosis mAb antibody design |
| url | https://www.mdpi.com/1422-0067/25/3/1593 |
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