Anti-Influenza Hyperimmune Immunoglobulin Enhances Fc-Functional Antibody Immunity During Human Influenza Infection

Vanderven, Hillary A.; Wragg, Kathleen; Ana-Sosa-Batiz, Fernanda; Kristensen, Anne B.; Jegaskanda, Sinthujan; Wheatley, Adam K.; Wentworth, Deborah; Wines, Bruce D.; Hogarth, P. Mark; Rockman, Steve; Kent, Stephen J.

doi:10.1093/infdis/jiy328

Cited by 8 publications

(14 citation statements)

References 40 publications

(53 reference statements)

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“…10A, 10B). We used clinically available IVIG as a positive control because IVIG is known to contain high concentrations of IgG Abs against a diverse range of influenza HAs (36).…”

Section: Resultsmentioning

confidence: 99%

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Blundell

Wilkinson

et al. 2019

The Journal of Immunology

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In therapeutic applications in which the Fc of IgG is critically important, the receptor binding and functional properties of the Fc are lost after deglycosylation or removal of the unique Asn 297 N-X-(T/S) sequon. A population of Fcs bearing sialylated glycans has been identified as contributing to this functionality, and high levels of sialylation also lead to longer serum retention times advantageous for therapy. The efficacy of sialylated Fc has generated an incentive to modify the unique N-linked glycosylation site at Asn 297 , either through chemical and enzymatic methods or by mutagenesis of the Fc, that disrupts the protein–Asn 297 carbohydrate interface. In this study, we took an alternative approach by inserting or deleting N-linked attachment sites into the body of the Fc to generate a portfolio of mutants with tailored effector functions. For example, we describe mutants with enhanced binding to low-affinity inhibitory human Fcγ and glycan receptors that may be usefully incorporated into existing Ab engineering approaches to treat or vaccinate against disease. The IgG1 Fc fragments containing complex sialylated glycans attached to the N-terminal Asn 221 sequon bound influenza virus hemagglutinin and disrupted influenza A–mediated agglutination of human erythrocytes.

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“…10A, 10B). We used clinically available IVIG as a positive control because IVIG is known to contain high concentrations of IgG Abs against a diverse range of influenza HAs (36).…”

Section: Resultsmentioning

confidence: 99%

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Blundell

Wilkinson

et al. 2019

The Journal of Immunology

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“…Here we provide evidence that anti-cluster A and anti-CoRBS Abs collaborate in engaging the dimeric form of the Fc␥RIIIa receptor when bound to the cognate epitopes within the same monomeric gp120. We utilized a novel probe, a covalent Fc␥RIIIa dimer, as a surrogate of Fc␥RIIIa present on effector cells (11,37,39,40,61) and showed that sequential binding of antibodies specific for these two CD4i epitope targets is required for effective receptor engagement and potent ADCC. Recent structural studies defined the Env epitopes recognized by anticluster A and anti-CoRBS Abs at the atomic level and mapped the cluster A epitope region to the C1-C2 regions of the gp120 inner domain in its CD4-bound conformation (12,32,33,62) and CoRBS to the bridging sheet and the base of the V3 loop of the CD4-triggered gp120 (63-65).…”

Section: Discussionmentioning

confidence: 99%

“…While it was demonstrated that anti-CoRBS Abs facilitate the binding of anti-cluster A Abs to Env (29), it is still not known whether these two families of Abs also coordinate for Fc␥R engagement. Here we took advantage of the availability of a recently characterized dimeric recombinant soluble Fc␥RIIIa protein (11,(37)(38)(39)(40) to evaluate whether these two families of anti-Env Abs coordinate for Fc␥R engagement and ADCC responses.…”

mentioning

confidence: 99%

Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells

Anand

Prévost

Baril

et al. 2019

J Virol

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HIV-1 conceals epitopes of its envelope glycoproteins (Env) recognized by antibody (Ab)-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These Abs, including anti-coreceptor binding site (CoRBS) and anti-cluster A antibodies, preferentially recognize Env in its “open” conformation. The binding of anti-CoRBS Abs has been shown to induce conformational changes that further open Env, allowing interaction of anti-cluster A antibodies. We explored the possibility that CoRBS Abs synergize with anti-cluster A Abs to engage Fc-gamma receptors to mediate ADCC. We found that binding of anti-CoRBS and anti-cluster A Abs to the same gp120 is required for interaction with soluble dimeric FcγRIIIa in enzyme-linked immunosorbent assays (ELISAs). We also found that Fc regions of both Abs are required to optimally engage FcγRIIIa and mediate robust ADCC. Taken together, our results indicate that these two families of Abs act together in a sequential and synergistic fashion to promote FcγRIIIa engagement and ADCC. IMPORTANCE The “open” CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV-positive (HIV+) sera, such as anti-coreceptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcγRIIIa and mediate ADCC.

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“…Humans who recovered from severe influenza infections (H7N9 and seasonal) had higher levels of FcγR‐binding antibodies against the homologous infecting strain and heterosubtypic influenza A viruses . Cross‐reactive ADCC‐mediating antibodies may be generated more rapidly than NAbs following natural influenza infection . As influenza is an acute infection, the early production of cross‐reactive Fc‐functional antibodies could be critically important in controlling infection prior to the generation of strain‐specific NAbs (Figure ).…”

Section: Fc‐mediated Antibody Functions In Human Influenza Vaccinatiomentioning

confidence: 99%

“…Antibody‐based therapies represent a promising treatment option for patients hospitalized with severe influenza. A small pilot study ( n = 24) showed that infusion of an influenza‐enriched IVIG (Flu‐IVIG) increased serum ADCC activity in patients with severe influenza infections . A larger clinical trial ( n = 308) carried out by the same INSIGHT group revealed that high titers of HAI antibodies in Flu‐IVIG‐infused patients were, overall, not associated with improved clinical outcomes .…”

Section: Fc‐mediated Antibody Functions In Human Influenza Vaccinatiomentioning

confidence: 99%

The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens

Vanderven

Kent

2020

Immunol Cell Biol

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In recent years, there has been a renewed interest in utilizing antibody fragment crystallizable (Fc) functions to prevent and control viral infections. The protective and therapeutic potential of Fc‐mediated antibody functions have been assessed for some clinically important human viruses, including HIV, hemorrhagic fever viruses and influenza virus. There is mounting evidence that influenza‐specific antibodies with Fc‐mediated functions, such as antibody‐dependent cellular cytotoxicity and antibody‐dependent phagocytosis, can aid in the clearance of influenza virus infection. Recent influenza challenge studies and intravenous immunoglobulin G therapy studies in humans suggest a protective role for Fc effector functions in vivo. Broadly reactive influenza antibodies with Fc‐mediated functions are prevalent in the human population and could inform the development of a universally protective influenza vaccine or therapy. In this review, we explore the utility of antibodies with Fc‐mediated effector functions against viral infections with a focus on influenza virus.

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Anti-Influenza Hyperimmune Immunoglobulin Enhances Fc-Functional Antibody Immunity During Human Influenza Infection

Cited by 8 publications

References 40 publications

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV-1-Infected Cells

The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens

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