scholarly journals Recombinant neutralizing secretory IgA antibodies for preventing mucosal carriage and transmission of SARS-CoV-2

2021 ◽  
Author(s):  
Kathrin Göritzer ◽  
Elisabetta Groppelli ◽  
Clemens Grünwald-Gruber ◽  
Rudolf Figl ◽  
Fengfeng Ni ◽  
...  
Keyword(s):  
Secretory Iga ◽  
Antigen Binding ◽  
Binding Affinities ◽  
Igg Antibody ◽  
Block Transmission ◽  
Valuable Adjunct ◽  
Iga Antibodies ◽  
Severe Infections ◽  
Mucosal Secretions

Abstract Passive delivery of antibodies to mucosal sites might be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. However, monoclonal IgG antibody therapies, currently used for treatment of severe infections, are unlikely to prove useful in mucosal sites where SARS-CoV-2 resides and replicates in early infection. Here, we investigated the feasibility of producing neutralising monoclonal IgA antibodies against SARS-COV-2. We identified two class-switched mAbs that express well as monomeric and secretory IgA variants with retained antigen binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralisation activities than IgG mAbs and were able to reduce SARS-CoV-2 infection in an in vivo murine model. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.

scholarly journals Receptor-mediated Immunoglobulin G Transport Across Mucosal Barriers in Adult Life

2002 ◽  
Vol 196 (3) ◽  
pp. 303-310 ◽  
Author(s):  
Gerburg M. Spiekermann ◽  
Patricia W. Finn ◽  
E. Sally Ward ◽  
Jennifer Dumont ◽  
Bonny L. Dickinson ◽  
...  
Keyword(s):  
Immune Surveillance ◽  
Adult Life ◽  
Secretory Iga ◽  
Mouse Lung ◽  
Bronchial Epithelial ◽  
Mucosal Surfaces ◽  
Dependent Absorption ◽  
Epithelial Barriers ◽  
Mucosal Secretions

Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain the immunoglobulins (Ig)G and secretory IgA (sIgA) that function together in host defense. Exactly how IgG crosses epithelial barriers to function in mucosal immunity remains unknown. Here, we test the idea that the MHC class I–related Fc-receptor, FcRn, transports IgG across the mucosal surface of the human and mouse lung from lumen to serosa. We find that bronchial epithelial cells of the human, nonhuman primate, and mouse, express FcRn in adult-life, and demonstrate FcRn-dependent absorption of a bioactive Fc-fusion protein across the respiratory epithelium of the mouse in vivo. Thus, IgG, like dimeric IgA, can cross epithelial barriers by receptor-mediated transcytosis in adult animals. These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically.

scholarly journals Antibody in Middle Ear Fluid of Children Originates Predominantly from Sera and Nasopharyngeal Secretions

2012 ◽  
Vol 19 (10) ◽  
pp. 1593-1596 ◽  
Author(s):  
Ravinder Kaur ◽  
Thomas Kim ◽  
Janet R. Casey ◽  
Michael E. Pichichero
Keyword(s):  
Middle Ear ◽  
Acute Otitis Media ◽  
Secretory Iga ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Two Dimensional Gel Electrophoresis ◽  
Middle Ear Fluid ◽  
Iga Antibodies ◽  
Iga Antibody ◽  
Entire Array

ABSTRACTThe human middle ear is devoid of any immunocompetent cells in normal mucosa. We sought to determine the source of antibody present in the middle ear of children. Total IgG, IgA, and secretory IgA antibodies were determined by enzyme-linked immunosorbent assay from the nasopharyngeal, middle ear, and serum samples of children with acute otitis media. The two-dimensional gel electrophoresis pattern of the entire array of IgA antibodies in the nasal wash (NW) and middle ear fluid (MEF) was compared from the MEF and NW samples using isoelectric focusing and Western blotting. The total IgG and IgA antibodies in the MEF and NW samples of 137 children were compared. The ratio of IgG to IgA in the MEF was significantly different (P< 0.008) compared to NW because IgA levels were higher and IgG levels lower in NW. The IgG/IgA ratio of MEF resembled serum consistent with transudation to the MEF. Small amounts of secretory IgA were detected in MEF but the electrophoresis patterns of the entire array of IgA antibodies in the MEF and NW were virtually identical in each child evaluated; thus, IgA in MEF derived predominantly from serum and the nasopharynx by reflux via the Eustachian tube. The IgG/IgA antibody levels in the MEF and the same composition of IgA antibody in the MEF and NW identifies the predominant source of antibody in the MEF as a transudate of serum combined with nasal secretions refluxed from the nasopharynx in children.

scholarly journals Surrogate post-coital testing for contraceptive efficacy against human sperm activity in the ovine vaginal model†

2020 ◽  
Author(s):  
Yong Zhu ◽  
Jamal Saada ◽  
Shrestha Bhawana ◽  
Sam Lai ◽  
Paula Villarreal ◽  
...  
Keyword(s):  
Human Sperm ◽  
Vaginal Fluid ◽  
Human Semen ◽  
Ovine Model ◽  
Igg Antibody ◽  
Study Objective ◽  
In Vivo Testing ◽  
Efficacy Assessment ◽  
Sperm Immobilization

Abstract High unintended pregnancy rates are partially due to lack of effective nonhormonal contraceptives; development of safe, effective topical vaginal methods will address this need. Preclinical product safety and efficacy assessment requires in vivo testing in appropriate models. The sheep is a good model for the evaluation of vaginally delivered products due to its close similarities to humans. The study objective was to develop an ovine model for efficacy testing of female nonhormonal contraceptives that target human sperm. Fresh human semen was pooled from male volunteers. Nonpregnant female Merino sheep were treated with control or vaginal contraceptive product (IgG antibody with action against sperm or nonoxynol-9 [N9]). Pooled semen was added to the sheep vagina and mixed with product and vaginal secretions. Microscopic assessment of samples was performed immediately and progressive motility (PM) of sperm was compared between treatments. Cytokines CXCL8 and IL1B were assessed in vaginal fluid after instillation of human semen. No adverse reactions or elevations in proinflammatory cytokines occurred in response to human semen. N9 produced signs of acute cellular toxicity while there were no cellular changes after IgG treatment. N9 and IgG had dose-related effects with the highest dose achieving complete sperm immobilization (no sperm with PM). Surrogate post-coital testing of vaginally administered contraceptives that target human semen was developed in an ovine model established for vaginal product preclinical testing. This expanded model can aid the development of much needed nonhormonal topical vaginal contraceptives, providing opportunities for rapid iterative drug development prior to costly, time-intensive human testing.

scholarly journals Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods

2021 ◽  
Vol 22 (13) ◽  
pp. 6696
Author(s):  
Heesu Chae ◽  
Seulki Cho ◽  
Munsik Jeong ◽  
Kiyoung Kwon ◽  
Dongwook Choi ◽  
...  
Keyword(s):  
Computational Methods ◽  
Human Monoclonal Antibody ◽  
Antibody Engineering ◽  
Antigen Binding ◽  
Post Translational Modification ◽  
Biophysical Properties ◽  
Preclinical Development ◽  
Cell Bank ◽  
Aggregation Propensity

The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)—which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue—exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612.

Immunological and In-Vivo Neurological Studies on a Benzoic Acid-Specific T-Cell-Derived Antigen-Binding Molecule from the Serum of a Toluene-Sensitive Patient

2000 ◽  
Vol 55 (5) ◽  
pp. 304-318 ◽  
Author(s):  
Zeinab Khalil ◽  
George M. Georgiou ◽  
Henry Ogedegbe ◽  
Robert E. Cone ◽  
Faye Simpson ◽  
...  
Keyword(s):  
T Cell ◽  
Benzoic Acid ◽  
Antigen Binding

Differences in Level and Avidity of Secretory IgA Antibodies in Breast Milk of Swedish, Indian and Japanese Mothers to Soybean Protein

1991 ◽  
Vol 95 (1) ◽  
pp. 13-16 ◽  
Author(s):  
A. Morikawa ◽  
U. Dahlgren ◽  
B. Carlsson ◽  
I. Narayanan ◽  
M. Hahn-Zoric ◽  
...  
Keyword(s):  
Breast Milk ◽  
Soybean Protein ◽  
Secretory Iga ◽  
Iga Antibodies ◽  
Japanese Mothers

scholarly journals Upregulated Expression of Cytotoxicity-Related Genes in IFN-γKnockout Mice withSchistosoma japonicumInfection

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Xiaotang Du ◽  
Jingjiao Wu ◽  
Meijuan Zhang ◽  
Yanan Gao ◽  
Donghui Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Schistosoma Japonicum ◽  
Fas Ligand ◽  
Acute Infection ◽  
Acquired Resistance ◽  
Parasite Burden ◽  
Cytotoxic T Cell ◽  
Igg Antibody

It is well accepted that IFN-γis important to the development of acquired resistance against murine schistosomiasis. However, thein vivorole of this immunoregulatory cytokine in helminth infection needs to be further investigated. In this study, parasite burden and host immune response were observed in IFN-γknockout mice (IFNg KO) infected withSchistosoma japonicumfor 6 weeks. The results suggested that deficiency in IFN-γled to decreased egg burden in mice, with low schistosome-specific IgG antibody response and enhanced activation of T cells during acute infection. Microarray and qRT-PCR data analyses showed significant upregulation of some cytotoxicity-related genes, including those from the granzyme family, tumor necrosis factor, Fas Ligand, and chemokines, in the spleen cells of IFNg KO mice. Furthermore, CD8+cells instead of NK cells of IFNg KO mice exhibited increased transcription of cytotoxic genes compared with WT mice. Additionally,Schistosoma japonicum-specific egg antigen immunization also could activate CD8+T cells to upregulate the expression of cytotoxic genes in IFNg KO mice. Our data suggest that IFN-γis not always a positive regulator of immune responses. In certain situations, the disruption of IFN-γsignaling may up-regulate the cytotoxic T-cell-mediated immune responses to the parasite.

In Vivo Tumor Targeting of a Recombinant Single-Chain Antigen-Binding Protein

1990 ◽  
Vol 82 (14) ◽  
pp. 1191-1197 ◽  
Author(s):  
D. Colcher ◽  
R. Bird ◽  
M. Roselli ◽  
K. D. Hardman ◽  
S. Johnson ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Binding Protein ◽  
Antigen Binding ◽  
Single Chain

scholarly journals Broadly Neutralizing Hemagglutinin Stalk-Specific Antibodies Induce Potent Phagocytosis of Immune Complexes by Neutrophils in an Fc-Dependent Manner

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Caitlin E. Mullarkey ◽  
Mark J. Bailey ◽  
Diana A. Golubeva ◽  
Gene S. Tan ◽  
Raffael Nachbagauer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Fc Receptor ◽  
Igg Antibodies ◽  
Specific Antibodies ◽  
Effector Functions ◽  
Iga Antibodies ◽  
Specific Igg ◽  
Optimal Protection ◽  
Specific Igg Antibodies

ABSTRACTBroadly neutralizing antibodies that recognize the conserved hemagglutinin (HA) stalk have emerged as exciting new biotherapeutic tools to combat seasonal and pandemic influenza viruses. Our general understanding of the mechanisms by which stalk-specific antibodies achieve protection is rapidly evolving. It has recently been demonstrated that broadly neutralizing HA stalk-specific IgG antibodies require Fc-Fcγ receptor (FcγR) interactions for optimal protectionin vivo. Here we examine the neutrophil effector functions induced by stalk-specific antibodies. As the most abundant subset of blood leukocytes, neutrophils represent a critical innate effector cell population and serve an instrumental role in orchestrating downstream adaptive responses to influenza virus infection. Yet, the interplay of HA stalk-specific IgG, Fc-FcγR engagement, and neutrophils has remained largely uncharacterized. Using anin vitroassay to detect the production of reactive oxygen species (ROS), we show that human and mouse monoclonal HA stalk-specific IgG antibodies are able to induce the production of ROS by neutrophils, while HA head-specific antibodies do not. Furthermore, our results indicate that the production of ROS is dependent on Fc receptor (FcR) engagement and phagocytosis. We went on to assess the ability of monoclonal HA stalk-specific IgA antibodies to induce ROS. Consistent with our findings for monoclonal IgGs, only HA stalk-specific IgA antibodies elicited ROS production by neutrophils. This induction is dependent on the engagement of FcαR1. Taken together, our findings describe a novel FcR-dependent effector function induced by HA stalk-specific IgG and IgA antibodies, and importantly, our studies shed light on the mechanisms by which HA stalk-specific antibodies achieve protection.IMPORTANCEThe present study provides evidence that broadly neutralizing HA stalk-specific antibodies induce downstream Fc-mediated neutrophil effector functions. In addition to their ability to neutralize, this class of antibodies has been shown to rely on Fc-Fc receptor interactions for optimal protectionin vivo. Curiously, neutralizing antibodies that bind the HA head domain do not require such interactions. Our findings build on these previous observations and provide a more complete picture of the relationship between stalk-specific antibodies and cells of the innate immune compartment. Furthermore, our data suggest that the ability of HA stalk-specific antibodies to mediate Fc-Fc receptor engagement is epitope dependent. Overall, this work will inform the rational design of improved influenza virus vaccines and therapeutics.

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