Identification of a secondary Fc gamma RI binding site within a genetically engineered human IgG antibody.

Chappel, M. S.; Isenman, David E.; Oomen, Ray; Xu, Yuan Yuan; Klein, Michel

doi:10.1016/s0021-9258(19)74578-5

Cited by 20 publications

(1 citation statement)

References 28 publications

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“…Residues Leu234 to Gly237 have been shown to be important in IgG 1 (Lund et al, 1991) and IgG 3 (Chappel et al, 1991) binding to FcγRI and also FcγRII (Lund et al, 1991). Furthermore, residues Arg427 and Met430 identified by Presta et al (1994) lie within the "hinge-proximal bend" (FG loop), the homologous residues to which in IgG 1 and IgG 3 have been shown to be important in IgG:FcγRI interactions (Woof et al, 1986;Canfield & Morrison, 1991;Chappel et al, 1993). It appears, therefore, that IgE interacts with Fc RI through a region that is structurally homologous to a receptor binding region of IgG.…”

Section: Discussionmentioning

confidence: 99%

Participation of the N-Terminal Region of Cε3 in the Binding of Human IgE to Its High-Affinity Receptor FcεRI

et al. 1997

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The binding of immunoglobulin E (IgE) to its high-affinity receptor (FcepsilonRI) expressed on mast cells and basophils is central to the development of an allergic reaction. Previous studies have implicated the third constant domain of IgE-Fc (Cepsilon3) as the site of the interaction with FcepsilonRI. We have prepared a series of site-directed mutants of human IgE-Fc, particularly focusing on the N-terminal "linker" region and AB loop of Cepsilon3. The kinetics of binding IgE and its Fc fragments to the immobilized receptor were determined by surface plasmon resonance (SPR), and two phases of binding were observed. We identified one mutation in the N-terminal linker region, R334S, that has a dramatic effect on binding. R334S lowers the affinity of IgE-Fc for FcepsilonRI by 120-fold, principally through an increase in the dissociation rate of the slower phase of the interaction. This mutation has a similar effect in Fcepsilon3-4, a truncated form of IgE-Fc which lacks the Cepsilon2 domain pair, and thus it does not exert its effect through altering the quaternary structure of IgE-Fc, firmly implicating Arg334 as a contact residue in the complex. However R334S has no effect on the binding of FcepsilonRII (CD23), the low-affinity receptor for IgE, demonstrating the structural integrity of the mutated IgE-Fc. Circular dichroism spectroscopy and thermal stability studies further indicate that the R334S mutation does not disorder or destabilize the structure of IgE-Fc or Fcepsilon3-4. These results demonstrate the importance of the N-terminal linker region of Cepsilon3 in the interaction of IgE with FcepsilonRI.

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Section: Discussionmentioning

confidence: 99%

Participation of the N-Terminal Region of Cε3 in the Binding of Human IgE to Its High-Affinity Receptor FcεRI

et al. 1997

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Solid-phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for FcγRI

1999

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A solid phase approach has been used to synthesize a large branched disulphide peptide from IgG Fc, Ac-F-C*-A-K-V-N-N-K-D-L-P-A-P-I-E-K(Ac-E-L-L-G-G-P-S-V-F)-C*-I-NH2. This peptide combines the lower hinge region of IgG and a proximal beta-hairpin loop, both implicated in binding to Fc gammaRI. Solid phase Tl(tfa)3 cyclization of the linear branched peptide resulted in a poor yield of cyclic hinge-loop peptide (11%) most likely due to steric hindrance caused by the branch. However, if addition of the branch was preceded by solid phase Tl(tfa)3 cyclization of the loop, the yield was excellent at 75%. Cyclic hinge-loop peptide was active in displacing IgG2a from Fc gammaRI expressed on monocyte cell lines with an IC50 of 40 microM, whereas the linear form of this peptide was inactive. The Fc hinge-loop peptide demonstrates the potential for a non-mAb high affinity, immunomodulatory ligand for Fc gammaRI.

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PhysiologicIgGBiodistribution, Transport, and Clearance: Implications for Monoclonal Antibody Products

Rojko

Price‐Schiavi

2010

Pharmaceutical Sciences Encyclopedia

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Following administration, monoclonal antibodies become part of the endogenous IgG pool for distribution, transport, and clearance unless these physiologic processes are altered by antibody CDR‐epitope interactions. This article aims to provide helpful information regarding potential monoclonal antibody IgG test article (non‐CDR‐mediated) binding to specific tissues, cell types or other tissue elements, and subcellular locations following exogenous intravenous administration in animal model test systems.

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Identification of a secondary Fc gamma RI binding site within a genetically engineered human IgG antibody.

Cited by 20 publications

References 28 publications

Participation of the N-Terminal Region of Cε3 in the Binding of Human IgE to Its High-Affinity Receptor FcεRI

Participation of the N-Terminal Region of Cε3 in the Binding of Human IgE to Its High-Affinity Receptor FcεRI

Solid-phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for FcγRI

PhysiologicIgGBiodistribution, Transport, and Clearance: Implications for Monoclonal Antibody Products

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