Abstract
A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG(1), IgG(2a), and IgG(2b) switch variants of murine monoclonal antibody (mAb) 3E5 IgG(3) with identical V domains revealed apparent specificity differences for Cryptococcus neoformans glucuronoxylomannan (GXM). Kinetic and thermodynamic binding properties of mAbs 3E5 to a 12-mer peptide mimetic of GXM revealed differences in the affinity of these mAbs for a monovalent ligand, a result that implied that the constant (C) region affects the secondary structure of the antigen binding site, thus accounting for variations in specificity. Structural models of mAbs 3E5 suggested that isotype-related differences in binding resulted from amino acid sequence polymorphisms in the C region. This study implies that isotype switching is another mechanism for generating diversity in antigen binding and that isotype restriction of certain antibody responses may reflect structural constraints imposed by C region on V region binding. Furthermore, isotype affected the polyreactivity of V region identical antibodies, implying a role for C region in determining self-reactivity.
Highlights
MAY 4, 2007 VOLUME 282 NUMBER 18 apparent affinity through avidity effects that result from the polyvalent nature of certain immunoglobulins (Ig) classes
Ethanol and pH Affect Binding Patterns of monoclonal antibody (mAb) 3E5—Be- changes caused by the removal of solvent molecules from the cause molecular modeling predicted that there were no signif- Ag binding site and its surroundings. This could cause polar icant changes in conformation of the V region of these mAbs, groups that were exposed to become buried inside the protein we considered whether the observed residue changes in the CH changing the IgG electrostatic and hydrophobic regions and the consequent perturbations in the solvent envi- surface properties of IgGs
For isotype-switched variant Abs with identical V regions to have different thermodynamic parameters in their interaction with a peptide, one must conclude that the molecular interactions between the peptide and the Ab paratope differ depending on the constant region
Summary
MAY 4, 2007 VOLUME 282 NUMBER 18 apparent affinity through avidity effects that result from the polyvalent nature of certain immunoglobulins (Ig) classes. Effect of Antibody Subclass on the Kinetic and Equilibrium Rate Constants—SPR analysis revealed differences between the binding kinetics of the mAbs 3E5-P1 complexes that were observed throughout the temperature range studied.
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