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Article ; Online: A novel mouse strain optimized for chronic human antibody administration.

Gupta, Aaron / Smith, Patrick / Bournazos, Stylianos / Ravetch, Jeffrey V

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 10, Page(s) e2123002119

Abstract: Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG ... ...

Abstract	Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex–mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antibodies, Monoclonal, Humanized/toxicity ; Antibody Formation/genetics ; Chronic Disease ; Humans ; Immune Tolerance ; Immunoglobulin G/administration & dosage ; Immunoglobulin G/genetics ; Immunoglobulin G/immunology ; Immunoglobulin Heavy Chains/genetics ; Melanoma, Experimental/immunology ; Melanoma, Experimental/therapy ; Mice ; Mice, Transgenic ; Models, Animal ; Purpura, Thrombocytopenic, Idiopathic/immunology ; Purpura, Thrombocytopenic, Idiopathic/therapy
Chemical Substances	Antibodies, Monoclonal, Humanized ; Immunoglobulin G ; Immunoglobulin Heavy Chains
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2123002119
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Article ; Online: The role of IgG Fc receptors in antibody-dependent enhancement.

Bournazos, Stylianos / Gupta, Aaron / Ravetch, Jeffrey V

Nature reviews. Immunology

2020 Volume 20, Issue 10, Page(s) 633–643

Abstract: Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed ... ...

Abstract	Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.
MeSH term(s)	Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/biosynthesis ; Antibodies, Neutralizing/administration & dosage ; Antibodies, Neutralizing/adverse effects ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Viral/administration & dosage ; Antibodies, Viral/adverse effects ; Antibodies, Viral/biosynthesis ; Antibody-Dependent Enhancement/drug effects ; Betacoronavirus/drug effects ; Betacoronavirus/immunology ; Betacoronavirus/pathogenicity ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Dengue/drug therapy ; Dengue/immunology ; Dengue/virology ; Dengue Virus/drug effects ; Dengue Virus/immunology ; Dengue Virus/pathogenicity ; Gene Expression Regulation ; Host-Pathogen Interactions/drug effects ; Host-Pathogen Interactions/immunology ; Humans ; Leukocytes/drug effects ; Leukocytes/immunology ; Leukocytes/virology ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/virology ; Receptors, IgG/antagonists & inhibitors ; Receptors, IgG/genetics ; Receptors, IgG/immunology ; SARS Virus/drug effects ; SARS Virus/immunology ; SARS Virus/pathogenicity ; SARS-CoV-2 ; Severe Acute Respiratory Syndrome/drug therapy ; Severe Acute Respiratory Syndrome/immunology ; Severe Acute Respiratory Syndrome/virology ; Signal Transduction ; Virus Internalization/drug effects
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral ; Receptors, IgG
Keywords	covid19
Language	English
Publishing date	2020-08-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/s41577-020-00410-0
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Zs.A 5565: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 34: Show issues

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Article: Mechanism of glycoform specificity and protection against antibody dependent enhancement by an anti-afucosylated IgG nanobody.

Gupta, Aaron / Kao, Kevin / Yamin, Rachel / Oren, Deena A / Goldgur, Yehuda / Du, Jonathan / Lollar, Pete / Sundberg, Eric J / Ravetch, Jeffrey V

bioRxiv : the preprint server for biology

2023

Abstract: Immunoglobulin G (IgG) antibodies contain a single, ... ...

Abstract	Immunoglobulin G (IgG) antibodies contain a single, complex
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.23.525277
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanism of glycoform specificity and in vivo protection by an anti-afucosylated IgG nanobody.

Gupta, Aaron / Kao, Kevin S / Yamin, Rachel / Oren, Deena A / Goldgur, Yehuda / Du, Jonathan / Lollar, Pete / Sundberg, Eric J / Ravetch, Jeffrey V

Nature communications

2023 Volume 14, Issue 1, Page(s) 2853

Abstract: Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, ... ...

Abstract	Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, thereby dictating distinct cellular responses. The variable construction of this glycan structure leads to highly-related, but non-equivalent glycoproteins known as glycoforms. We previously reported synthetic nanobodies that distinguish IgG glycoforms. Here, we present the structure of one such nanobody, X0, in complex with the Fc fragment of afucosylated IgG1. Upon binding, the elongated CDR3 loop of X0 undergoes a conformational shift to access the buried N-glycan and acts as a 'glycan sensor', forming hydrogen bonds with the afucosylated IgG N-glycan that would otherwise be sterically hindered by the presence of a core fucose residue. Based on this structure, we designed X0 fusion constructs that disrupt pathogenic afucosylated IgG1-FcγRIIIa interactions and rescue mice in a model of dengue virus infection.
MeSH term(s)	Animals ; Mice ; Immunoglobulin G ; Glycosylation ; Receptors, IgG/metabolism ; Immunoglobulin Fc Fragments/metabolism ; Polysaccharides/chemistry
Chemical Substances	Immunoglobulin G ; Receptors, IgG ; Immunoglobulin Fc Fragments ; Polysaccharides
Language	English
Publishing date	2023-05-18
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38453-1
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Article: The role of IgG Fc receptors in antibody-dependent enhancement

Bournazos, Stylianos / Gupta, Aaron / Ravetch, Jeffrey V

Nat Rev Immunol

Abstract	Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to FcÎ³ receptor (FcÎ³R)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcÎ³R-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcÎ³R engagement and review the available experimental evidence supporting the role of FcÎ³Rs in antiviral protection and pathogenesis through ADE. We explore FcÎ³R engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #711937
Database	COVID19

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Article ; Online: Synthetic nanobodies as tools to distinguish IgG Fc glycoforms.

Kao, Kevin S / Gupta, Aaron / Zong, Guanghui / Li, Chao / Kerschbaumer, Isabell / Borghi, Sara / Achkar, Jacqueline M / Bournazos, Stylianos / Wang, Lai-Xi / Ravetch, Jeffrey V

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 48, Page(s) e2212658119

Abstract: Protein glycosylation is a crucial mediator of biological functions and is tightly regulated in health and disease. However, interrogating complex protein glycoforms is challenging, as current lectin tools are limited by cross-reactivity while mass ... ...

Abstract	Protein glycosylation is a crucial mediator of biological functions and is tightly regulated in health and disease. However, interrogating complex protein glycoforms is challenging, as current lectin tools are limited by cross-reactivity while mass spectrometry typically requires biochemical purification and isolation of the target protein. Here, we describe a method to identify and characterize a class of nanobodies that can distinguish glycoforms without reactivity to off-target glycoproteins or glycans. We apply this technology to immunoglobulin G (IgG) Fc glycoforms and define nanobodies that specifically recognize either IgG lacking its core-fucose or IgG bearing terminal sialic acid residues. By adapting these tools to standard biochemical methods, we can clinically stratify dengue virus and SARS-CoV-2 infected individuals based on their IgG glycan profile, selectively disrupt IgG-Fcγ receptor binding both in vitro and in vivo, and interrogate the B cell receptor (BCR) glycan structure on living cells. Ultimately, we provide a strategy for the development of reagents to identify and manipulate IgG Fc glycoforms.
MeSH term(s)	Humans ; Immunoglobulin G/metabolism ; Single-Domain Antibodies ; SARS-CoV-2 ; COVID-19 ; Immunoglobulin Fc Fragments/metabolism ; Polysaccharides/metabolism
Chemical Substances	Immunoglobulin G ; Single-Domain Antibodies ; Immunoglobulin Fc Fragments ; Polysaccharides
Language	English
Publishing date	2022-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2212658119
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Article ; Online: Discovery of a caspase cleavage motif antibody reveals insights into noncanonical inflammasome function.

Davies, Christopher W / Stowe, Irma / Phung, Qui T / Ho, Hoangdung / Bakalarski, Corey E / Gupta, Aaron / Zhang, Yingnan / Lill, Jennie R / Payandeh, Jian / Kayagaki, Nobuhiko / Koerber, James T

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 12

Abstract: Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and ... ...

Abstract	Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and activation of the pore-forming protein gasdermin D. Caspase-1 also activates proinflammatory interleukins, IL-1β and IL-18, via proteolysis. However, compared to the well-studied apoptotic caspases, the identity of substrates and therefore biological functions of the inflammatory caspases remain limited. Here, we construct, validate, and apply an antibody toolset for direct detection of neo-C termini generated by inflammatory caspase proteolysis. By combining rabbit immune phage display with a set of degenerate and defined target peptides, we discovered two monoclonal antibodies that bind peptides with a similar degenerate recognition motif as the inflammatory caspases without recognizing the canonical apoptotic caspase recognition motif. Crystal structure analyses revealed the molecular basis of this strong yet paradoxical degenerate mode of peptide recognition. One antibody selectively immunoprecipitated cleaved forms of known and unknown inflammatory caspase substrates, allowing the identification of over 300 putative substrates of the caspase-4 noncanonical inflammasome, including caspase-7. This dataset will provide a path toward developing blood-based biomarkers of inflammasome activation. Overall, our study establishes tools to discover and detect inflammatory caspase substrates and functions, provides a workflow for designing antibody reagents to study cell signaling, and extends the growing evidence of biological cross talk between the apoptotic and inflammatory caspases.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Antibodies/chemistry ; Antibodies/metabolism ; Binding Sites ; Caspases/chemistry ; Caspases/metabolism ; Inflammasomes/metabolism ; Models, Molecular ; Peptides/chemistry ; Peptides/metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Proteolysis ; Signal Transduction ; Structure-Activity Relationship
Chemical Substances	Antibodies ; Inflammasomes ; Peptides ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2018024118
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Article ; Online: A conserved Bacteroidetes antigen induces anti-inflammatory intestinal T lymphocytes.

Science (New York, N.Y.)

2022 Volume 377, Issue 6606, Page(s) 660–666

Abstract: The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal ... ...

Abstract	The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal CD4
MeSH term(s)	Animals ; Bacteroidetes/enzymology ; Bacteroidetes/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8 Antigens/immunology ; Colitis/immunology ; Colitis/microbiology ; Disease Models, Animal ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Mice ; Mice, Inbred C57BL ; beta-N-Acetylhexosaminidases/immunology
Chemical Substances	CD8 Antigens ; beta-N-Acetylhexosaminidases (EC 3.2.1.52)
Language	English
Publishing date	2022-08-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abg5645
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 77: Show issues

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Article ; Online: Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation.

Lee, Bettina L / Stowe, Irma B / Gupta, Aaron / Kornfeld, Opher S / Roose-Girma, Merone / Anderson, Keith / Warming, Søren / Zhang, Juan / Lee, Wyne P / Kayagaki, Nobuhiko

The Journal of experimental medicine

2018 Volume 215, Issue 9, Page(s) 2279–2288

Abstract: Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, ...

Abstract	Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11-processing dead KI mice (
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/immunology ; Caspases/genetics ; Caspases/immunology ; Caspases, Initiator ; Gene Knock-In Techniques ; Gram-Negative Bacteria/immunology ; Gram-Negative Bacterial Infections/genetics ; Gram-Negative Bacterial Infections/immunology ; Gram-Negative Bacterial Infections/pathology ; Inflammasomes/genetics ; Inflammasomes/immunology ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharides/immunology ; Macrophages/immunology ; Macrophages/microbiology ; Macrophages/pathology ; Mice ; Mice, Knockout ; Phosphate-Binding Proteins ; Proteolysis
Chemical Substances	Apoptosis Regulatory Proteins ; Gsdmd protein, mouse ; Inflammasomes ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharides ; Phosphate-Binding Proteins ; Casp4 protein, mouse (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-)
Language	English
Publishing date	2018-08-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20180589
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Ua VI Zs.107: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 45: Show issues

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Article ; Online: GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes.

Aglietti, Robin A / Estevez, Alberto / Gupta, Aaron / Ramirez, Monica Gonzalez / Liu, Peter S / Kayagaki, Nobuhiko / Ciferri, Claudio / Dixit, Vishva M / Dueber, Erin C

Proceedings of the National Academy of Sciences of the United States of America

2016 Volume 113, Issue 28, Page(s) 7858–7863

Abstract: Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, a death program important for the elimination of ... ...

Abstract	Gasdermin-D (GsdmD) is a critical mediator of innate immune defense because its cleavage by the inflammatory caspases 1, 4, 5, and 11 yields an N-terminal p30 fragment that induces pyroptosis, a death program important for the elimination of intracellular bacteria. Precisely how GsdmD p30 triggers pyroptosis has not been established. Here we show that human GsdmD p30 forms functional pores within membranes. When liberated from the corresponding C-terminal GsdmD p20 fragment in the presence of liposomes, GsdmD p30 localized to the lipid bilayer, whereas p20 remained in the aqueous environment. Within liposomes, p30 existed as higher-order oligomers and formed ring-like structures that were visualized by negative stain electron microscopy. These structures appeared within minutes of GsdmD cleavage and released Ca(2+) from preloaded liposomes. Consistent with GsdmD p30 favoring association with membranes, p30 was only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharide. We found that the mouse I105N/human I104N mutation, which has been shown to prevent macrophage pyroptosis, attenuated both cell killing by p30 in a 293T transient overexpression system and membrane permeabilization in vitro, suggesting that the mutants are actually hypomorphs, but must be above certain concentration to exhibit activity. Collectively, our data suggest that GsdmD p30 kills cells by forming pores that compromise the integrity of the cell membrane.
Language	English
Publishing date	2016--12
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1607769113
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