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Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants.
PLoS Med. 2006 Jul; 3(7):e237.PM

Abstract

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.

Authors+Show Affiliations

Crucell Holland B.V., Leiden, Netherlands. j.termeulen@crucell.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16796401

Citation

ter Meulen, Jan, et al. "Human Monoclonal Antibody Combination Against SARS Coronavirus: Synergy and Coverage of Escape Mutants." PLoS Medicine, vol. 3, no. 7, 2006, pp. e237.
ter Meulen J, van den Brink EN, Poon LL, et al. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006;3(7):e237.
ter Meulen, J., van den Brink, E. N., Poon, L. L., Marissen, W. E., Leung, C. S., Cox, F., Cheung, C. Y., Bakker, A. Q., Bogaards, J. A., van Deventer, E., Preiser, W., Doerr, H. W., Chow, V. T., de Kruif, J., Peiris, J. S., & Goudsmit, J. (2006). Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Medicine, 3(7), e237.
ter Meulen J, et al. Human Monoclonal Antibody Combination Against SARS Coronavirus: Synergy and Coverage of Escape Mutants. PLoS Med. 2006;3(7):e237. PubMed PMID: 16796401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. AU - ter Meulen,Jan, AU - van den Brink,Edward N, AU - Poon,Leo L M, AU - Marissen,Wilfred E, AU - Leung,Cynthia S W, AU - Cox,Freek, AU - Cheung,Chung Y, AU - Bakker,Arjen Q, AU - Bogaards,Johannes A, AU - van Deventer,Els, AU - Preiser,Wolfgang, AU - Doerr,Hans Wilhelm, AU - Chow,Vincent T, AU - de Kruif,John, AU - Peiris,Joseph S M, AU - Goudsmit,Jaap, PY - 2005/09/07/received PY - 2006/04/03/accepted PY - 2006/6/27/pubmed PY - 2007/2/13/medline PY - 2006/6/27/entrez SP - e237 EP - e237 JF - PLoS medicine JO - PLoS Med VL - 3 IS - 7 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/16796401/Human_monoclonal_antibody_combination_against_SARS_coronavirus:_synergy_and_coverage_of_escape_mutants_ L2 - https://dx.plos.org/10.1371/journal.pmed.0030237 DB - PRIME DP - Unbound Medicine ER -