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Article: Novel approaches for identification of broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies and improvement of their potency

TitleNovel approaches for identification of broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies and improvement of their potency
Authors
Issue Date2007
PublisherBentham Science Publishers Ltd. The Journal's web site is located at http://www.bentham.org/cpd/index.htm
Citation
Current Pharmaceutical Design, 2007, v. 13 n. 2, p. 203-212 How to Cite?
AbstractHuman monoclonal antibodies (hmAbs) that neutralize HIV isolates from different clades at physiologically relevant concentrations (broadly cross-reactive neutralizing antibodies (bcnAbs)) are rare in infected individuals. Only small number of such antibodies have been identified and extensively characterized, but efforts to elicit them in vivo have not been successful. We have recently developed novel approaches, based on sequential (SAP) and competitive (CAP) antigen panning methodologies, and the use of antigens with increased exposure of conserved epitopes, for enhanced identification of bcnAbs to gp120-gp41. Some of the antibodies identified by using these approaches (X5, m6, m9) bind better to gp120-CD4 complexes than to gp120 alone (CD4i antibodies); they exhibit exceptional neutralizing activity and breadth of neutralization as scFvs and on average lower potency as Fabs and IgGs. Other antibodies that compete with CD4 for binding to gp120 (m14, m18) (CD4bs antibodies) are weaker neutralizers but also exhibit broad neutralizing activity although at relatively high concentrations. The anti-gp41 antibodies (m43, m44, m45, m47 and m48) appear to have broad cross-reactivity and bind to a new group of conserved conformational epitopes distinct from those of the bcnAbs 4E10, 2F5 and Z13. Recently, the crystal structures of X5, m14 and m18 have been solved and compared to those of 17b and b12; they all contain long H3s that play a major role in their mechanism of binding. The H3s of X5, m6 and m9, unlike the others known, appear to be very flexible which may be related to the mechanism of their exceptional neutralizing activity. The further characterization of the molecular interactions of the bcnAbs with gp120-gp41 will undoubtedly help in our understanding of the mechanisms of virus neutralization, and in the design of entry inhibitors and vaccines. © 2007 Bentham Science Publishers Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/157468
ISSN
2015 Impact Factor: 3.052
2015 SCImago Journal Rankings: 1.220
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorZhang, MYen_US
dc.contributor.authorDimitrov, DSen_US
dc.date.accessioned2012-08-08T08:50:12Z-
dc.date.available2012-08-08T08:50:12Z-
dc.date.issued2007en_US
dc.identifier.citationCurrent Pharmaceutical Design, 2007, v. 13 n. 2, p. 203-212en_US
dc.identifier.issn1381-6128en_US
dc.identifier.urihttp://hdl.handle.net/10722/157468-
dc.description.abstractHuman monoclonal antibodies (hmAbs) that neutralize HIV isolates from different clades at physiologically relevant concentrations (broadly cross-reactive neutralizing antibodies (bcnAbs)) are rare in infected individuals. Only small number of such antibodies have been identified and extensively characterized, but efforts to elicit them in vivo have not been successful. We have recently developed novel approaches, based on sequential (SAP) and competitive (CAP) antigen panning methodologies, and the use of antigens with increased exposure of conserved epitopes, for enhanced identification of bcnAbs to gp120-gp41. Some of the antibodies identified by using these approaches (X5, m6, m9) bind better to gp120-CD4 complexes than to gp120 alone (CD4i antibodies); they exhibit exceptional neutralizing activity and breadth of neutralization as scFvs and on average lower potency as Fabs and IgGs. Other antibodies that compete with CD4 for binding to gp120 (m14, m18) (CD4bs antibodies) are weaker neutralizers but also exhibit broad neutralizing activity although at relatively high concentrations. The anti-gp41 antibodies (m43, m44, m45, m47 and m48) appear to have broad cross-reactivity and bind to a new group of conserved conformational epitopes distinct from those of the bcnAbs 4E10, 2F5 and Z13. Recently, the crystal structures of X5, m14 and m18 have been solved and compared to those of 17b and b12; they all contain long H3s that play a major role in their mechanism of binding. The H3s of X5, m6 and m9, unlike the others known, appear to be very flexible which may be related to the mechanism of their exceptional neutralizing activity. The further characterization of the molecular interactions of the bcnAbs with gp120-gp41 will undoubtedly help in our understanding of the mechanisms of virus neutralization, and in the design of entry inhibitors and vaccines. © 2007 Bentham Science Publishers Ltd.en_US
dc.languageengen_US
dc.publisherBentham Science Publishers Ltd. The Journal's web site is located at http://www.bentham.org/cpd/index.htmen_US
dc.relation.ispartofCurrent Pharmaceutical Designen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntibodies, Monoclonal - Metabolism - Pharmacologyen_US
dc.subject.meshCross Reactions - Immunologyen_US
dc.subject.meshDose-Response Relationship, Immunologicen_US
dc.subject.meshHiv Antibodies - Immunology - Metabolismen_US
dc.subject.meshHiv Envelope Protein Gp41 - Immunology - Metabolismen_US
dc.subject.meshHiv-1 - Immunology - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshNeutralization Tests - Methodsen_US
dc.titleNovel approaches for identification of broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies and improvement of their potencyen_US
dc.typeArticleen_US
dc.identifier.emailZhang, MY:zhangmy@hku.hken_US
dc.identifier.authorityZhang, MY=rp01409en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.2174/138161207779313669en_US
dc.identifier.pmid17269928-
dc.identifier.scopuseid_2-s2.0-33846175669en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33846175669&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume13en_US
dc.identifier.issue2en_US
dc.identifier.spage203en_US
dc.identifier.epage212en_US
dc.identifier.isiWOS:000244167600007-
dc.publisher.placeNetherlandsen_US
dc.identifier.scopusauthoridZhang, MY=35316639300en_US
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_US

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