Influence of the Hinge Region on Complement Activation, C1q Binding, and Segmental Flexibility in Chimeric Human Immunoglobulins

We have characterized a series of genetically engineered chimeric human IgG3 and IgG4 anti-dansyl (DNS) antibodies with identical antibody-combining sites but different hinge region amino acid compositions to determine how the hinge region influences Fab fragment segmental flexibility, C1q binding,...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1990-01, Vol.87 (1), p.162-166
Main Authors: Tan, Lee K., Shopes, Robert J., Oi, Vernon T., Morrison, Sherie L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
Animals
Antibodies
Antibodies, immunoglobulins
Antigen-Antibody Complex
Binding sites
Biological and medical sciences
Cell Line
Chemical composition
Chimera
Complement activation
Complement C1q - metabolism
Disulfides
Exons
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Genetic engineering
Humans
Immunoglobulin Fab Fragments - genetics
Immunoglobulin Fab Fragments - immunology
Immunoglobulin Fab Fragments - metabolism
Immunoglobulin G - genetics
Immunoglobulin G - immunology
Immunoglobulin G - metabolism
Kinetics
Mice
Molecular chains
Molecular immunology
Molecular Sequence Data
Molecules
Protein Binding
Protein Conformation
Spectrometry, Fluorescence
Structure
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Summary:We have characterized a series of genetically engineered chimeric human IgG3 and IgG4 anti-dansyl (DNS) antibodies with identical antibody-combining sites but different hinge region amino acid compositions to determine how the hinge region influences Fab fragment segmental flexibility, C1q binding, and complement activation. Our data support the correlation between "upper hinge" length and Fab segmental flexibility; moreover, we confirm that a hinge region is essential for C1q binding and complement activation. However, the hinge length by itself is not sufficient for complement activity in IgG molecules. We have demonstrated that the IgG4 hinge, which imparts restricted segmental flexibility, reduces the ability of IgG3 molecules to activate complement. We also find that the IgG3 hinge region, which imparts greater segmental motion, is not sufficient to create complement activation activity in IgG4 anti-DNS antibodies. Finally, we conclude that (i) segmental motion is correlated with "upper hinge" length, (ii) hinge length and segmental flexibility is not enough to alter complement binding and activation, and (iii) segmental flexibility does not correlate with proficiency to activate the complement cascade.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.87.1.162