scholarly journals Structural basis for the neutralization of MERS-CoV by a human monoclonal antibody MERS-27

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Xiaojuan Yu ◽  
Senyan Zhang ◽  
Liwei Jiang ◽  
Ye Cui ◽  
Dongxia Li ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Monoclonal Antibody ◽  
Structural Basis

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 Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope

2019 ◽  
Vol 116 (5) ◽  
pp. 1591-1596 ◽  
Author(s):  
Feng Long ◽  
Michael Doyle ◽  
Estefania Fernandez ◽  
Andrew S. Miller ◽  
Thomas Klose ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Human Monoclonal Antibody ◽  
Structural Basis ◽  
E Proteins ◽  
Fab Fragment ◽  
Cryo Electron Microscopy ◽  
E Protein ◽  
Mouse Model Of Infection

Zika virus (ZIKV) is a major human pathogen and member of the Flavivirus genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.

scholarly journals A human monoclonal antibody targeting a conserved pocket in the SARS-CoV-2 receptor-binding domain core

2020 ◽  
Author(s):  
Juliette Fedry ◽  
Daniel L. Hurdiss ◽  
Chunyan Wang ◽  
Wentao Li ◽  
Gonzalo Obal ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Receptor Binding ◽  
Human Monoclonal Antibody ◽  
Binding Domain ◽  
Structural Basis ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Hamster Model ◽  
Health Crisis

AbstractSARS-CoV-2 has caused a global outbreak of severe respiratory disease (COVID-19), leading to an unprecedented public health crisis. To date, there has been over thirty-three million diagnosed infections, and over one million deaths. No vaccine or targeted therapeutics are currently available. We previously identified a human monoclonal antibody, 47D11, capable of cross-neutralising SARS-CoV-2 and the related 2002/2003 SARS-CoV in vitro, and preventing SARS-CoV-2 induced pneumonia in a hamster model. Here we present the structural basis of its neutralization mechanism. We describe cryo-EM structures of trimeric SARS-CoV and SARS-CoV-2 spike ectodomains in complex with the 47D11 Fab. These data reveal that 47D11 binds specifically to the closed conformation of the receptor binding domain, distal to the ACE2 binding site. The CDRL3 stabilises the N343 glycan in an upright conformation, exposing a conserved and mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. Interestingly, 47D11 preferentially selects for the partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies that target the exposed receptor-binding motif. Taken together, these results expose a cryptic site of vulnerability on the SARS-CoV-2 RBD and provide a structural roadmap for the development of 47D11 as a prophylactic or post-exposure therapy for COVID-19.

COVID-19: Update on Pathogenesis and Treatment Strategies

2020 ◽  
Vol 16 (1) ◽  
pp. 1-5
Author(s):  
Rakesh K. Chauhan ◽  
Pramod K. Sharma ◽  
Shikha Srivastava
Keyword(s):  
Monoclonal Antibody ◽  
Plasma Membrane ◽  
Human Monoclonal Antibody ◽  
Cardiac Injury ◽  
Treatment Strategies ◽  
Severe Pneumonia ◽  
Ground Glass Opacity ◽  
Golgi Membrane ◽  
Virus Particles ◽  
Global Pandemic

COVID-19 (Coronavirus disease) is the most contagious virus, which has been characterized as a global pandemic by WHO. The pathological cycle of COVID-19 virus can be specified as RNAaemia, severe pneumonia, along with the Ground-glass opacity (GGO), and acute cardiac injury. The S protein of Coronavirus has been reported to be involved in the entry of the virus into the host cell, which can be accomplished by direct membrane fusion between the virus and plasma membrane. In the endoplasmic reticulum or Golgi membrane, the newly formed enveloped glycoproteins are introduced. The spread of disease occurs due to contact and droplets unleashed by the vesicles holding the virus particles combined with the plasma membrane to the virus released by the host. The present manuscript describes the pathogenesis of COVID-19 and various treatment strategies that include drugs such as chloroquine and hydroxychloroquine, an anti-malarial drug, antibodies: SARS-CoV-specific human monoclonal antibody CR3022 and plasma treatment facilitate the therapeutic effect.

scholarly journals A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma

2021 ◽  
Author(s):  
Monica Balzarotti ◽  
Massimo Magagnoli ◽  
Miguel Ángel Canales ◽  
Paolo Corradini ◽  
Carlos Grande ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Human Monoclonal Antibody ◽  
B Cell Lymphoma ◽  
Chimeric Mouse ◽  
Open Label ◽  
Large B Cell Lymphoma ◽  
Large B Cell

SummaryBackground BI 836826 is a chimeric mouse–human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.

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