Synthetic Antibody-Rhamnose Cluster Conjugates Show Potent Complement-Dependent Cell Killing by Recruiting Natural Antibodies.
Synthetic Antibody-Rhamnose Cluster Conjugates Show Potent Complement-Dependent Cell Killing by Recruiting Natural Antibodies.
复制标题
DOI：
10.1002/chem.202200146
复制
发表时间：
2022-03-16
期刊：
影响因子：
--
通讯作者：
Wang LX
中科院分区：
文献类型：
--
作者：
Ou C;Prabhu SK;Zhang X;Zong G;Yang Q;Wang LX
单克隆抗体 (mAb) 是用于治疗癌症、传染病和自身免疫性疾病的增长最快的药物类别之一。补体依赖性细胞毒性（CDC）是抗体消耗靶细胞的效应功能之一。我们在这里报告了一种结构明确的单克隆抗体与鼠李糖和αGal三糖簇的缀合物的有效化学酶合成，以分别招募天然抗鼠李糖和抗αGal抗体，以增强CDC依赖性靶向细胞杀伤。该合成是通过使用模块化抗体 Fc-聚糖重构方法实现的，该方法包括位点特异性化学酶 Fc-聚糖功能化以及随后合成鼠李糖和 αGal 三糖簇的点击缀合，以提供各自的均质抗体缀合物。基于细胞的测定表明，抗体-鼠李糖簇缀合物可以介导有效的 CDC 活性，从而靶向杀死癌细胞，并且比抗体-αGal 三糖簇缀合物对 CDC 作用表现出更有效的功效。描述了均质抗体-鼠李糖和抗体-αGal 簇缀合物的高效化学酶合成。该合成是通过模块化抗体 Fc-聚糖重构实现的，其中包括位点特异性化学酶 Fc-聚糖功能化以及随后合成鼠李糖和 αGal 三糖簇的点击缀合。基于细胞的比较分析表明，抗体-鼠李糖簇缀合物通过招募天然抗鼠李糖抗体，表现出有效的补体依赖性靶向癌细胞杀伤作用。
Monoclonal antibodies (mAbs) are one of the most rapidly growing drug classes used for the treatment of cancer, infectious and autoimmune diseases. Complement-dependent cytotoxicity (CDC) is one of the effector functions for antibodies to deplete target cells. We report here an efficient chemoenzymatic synthesis of structurally well-defined conjugates of a monoclonal antibody with a rhamnose- and an αGal trisaccharide-cluster to recruit natural anti-rhamnose and anti-αGal antibodies, respectively, to enhance the CDC-dependent targeted cell killing. The synthesis was achieved by using a modular antibody Fc-glycan remodeling method that includes site-specific chemoenzymatic Fc-glycan functionalization and subsequent click conjugation of synthetic rhamnose- and αGal trisaccharide-cluster to provide the respective homogeneous antibody conjugates. Cell-based assays indicated that the antibody-rhamnose cluster conjugates could mediate potent CDC activity for targeted cancer cell killing and showed much more potent efficacy than the antibody-αGal trisaccharide cluster conjugates for CDC effects. A highly efficient chemoenzymatic synthesis of homogeneous antibody-rhamnose and antibody-αGal cluster conjugates is described. The synthesis was achieved through a modular antibody Fc-glycan remodeling that includes site-specific chemoenzymatic Fc-glycan functionalization and subsequent click conjugation of synthetic rhamnose- and αGal trisaccharide clusters. A comparative cell-based assay indicated that the antibody-rhamnose cluster conjugates showed potent complement-dependent targeted cancer cell killing by recruiting natural anti-rhamnose antibodies.
登录
查看更多内容
使用鼠李糖功能化脂质体通过天然抗碳水化合物抗体靶向肿瘤细胞
影响因子：
4
作者：
Li, Xuexia;Rao, Xiongjian;Yi, Wen
通讯作者：
Yi, Wen
影响因子：
3.2
作者：
Naicker, KP;Li, HG;Wang, LX
通讯作者：
Wang, LX
影响因子：
4.9
作者：
Elgersma, Ronald C.;Coumans, Ruud G. E.;Beusker, Patrick H.
通讯作者：
Beusker, Patrick H.
影响因子：
3.2
作者：
Owen, Robert M.;Carlson, Coby B.;Kiessling, Laura L.
通讯作者：
Kiessling, Laura L.
DOI：
10.1073/pnas.1702173114
发表时间：
2017-03-28
影响因子：
11.1
作者：
Li, Tiezheng;DiLillo, David J.;Wang, Lai-Xi
通讯作者：
Wang, Lai-Xi