Academic Journal
Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates
| العنوان: | Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody–Drug Conjugates |
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| المؤلفون: | Wei Shi (68167), Jianxin Zhang (303858), Liya Liu (6158897), Wanzhen Li (2256664), Zhi Liu (165121), Anni Ren (1528642), Jie Wang (16762), Caihong Tang (14049126), Yang Yang (45629), Dandan Xu (149923), Qianqian Huang (1409008), Yongqin Wang (515167), Caili Luo (14312769), Wei Huang (36889), Feng Tang (136667) |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Biochemistry, Medicine, Microbiology, Pharmacology, Biotechnology, Immunology, Cancer, Infectious Diseases, Space Science, Chemical Sciences not elsewhere classified, showed excellent hydrophilicity, ones conjugated onto, immunoglobulin class g, extra hydrophilic linkers, terminal sialic acid, drug complexes onto, hiding payload inside, terminal galactose, vivo <, therapeutic index, significantly enhance, optimal druggability, intact glycan, inadequate understanding, fc cavity, drug combinations, achieve better |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Hiding_Payload_Inside_the_IgG_Fc_Cavity_Significantly_Enhances_the_Therapeutic_Index_of_Antibody_Drug_Conjugates/21799041 |
| DOI: | 10.1021/acs.jmedchem.2c01812.s001 |
| الاتاحة: | https://doi.org/10.1021/acs.jmedchem.2c01812.s001 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.7905C160 |
| قاعدة البيانات: | BASE |
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