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

  • Background: 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.
Author:Jan ter Meulen, Edward van den Brink, Poon Leo L. M., Wilfred E. Marissen, Cynthia S. W. Leung, Freek Cox, Chung Y. Cheung, Arjen Q. Bakker, Johannes A. Bogaards, Els van Deventer, Wolfgang Preiser, Hans Wilhelm DoerrGND, Tak-Kwong Vincent Chow, John de Kruif, Joseph Sriyal Malik Peiris, Jaap Goudsmit
Pubmed Id:
Parent Title (English):PLoS medicine
Place of publication:Lawrence, Kan.
Contributor(s):Dennis R. Burton
Document Type:Article
Year of Completion:2006
Date of first Publication:2006/07/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2006/08/25
Tag:Antibodies; Cats; Enzyme-linked immunoassays; Macrophages; Monoclonal antibodies; Respiratory infections; SARS; SARS coronavirus
Issue:(7): e237
Page Number:9
First Page:1071
Last Page:1079
Copyright: © 2006 ter Meulen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation: ter Meulen J, van den Brink EN, Poon LLM, Marissen WE, Leung CSW, et al. (2006). 
PLoS Med 3(7): e237. DOI: 10.1371/journal.pmed.0030237
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 3.0