Fc-engineered antibodies leverage neutrophils to drive control of Mycobacterium tuberculosis
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ABSTRACT:
PROVIDER: PRJNA1129572 | ENA |
REPOSITORIES: ENA
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Project description:Novel vaccination and therapeutic strategies are urgently needed to mitigate the tuberculosis (TB) epidemic. While extensive efforts have focused on potentiating cell-mediated immunity to control Mycobacterium tuberculosis (Mtb) infection, less effort has been invested in exploiting the humoral immune system to combat Mtb. Emerging data point to a role for antibodies in microbial control of Mtb, however the precise mechanism(s) of this control remain incompletely understood. Here we took an antibody Fc-engineering approach to determine whether Fc-modifications could improve the ability of antibodies to restrict Mtb, and to define Fc-mediated mechanism(s) antibodies leverage for this restriction. Using an antibody specific to the capsular polysaccharide α-glucan, we engineer a panel of Fc variants to augment or dampen select antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole blood model of infection. Surprisingly, restrictive Fc-engineered antibodies drive Mtb control in a neutrophil, not monocyte, dependent manner. Using single cell RNA sequencing, we show that restrictive antibodies promote neutrophil survival and expression of cell intrinsic antimicrobial programs. These data provide a roadmap for exploiting Fc-engineered antibodies as a novel class of TB therapeutics able to harness the protective functions of neutrophils to achieve disease control.
2024-07-01 | GSE271079 | GEO
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2024-10-12 | PXD056766 |
Project description:This study is an open-label, Phase 1, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profiles of a novel fragment crystallizable (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody (botensilimab) monotherapy and in combination with an anti-programmed cell death protein-1 (PD-1) antibody (balstilimab), and to assess the maximum tolerated dose (MTD) in participants with advanced solid tumors. This study will also determine the recommended phase 2 dose (RP2D) of botensilimab monotherapy and in combination with balstilimab.
| 2298670 | ecrin-mdr-crc
Project description:SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.
2021-03-01 | GSE161615 | GEO
Project description:The uploaded dateset corresponds to MS1 and MS2 spectra obtained for Fc gamma receptor IIIb isolated from neutrophils of individual healthy donors. They represent NA1/NA2, NA2/NA2, NA2/NA2 allotype respectively. Based on the data, the targeted analysis of the N-glycosylation has been performed for the article: Wojcik et. al, Site-specific glycosylation mapping of Fc gamma receptor IIIb from neutrophils of individual healthy donors.
2020-08-05 | MSV000085913 | MassIVE
Project description:Chemically Engineered Antibodies for Autophagy-based Receptor Degradation
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Project description:Conjugate vaccine against typhoid fever has been shown to be safe and effective in field trials. The mechanism through which the vaccine protects remains elusive. Recent data have implicated antibody glycosylation, and specifically afucosylated antibodies, as an important factor in vaccine-induced effector function for a range of viral infections. Here, we studied IgG glycosylation after conjugate vaccine in a UK cohort, who were then challenged with virulent S.typhi, and among Nepalese children living in a typhoid endemic region. We compared vaccine-induced responses to another licensed typhoid polysaccharide vaccine and correlated these measures with antibody-dependent function to understand if a vaccine against a bacterial infection elicited similar glycosylation/function associations as has been seen for viral infections. Robust antigen-specific IgG Fc galactosylation and sialylation modifications were induced by both polysaccharide and tetanus toxoid-conjugated Salmonella Typhi vaccines in UK adults. These modifications were not able to differentiate controlled human infection model (CHIM) participants who became ill after ingestion of virulent S.typhi from those who remained well after infection. However, among those who did become ill, disease severity was associated with a distinct glycosylation profile. Interestingly, both vaccines induced vaccine-specific IgG1 antibodies that were more fucosylated than total circulating IgG1 and these were not associated with a particular functional profile. While bulk IgG glycosylation was different between Nepalese children and UK adults, vaccination with the Vi-tetanus toxoid-conjugate vaccine resulted in similar Vi-specific IgG glycosylation profiles 28 days after vaccination in both cohorts.
2024-05-30 | PXD037239 | Pride
Project description:Antibodies are central to the immune response against microbes. We have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the M protein of Streptococcus pyogenes. Here, we engineered Ab25 into the IgG2-4 subclasses. Despite reduced binding, the IgG3 version demonstrated enhanced opsonic function. Molecular dynamics (MD) simulations showed that IgG3s Fc exhibits extensive mobility in 3D space relative to the antigen due to its extended hinge region. The MD simulations also showed altered Fab-antigen interactions, in line with IgG3s diminished affinity. We explored the impact of hinge-engineering by generating a panel of IgG antibodies, IgGhxx, containing the CH1-3 domains of IgG1 and different segments of IgG3s hinge. Hinge-engineering enhanced opsonic function, with the most potent hinge having 47 amino acids. IgGh47 exceeded the parent IgG1 and, in some instances, the IgG3 version. The IgGh47 was protective against Streptococcus pyogenes in a systemic infection mouse model, contrary to parent IgG3 and IgG1. The in vitro phenotype of IgGh47 was generalizable to clinical isolates with different emm types. Finally, we generated IgGh47 versions of anti-SARS-CoV-2 mAbs, which exhibited strongly enhanced in vitro opsonic function compared to the original IgG1s. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function and how to enhance it for opsonic function.
2024-03-10 | MSV000094287 | MassIVE
Project description:Treatment of HIV infection with either anti-retroviral therapy (ART) or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ART and NAbs prevent new rounds of viral infection but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcgR) mediated effector functions, which should affect the kinetics of plasma virus decline. Here we formally test this premise in vivo by comparing the plasma virus response to a single dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic SHIV-infected rhesus macaques, there was a 21% difference in slope of plasma virus decline between wt NAb and NAb with reduced Fc function. NAb engineered to increase FcgRIII binding and improve ADCC in vitro resulted in arming of effector cells in vivo yet led to viral decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function does contribute to the overall antiviral activity, making them unique from standard ART. However, these data also show that increased FcgRIII engagement is insufficient to improve in vivo virus clearance.
2020-07-20 | GSE136938 | GEO
Project description:Geitlerinema sp. FC II strain:FC II Genome sequencing and assembly
| PRJNA399071 | ENA