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Article: Human monoclonal antibody combination against SARS coronavirus: Synergy and coverage of escape mutants

TitleHuman monoclonal antibody combination against SARS coronavirus: Synergy and coverage of escape mutants
Authors
Issue Date2006
PublisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676
Citation
Plos Medicine, 2006, v. 3 n. 7, p. 1071-1079 How to Cite?
AbstractBackground: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. Methods and Findings: Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318-510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. Conclusions: The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection. Copyright: © 2006 ter Meulen et al.
Persistent Identifierhttp://hdl.handle.net/10722/78863
ISSN
2011 Impact Factor: 16.269
2015 SCImago Journal Rankings: 5.667
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTer Meulen, Jen_HK
dc.contributor.authorVan Den Brink, ENen_HK
dc.contributor.authorPoon, LLMen_HK
dc.contributor.authorMarissen, WEen_HK
dc.contributor.authorLeung, CSWen_HK
dc.contributor.authorCox, Fen_HK
dc.contributor.authorCheung, CYen_HK
dc.contributor.authorBakker, AQen_HK
dc.contributor.authorBogaards, JAen_HK
dc.contributor.authorVan Deventer, Een_HK
dc.contributor.authorPreiser, Wen_HK
dc.contributor.authorDoerr, HWen_HK
dc.contributor.authorChow, VTen_HK
dc.contributor.authorDe Kruif, Jen_HK
dc.contributor.authorPeiris, JSMen_HK
dc.contributor.authorGoudsmit, Jen_HK
dc.date.accessioned2010-09-06T07:47:44Z-
dc.date.available2010-09-06T07:47:44Z-
dc.date.issued2006en_HK
dc.identifier.citationPlos Medicine, 2006, v. 3 n. 7, p. 1071-1079en_HK
dc.identifier.issn1549-1277en_HK
dc.identifier.urihttp://hdl.handle.net/10722/78863-
dc.description.abstractBackground: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. Methods and Findings: Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318-510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. Conclusions: The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection. Copyright: © 2006 ter Meulen et al.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://medicine.plosjournals.org/perlserv/?request=index-html&issn=1549-1676en_HK
dc.relation.ispartofPLoS Medicineen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong Licenseen_HK
dc.subject.meshAntibodies, Monoclonal - administration and dosage - genetics - immunology - therapeutic use-
dc.subject.meshAntigens, Viral - immunology-
dc.subject.meshImmunization, Passive-
dc.subject.meshMembrane Glycoproteins - genetics - immunology - physiology-
dc.subject.meshSARS Virus - genetics - immunology-
dc.titleHuman monoclonal antibody combination against SARS coronavirus: Synergy and coverage of escape mutantsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1549-1277&volume=3 &issue=7&spage=1071&epage=1079&date=2006&atitle=Human+Monoclonal+Antibody+Combination+against+SARS+Coronavirus:+Synergy+and+Coverage+of+Escape+Mutantsen_HK
dc.identifier.emailPoon, LLM: llmpoon@hkucc.hku.hken_HK
dc.identifier.emailCheung, CY: chungey@hkucc.hku.hken_HK
dc.identifier.emailPeiris, JSM: malik@hkucc.hku.hken_HK
dc.identifier.authorityPoon, LLM=rp00484en_HK
dc.identifier.authorityCheung, CY=rp00404en_HK
dc.identifier.authorityPeiris, JSM=rp00410en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pmed.0030237en_HK
dc.identifier.pmid16796401-
dc.identifier.pmcidPMC1483912-
dc.identifier.scopuseid_2-s2.0-33746424849en_HK
dc.identifier.hkuros118019en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33746424849&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue7en_HK
dc.identifier.spage1071en_HK
dc.identifier.epage1079en_HK
dc.identifier.isiWOS:000239493300026-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001000876-
dc.identifier.scopusauthoridTer Meulen, J=7006803276en_HK
dc.identifier.scopusauthoridVan Den Brink, EN=6602122667en_HK
dc.identifier.scopusauthoridPoon, LLM=7005441747en_HK
dc.identifier.scopusauthoridMarissen, WE=6602339822en_HK
dc.identifier.scopusauthoridLeung, CSW=7402612654en_HK
dc.identifier.scopusauthoridCox, F=8679913700en_HK
dc.identifier.scopusauthoridCheung, CY=7202061836en_HK
dc.identifier.scopusauthoridBakker, AQ=7201772292en_HK
dc.identifier.scopusauthoridBogaards, JA=7003619277en_HK
dc.identifier.scopusauthoridVan Deventer, E=8679914200en_HK
dc.identifier.scopusauthoridPreiser, W=7004338253en_HK
dc.identifier.scopusauthoridDoerr, HW=7102740671en_HK
dc.identifier.scopusauthoridChow, VT=7006616202en_HK
dc.identifier.scopusauthoridDe Kruif, J=6604049538en_HK
dc.identifier.scopusauthoridPeiris, JSM=7005486823en_HK
dc.identifier.scopusauthoridGoudsmit, J=35374719700en_HK

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