Trimming Crystallizable Fragment (Fc) Glycans Enables the Direct Enzymatic Transfer of Biomacromolecules to Antibodies as Therapeutics**
Yang Yang
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorZhentao Song
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
These authors contributed equally to this work.
Search for more papers by this authorDr. Tian Tian
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorZihan Zhao
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorJi Chen
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorJiangping Hu
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorXin Jiang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorGuoli Yang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorQi Xue
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorXinlu Zhao
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorDr. Wanxing Sha
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorCorresponding Author
Dr. Yi Yang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Jie P. Li
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorYang Yang
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorZhentao Song
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
These authors contributed equally to this work.
Search for more papers by this authorDr. Tian Tian
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorZihan Zhao
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorJi Chen
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorJiangping Hu
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorXin Jiang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorGuoli Yang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorQi Xue
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorXinlu Zhao
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorDr. Wanxing Sha
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorCorresponding Author
Dr. Yi Yang
Glyco therapy Biotechnology Co., Ltd., 601/606 Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha street, Qiantang Distirct, Hangzhou, Zhejiang, 310058 China
Search for more papers by this authorCorresponding Author
Prof. Dr. Jie P. Li
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023 China
Search for more papers by this authorA previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.1101/2022.09.04.506510).
Graphical Abstract
Reducing the complexity of crystallizable fragment glycans dramatically increased the efficiency of the conjugation of large payloads to antibodies via fucosyltransferase-mediated unnatural fucosylation. An anti-human epidermal growth factor receptor 2 and anti-cluster of differentiation 3 bispecific antibody was synthesized which enabled the recruitment and activation of endogenous cytolytic T lymphocyte cells for tumor killing within organoids.
Abstract
Glycoengineering has provided powerful tools to construct site-specific antibody conjugates. However, only small-molecule payloads can be directly transferred to native or engineered antibodies using existing glycoengineering strategies. Herein, we demonstrate that reducing the complexity of crystallizable fragment (Fc) glycans could dramatically boost the chemoenzymatic modification of immunoglobulin G (IgG) via an engineered fucosyltransferase. In this platform, antibodies with Fc glycans engineered to a simple N-acetyllactosamine (LacNAc) disaccharide are successfully conjugated to biomacromolecules, such as oligonucleotides and nanobodies, in a single step within hours. Accordingly, we synthesized an antibody-conjugate-based anti-human epidermal growth factor receptor 2 (HER2)/ cluster of differentiation 3 (CD3) bispecific antibody and used it to selectively destroy patient-derived cancer organoids by reactivating endogenous T lymphocyte cells (T cells) inside the organoid. Our results highlight that this platform is a general approach to construct antibody-biomacromolecule conjugates with translational values.
Conflict of interest
Competing financial interests: Relevant patent applications have been filed by Glyco-therapy Biotechnology Co., Ltd. and/or Nanjing University.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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