SrasV1, Main, Exploration, bibRecord, 001F80

Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

Identifieur interne : 001F80 ( Main/Exploration ); précédent : 001F79; suivant : 001F81

Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

Auteurs : Mridula Rani [États-Unis] ; Meagan Bolles [États-Unis] ; Eric F. Donaldson [États-Unis] ; Thomas Van Blarcom [États-Unis] ; Ralph Baric [États-Unis] ; Brent Iverson [États-Unis] ; George Georgiou [États-Unis]

Source :

Journal of virology [ 0022-538X ] ; 2012.

RBID : Pascal:12-0347769

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence, Animals, Antibodies, Neutralizing (chemistry), Antibodies, Neutralizing (genetics), Antibodies, Neutralizing (immunology), Antibodies, Neutralizing (pharmacology), Antibodies, Viral (chemistry), Antibodies, Viral (genetics), Antibodies, Viral (immunology), Antibodies, Viral (pharmacology), Antibody, Antibody Affinity, Cell Line, Coronavirus, Humans, In vitro, Kinetics, Molecular Sequence Data, Mutation, Neutralization Tests, SARS Virus (chemistry), SARS Virus (drug effects), SARS Virus (genetics), SARS Virus (immunology), Sequence Alignment, Severe Acute Respiratory Syndrome (immunology), Severe Acute Respiratory Syndrome (prevention & control), Severe Acute Respiratory Syndrome (virology), Severe acute respiratory syndrome, Single-Chain Antibodies (genetics), Single-Chain Antibodies (immunology), Single-Chain Antibodies (pharmacology).
MESH :
- chemical , chemistry : Antibodies, Neutralizing, Antibodies, Viral.
- chemical , genetics : Antibodies, Neutralizing, Antibodies, Viral, Single-Chain Antibodies.
- chemical , immunology : Antibodies, Neutralizing, Antibodies, Viral, Single-Chain Antibodies.
- chemical , pharmacology : Antibodies, Neutralizing, Antibodies, Viral, Single-Chain Antibodies.
- chemistry : SARS Virus.
- drug effects : SARS Virus.
- genetics : SARS Virus.
- immunology : SARS Virus, Severe Acute Respiratory Syndrome.
- prevention & control : Severe Acute Respiratory Syndrome.
- virology : Severe Acute Respiratory Syndrome.
- Amino Acid Sequence, Animals, Antibody Affinity, Cell Line, Humans, Kinetics, Molecular Sequence Data, Mutation, Neutralization Tests, Sequence Alignment.

Abstract

Even though the effect of antibody affinity on neutralization potency is well documented, surprisingly, its impact on neutralization breadth and escape has not been systematically determined. Here, random mutagenesis and DNA shuffling of the single-chain variable fragment of the neutralizing antibody 80R followed by bacterial display screening using anchored periplasmic expression (APEx) were used to generate a number of higher-affinity variants of the severe acute respiratory syndrome coronavirus (SARS-CoV)-neutralizing antibody 80R with equilibrium dissociation constants (K_D) as low as 37 pM, a >270-fold improvement relative to that of the parental 80R single-chain variable fragment (scFv). As expected, antigen affinity was shown to correlate directly with neutralization potency toward the icUrbani strain of SARS-CoV. Additionally, the highest-affinity antibody fragment displayed 10-fold-increased broad neutralization in vitro and completely protected against several SARS-CoV strains containing substitutions associated with antibody escape. Importantly, higher affinity also led to the suppression of viral escape mutants in vitro. Escape from the highest-affinity variant required reduced selective pressure and multiple substitutions in the binding epitope. Collectively, these results support the hypothesis that engineered antibodies with picomolar dissociation constants for a neutralizing epitope can confer escape-resistant protection.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416138

Affiliations:

Le document en format XML

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<term>Animals</term>
<term>Antibodies, Neutralizing (chemistry)</term>
<term>Antibodies, Neutralizing (genetics)</term>
<term>Antibodies, Neutralizing (immunology)</term>
<term>Antibodies, Neutralizing (pharmacology)</term>
<term>Antibodies, Viral (chemistry)</term>
<term>Antibodies, Viral (genetics)</term>
<term>Antibodies, Viral (immunology)</term>
<term>Antibodies, Viral (pharmacology)</term>
<term>Antibody</term>
<term>Antibody Affinity</term>
<term>Cell Line</term>
<term>Coronavirus</term>
<term>Humans</term>
<term>In vitro</term>
<term>Kinetics</term>
<term>Molecular Sequence Data</term>
<term>Mutation</term>
<term>Neutralization Tests</term>
<term>SARS Virus (chemistry)</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (genetics)</term>
<term>SARS Virus (immunology)</term>
<term>Sequence Alignment</term>
<term>Severe Acute Respiratory Syndrome (immunology)</term>
<term>Severe Acute Respiratory Syndrome (prevention & control)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Severe acute respiratory syndrome</term>
<term>Single-Chain Antibodies (genetics)</term>
<term>Single-Chain Antibodies (immunology)</term>
<term>Single-Chain Antibodies (pharmacology)</term>
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<term>Alignement de séquences</term>
<term>Animaux</term>
<term>Anticorps antiviraux ()</term>
<term>Anticorps antiviraux (génétique)</term>
<term>Anticorps antiviraux (immunologie)</term>
<term>Anticorps antiviraux (pharmacologie)</term>
<term>Anticorps neutralisants ()</term>
<term>Anticorps neutralisants (génétique)</term>
<term>Anticorps neutralisants (immunologie)</term>
<term>Anticorps neutralisants (pharmacologie)</term>
<term>Anticorps à chaîne unique (génétique)</term>
<term>Anticorps à chaîne unique (immunologie)</term>
<term>Anticorps à chaîne unique (pharmacologie)</term>
<term>Cinétique</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
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<term>Mutation</term>
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<term>Syndrome respiratoire aigu sévère (immunologie)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Séquence d'acides aminés</term>
<term>Tests de neutralisation</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (génétique)</term>
<term>Virus du SRAS (immunologie)</term>
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<term>Antibodies, Viral</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antibodies, Neutralizing</term>
<term>Antibodies, Viral</term>
<term>Single-Chain Antibodies</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antibodies, Neutralizing</term>
<term>Antibodies, Viral</term>
<term>Single-Chain Antibodies</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antibodies, Neutralizing</term>
<term>Antibodies, Viral</term>
<term>Single-Chain Antibodies</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term>
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<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Anticorps antiviraux</term>
<term>Anticorps neutralisants</term>
<term>Anticorps à chaîne unique</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Anticorps antiviraux</term>
<term>Anticorps neutralisants</term>
<term>Anticorps à chaîne unique</term>
<term>Syndrome respiratoire aigu sévère</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>SARS Virus</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Anticorps antiviraux</term>
<term>Anticorps neutralisants</term>
<term>Anticorps à chaîne unique</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Animals</term>
<term>Antibody Affinity</term>
<term>Cell Line</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Molecular Sequence Data</term>
<term>Mutation</term>
<term>Neutralization Tests</term>
<term>Sequence Alignment</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Affinité des anticorps</term>
<term>Alignement de séquences</term>
<term>Animaux</term>
<term>Anticorps antiviraux</term>
<term>Anticorps neutralisants</term>
<term>Cinétique</term>
<term>Coronavirus</term>
<term>Anticorps</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>In vitro</term>
<term>Lignée cellulaire</term>
<term>Mutation</term>
<term>Syndrome respiratoire aigu sévère</term>
<term>Séquence d'acides aminés</term>
<term>Tests de neutralisation</term>
<term>Virus du SRAS</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Even though the effect of antibody affinity on neutralization potency is well documented, surprisingly, its impact on neutralization breadth and escape has not been systematically determined. Here, random mutagenesis and DNA shuffling of the single-chain variable fragment of the neutralizing antibody 80R followed by bacterial display screening using anchored periplasmic expression (APEx) were used to generate a number of higher-affinity variants of the severe acute respiratory syndrome coronavirus (SARS-CoV)-neutralizing antibody 80R with equilibrium dissociation constants (K<sub>D</sub>
) as low as 37 pM, a >270-fold improvement relative to that of the parental 80R single-chain variable fragment (scFv). As expected, antigen affinity was shown to correlate directly with neutralization potency toward the icUrbani strain of SARS-CoV. Additionally, the highest-affinity antibody fragment displayed 10-fold-increased broad neutralization in vitro and completely protected against several SARS-CoV strains containing substitutions associated with antibody escape. Importantly, higher affinity also led to the suppression of viral escape mutants in vitro. Escape from the highest-affinity variant required reduced selective pressure and multiple substitutions in the binding epitope. Collectively, these results support the hypothesis that engineered antibodies with picomolar dissociation constants for a neutralizing epitope can confer escape-resistant protection.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Caroline du Nord</li>
<li>Texas</li>
</region>
<settlement><li>Austin (Texas)</li>
<li>Chapel Hill (Caroline du Nord)</li>
</settlement>
<orgName><li>Université de Caroline du Nord à Chapel Hill</li>
<li>Université du Texas à Austin</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Texas"><name sortKey="Rani, Mridula" sort="Rani, Mridula" uniqKey="Rani M" first="Mridula" last="Rani">Mridula Rani</name>
</region>
<name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name>
<name sortKey="Bolles, Meagan" sort="Bolles, Meagan" uniqKey="Bolles M" first="Meagan" last="Bolles">Meagan Bolles</name>
<name sortKey="Donaldson, Eric F" sort="Donaldson, Eric F" uniqKey="Donaldson E" first="Eric F." last="Donaldson">Eric F. Donaldson</name>
<name sortKey="Georgiou, George" sort="Georgiou, George" uniqKey="Georgiou G" first="George" last="Georgiou">George Georgiou</name>
<name sortKey="Georgiou, George" sort="Georgiou, George" uniqKey="Georgiou G" first="George" last="Georgiou">George Georgiou</name>
<name sortKey="Georgiou, George" sort="Georgiou, George" uniqKey="Georgiou G" first="George" last="Georgiou">George Georgiou</name>
<name sortKey="Iverson, Brent" sort="Iverson, Brent" uniqKey="Iverson B" first="Brent" last="Iverson">Brent Iverson</name>
<name sortKey="Iverson, Brent" sort="Iverson, Brent" uniqKey="Iverson B" first="Brent" last="Iverson">Brent Iverson</name>
<name sortKey="Van Blarcom, Thomas" sort="Van Blarcom, Thomas" uniqKey="Van Blarcom T" first="Thomas" last="Van Blarcom">Thomas Van Blarcom</name>
</country>
</tree>
</affiliations>
</record>

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Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

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