The careful design of the antibody architecture is becoming more and more important, especially when the purpose is agonism. We present the design of a novel antibody format that is able to promote receptor dimerization and induce signal transduction resulting in cell proliferation. Mono-specific bivalent Y-shape IgGs made of two light chains and two heavy chains are engineered into single chain dimers of two modified heavy chains, resulting in the fixation of the two Fab fragments along the Fc dimerizing moiety. By this, an antagonist of the Her-receptor family, Trastuzumab, is re-formatted into an agonist by simply incorporating the original binding motif into a different geometrically and sterically constrained conformation. This novel format, named Contorsbody, retains antigen binding properties of the parental IgGs and can be produced by standard technologies established for recombinant IgGs. Structural analyses using molecular dynamics and electron microscopy are described to guide the initial design and to confirm the Contorsbody as a very compact molecule, respectively. Contorsbodies show increased rigidity compared to IgGs and their Fab moieties are positioned parallel and adjacent to each other. This geometry has an increased potential to trigger cell surface antigen or receptor ‘cis’-dimerization without ‘trans’-bridging of cells or mere receptor blockade.

抗体体系结构的仔细设计变得越来越重要，尤其是当目的是激动时。我们目前设计的新型抗体形式，能够促进受体二聚化并诱导信号转导导致细胞增殖。将由两条轻链和两条重链组成的单特异性二价Y形IgG工程化为两条修饰的重链的单链二聚体，从而使两个Fab片段沿着Fc二聚化部分固定。这样，通过简单地将原始结合基序并入不同的几何和空间约束构象中，将其受体家族的拮抗剂曲妥珠单抗重新格式化为激动剂。这种名为Contorsbody的新颖格式 保留亲本IgG的抗原结合特性，并且可以通过针对重组IgG建立的标准技术来生产。描述了使用分子动力学和电子显微镜进行结构分析，以指导初始设计并确认Contorsbody是非常紧凑的分子。与IgG相比，共旋体显示出更高的刚性，并且它们的Fab部分平行且彼此相邻。这种几何形状具有触发细胞表面抗原或受体“顺式”二聚化而不增加细胞“反式”桥接或仅阻断受体的潜力。与IgG相比，共旋体显示出更高的刚性，并且它们的Fab部分平行且彼此相邻。这种几何形状具有触发细胞表面抗原或受体“顺式”二聚化而不增加细胞“反式”桥接或仅阻断受体的潜力。与IgG相比，共旋体显示出更高的刚性，并且它们的Fab部分平行且彼此相邻。这种几何形状具有触发细胞表面抗原或受体“顺式”二聚化而不增加细胞“反式”桥接或仅阻断受体的潜力。