Perspectives on #Monoclonal #Antibody #Therapy as Potential Therapeutic Intervention for #Coronavirus disease-19 (#COVID19) (Asian Pac J Allergy Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Asian Pac J Allergy Immunol 2020 Mar 4 [Online ahead of print]

Perspectives on Monoclonal Antibody Therapy as Potential Therapeutic Intervention for Coronavirus disease-19 (COVID-19)

Balamurugan Shanmugaraj 1 2, Konlavat Siriwattananon 1 2, Kittikhun Wangkanont 3, Waranyoo Phoolcharoen 1 2

Affiliations: 1 Research unit for Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand. 2 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 3 Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.

PMID: 32134278 DOI: 10.12932/AP-200220-0773

 

Abstract

Last decade witnessed the outbreak of many life-threatening human pathogens including Nipah, Ebola, Chikungunya, Zika, Middle East respiratory syndrome coronavirus (MERS-CoV), Severe Acute respiratory syndrome coronavirus (SARS-CoV) and more recently novel coronavirus (2019-nCoV or SARS-CoV-2). The disease condition associated with novel coronavirus, referred to as Coronavirus disease (COVID-19). The emergence of novel coronavirus in 2019 in Wuhan, China marked the third highly pathogenic coronavirus infecting humans in the 21st century. The continuing emergence of coronaviruses at regular intervals poses a significant threat to human health and economy. Ironically, even after a decade of research on coronavirus, still there are no licensed vaccines or therapeutic agents to treat coronavirus infection which highlights an urgent need to develop effective vaccines or post-exposure prophylaxis to prevent future epidemics. Several clinical, genetic and epidemiological features of COVID-19 resemble SARS-CoV infection. Hence, the research advancements on SARS-CoV treatment might help scientific community in quick understanding of this virus pathogenesis and develop effective therapeutic/prophylactic agents to treat and prevent this infection. Monoclonal antibodies represent the major class of biotherapeutics for passive immunotherapy to fight against viral infection. The therapeutic potential of monoclonal antibodies has been well recognized in the treatment of many diseases. Here, we summarize the potential monoclonal antibody based therapeutic intervention for COVID-19 by considering the existing knowledge on the neutralizing monoclonal antibodies against similar coronaviruses SARS-CoV and MERS-CoV. Further research on COVID-19 pathogenesis could identify appropriate therapeutic targets to develop specific anti-virals against this newly emerging pathogen.

Keywords: SARS-CoV-2; COVID-19; Monoclonal antibodies.

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Potent #Binding of 2019 Novel #Coronavirus #Spike Protein by a #SARS Coronavirus-Specific Human #mAb (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect, 9 (1), 382-385 Dec 2020

Potent Binding of 2019 Novel Coronavirus Spike Protein by a SARS Coronavirus-Specific Human Monoclonal Antibody

Xiaolong Tian 1, Cheng Li 1, Ailing Huang 1, Shuai Xia 1, Sicong Lu 1, Zhengli Shi 2, Lu Lu 1, Shibo Jiang 1, Zhenlin Yang 3, Yanling Wu 1, Tianlei Ying 1

Affiliations: 1 MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China. 2 CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People’s Republic of China. 3 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China.

PMID: 32065055 DOI: 10.1080/22221751.2020.1729069

 

Abstract

The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 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. These results suggest that CR3022 may have 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, implying 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.

Keywords: 2019-nCoV; ACE2; RBD; SARS-CoV; monoclonal antibody.

Keywords: SARS-CoV-2; COVID-19; Monoclonal antibodies; SARS.

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Safety, tolerability, pharmacokinetics, and #immunogenicity of a #human #mAb targeting the G glycoprotein of #henipaviruses in healthy adults… (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study

Elliott Geoffrey Playford, PhD, Trent Munro, PhD, Stephen M Mahler, PhD, Suzanne Elliott, PhD, Michael Gerometta, PhD, Kym L Hoger, BSc, Martina L Jones, PhD, Paul Griffin, MBBS, Kathleen D Lynch, MPHTM, Heidi Carroll, MBBS, Debra El Saadi, MAPH, Margaret E Gilmour, RN, Benjamin Hughes, BEng, Karen Hughes, BSc, Edwin Huang, PhD, Christopher de Bakker, PGBSc, Reuben Klein, BSc, Mark G Scher, PhD, Ina L Smith, PhD, Lin-Fa Wang, PhD, Stephen B Lambert, PhD, Dimiter S Dimitrov, PhD, Peter P Gray, PhD, Christopher C Broder, PhD

Published: February 03, 2020 / DOI: https://doi.org/10.1016/S1473-3099(19)30634-6

 

Summary

Background

The monoclonal antibody m102.4 is a potent, fully human antibody that neutralises Hendra and Nipah viruses in vitro and in vivo. We aimed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4 in healthy adults.

Methods

In this double-blind, placebo-controlled, single-centre, dose-escalation, phase 1 trial of m102.4, we randomly assigned healthy adults aged 18–50 years with a body-mass index of 18·0–35·0 kg/m 2 to one of five cohorts. A sentinel pair for each cohort was randomly assigned to either m102.4 or placebo. The remaining participants in each cohort were randomly assigned (5:1) to receive m102.4 or placebo. Cohorts 1–4 received a single intravenous infusion of m102.4 at doses of 1 mg/kg (cohort 1), 3 mg/kg (cohort 2), 10 mg/kg (cohort 3), and 20 mg/kg (cohort 4), and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg 72 h apart and were monitored for 123 days. The primary outcomes were safety and tolerability. Secondary outcomes were pharmacokinetics and immunogenicity. Analyses were completed according to protocol. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12615000395538.

Findings

Between March 27, 2015, and June 16, 2016, 40 (52%) of 77 healthy screened adults were enrolled in the study. Eight participants were assigned to each cohort (six received m102.4 and two received placebo). 86 treatment-emergent adverse events were reported, with similar rates between placebo and treatment groups. The most common treatment-related event was headache (12 [40%] of 30 participants in the combined m102.4 group, and three [30%] of ten participants in the pooled placebo group). No deaths or severe adverse events leading to study discontinuation occurred. Pharmacokinetics based on those receiving m102.4 (n=30) were linear, with a median half-life of 663·3 h (range 474·3–735·1) for cohort 1, 466·3 h (382·8–522·3) for cohort 2, 397·0 h (333·9–491·8) for cohort 3, and 466·7 h (351·0–889·6) for cohort 4. The elimination kinetics of those receiving repeated dosing (cohort 5) were similar to those of single-dose recipients (median elimination half-time 472·0 [385·6–592·0]). Anti-m102.4 antibodies were not detected at any time-point during the study.

Interpretation

Single and repeated dosing of m102.4 were well tolerated and safe, displayed linear pharmacokinetics, and showed no evidence of an immunogenic response. This study will inform future dosing regimens for m102.4 to achieve prolonged exposure for systemic efficacy to prevent and treat henipavirus infections.

Funding

Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program.

Keywords: Henipavirus; Monoclonal antibodies.

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Protective efficacy of anti-neuraminidase #monoclonal #antibodies against #H7N9 #influenza virus #infection (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect. 2020 Dec;9(1):78-87. doi: 10.1080/22221751.2019.1708214.

Protective efficacy of anti-neuraminidase monoclonal antibodies against H7N9 influenza virus infection.

Xiong FF1, Liu XY1, Gao FX1,2, Luo J1, Duan P1, Tan WS2, Chen Z1.

Author information: 1 Shanghai Institute of Biological Products, Shanghai, People’s Republic of China. 2 East China University of Science and Technology, Shanghai, People’s Republic of China.

 

Abstract

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.

KEYWORDS: H7N9 influenza virus; NA epitope; monoclonal antibodies; neuraminidase; protection

PMID: 31894728 DOI: 10.1080/22221751.2019.1708214

Keywords: Avian Influenza; H7N9; Monoclonal antibodies; Animal models.

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Protective Efficacy of #Monoclonal #Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in Rabbit Model of #Staphylococcus aureus Necrotizing #Pneumonia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia

Trang T. T. Vu, Nhu T.Q. Nguyen, Vuvi G. Tran, Emmanuelle Gras, Yanjie Mao, David H. Jung, Christine Tkaczyk, Bret R. Sellman, Binh An Diep

DOI: 10.1128/AAC.02220-19

 

ABSTRACT

Staphylococcus aureus is a major human pathogen, causing a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (mAb) neutralizing alpha-hemolysin or a broadly cross-reactive mAb that neutralize Panton-Valentine leukocidin, leukocidin ED and gamma-hemolysins HlgAB/HlgCB only conferred partial protection, whereas the combination of those two mAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 MRSA epidemic clone.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Staphylococcus aureus; Monoclonal antibodies; Animal models.

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Molecular #mechanism for #ADE of #coronavirus entry (J Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Virol. 2019 Dec 11. pii: JVI.02015-19. doi: 10.1128/JVI.02015-19. [Epub ahead of print]

Molecular mechanism for antibody-dependent enhancement of coronavirus entry.

Wan Y1, Shang J1, Sun S, Tai W2, Chen J3, Geng Q1, He L4, Chen Y4, Wu J1, Shi Z3, Zhou Y, Du L5, Li F6.

Author information: 1 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA. 2 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA. 3 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China. 4 Laboratory of infection and immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 5 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA lifang@umn.edu LDu@nybc.org. 6 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA lifang@umn.edu LDu@nybc.org.

 

Abstract

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on host cell surface and then fusing viral and host membranes. Here we investigated how a neutralizing monoclonal antibody (mAb), which targets the receptor-binding domain (RBD) of MERS coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that mAb binds to the virus-surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, mAb binds to cell-surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized mAb dosages in viral-receptor-dependent, antibody-dependent, and both-receptors-dependent entry pathways, delineating guidelines on mAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.

 

Significance

Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only sub-neutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the virus-surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG-Fc-receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.

Copyright © 2019 American Society for Microbiology.

PMID: 31826992 DOI: 10.1128/JVI.02015-19

Keywords: Coronavirus; MERS-CoV; Monoclonal antibodies; ADE.

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Mapping of a Novel #H3-Specific Broadly Neutralizing #Monoclonal #Antibody Targeting the #Hemagglutinin Globular Head Isolated from an Elite #Influenza Virus-Immunized Donor Exhibiting Serological Breadth (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

Yu Qiu, Svetlana Stegalkina, Jianxin Zhang, Ekaterina Boudanova, Anna Park, Yanfeng Zhou, Ponraj Prabakaran, Svetlana Pougatcheva, Irina V. Ustyugova, Thorsten U. Vogel, Sophia T. Mundle, Ray Oomen, Simon Delagrave, Ted M. Ross, Harry Kleanthous, Huawei Qiu

DOI: 10.1128/JVI.01035-19

 

ABSTRACT

The discovery of potent and broadly protective influenza epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains which emerged up to four years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA, and differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design.

 

Importance

Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAb) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous to protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency; while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; H3N2; Monoclonal antibodies.

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