Harnessing acylhydrazone-oxime exchange reaction to achieve diverse synthesis of glycosite-specific antibody–drug conjugates
Glycosite-specific antibody-drug conjugates (gsADCs), which carry cytotoxic payloads at the conserved <i>N</i>-glycosylation site, N297, of an IgG, have emerged as a promising ADC format with better therapeutic index. Conjugating the payloads <i>via</i> aldehyde-based chemistry is more friendly to IgGs, and has been widely investigated. However, the efficiency of introducing an aldehyde tag at the N297 site is poor due to the complicated procedures required, such as the multiple-enzyme-catalyzed IgG glycoengineering process and the successive oxidation step, which always results in heterogeneous products and poor stability. Herein, we report an efficient approach to assemble aldehyde-based gsADCs, in which the aldehyde group is first protected by hydrazine and conjugates linker-payloads <i>via</i> an acylhydrazone-oxime exchange reaction. This method exhibits remarkable coupling efficiency to various linker-payloads, and the corresponding gsADCs demonstrate good homogeneity, stability, and <i>in vitro</i> and <i>in vivo</i> efficacy.
Authors
- Yuting Xiao (ORCID: https://orcid.org/0000-0003-4056-2801)
- Feng Tang (ORCID: https://orcid.org/0000-0002-2156-7271)
- Fei Xia (ORCID: https://orcid.org/0000-0001-9458-9175)
- Weitong Huang (ORCID: https://orcid.org/0000-0001-6432-1848)
- S. Niu (ORCID: https://orcid.org/0009-0009-0652-3076)
- Jiaying Hang
- Zhi Liu (ORCID: https://orcid.org/0000-0002-1417-9852)
- Yang Yang (ORCID: https://orcid.org/0000-0003-4981-4745)
- Bo Liu (ORCID: https://orcid.org/0000-0003-0342-8144)
- Hao Xu (ORCID: https://orcid.org/0000-0002-8294-5897)
- Wei Shi (ORCID: https://orcid.org/0000-0002-9924-8756)
- Shanning Lou (ORCID: https://orcid.org/0000-0003-0562-1415)
- Ji Qin
Institutions
- Shenyang Pharmaceutical University (CN)
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- Viva Biotech (China) (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Organic & Biomolecular Chemistry
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1039/d4ob01826e
- Citations
- 2
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- National Science Fund for Distinguished Young Scholars