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Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2023, 66, 1, 1011-1026
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    Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates
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    • Wei Shi
      Wei Shi
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Wei Shi
    • Jianxin Zhang
      Jianxin Zhang
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing 210023, China
      More by Jianxin Zhang
    • Liya Liu
      Liya Liu
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
      More by Liya Liu
    • Wanzhen Li
      Wanzhen Li
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing 210023, China
      More by Wanzhen Li
    • Zhi Liu
      Zhi Liu
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing 210023, China
      More by Zhi Liu
    • Anni Ren
      Anni Ren
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Anni Ren
    • Jie Wang
      Jie Wang
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Jie Wang
    • Caihong Tang
      Caihong Tang
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      More by Caihong Tang
    • Yang Yang
      Yang Yang
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Yang Yang
    • Dandan Xu
      Dandan Xu
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Dandan Xu
    • Qianqian Huang
      Qianqian Huang
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Qianqian Huang
    • Yongqin Wang
      Yongqin Wang
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Yongqin Wang
    • Caili Luo
      Caili Luo
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      More by Caili Luo
    • Wei Huang*
      Wei Huang
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing 210023, China
      University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
      Shanghai GlycanLink Biotech. Co. Ltd. Minhang, Shanghai 201203, China
      *Email: [email protected]. Tel: +86-021-20231000-2517.
      More by Wei Huang
      Orcidhttps://orcid.org/0000-0001-6432-1848
    • Feng Tang*
      Feng Tang
      CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai 201203, China
      School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
      University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
      *Email: [email protected]. Tel: +86-021-20231000-2517.
      More by Feng Tang
      Orcidhttps://orcid.org/0000-0002-2156-7271
    Other Access OptionsSupporting Information (3)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 1, 1011–1026
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.2c01812
    Published December 30, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

    Abstract

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    Abstract Image

    The inadequate understanding of the structure–activity relationship (SAR) of glycosite-specific antibody–drug conjugates (ADCs) hinders its design and development. Herein, we revealed the systemic SAR and structure–toxicity relationship (STR) of gsADCs by constructing 50 gsADC structures bearing three glycan subtypes and diverse linker-drug combinations. According to the results, extra hydrophilic linkers are indispensable for the intact glycan-based gsADCs to achieve better in vivo efficacy. Meanwhile, the gsADCs that conjugate linker-drug complexes onto the terminal sialic acid are more stable and potent than the ones conjugated onto the terminal galactose in vivo. Notably, the LacNAc-based gsADCs, which shortened the spacer and located the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, showed excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Conclusively, we found that hiding the linker-toxin into the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, which will benefit the further design of ADCs with optimal druggability.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01812.

    • Extra schemes, figures, and tables; detailed experimental process; LC–MS profiles of the glycoengineered mAb and glycosite-specific ADCs; homogeneity analysis of gsADCs; stability analysis of gsADCs; detailed in vitro data of gsADCs; serum pharmacokinetics in rats; detailed DSF values; and detailed binding affinity of gsADCs to various Fc receptors (PDF)

    • Crystallographic data (CIF)

    • PDB files of Figure 8c,d (PDB)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

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    This article is cited by 8 publications.

    1. Yen-Pang Hsu, Omar Nourzaie, Ariel E. Tocher, Kavitha Nerella, Grigori Ermakov, Jiwon Jung, Alexandra Fowler, Peidong Wu, Umme Ayesa, Aarron Willingham, Maribel Beaumont, Sampat Ingale. Site-Specific Antibody Conjugation Using Modified Bisected N-Glycans: Method Development and Potential toward Tunable Effector Function. Bioconjugate Chemistry 2023, 34 (9) , 1633-1644. https://doi.org/10.1021/acs.bioconjchem.3c00302
    2. Caihong Tang, Yue Zeng, Jianxin Zhang, Xing Zheng, Feng Tang, Xu Yao, Zhong-Xing Jiang, Wei Shi, Wei Huang. One-Pot Assembly of Dual-Site-Specific Antibody–Drug Conjugates via Glycan Remodeling and Affinity-Directed Traceless Conjugation. Bioconjugate Chemistry 2023, 34 (4) , 748-755. https://doi.org/10.1021/acs.bioconjchem.3c00048
    3. Qiang Yang, Yunpeng Liu. Technical, preclinical, and clinical developments of Fc-glycan-specific antibody–drug conjugates. RSC Medicinal Chemistry 2025, 402 https://doi.org/10.1039/D4MD00637B
    4. Fei Xia, Zhi Liu, Jiaying Hang, Hao Xu, Yuting Xiao, Shuyue Niu, Ji Qin, Songyue Lou, Bo Liu, Feng Tang, Wei Huang, Yang Yang, Wei Shi. Harnessing acylhydrazone-oxime exchange reaction to achieve diverse synthesis of glycosite-specific antibody–drug conjugates. Organic & Biomolecular Chemistry 2025, 3 https://doi.org/10.1039/D4OB01826E
    5. Caili Luo, Anni Ren, Zixuan Jin, Jianxin Zhang, Wei Shi, Yue Zeng, Zhaojun Liu, Mengru Lu, Yajing Hou, Feng Tang, Wei Huang. Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2. Bioorganic & Medicinal Chemistry 2024, 110 , 117828. https://doi.org/10.1016/j.bmc.2024.117828
    6. Xinyu Gao, Keke Ren, Lijuan Ma, Nengzhong Wang, Nianyu Huang, Hui Yao. Highly Regio-/Stereoselective Synthesis of Carbohydrates with Unsaturated Glycosyl Donors under Mild Conditions. Synlett 2024, 52 https://doi.org/10.1055/a-2348-2803
    7. Preeti Chauhan, Ragendu V., Mohan Kumar, Rajib Molla, Surya Dev Mishra, Sneha Basa, Vishal Rai. Chemical technology principles for selective bioconjugation of proteins and antibodies. Chemical Society Reviews 2024, 53 (1) , 380-449. https://doi.org/10.1039/D3CS00715D
    8. Qiang Yang, He Chen, Chong Ou, Zhihao Zheng, Xiao Zhang, Yunpeng Liu, Guanghui Zong, Lai-Xi Wang. Evaluation of Two Chemoenzymatic Glycan Remodeling Approaches to Generate Site-Specific Antibody–Drug Conjugates. Antibodies 2023, 12 (4) , 71. https://doi.org/10.3390/antib12040071
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2023, 66, 1, 1011–1026
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.2c01812
    Published December 30, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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