The breadth of cross sub-type neutralisation activity of a single domain antibody to influenza hemagglutinin can be increased by antibody valency.
Identifieur interne : 000653 ( Main/Exploration ); précédent : 000652; suivant : 000654The breadth of cross sub-type neutralisation activity of a single domain antibody to influenza hemagglutinin can be increased by antibody valency.
Auteurs : Simon E. Hufton [Royaume-Uni] ; Paul Risley [Royaume-Uni] ; Christina R. Ball [Royaume-Uni] ; Diane Major [Royaume-Uni] ; Othmar G. Engelhardt [Royaume-Uni] ; Stephen Poole [Royaume-Uni]Source :
- PloS one [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Affinité des anticorps (immunologie), Alignement de séquences, Animaux, Anticorps antiviraux (immunologie), Anticorps neutralisants (immunologie), Anticorps à domaine unique (), Anticorps à domaine unique (immunologie), Antigènes viraux (immunologie), Camélidés du Nouveau Monde, Données de séquences moléculaires, Glycoprotéine hémagglutinine du virus influenza (immunologie), Grippe humaine (immunologie), Humains, Mâle, Réactions croisées (immunologie), Spécificité des anticorps (immunologie), Séquence d'acides aminés, Techniques d'exposition à la surface cellulaire, Tests de neutralisation, Virus de la grippe A (), Virus de la grippe A (immunologie), Épitopes (immunologie).
- MESH :
- immunologie : Affinité des anticorps, Anticorps antiviraux, Anticorps neutralisants, Anticorps à domaine unique, Antigènes viraux, Glycoprotéine hémagglutinine du virus influenza, Grippe humaine, Réactions croisées, Spécificité des anticorps, Virus de la grippe A, Épitopes.
- Alignement de séquences, Animaux, Anticorps à domaine unique, Camélidés du Nouveau Monde, Données de séquences moléculaires, Humains, Mâle, Séquence d'acides aminés, Techniques d'exposition à la surface cellulaire, Tests de neutralisation, Virus de la grippe A.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Antibodies, Neutralizing (immunology), Antibodies, Viral (immunology), Antibody Affinity (immunology), Antibody Specificity (immunology), Antigens, Viral (immunology), Camelids, New World, Cell Surface Display Techniques, Cross Reactions (immunology), Epitopes (immunology), Hemagglutinin Glycoproteins, Influenza Virus (immunology), Humans, Influenza A virus (classification), Influenza A virus (immunology), Influenza, Human (immunology), Male, Molecular Sequence Data, Neutralization Tests, Sequence Alignment, Single-Domain Antibodies (chemistry), Single-Domain Antibodies (immunology).
- MESH :
- chemical , chemistry : Single-Domain Antibodies.
- chemical , immunology : Antibodies, Neutralizing, Antibodies, Viral, Antigens, Viral, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Single-Domain Antibodies.
- classification : Influenza A virus.
- immunology : Antibody Affinity, Antibody Specificity, Cross Reactions, Influenza A virus, Influenza, Human.
- Amino Acid Sequence, Animals, Camelids, New World, Cell Surface Display Techniques, Humans, Male, Molecular Sequence Data, Neutralization Tests, Sequence Alignment.
Abstract
The response to the 2009 A(H1N1) influenza pandemic has highlighted the need for additional strategies for intervention which preclude the prior availability of the influenza strain. Here, 18 single domain VHH antibodies against the 2009 A(H1N1) hemagglutinin (HA) have been isolated from a immune alpaca phage displayed library. These antibodies have been grouped as having either (i) non-neutralising, (ii) H1N1 restricted neutralising or (iii) broad cross-subtype neutralising activity. The ability to neutralise different viral subtypes, including highly pathogenic avian influenza (H5N1), correlated with the absence of hemagglutination inhibition activity, loss of binding to HA at acid pH and the absence of binding to the head domain containing the receptor binding site. This data supports their binding to epitopes in the HA stem region and a mechanism of action other than blocking viral attachment to cell surface receptors. After conversion of cross-neutralising antibodies R1a-B6 and R1a-A5 into a bivalent format, no significant enhancement in neutralisation activity was seen against A(H1N1) and A(H5N1) viruses. However, bivalent R1a-B6 showed an 18 fold enhancement in potency against A(H9N2) virus and, surprisingly, gained the ability to neutralise an A(H2N2) virus. This demonstrates that cross-neutralising antibodies, which make lower affinity interactions with the membrane proximal stem region of more divergent HA sub-types, can be optimised by bivalency so increasing their breadth of anti-viral activity. The broad neutralising activity and favourable characteristics, such as high stability, simple engineering into bivalent molecules and low cost production make these single domain antibodies attractive candidates for diagnostics and immunotherapy of pandemic influenza.
DOI: 10.1371/journal.pone.0103294
PubMed: 25084445
Affiliations:
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Le document en format XML
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Hufton</name><affiliation wicri:level="1"><nlm:affiliation>Biotherapeutics Group, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotherapeutics Group, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire</wicri:regionArea><wicri:noRegion>Hertfordshire</wicri:noRegion></affiliation></author><author><name sortKey="Risley, Paul" sort="Risley, Paul" uniqKey="Risley P" first="Paul" last="Risley">Paul Risley</name><affiliation wicri:level="1"><nlm:affiliation>Biotherapeutics Group, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotherapeutics Group, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire</wicri:regionArea><wicri:noRegion>Hertfordshire</wicri:noRegion></affiliation></author><author><name sortKey="Ball, Christina R" sort="Ball, Christina R" uniqKey="Ball C" first="Christina R" last="Ball">Christina R. Ball</name><affiliation wicri:level="1"><nlm:affiliation>Technology Development and Infrastructure, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Technology Development and Infrastructure, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire</wicri:regionArea><wicri:noRegion>Hertfordshire</wicri:noRegion></affiliation></author><author><name sortKey="Major, Diane" sort="Major, Diane" uniqKey="Major D" first="Diane" last="Major">Diane Major</name><affiliation wicri:level="1"><nlm:affiliation>Division of Virology, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Virology, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire</wicri:regionArea><wicri:noRegion>Hertfordshire</wicri:noRegion></affiliation></author><author><name sortKey="Engelhardt, Othmar G" sort="Engelhardt, Othmar G" uniqKey="Engelhardt O" first="Othmar G" last="Engelhardt">Othmar G. 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Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotherapeutics Group, National Institute for Biological Standards and Control, a centre of the Medicines and Healthcare Products Regulatory Agency, South Mimms, Potters Bar, Hertfordshire</wicri:regionArea><wicri:noRegion>Hertfordshire</wicri:noRegion></affiliation></author></analytic><series><title level="j">PloS one</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Antibodies, Neutralizing (immunology)</term><term>Antibodies, Viral (immunology)</term><term>Antibody Affinity (immunology)</term><term>Antibody Specificity (immunology)</term><term>Antigens, Viral (immunology)</term><term>Camelids, New World</term><term>Cell Surface Display Techniques</term><term>Cross Reactions (immunology)</term><term>Epitopes (immunology)</term><term>Hemagglutinin Glycoproteins, Influenza Virus (immunology)</term><term>Humans</term><term>Influenza A virus (classification)</term><term>Influenza A virus (immunology)</term><term>Influenza, Human (immunology)</term><term>Male</term><term>Molecular Sequence Data</term><term>Neutralization Tests</term><term>Sequence Alignment</term><term>Single-Domain Antibodies (chemistry)</term><term>Single-Domain Antibodies (immunology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Affinité des anticorps (immunologie)</term><term>Alignement de séquences</term><term>Animaux</term><term>Anticorps antiviraux (immunologie)</term><term>Anticorps neutralisants (immunologie)</term><term>Anticorps à domaine unique ()</term><term>Anticorps à domaine unique (immunologie)</term><term>Antigènes viraux (immunologie)</term><term>Camélidés du Nouveau Monde</term><term>Données de séquences moléculaires</term><term>Glycoprotéine hémagglutinine du virus influenza (immunologie)</term><term>Grippe humaine (immunologie)</term><term>Humains</term><term>Mâle</term><term>Réactions croisées (immunologie)</term><term>Spécificité des anticorps (immunologie)</term><term>Séquence d'acides aminés</term><term>Techniques d'exposition à la surface cellulaire</term><term>Tests de neutralisation</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (immunologie)</term><term>Épitopes (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Single-Domain Antibodies</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antibodies, Neutralizing</term><term>Antibodies, Viral</term><term>Antigens, Viral</term><term>Epitopes</term><term>Hemagglutinin Glycoproteins, Influenza Virus</term><term>Single-Domain Antibodies</term></keywords><keywords scheme="MESH" qualifier="classification" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Affinité des anticorps</term><term>Anticorps antiviraux</term><term>Anticorps neutralisants</term><term>Anticorps à domaine unique</term><term>Antigènes viraux</term><term>Glycoprotéine hémagglutinine du virus influenza</term><term>Grippe humaine</term><term>Réactions croisées</term><term>Spécificité des anticorps</term><term>Virus de la grippe A</term><term>Épitopes</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Antibody Affinity</term><term>Antibody Specificity</term><term>Cross Reactions</term><term>Influenza A virus</term><term>Influenza, Human</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Camelids, New World</term><term>Cell Surface Display Techniques</term><term>Humans</term><term>Male</term><term>Molecular Sequence Data</term><term>Neutralization Tests</term><term>Sequence Alignment</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term><term>Animaux</term><term>Anticorps à domaine unique</term><term>Camélidés du Nouveau Monde</term><term>Données de séquences moléculaires</term><term>Humains</term><term>Mâle</term><term>Séquence d'acides aminés</term><term>Techniques d'exposition à la surface cellulaire</term><term>Tests de neutralisation</term><term>Virus de la grippe A</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The response to the 2009 A(H1N1) influenza pandemic has highlighted the need for additional strategies for intervention which preclude the prior availability of the influenza strain. Here, 18 single domain VHH antibodies against the 2009 A(H1N1) hemagglutinin (HA) have been isolated from a immune alpaca phage displayed library. These antibodies have been grouped as having either (i) non-neutralising, (ii) H1N1 restricted neutralising or (iii) broad cross-subtype neutralising activity. The ability to neutralise different viral subtypes, including highly pathogenic avian influenza (H5N1), correlated with the absence of hemagglutination inhibition activity, loss of binding to HA at acid pH and the absence of binding to the head domain containing the receptor binding site. This data supports their binding to epitopes in the HA stem region and a mechanism of action other than blocking viral attachment to cell surface receptors. After conversion of cross-neutralising antibodies R1a-B6 and R1a-A5 into a bivalent format, no significant enhancement in neutralisation activity was seen against A(H1N1) and A(H5N1) viruses. However, bivalent R1a-B6 showed an 18 fold enhancement in potency against A(H9N2) virus and, surprisingly, gained the ability to neutralise an A(H2N2) virus. This demonstrates that cross-neutralising antibodies, which make lower affinity interactions with the membrane proximal stem region of more divergent HA sub-types, can be optimised by bivalency so increasing their breadth of anti-viral activity. The broad neutralising activity and favourable characteristics, such as high stability, simple engineering into bivalent molecules and low cost production make these single domain antibodies attractive candidates for diagnostics and immunotherapy of pandemic influenza. </div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Hufton, Simon E" sort="Hufton, Simon E" uniqKey="Hufton S" first="Simon E" last="Hufton">Simon E. Hufton</name></noRegion><name sortKey="Ball, Christina R" sort="Ball, Christina R" uniqKey="Ball C" first="Christina R" last="Ball">Christina R. Ball</name><name sortKey="Engelhardt, Othmar G" sort="Engelhardt, Othmar G" uniqKey="Engelhardt O" first="Othmar G" last="Engelhardt">Othmar G. Engelhardt</name><name sortKey="Major, Diane" sort="Major, Diane" uniqKey="Major D" first="Diane" last="Major">Diane Major</name><name sortKey="Poole, Stephen" sort="Poole, Stephen" uniqKey="Poole S" first="Stephen" last="Poole">Stephen Poole</name><name sortKey="Risley, Paul" sort="Risley, Paul" uniqKey="Risley P" first="Paul" last="Risley">Paul Risley</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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