Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers

AbstractSARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10−14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.

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Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers

10.1101/2020.10.15.341636 ◽

2020 ◽

Author(s):

Edurne Rujas ◽

Iga Kucharska ◽

Yong Zi Tan ◽

Samir Benlekbir ◽

Hong Cui ◽

...

Keyword(s):

Inhibitory Concentration ◽

Viral Infections ◽

Antibody Fragments ◽

The Novel ◽

Viral Sequence ◽

New Class ◽

Global Pandemic ◽

Antibody Specificities ◽

Medical Countermeasures

AbstractThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), has caused a global pandemic. Antibodies are powerful biotherapeutics to fight viral infections; however, discovery of the most potent and broadly acting clones can be lengthy. Here, we used the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10−14 M were achieved as a result of up to 10,000-fold potency enhancements. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and Ig-like in vivo bioavailability. This MULTi-specific, multi-Affinity antiBODY (Multabody; or MB) platform contributes a new class of medical countermeasures against COVID-19 and an efficient approach to rapidly deploy potent and broadly-acting therapeutics against infectious diseases of global health importance.One Sentence Summarymultimerization platform transforms antibodies emerging from discovery screens into potent neutralizers that can overcome SARS-CoV-2 sequence diversity.

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Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries

10.1101/2020.06.06.137513 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yan Lou ◽

Wenxiang Zhao ◽

Haitao Wei ◽

Min Chu ◽

Ruihua Chao ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Viral Infections ◽

Therapeutic Agents ◽

Therapeutic Interventions ◽

Receptor Binding Domain ◽

Angiotensin Converting Enzyme 2 ◽

Human Antibodies ◽

Global Pandemic ◽

Antibody Libraries ◽

Cross Neutralization

AbstractThe emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.

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Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00024-15 ◽

2016 ◽

Vol 80 (4) ◽

pp. 989-1010 ◽

Cited By ~ 34

Author(s):

Laura A. VanBlargan ◽

Leslie Goo ◽

Theodore C. Pierson

Keyword(s):

Antibody Response ◽

Polyclonal Antibody ◽

Neutralizing Antibodies ◽

Viral Infections ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Distinct Structure ◽

Antibody Specificities ◽

The Individual

SUMMARYThe antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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Physical Exercise and Yoga: as an alternative approach towards COVID-19 management

Current Traditional Medicine ◽

10.2174/2215083807666210322152352 ◽

2021 ◽

Vol 07 ◽

Author(s):

Saurabh Kumar ◽

Sakshi Sudha ◽

Madhu Chopra ◽

Famida Khan ◽

Kanupriya Sharma

Keyword(s):

Physical Exercise ◽

Literature Search ◽

Viral Infections ◽

Cost Effective ◽

Mental Wellbeing ◽

World Population ◽

Cd8 Cells ◽

Global Pandemic ◽

Potential Benefits ◽

Novel Coronavirus

Background: Novel Coronavirus (COVID-19), a highly contagious ssRNA +Ve sense virus that emerged in late 2019, has created a global panic. With no effective therapy available, the virus has significantly affected the world population causing millions of death. Therefore, it is the utmost need to look towards all the possible strategies to benefit the community. Objectives: In view of the current global pandemic, we tried to discuss the potential benefits of two cost-effective alternative approaches, i.e., physical exercise and yoga. Method: The editorial is based on a literature search available on PubMed, Google Scholar, and WHO portal. Search terminologies include “yoga”, “physical exercise”, “COVID-19”, “viral infections”, and a combination of these words. Results: A literature search defines yoga and physical exercise efficacy in different viral diseases, including HIV, influenza, and HSV. It ameliorates the quality of life (QoL) by improving both the physical and mental wellbeing of an individual. This is mainly done by promoting the better functioning of the immune system (increases CD4+ and CD8+ cells and reduces pro-inflammatory response). Conclusions: Regular involvement of these activities in day-to-day life may limit latent virus reactivations and reduce infection chances.

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Virus-Neutralizing Monoclonal Antibody Expressed in Milk of Transgenic Mice Provides Full Protection against Virus-Induced Encephalitis

Journal of Virology ◽

10.1128/jvi.75.6.2803-2809.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 2803-2809 ◽

Cited By ~ 21

Author(s):

Andreas F. Kolb ◽

Lecia Pewe ◽

John Webster ◽

Stanley Perlman ◽

C. Bruce A. Whitelaw ◽

...

Keyword(s):

Transgenic Mice ◽

Neutralizing Antibodies ◽

Defense Mechanism ◽

Viral Infections ◽

Hepatitis Virus ◽

Recombinant Antibody ◽

Lethal Dose ◽

Neutralizing Antibody ◽

Murine Hepatitis Virus

ABSTRACT Neutralizing antibodies represent a major host defense mechanism against viral infections. In mammals, passive immunity is provided by neutralizing antibodies passed to the offspring via the placenta or the milk as immunoglobulin G and secreted immunoglobulin A. With the long-term goal of producing virus-resistant livestock, we have generated mice carrying transgenes that encode the light and heavy chains of an antibody that is able to neutralize the neurotropic JHM strain of murine hepatitis virus (MHV-JHM). MHV-JHM causes acute encephalitis and acute and chronic demyelination in susceptible strains of mice and rats. Transgene expression was targeted to the lactating mammary gland by using the ovine β-lactoglobulin promoter. Milk from these transgenic mice contained up to 0.7 mg of recombinant antibody/ml. In vitro analysis of milk derived from different transgenic lines revealed a linear correlation between antibody expression and virus-neutralizing activity, indicating that the recombinant antibody is the major determinant of MHV-JHM neutralization in murine milk. Offspring of transgenic and control mice were challenged with a lethal dose of MHV-JHM. Litters suckling nontransgenic dams succumbed to fatal encephalitis, whereas litters suckling transgenic dams were fully protected against challenge, irrespective of whether they were transgenic. This demonstrates that a single neutralizing antibody expressed in the milk of transgenic mice is sufficient to completely protect suckling offspring against MHV-JHM-induced encephalitis.

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Research progress of siRNA in anti-influenza viral infection

Infection International ◽

10.2478/ii-2018-0019 ◽

2018 ◽

Vol 7 (2) ◽

pp. 50-55

Author(s):

Li Han

Keyword(s):

Viral Infection ◽

Small Interfering Rna ◽

Viral Infections ◽

High Specificity ◽

Research Progress ◽

Global Pandemic ◽

New Concepts ◽

Seasonal Flu ◽

Influenza Viral Infection ◽

Interfering Rna

AbstractThe harms of seasonal flu and global pandemic influenza have generally attracted attention. However, the currently administered influenza drugs and flu vaccines have certain limitations. Since the discovery of the small interfering RNA (siRNA) and its mediated RNA interference process, this molecule has been widely used in the study of anti-influenza viral infections because of its high specificity and strong selectivity. The results provided new concepts for the prevention and treatment of influenza virus. However, the siRNA still faces an enormous challenge despite extensive studies on this molecule. The research progress of siRNA in anti-influenza viral infection was reviewed in this study.

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Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

10.1101/2021.05.27.446054 ◽

2021 ◽

Author(s):

Elizabeth E. McCarthy ◽

Pamela M. Odorizzi ◽

Emma Lutz ◽

Carolyn P. Smullin ◽

Iliana Tenvooren ◽

...

Keyword(s):

Zika Virus ◽

Neutralizing Antibodies ◽

Viral Infections ◽

Immune Cell ◽

Acute Infection ◽

Neutralizing Antibody ◽

Natural Immunity ◽

Zikv Infection ◽

Antibody Titers ◽

Cellular Immune

Although the formation of a durable neutralizing antibody response after an acute viral infection is a key component of protective immunity, little is known about why some individuals generate high versus low neutralizing antibody titers to infection or vaccination. Infection with Zika virus (ZIKV) during pregnancy can cause devastating fetal outcomes, and efforts to understand natural immunity to this infection are essential for optimizing vaccine design. In this study, we leveraged the high-dimensional single-cell profiling capacity of mass cytometry (CyTOF) to deeply characterize the cellular immune response to acute and convalescent ZIKV infection in a cohort of blood donors in Puerto Rico incidentally found to be viremic during the 2015-2016 epidemic in the Americas. During acute ZIKV infection, we identified widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated innate immune subsets, as well as activated follicular helper CD4+ T cells and proliferating CD27-IgD- B cells, during acute infection were associated with high titers of ZIKV neutralizing antibodies at 6 months post-infection. On the other hand, low titers of ZIKV neutralizing antibodies were associated with immune features that suggested a cytotoxic-skewed immune "set-point." Our study offers insight into the cellular coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials for ZIKV and other acute viral infections aimed at inducing high titers of neutralizing antibodies.

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Quantifying synergy in the bioassay-guided fractionation of natural product extracts

10.1101/2020.06.23.166686 ◽

2020 ◽

Cited By ~ 1

Author(s):

Micah Dettweiler ◽

Lewis Marquez ◽

Max Bao ◽

Cassandra L. Quave

Keyword(s):

Inhibitory Concentration ◽

Viral Infections ◽

Fractional Inhibitory Concentration ◽

Drug Mixtures ◽

Natural Substances ◽

Complex Interactions ◽

Bioassay Guided Fractionation ◽

Using Data ◽

Living Organisms

AbstractMixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.

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ANTIBODY RESPONSES OF YOUNG INFANTS TO NATURALLY OCCURRING VIRAL INFECTIONS

PEDIATRICS ◽

10.1542/peds.38.4.564 ◽

1966 ◽

Vol 38 (4) ◽

pp. 564-570

Author(s):

Hugh L. Moffet ◽

Henry G. Cramblett

Keyword(s):

Neutralizing Antibodies ◽

Virus Isolation ◽

Viral Infections ◽

Low Frequency ◽

Severity Of Illness ◽

Antibody Responses ◽

Older Children ◽

Young Infants ◽

Naturally Occurring ◽

Significant Difference

A fourfold rise in neutralizing antibodies was demonstrated for 45% of infants 1 through 6 months of age compared to 63% of older children or adults from whom an adenovirus or an enterovirus was recovered. This difference appeared to be related to severity of illness rather than to age, as there was no significant difference between young infants and older patients when only clinically severe illnesses were analyzed. The isolation of virus from more than one specimen increased the probability of a significant response in either age group. Infants with minor symptoms had a low frequency of significant fourfold antibody responses after virus isolation, but this was not significantly different from older children with minor symptoms. Failure to develop an increase in antibody titer could not be related to the presence of maternal antibodies.

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