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Article: Properties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses

TitleProperties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza viruses
Authors
Issue Date2011
PublisherAmerican Society for Microbiology.
Citation
Antimicrobial Agents And Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357 How to Cite?
Abstract
Highly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection. Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/142417
ISSN
2013 Impact Factor: 4.451
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Science and Technology Foundation of Fujian Province2009YZ0002
National Natural Science Foundation of China30901077
Ministry of Health2008ZX10004-006
University Grants CommitteeAoE/M-12/06
National Institutes of HealthHHSN2662007 00005C
Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR
Funding Information:

This study was supported by the Key Project of the Science and Technology Foundation of Fujian Province (grant no. 2009YZ0002), the National Natural Science Foundation of China (grant no. 30901077), the Key Project of the Ministry of Health (grant no. 2008ZX10004-006), the Areas of Excellence Scheme of the University Grants Committee (grant AoE/M-12/06), the National Institutes of Health (NIAID contract HHSN2662007 00005C), and the Research Fund for the Control of Infectious Diseases of the Health, Welfare, and Food Bureau of the Hong Kong SAR).

References
Grants

 

Author Affiliations
  1. Xiamen University
  2. The University of Hong Kong
DC FieldValueLanguage
dc.contributor.authorZheng, Qen_HK
dc.contributor.authorXia, Len_HK
dc.contributor.authorWu, WLen_HK
dc.contributor.authorZheng, Zen_HK
dc.contributor.authorHuo, Yen_HK
dc.contributor.authorWu, Jen_HK
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorYu, Hen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorLau, SYen_HK
dc.contributor.authorChen, Hen_HK
dc.contributor.authorLuo, Wen_HK
dc.contributor.authorXia, Nen_HK
dc.date.accessioned2011-10-28T02:45:35Z-
dc.date.available2011-10-28T02:45:35Z-
dc.date.issued2011en_HK
dc.identifier.citationAntimicrobial Agents And Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357en_HK
dc.identifier.issn0066-4804en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142417-
dc.description.abstractHighly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection. Copyright © 2011, American Society for Microbiology. All Rights Reserved.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Microbiology.-
dc.relation.ispartofAntimicrobial Agents and Chemotherapyen_HK
dc.rightsAntimicrobial Agents and Chemotherapy. Copyright © American Society for Microbiology.-
dc.rightsCopyright © American Society for Microbiology, Antimicrobial Agents and Chemotherapy, 2011, v. 55 n. 4, p. 1349-1357-
dc.subject.meshAntibodies, Monoclonal - chemistry - immunology - therapeutic use-
dc.subject.meshAntibodies, Viral - chemistry - immunology - therapeutic use-
dc.subject.meshCHO Cells-
dc.subject.meshCricetinae-
dc.subject.meshInfluenza A Virus, H5N1 Subtype - immunology-
dc.titleProperties and therapeutic efficacy of broadly reactive chimeric and humanized H5-specific monoclonal antibodies against H5N1 influenza virusesen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, H:hlchen@hkucc.hku.hken_HK
dc.identifier.authorityChen, H=rp00383en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1128/AAC.01436-10en_HK
dc.identifier.pmid21245446en_HK
dc.identifier.pmcidPMC3067186-
dc.identifier.scopuseid_2-s2.0-79953208049en_HK
dc.identifier.hkuros197190en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79953208049&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume55en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1349en_HK
dc.identifier.epage1357en_HK
dc.identifier.isiWOS:000288594600004-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectControl of Pandemic and Inter-pandemic Influenza-
dc.identifier.scopusauthoridZheng, Q=35202845100en_HK
dc.identifier.scopusauthoridXia, L=36674086100en_HK
dc.identifier.scopusauthoridWu, WL=36674119200en_HK
dc.identifier.scopusauthoridZheng, Z=23972049100en_HK
dc.identifier.scopusauthoridHuo, Y=45961166700en_HK
dc.identifier.scopusauthoridWu, J=45961733300en_HK
dc.identifier.scopusauthoridLiu, Y=45961207200en_HK
dc.identifier.scopusauthoridYu, H=7405854119en_HK
dc.identifier.scopusauthoridChen, Y=35573045900en_HK
dc.identifier.scopusauthoridLau, SY=35083705100en_HK
dc.identifier.scopusauthoridChen, H=26643315400en_HK
dc.identifier.scopusauthoridLuo, W=7202199022en_HK
dc.identifier.scopusauthoridXia, N=35187953700en_HK

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