scholarly journals Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ronit Rosenfeld ◽  
Tal Noy-Porat ◽  
Adva Mechaly ◽  
Efi Makdasi ◽  
Yinon Levy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Transgenic Mice ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Human Life ◽  
Human Monoclonal Antibody ◽  
Human Monoclonal Antibodies ◽  
Mortality And Morbidity ◽  
Life Saving ◽  
Therapeutic Value

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6–9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.

scholarly journals Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody

2020 ◽  
Author(s):  
Ronit Rosenfeld ◽  
Tal Noy-Porat ◽  
Adva Mechaly ◽  
Efi Makdasi ◽  
Yinon Levy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Transgenic Mice ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Human Monoclonal Antibody ◽  
Human Monoclonal Antibodies ◽  
Mortality And Morbidity ◽  
Life Saving ◽  
Therapeutic Value

AbstractCoronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human live, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterized and further evaluated the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. 75% of the untreated mice succumbed 6-9 days post-infection while administration of the MD65 antibody as late as 3 days after exposure, rescued all infected animals. The data unprecedentedly demonstrate, the therapeutic value of human monoclonal antibodies as a life-saving treatment of severe COVID-19 infection.

scholarly journals Isolation of a human monoclonal antibody specific for the receptor binding domain of SARS-CoV-2 using a competitive phage biopanning strategy

2020 ◽  
Vol 3 (2) ◽  
pp. 95-100 ◽  
Author(s):  
Xin Zeng ◽  
Lingfang Li ◽  
Jing Lin ◽  
Xinlei Li ◽  
Bin Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Magnetic Beads ◽  
Human Monoclonal Antibody ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Antibody Library ◽  
Synthetic Antibody ◽  
Blocking Antibodies

Abstract The infection of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 200 000 deaths, but no vaccine or therapeutic monoclonal antibody is currently available. SARS-CoV-2 relies on its spike protein, in particular the receptor-binding domain (RBD), to bind human cell receptor angiotensin-converting enzyme 2 (ACE2) for viral entry, and thus targeting RBD holds the promise for preventing SARS-CoV-2 infection. In this work, a competitive biopanning strategy of a phage display antibody library was applied to screen blocking antibodies against RBD. High-affinity antibodies were enriched after the first round using a standard panning process in which RBD-His was immobilized as a bait. At the next two rounds, immobilized ACE2-Fc and free RBD-His were mixed with the enriched phage antibodies. Antibodies binding to RBD at epitopes different from ACE2-binding site were captured by the immobilized ACE2-Fc, forming a “sandwich” complex. Only antibodies competed with ACE2 can bind to the free RBD-His in the supernatant and be subsequently separated by the nickel-nitrilotriacetic acid magnetic beads. rRBD-15 from the competitive biopanning of our synthetic antibody library, Lib AB1, was produced as the full-length IgG1 format. It was proved to competitively block the binding of RBD to ACE2 and potently inhibit SARS-CoV-2 pseudovirus infection with IC50 values of 12 nM. Nevertheless, rRBD-16 from the standard biopanning can only bind to RBD in vitro, but not have the blocking or neutralization activity. Our strategy can efficiently isolate the blocking antibodies of RBD, and it would speed up the discovery of neutralizing antibodies against SARS-CoV-2.

scholarly journals Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1

2016 ◽  
Vol 90 (10) ◽  
pp. 5090-5097 ◽  
Author(s):  
William B. Messer ◽  
Boyd L. Yount ◽  
Scott R. Royal ◽  
Ruklanthi de Alwis ◽  
Douglas G. Widman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Human Monoclonal Antibody ◽  
Viral Envelope ◽  
Severe Dengue ◽  
Denv Serotypes ◽  
The Core ◽  
Antibody Epitope ◽  
Virus Serotype

ABSTRACTThe four dengue virus (DENV) serotypes, DENV1 through 4, are endemic throughout tropical and subtropical regions of the world. While first infection confers long-term protective immunity against viruses of the infecting serotype, a second infection with virus of a different serotype carries a greater risk of severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. Recent studies demonstrate that humans exposed to DENV infections develop neutralizing antibodies that bind to quaternary epitopes formed by the viral envelope (E) protein dimers or higher-order assemblies required for the formation of the icosahedral viral envelope. Here we show that the quaternary epitope target of the human DENV3-specific neutralizing monoclonal antibody (MAb) 5J7 can be partially transplanted into a DENV1 strain by changing the core residues of the epitope contained within a single monomeric E molecule. MAb 5J7 neutralized the recombinant DENV1/3 strain in cell culture and was protective in a mouse model of infection with the DENV1/3 strain. However, the 5J7 epitope was only partially recreated by transplantation of the core residues because MAb 5J7 bound and neutralized wild-type (WT) DENV3 better than the DENV1/3 recombinant. Our studies demonstrate that it is possible to transplant a large number of discontinuous residues between DENV serotypes and partially recreate a complex antibody epitope, while retaining virus viability. Further refinement of this approach may lead to new tools for measuring epitope-specific antibody responses and new vaccine platforms.IMPORTANCEDengue virus is the most important mosquito-borne pathogen of humans worldwide, with approximately one-half the world's population living in regions where dengue is endemic. Dengue immunity following infection is robust and thought to be conferred by antibodies raised against the infecting virus. However, the specific viral components that these antibodies recognize and how they neutralize the virus have been incompletely described. Here we map a region on dengue virus serotype 3 recognized by the human neutralizing antibody 5J7 and then test the functional significance of this region by transplanting it into a serotype 1 virus. Our studies demonstrate a region on dengue virus necessary for 5J7 binding and neutralization. Our work also demonstrates the technical feasibility of engineering dengue viruses to display targets of protective antibodies. This technology can be used to develop new dengue vaccines and diagnostic assays.

scholarly journals Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

2020 ◽  
Author(s):  
Xiaolong Tian ◽  
Cheng Li ◽  
Ailing Huang ◽  
Shuai Xia ◽  
Sicong Lu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Binding Site ◽  
Neutralizing Antibodies ◽  
Rapid Development ◽  
Antiviral Treatment ◽  
Human Monoclonal Antibody ◽  
Cross Reactivity ◽  
Spike Protein ◽  
The Cross ◽  
Novel Coronavirus

ABSTRACTThe newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 800 laboratory-confirmed human infections, including 25 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. Therefore, CR3022 has the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g., m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, indicating that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.

scholarly journals Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody

2021 ◽  
Author(s):  
M. Alejandra Tortorici ◽  
Nadine Czudnochowski ◽  
Tyler N Starr ◽  
Roberta Marzi ◽  
Alexandra C. Walls ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neutralizing Antibodies ◽  
Wide Spectrum ◽  
Human Monoclonal Antibody ◽  
Antigenic Site ◽  
Antigenic Drift ◽  
Structural Basis ◽  
Broadly Neutralizing Antibodies ◽  
Zoonotic Infections ◽  
Recent Emergence

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2X259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

scholarly journals Recognition of Native Hepatitis C Virus E1E2 Heterodimers by a Human Monoclonal Antibody

2003 ◽  
Vol 77 (2) ◽  
pp. 1604-1609 ◽  
Author(s):  
Laurence Cocquerel ◽  
Elizabeth R. Quinn ◽  
Mike Flint ◽  
Kenneth G. Hadlock ◽  
Steven K. H. Foung ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
High Molecular Weight ◽  
Mammalian Cells ◽  
Human Monoclonal Antibody ◽  
Human Monoclonal Antibodies ◽  
Humoral Immune ◽  
Endoplasmic Reticulum Chaperone

ABSTRACT The majority of hepatitis C virus (HCV)-infected individuals progress from acute to chronic disease, despite the presence of a strong humoral immune response to the envelope glycoproteins E1 and E2. When expressed in mammalian cells, E1 and E2 form both noncovalently linked E1E2 heterodimers, believed to be properly folded, and disulfide-linked, high-molecular-weight aggregates that are misfolded. Previously, we identified 10 human monoclonal antibodies (HMAbs) that bind E2 glycoproteins from different genotypes. Here we demonstrate that one of these HMAbs, CBH-2, is unique in its ability to distinguish between properly folded and misfolded envelope proteins. This HMAb recognizes HCV-E2 only when complexed with E1. The E1E2 complexes recognized by CBH-2 are noncovalently linked heterodimers and not misfolded disulfide-linked, high-molecular-weight aggregates. The E1E2 heterodimers seen by CBH-2 no longer associate with the endoplasmic reticulum chaperone calnexin and are likely to represent the prebudding form of the HCV virion.

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