Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis against Enterotoxigenic Escherichia coli Infection

Giuntini, Stefano; Stoppato, Matteo; Sedic, Maja; Ejemel, Monir; Pondish, Jessica R.; Wisheart, Danielle; Schiller, Zachary A.; Thomas, William D.; Barry, Eileen M.; Cavacini, Lisa A.; Klempner, Mark S.; Wang, Yang

doi:10.1128/iai.00355-18

Cited by 18 publications

(19 citation statements)

References 34 publications

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“…The vector was transformed in NEB5-α competent cells, and sequences were verified ahead of transient transfection. IgG and IgA1 antibodies were transfected in Expi293 cells and purified as previously described 32 . For dimeric IgA (dIgA), the heavy and light chain vectors were cotransfected with pcDNA-containing DNA for the connecting J chain.…”

Section: Methodsmentioning

confidence: 99%

IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

Ejemel¹,

Qi²,

Hou

et al. 2020

Preprint

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SummaryCOVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal immunity or as a therapeutic has yet been developed to SARS-CoV-2. In this study we discover and characterize a cross-reactive human IgA monoclonal antibody, MAb362. MAb362 binds to both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks hACE2 receptor binding, by completely overlapping the hACE2 structural binding epitope. Furthermore, MAb362 IgA neutralizes both pseudotyped SARS-CoV and SARS-CoV-2 in human epithelial cells expressing hACE2. SARS-CoV-2 specific IgA antibodies, such as MAb362, may provide effective immunity against SARS-CoV-2 by inducing mucosal immunity within the respiratory system, a potentially critical feature of an effective vaccine.

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Section: Methodsmentioning

confidence: 99%

IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

Ejemel¹,

Qi²,

Hou

et al. 2020

Preprint

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“…In clinical trials, ingestion of bovine milk-or colostrum-derived immunoglobulins consisting mainly of IgG from immunized dairy cows is sufficient to significantly reduce ETEC infection in adult volunteers [7,35], indicating a role for IgG in passive oral immunizations. In fact, in a recent report, orally delivered anti-colonization factor antigen CFA/I IgG and SIgA human mAbs were equally effective at blocking ETEC infection in a mouse model [9].…”

Section: Potential Of Orally Administered Sal4 Igg To Passively Immunmentioning

confidence: 97%

“…Sears and colleagues recently presented evidence that IgG and possibly IgA antibodies in Travelan and a related HBC product (IMM-24E) may exert their protective effects through arresting ETEC motility and complement-mediated killing [8]. More recently, Guintini and colleagues demonstrated that oral administration of IgG or IgA mAbs targeting a single adhesin (CfaE) were able to reduce ETEC colonization by several orders of magnitude in a mouse model [9]. In the case of invasive Salmonella enterica serovar Typhimurium (STm), Corthésy and colleagues reported that polyreactive secretory-like IgA/ IgM mixtures were capable of reducing bacterial entry into Peyer's patch tissues [10,11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of invasive salmonella by orally administered IgA and IgG monoclonal antibodies

et al. 2020

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Non-typhoidal Salmonella enterica strains, including serovar Typhimurium (STm), are an emerging cause of invasive disease among children and the immunocompromised, especially in regions of sub-Saharan Africa. STm invades the intestinal mucosa through Peyer's patch tissues before disseminating systemically. While vaccine development efforts are ongoing, the emergence of multidrug resistant strains of STm affirms the need to seek alternative strategies to protect high-risk individuals from infection. In this report, we investigated the potential of an orally administered O5 serotype-specific IgA monoclonal antibody (mAb), called Sal4, to prevent infection of invasive Salmonella enterica serovar Typhimurium (STm) in mice. Sal4 IgA was delivered to mice prior to or concurrently with STm challenge. Infectivity was measured as bacterial burden in Peyer's patch tissues one day after challenge. Using this model, we defined the minimal amount of Sal4 IgA required to significantly reduce STm uptake into Peyer's patches. The relative efficacy of Sal4 in dimeric and secretory IgA (SIgA) forms was compared. To assess the role of isotype in oral passive immunization, we engineered a recombinant IgG1 mAb carrying the Sal4 variable regions and evaluated its ability to block invasion of STm into epithelial cells in vitro and Peyer's patch tissues. Our results demonstrate the potential of orally administered monoclonal IgA and SIgA, but not IgG, to passively immunize against invasive Salmonella. Nonetheless, the prophylactic window of IgA/SIgA in the mouse was on the order of minutes, underscoring the need to develop formulations to protect mAbs in the gastric environment and to permit sustained release in the small intestine.

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“…[6][7][8][9] To further complicate these problems, enhanced antibiotic resistance has been found in many ETEC strains. [10][11][12] Thus, the development of an ETEC vaccine is considered the most effective and feasible strategy to prevent diarrheal diseases among children in developing countries 13,14 and has become a high priority for the World Health Organization. 15 Currently, however, there are no ETEC vaccines commercially available and there are numerous scientific challenges (e.g., heterogeneity of potential target antigens, 4 poor mucosal immunogenicity responses, and potential safety issues of with antigens) as well as cost hurdles (e.g., develop, manufacture, and commercialize for use in the developing world) that impede ETEC vaccine development.…”

Section: Introductionmentioning

confidence: 99%

“…For example, local delivery of antibodies that bind and neutralize ETEC in the GI tract could be used to prevent infection. Multiple virulence factors from ETEC have been recognized as potential antigens for passive immunity, 10,16 including secretion heat-labile enterotoxin (LT) that directly induces diarrhea by prompting solute retention and loss of water absorption in the intestinal lumen. LT is a heterohexameric A-B subunit toxin comprised of a catalytically active A-subunit and 5 B subunits.…”

Section: Introductionmentioning

confidence: 99%

Preformulation Characterization and Stability Assessments of Secretory IgA Monoclonal Antibodies as Potential Candidates for Passive Immunization by Oral Administration

Kumru

Xiong

et al. 2020

Journal of Pharmaceutical Sciences

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Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal disease among children in developing countries, and there are no licensed vaccines to protect against ETEC. Passive immunization by oral delivery of ETEC-specific secretory IgAs (sIgAs) could potentially provide an alternative approach for protection in targeted populations. In this study, a series of physiochemical techniques and an in vitro gastric digestion model were used to characterize and compare key structural attributes and stability profiles of 3 antieheat-labile enterotoxin mAbs (sIgA1, sIgA2, and IgG1 produced in CHO cells). The mAbs were evaluated in terms of primary structure, N-linked glycan profiles, size and aggregate content, relative apparent solubility, conformational stability, and in vitro antigen binding. Compared to IgG1 mAb, sIgA1 and sIgA2 mAbs showed increased sample heterogeneity, especially in terms of N-glycan composition and the presence of higher molecular weight species. The sIgA mAbs showed overall better physical stability and were more resistant to loss of antigen binding activity during incubation at low pH, 37 C with pepsin. These results are discussed in terms of future challenges to design stable, low-cost formulations of sIgA mAbs as an oral supplement for passive immunization to protect against enteric diseases in the developing world.

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Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis against Enterotoxigenic Escherichia coli Infection

Cited by 18 publications

References 34 publications

IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

Inhibition of invasive salmonella by orally administered IgA and IgG monoclonal antibodies

Preformulation Characterization and Stability Assessments of Secretory IgA Monoclonal Antibodies as Potential Candidates for Passive Immunization by Oral Administration

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