scholarly journals ZRC3308 Monoclonal Antibody Cocktail Shows Protective Efficacy in Syrian Hamsters against SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2424
Author(s):  
Pragya D. Yadav ◽  
Sanjeev Kumar Mendiratta ◽  
Sreelekshmy Mohandas ◽  
Arun K. Singh ◽  
Priya Abraham ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Binding Affinities ◽  
Immune Effector ◽  
Syrian Hamsters ◽  
Effector Functions ◽  
Prophylactic Use ◽  
Antibody Cocktail

We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2, and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for prophylactic use and for therapy in early COVID-19 cases that have not progressed to severe disease.

scholarly journals ZRC3308 monoclonal antibody cocktail shows protective efficacy in Syrian hamsters against SARS-CoV-2 infection

2021 ◽  
Author(s):  
Pragya Yadav ◽  
Sanjeev Kumar Mendiratta ◽  
Sreelekshmy Mohandas ◽  
Arun K Singh ◽  
Priya Abraham ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Binding Affinities ◽  
Immune Effector ◽  
Syrian Hamsters ◽  
Effector Functions ◽  
Prophylactic Use ◽  
Antibody Cocktail

We have developed a monoclonal antibody (mAb) cocktail (ZRC-3308) comprising of ZRC3308-A7 and ZRC3308-B10 in the ratio 1:1 for COVID-19 treatment. The mAbs were designed to have reduced immune effector functions and increased circulation half-life. mAbs showed good binding affinities to non-competing epitopes on RBD of SARS-CoV-2 spike protein and were found neutralizing SARS-CoV-2 variants B.1, B.1.1.7, B.1.351, B.1.617.2 and B.1.617.2 AY.1 in vitro. The mAb cocktail demonstrated effective prophylactic and therapeutic activity against SARS-CoV-2 infection in Syrian hamsters. The antibody cocktail appears to be a promising candidate for the prophylactic use and for therapy in early COVID-19 cases which have not progressed to severe disease.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters

2020 ◽  
Author(s):  
Rebecca L. Brocato ◽  
Lucia M. Principe ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Janice A. Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
Spike Protein ◽  
Syrian Hamsters ◽  
Viral Loads ◽  
Neutralizing Monoclonal Antibody

AbstractAnimal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease.One Sentence SummaryAn antibody targeting the spike protein of SARS-CoV-2 limits infection in immunosuppressed Syrian hamster models.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Rebecca L. Brocato ◽  
Lucia M. Principe ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Janice A. Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Weight Loss ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
High Dose ◽  
Syrian Hamsters ◽  
Neutralizing Monoclonal Antibody

ABSTRACT Animal models recapitulating human COVID-19 disease, especially severe disease, are urgently needed to understand pathogenesis and to evaluate candidate vaccines and therapeutics. Here, we develop novel severe-disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than those in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and was uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2 but also play an early role in protection from acute disease. IMPORTANCE Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis.

scholarly journals Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2 Infected Syrian Hamsters

2020 ◽  
Author(s):  
Rebecca Brocato ◽  
Lucia Principe ◽  
Robert Kimi ◽  
Xiankun Zeng ◽  
Janice Williams ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Weight Loss ◽  
Animal Models ◽  
Adaptive Immunity ◽  
Protective Efficacy ◽  
Severe Disease ◽  
Clinical Signs ◽  
Syrian Hamsters ◽  
Viral Loads ◽  
Neutralizing Monoclonal Antibody

Abstract Animal models recapitulating human COVID-19 disease, especially with severe disease, are urgently needed to understand pathogenesis and evaluate candidate vaccines and therapeutics. Here, we develop novel severe disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to SARS-CoV-2 by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2, but also play an early role in protection from acute disease.

scholarly journals Protective efficacy of a SARS-CoV-2 DNA vaccine in wild-type and immunosuppressed Syrian hamsters

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rebecca L. Brocato ◽  
Steven A. Kwilas ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Lucia M. Principe ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Severe Disease ◽  
Disease Model ◽  
Wild Type ◽  
Jet Injection ◽  
Syrian Hamsters ◽  
Dna Targeting

AbstractA worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.

scholarly journals A Potent SARS-CoV-2 Neutralizing Human Monoclonal Antibody That Reduces Viral Burden and Disease Severity in Syrian Hamsters

2020 ◽  
Vol 11 ◽  
Author(s):  
Anna C. Fagre ◽  
John Manhard ◽  
Rachel Adams ◽  
Miles Eckley ◽  
Shijun Zhan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Disease Severity ◽  
Disease Burden ◽  
Human Monoclonal Antibody ◽  
Receptor Binding Domain ◽  
Yeast Display ◽  
Syrian Hamsters ◽  
Limited Efficacy ◽  
Protein Receptor

The emergence of COVID-19 has led to a pandemic that has caused millions of cases of disease, variable morbidity and hundreds of thousands of deaths. Currently, only remdesivir and dexamethasone have demonstrated limited efficacy, only slightly reducing disease burden, thus novel approaches for clinical management of COVID-19 are needed. We identified a panel of human monoclonal antibody clones from a yeast display library with specificity to the SARS-CoV-2 spike protein receptor binding domain that neutralized the virus in vitro. Administration of the lead antibody clone to Syrian hamsters challenged with SARS-CoV-2 significantly reduced viral load and histopathology score in the lungs. Moreover, the antibody interrupted monocyte infiltration into the lungs, which may have contributed to the reduction of disease severity by limiting immunopathological exacerbation. The use of this antibody could provide an important therapy for treatment of COVID-19 patients.

scholarly journals Characterization of Chimpanzee/Human Monoclonal Antibodies to Vaccinia Virus A33 Glycoprotein and Its Variola Virus Homolog In Vitro and in a Vaccinia Virus Mouse Protection Model

2007 ◽  
Vol 81 (17) ◽  
pp. 8989-8995 ◽  
Author(s):  
Zhaochun Chen ◽  
Patricia Earl ◽  
Jeffrey Americo ◽  
Inger Damon ◽  
Scott K. Smith ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Vaccinia Virus ◽  
Protective Efficacy ◽  
Variola Virus ◽  
Binding Affinities ◽  
Amino Acid Residues ◽  
C Terminus ◽  
20 Nm

ABSTRACT Three distinct chimpanzee Fabs against the A33 envelope glycoprotein of vaccinia virus were isolated and converted into complete monoclonal antibodies (MAbs) with human γ1 heavy-chain constant regions. The three MAbs (6C, 12C, and 12F) displayed high binding affinities to A33 (Kd of 0.14 nM to 20 nM) and may recognize the same epitope, which was determined to be conformational and located within amino acid residues 99 to 185 at the C terminus of A33. One or more of the MAbs were shown to reduce the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro and to more effectively protect mice when administered before or 2 days after intranasal challenge with virulent vaccinia virus than a previously isolated mouse anti-A33 MAb (1G10) or vaccinia virus immunoglobulin. The protective efficacy afforded by anti-A33 MAb was comparable to that of a previously isolated chimpanzee/human anti-B5 MAb. The combination of anti-A33 MAb and anti-B5 MAb did not synergize the protective efficacy. These chimpanzee/human anti-A33 MAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox and other orthopoxvirus diseases.

scholarly journals A potent SARS-CoV-2 neutralizing human monoclonal antibody that reduces viral burden and disease severity in Syrian hamsters

2020 ◽  
Author(s):  
Anna C. Fagre ◽  
John Manhard ◽  
Rachel Adams ◽  
Miles Eckley ◽  
Shijun Zhan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Disease Severity ◽  
Disease Burden ◽  
Human Monoclonal Antibody ◽  
Receptor Binding Domain ◽  
Yeast Display ◽  
Syrian Hamsters ◽  
Limited Efficacy ◽  
Protein Receptor

AbstractThe emergence of COVID-19 has led to a pandemic that has caused millions of cases of disease, variable morbidity and hundreds of thousands of deaths. Currently, only remdesivir and dexamethasone have demonstrated limited efficacy, only slightly reducing disease burden, thus novel approaches for clinical management of COVID-19 are needed. We identified a panel of human monoclonal antibody clones from a yeast display library with specificity to the SARS-CoV-2 spike protein receptor binding domain that neutralized the virus in vitro. Administration of the lead antibody clone to Syrian hamsters challenged with SARS-CoV-2 significantly reduced viral load and histopathology score in the lungs. Moreover, the antibody interrupted monocyte infiltration into the lungs, which may have contributed to the reduction of disease severity by limiting immunopathological exacerbation. The use of this antibody could provide an important therapy for treatment of COVID-19 patients.

scholarly journals Development of an antibody cocktail for treatment of Sudan virus infection

2020 ◽  
Vol 117 (7) ◽  
pp. 3768-3778 ◽  
Author(s):  
Andrew S. Herbert ◽  
Jeffery W. Froude ◽  
Ramon A. Ortiz ◽  
Ana I. Kuehne ◽  
Danielle E. Dorosky ◽  
...  
Keyword(s):  
Treatment Option ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Macaque Model ◽  
Mammalian Expression ◽  
Significant Difference ◽  
Antibody Cocktail

Antibody-based therapies are a promising treatment option for managing ebolavirus infections. Several Ebola virus (EBOV)-specific and, more recently, pan-ebolavirus antibody cocktails have been described. Here, we report the development and assessment of a Sudan virus (SUDV)-specific antibody cocktail. We produced a panel of SUDV glycoprotein (GP)-specific human chimeric monoclonal antibodies (mAbs) using both plant and mammalian expression systems and completed head-to-head in vitro and in vivo evaluations. Neutralizing activity, competitive binding groups, and epitope specificity of SUDV mAbs were defined before assessing protective efficacy of individual mAbs using a mouse model of SUDV infection. Of the mAbs tested, GP base-binding mAbs were more potent neutralizers and more protective than glycan cap- or mucin-like domain-binding mAbs. No significant difference was observed between plant and mammalian mAbs in any of our in vitro or in vivo evaluations. Based on in vitro and rodent testing, a combination of two SUDV-specific mAbs, one base binding (16F6) and one glycan cap binding (X10H2), was down-selected for assessment in a macaque model of SUDV infection. This cocktail, RIID F6-H2, provided protection from SUDV infection in rhesus macaques when administered at 50 mg/kg on days 4 and 6 postinfection. RIID F6-H2 is an effective postexposure SUDV therapy and provides a potential treatment option for managing human SUDV infection.

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