Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange

Kolfschoten, Marijn van der Neut; Schuurman, Janine; Losen, Mario; Bleeker, Wim K.; Martínez‐Martínez, Pilar; Vermeulen, Ellen; Bleker, Tamara H. den; Wiegman, Luus; Vink, Tom; Aarden, Lucien A.; Baets, Marc H. De; Winkel, Jan G. J. van de; Aalberse, Rob C.; Parren, Paul W.H.I.

doi:10.1126/science.1144603

Cited by 856 publications

(752 citation statements)

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“…The elevated serum IgG4 concentration and tissue infiltration of IgG4-positive plasma cells are characteristic features of IgG4RD. Because IgG4 antibodies are dynamic molecules that can exchange Fab arms by swapping a heavy chain and attached light chain, IgG4 can form bi-specific antibodies, as well as functioning as a monovalent molecule [66, 67]. These properties may protect against type I allergy by inhibiting IgE functions, and may prevent type II and III allergy by blocking the Fc-mediated effector functions of IgG1 and inhibiting the formation of large immune complexes.…”

Section: Pathogenesis and Pathophysiology Of Igg4rdmentioning

confidence: 99%

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

et al. 2011

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IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.

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Section: Pathogenesis and Pathophysiology Of Igg4rdmentioning

confidence: 99%

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

et al. 2011

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“…Serum IgG4 concentrations are generally elevated in IgG4‐RD but the biological implications thereof have not been explained 3. IgG4, traditionally regarded as a regulatory antibody, has been consistently reported to be upregulated in chronic immune stimulation, as illustrated by an elevation of bee‐venom‐specific IgG4 in beekeepers 4.…”

Section: Tablementioning

confidence: 99%

Exposure to occupational antigens might predispose to IgG4‐related disease

2014

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“…IgG4 Abs, including TGN1412, engage in Fab arm-exchange in which H-L chain pairs are exchanged between molecules. Interactions in both the IgG4 core hinge sequence and the IgG4 CH3 domain are critical for this process to occur (31,32). Substitution of serine with proline at position 228, as found in IgG1 and IgG2 core hinge sequences (i.e., CPSCP to CPPCP) stabilized the inter-H chain disulfide linkage in NIB(28SA)-G4-S228P with the resulting loss of half-molecules after SDS-PAGE, as shown for other IgG4 mAbs with "wild-type" hinges (10,16,33,34).…”

Section: Responses Of Pbmcs To Nib(28sa)-g4 Nib(28sa)-g1 and Nib(28mentioning

confidence: 99%

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

Ball

Fox

Hufton

et al. 2012

The Journal of Immunology

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The unexpected outcome of the clinical trial of the superagonistic CD28 mAb TGN1412 (IgG4κ) continues to stimulate interest. We show that TGN1412 binds similarly to human and cynomolgus macaque FcγR, eliminating the possibility that differences in Fc-mediated interactions with FcγR contributed to the failure of preclinical testing in macaques to predict toxicity in humans. The influence of the Fc domain and C region structure on the in vitro functional activity of TGN1412 was investigated using F(ab′)2 and Fab fragments derived from TGN1412 recovered from the trial and recombinant TGN1412 subclass variants and mutants. Superagonistic activity, as measured by cytokine release and proliferation, was assessed by exposing PBMCs to immobilized mAbs/fragments or to aqueous mAbs/fragments in the presence of HUVEC monolayers. Removing the Fc generally curtailed or abolished PBMC activation. However, eliminating detectable FcγR-binding of the IgG4 by mutation (L235E) did not abrogate activity. Stabilizing the “wild-type” IgG4 hinge (S228P) enhanced activity without increasing FcγR binding, which could only partially be explained by inhibition of Fab arm–exchange. Subclass switching the IgG4 mAb to IgG1 decreased activity, whereas switching to IgG2 markedly increased activity. We conclude that the C region strongly influences in vitro CD28-mediated superagonistic signaling. Superagonism requires an intact Fc, as shown by the absence of activity of TGN1412 Fab and F(ab′)2 fragments, but, notably, appears to be relatively independent of FcγR-binding properties. We propose that the Fc, potentially through restricting flexibility, maintains a favorable V region conformation to allow superagonistic activity. These findings have important implications for Ab design strategies.

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Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange

Cited by 856 publications

References 21 publications

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

Exposure to occupational antigens might predispose to IgG4‐related disease

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

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