Synthesis and Evaluation of Three Azide-Modified Disaccharide Oxazolines as Enzyme Substrates for Single-Step Fc Glycan-Mediated Antibody-Drug Conjugation.
Synthesis and Evaluation of Three Azide-Modified Disaccharide Oxazolines as Enzyme Substrates for Single-Step Fc Glycan-Mediated Antibody-Drug Conjugation.
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DOI：
10.1021/acs.bioconjchem.2c00142
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发表时间：
2022-06-15
影响因子：
4.7
通讯作者：
Wang, Lai-Xi
中科院分区：
文献类型：
--
作者：
Zhang, Xiao;Ou, Chong;Liu, Huiying;Wang, Lai-Xi
抗体-药物缀合物（ADC）在靶向癌细胞杀伤方面具有很大的前景。位点特异性抗体-药物缀合对于合成具有最佳安全性特征和高功效的均质ADC是高度期望的。我们最近报道了Manβ1，4GlcNAc核心的叠氮官能化二糖恶唑啉是野生型糖苷内切酶Endo-S2用于Fc聚糖重塑和缀合的有效底物。在本文中，我们报告了作为酶底物的新二糖恶唑啉的合成和评估，以检查位点特异性缀合的范围。因此，合成了衍生自Manβ1，4GlcNAc、Glcβ1，4GlcNAc和Galβ1，4GlcNAc（LacNAc）的叠氮化物官能化二糖恶唑啉。酶促评价显示，野生型Endo-S2表现出高度松弛的底物特异性，并且可以容纳所有三种类型的二糖衍生物用于转糖基化，以提供位点特异性叠氮化物标记的抗体，其容易与有效载荷点击以产生均质ADC。此外，我们还发现Endo-S2能够容纳药物预载的最小二糖恶唑啉作为供体底物，用于有效的聚糖转移，从而实现单步和位点特异性抗体-药物缀合，而不需要抗体点击反应。Endo-S2容纳更简单和更容易合成的二糖恶唑啉衍生物用于Fc聚糖重塑的能力进一步扩展了这种生物缀合方法的范围，用于以单步方式构建均质抗体-药物缀合物。最后，基于细胞的测定表明，合成的均质ADC表现出有效的靶向癌细胞杀伤。
Antibody-drug conjugates (ADCs) hold great promise for targeted cancer cell killing. Site-specific antibody-drug conjugation is highly desirable for synthesizing homogeneous ADCs with optimal safety profiles and high efficacy. We have recently reported that azide-functionalized disaccharide oxazolines of the Manβ1,4GlcNAc core were an efficient substrate of wild-type endoglycosidase Endo-S2 for Fc glycan remodeling and conjugation. In this paper, we report the synthesis and evaluation of new disaccharide oxazolines as enzyme substrates for examining the scope of the site-specific conjugation. Thus, azide-functionalized disaccharide oxazolines derived from Manβ1,4GlcNAc, Glcβ1,4GlcNAc, and Galβ1,4GlcNAc (LacNAc) were synthesized. Enzymatic evaluation revealed that wild-type Endo-S2 demonstrated highly relaxed substrate specificity and could accommodate all the three types of disaccharide derivatives for transglycosylation to provide site-specific azide-tagged antibodies, which were readily clicked with a payload to generate homogeneous ADCs. Moreover, we also found that Endo-S2 was able to accommodate drug-preloaded minimal disaccharide oxazolines as donor substrates for efficient glycan transfer, enabling a single-step and site-specific antibody-drug conjugation without the need of an antibody click reaction. The ability of Endo-S2 to accommodate simpler and more easily synthesized disaccharide oxazoline derivatives for Fc glycan remodeling further expanded the scope of this bioconjugation method for constructing homogeneous antibody-drug conjugates in a single-step manner. Finally, cell-based assays indicated that the synthetic homogeneous ADCs demonstrated potent targeted cancer cell killing.
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通过使用基于 LacNAc 的底物重编程 IgG 糖工程一步合成位点特异性抗体-药物缀合物
影响因子：
14.5
作者：
Shi, Wei;Li, Wanzhen;Zhang, Jianxin;Li, Tiehai;Song, Yakai;Zeng, Yue;Dong, Qian;Lin, Zeng;Gong, Likun;Fan, Shuquan;Tang, Feng;Huang, Wei
通讯作者：
Huang, Wei
DOI：
10.1126/science.1236231
发表时间：
2013-07-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wang Z;Chinoy ZS;Ambre SG;Peng W;McBride R;de Vries RP;Glushka J;Paulson JC;Boons GJ
通讯作者：
Boons GJ
影响因子：
15
作者：
Zou G;Ochiai H;Huang W;Yang Q;Li C;Wang LX
通讯作者：
Wang LX
影响因子：
46.9
作者：
Shen, Ben-Quan;Xu, Keyang;Junutula, Jagath R.
通讯作者：
Junutula, Jagath R.
影响因子：
4
作者：
Zhang X;Ou C;Liu H;Prabhu SK;Li C;Yang Q;Wang LX
通讯作者：
Wang LX