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The structure of dual-variable-domain immunoglobulin molecules alone and bound to antigen.
- Source :
-
MAbs [MAbs] 2013 May-Jun; Vol. 5 (3), pp. 364-72. Date of Electronic Publication: 2013 Apr 09. - Publication Year :
- 2013
-
Abstract
- A dual-specific, tetravalent immunoglobulin G-like molecule, termed dual variable domain immunoglobulin (DVD-Ig™), is engineered to block two targets. Flexibility modulates Fc receptor and complement binding, but could result in undesirable cross-linking of surface antigens and downstream signaling. Understanding the flexibility of parental mAbs is important for designing and retaining functionality of DVD-Ig™ molecules. The architecture and dynamics of a DVD-Ig™ molecule and its parental mAbs was examined using single particle electron microscopy. Hinge angles measured for the DVD-Ig™ molecule were similar to the inner antigen parental mAb. The outer binding domain of the DVD-Ig™ molecule was highly mobile and three-dimensional (3D) analysis showed binding of inner antigen caused the outer domain to fold out of the plane with a major morphological change. Docking high-resolution X-ray structures into the 3D electron microscopy map supports the extraordinary domain flexibility observed in the DVD-Ig™ molecule allowing antigen binding with minimal steric hindrance.
- Subjects :
- Antibodies, Monoclonal therapeutic use
Antigens immunology
Crystallography, X-Ray
Humans
Interleukin-12 chemistry
Interleukin-12 immunology
Interleukin-18 chemistry
Interleukin-18 immunology
Microscopy, Electron, Transmission
Protein Binding
Protein Engineering methods
Protein Structure, Tertiary
Antibodies, Bispecific chemistry
Antibodies, Monoclonal chemistry
Immunoglobulin G chemistry
Immunoglobulin Variable Region chemistry
Immunotherapy
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0870
- Volume :
- 5
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- MAbs
- Publication Type :
- Academic Journal
- Accession number :
- 23572180
- Full Text :
- https://doi.org/10.4161/mabs.24258