Constant domains influence binding of mouse–human chimeric antibodies to the capsular polypeptide of<i>Bacillus anthracis</i>

Hubbard, Mark; Thorkildson, Peter; Kozel, Thomas R.; AuCoin, David P.

doi:10.4161/viru.25711

Cited by 14 publications

(16 citation statements)

References 26 publications

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“…When altering this same murine IgG3 Fc region by engineering human chimeric antibodies (chAbs), the resulting chAbs have significantly reduced binding affinities for the capsular polypeptide. 46 Together, these studies strongly support that changes in the Fc region can alter antibody-antigen interactions.…”

Section: Discussionmentioning

confidence: 67%

Contribution of murine IgG Fc regions to antibody binding to the capsule ofBurkholderia pseudomallei

et al. 2016

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Section: Discussionmentioning

confidence: 67%

Contribution of murine IgG Fc regions to antibody binding to the capsule ofBurkholderia pseudomallei

et al. 2016

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“…1). The variable domains (V H and V L ) mediate antigen binding, whereas the Fc constant domains (C H 2 and C H 3) perform effector functions (1,2). The Fc region also possesses an N-linked glycosylation site at Asn297.…”

Section: Introductionmentioning

confidence: 99%

Atomistic Modeling of Scattering Curves for Human IgG1/4 Reveals New Structure-Function Insights

Wright

Elliston

Hui

et al. 2019

Biophysical Journal

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Small angle x-ray and neutron scattering are techniques that give solution structures for large macromolecules. The creation of physically realistic atomistic models from known high-resolution structures to determine joint x-ray and neutron scattering best-fit structures offers a, to our knowledge, new method that significantly enhances the utility of scattering. To validate this approach, we determined scattering curves for two human antibody subclasses, immunoglobulin G (IgG) 1 and IgG4, on five different x-ray and neutron instruments to show that these were reproducible, then we modeled these by Monte Carlo simulations. The two antibodies have different hinge lengths that connect their antigen-binding Fab and effector-binding Fc regions. Starting from 231,492 and 190,437 acceptable conformations for IgG1 and IgG4, respectively, joint x-ray and neutron scattering curve fits gave low goodness-of-fit R factors for 28 IgG1 and 2748 IgG4 structures that satisfied the disulphide connectivity in their hinges. These joint best-fit structures showed that the best-fit IgG1 models had a greater separation between the centers of their Fab regions than those for IgG4, in agreement with their hinge lengths of 15 and 12 residues, respectively. The resulting asymmetric IgG1 solution structures resembled its crystal structure. Both symmetric and asymmetric solution structures were determined for IgG4. Docking simulations with our best-fit IgG4 structures showed greater steric clashes with its receptor to explain its weaker FcgRI receptor binding compared to our best-fit IgG1 structures with fewer clashes and stronger receptor binding. Compared to earlier approaches for fitting molecular antibody structures by solution scattering, we conclude that this joint fit approach based on x-ray and neutron scattering data, combined with Monte Carlo simulations, significantly improved our understanding of antibody solution structures. The atomistic nature of the output extended our understanding of known functional differences in Fc receptor binding between IgG1 and IgG4.

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“…43,44 The IgG subclass influences antigen binding by a bivalent antibody. [45][46][47] For example, changing the IgG subclass from IgG1 to IgG4 and adding hinge modifications resulted in enhancement of the agonistic activity of an anti-thrombopoietin-receptor antibody. 48 Similarly, the F-VIII-mimetic activity was optimal if the FIXa x FX BsAb was used as IgG4 instead of IgG2 or IgG1.…”

Section: Discussionmentioning

confidence: 99%

Influence of the bispecific antibody IgG subclass on T cell redirection

Kapelski

Cleiren

Attar

et al. 2019

mAbs

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T cell redirection mediated by bispecific antibodies (BsAbs) is a promising cancer therapy. Dual antigen binding is necessary for potent T cell redirection and is influenced by the structural characteristics of a BsAb, which are dependent on its IgG subclass. In this study, model BsAbs targeting CD19xCD3 were generated in variants of IgG1, IgG2, and IgG4 carrying Fc mutations that reduce FcγR interaction, and two chimeric IgG subclasses termed IgG1:2 and IgG4:2, in which the IgG1-or IgG4-F(ab) 2 are grafted on an IgG2 Fc. Molecules containing an IgG2 or IgG4-F(ab) 2 domain were confirmed to be the most structurally compact molecules. All BsAbs were shown to bind both of their target proteins (and corresponding cells) equally well. However, CD19xCD3 IgG2 did not bind both antigens simultaneously as measured by the absence of cellular clustering of T cells with target cells. This translated to a reduced potency of IgG2 BsAbs in T-cell redirection assays. The activity of IgG2 BsAbs was fully restored in the chimeric subclasses IgG4:2 and IgG1:2. This confirmed the major contribution of the F(ab) 2 region to the BsAb's functional activity and demonstrated that function of BsAbs can be modulated by engineering molecules combining different Fc and F(ab) 2 domains.

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Constant domains influence binding of mouse–human chimeric antibodies to the capsular polypeptide ofBacillus anthracis

Cited by 14 publications

References 26 publications

Contribution of murine IgG Fc regions to antibody binding to the capsule ofBurkholderia pseudomallei

Contribution of murine IgG Fc regions to antibody binding to the capsule ofBurkholderia pseudomallei

Atomistic Modeling of Scattering Curves for Human IgG1/4 Reveals New Structure-Function Insights

Influence of the bispecific antibody IgG subclass on T cell redirection

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