The structure of dual-variable-domain immunoglobulin molecules alone and bound to antigen |
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Authors: | Ivan Correia Joyce Sung Randall Burton Clarissa G Jakob Bridget Carragher Tariq Ghayur Czeslaw Radziejewski |
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Institution: | 1.Protein Analytics; AbbVie Bioresearch Center; Worcester, MA USA;2.NanoImaging Services, Inc.; La Jolla, CA USA;3.Department of Structural Biology; AbbVie Laboratories; Abbott Park, IL USA;4.Biologics; AbbVie Bioresearch Center; Worcester, MA USA |
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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. |
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Keywords: | immunoglobulin bispecific antibodies transmission electron microscopy dual variable domain molecules structure crystallography |
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