Jakob Clarissa G, Edalji Rohinton, Judge Russell A, DiGiammarino Enrico, Li Yingchun, Gu Jijie, Ghayur Tariq
Department of Structural Biology; AbbVie Inc.; North Chicago, IL USA.
Global Protein Sciences; AbbVie Inc.; North Chicago, IL USA.
MAbs. 2013 May-Jun;5(3):358-63. doi: 10.4161/mabs.23977. Epub 2013 Apr 2.
Several bispecific antibody-based formats have been developed over the past 25 years in an effort to produce a new generation of immunotherapeutics that target two or more disease mechanisms simultaneously. One such format, the dual-variable domain immunoglobulin (DVD-Ig™), combines the target binding domains of two monoclonal antibodies via flexible naturally occurring linkers, which yields a tetravalent IgG - like molecule. We report the structure of an interleukin (IL)12-IL18 DVD-Ig™ Fab (DFab) fragment with IL18 bound to the inner variable domain (VD) that reveals the remarkable flexibility of the DVD-Ig™ molecule and how the DVD-Ig™ format can function to bind four antigens simultaneously. An understanding of how the inner variable domain retains function is of critical importance for designing DVD-Ig™ molecules, and for better understanding of the flexibility of immunoglobulin variable domains and linkers, which may aid in the design of improved bi- and multi-specific biologics in general.
在过去25年里，人们开发了几种基于双特异性抗体的形式，试图制造出新一代能同时靶向两种或更多疾病机制的免疫疗法。其中一种形式，即双可变域免疫球蛋白（DVD-Ig™），通过灵活的天然连接子将两种单克隆抗体的靶标结合域结合在一起，产生一种四价的IgG样分子。我们报道了一种白细胞介素（IL）12-IL18 DVD-Ig™ Fab（DFab）片段的结构，其中IL18与内部可变域（VD）结合，该结构揭示了DVD-Ig™分子显著的灵活性以及DVD-Ig™形式如何能够同时结合四种抗原。了解内部可变域如何保持功能对于设计DVD-Ig™分子以及更好地理解免疫球蛋白可变域和连接子的灵活性至关重要，这总体上可能有助于设计改进的双特异性和多特异性生物制剂。
