Compact Seahorse-Shaped T Cell-Activating Antibody for Cancer Therapy
Compact Seahorse-Shaped T Cell-Activating Antibody for Cancer Therapy
复制标题
DOI：
10.1002/adtp.201700031
复制
发表时间：
2018-07-01
影响因子：
4.6
通讯作者：
Umetsu, Mitsuo
中科院分区：
文献类型：
--
作者：
Fujii, Hiroto;Tanaka, Yoshikazu;Umetsu, Mitsuo
关于分层结构蛋白质的大量信息使得能够通过组装独立的功能组件模块来创建具有定制功能的新型蛋白质。在此，从可变结构域的抗原结合模块构建紧凑的T细胞活化抗体。重链美洲驼抗体（VHH）重链的单个可变结构域与抗原结合片段的人单链可变区（scFv）（设计为二聚化）的基因融合，产生了紧凑的双特异性和双价抗体（BiBian）具有海马形状的结构。BiBiBian识别癌细胞上的表皮生长因子受体（EGFR）和T细胞上的CD 3受体;这两种VHH和二聚化scFv在结构上是独立的，并且定位成使得它们容易接近每个靶标。BiBiBian与癌细胞和T细胞都有很强的粘附性，促进T细胞活化（由于二价CD 3模块），并在体外和体内诱导对肿瘤球体的显著细胞毒性。这种紧凑的结构被认为是同质的、高细胞毒性的、细菌表达的抗体的基本形式。
The vast information available on hierarchically structured proteins enables the creation of novel proteins with customized functions through the assembly of independent functional component modules. Here, a compact T cell-activating antibody is constructed from the antigen-binding modules of variable domains. Genetic fusion of a single variable domain of the heavy chain of a heavy chain llama antibody (VHH) to the human single-chain variable region of an antigen-binding fragment (scFv), which is designed to be dimerized, yields a compact bispecific and bivalent antibody (BiBian) with a seahorse-shaped structure. BiBian recognizes epidermal growth factor receptor (EGFR) on cancer cells and CD3 receptors on T cells; the two VHHs and dimerized scFv are structurally independent and positioned such that they are easily accessible to each target. BiBian adhered strongly to both cancer cells and T cells, promoted T cell activation (due to the bivalent CD3 modules), and induced dramatic cytotoxicity against tumor spheroids in vitro and in vivo. This compact structure is proposed as a fundamental format for homogeneous, highly cytotoxic, bacterially expressed antibodies.