Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association

Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2536-41. doi: 10.1073/pnas.0307140101.

Abstract

Effective prophylaxis and antiviral therapies are urgently needed in the event of reemergence of the highly contagious and often fatal severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) infection. We have identified eight recombinant human single-chain variable region fragments (scFvs) against the S1 domain of spike (S) protein of the SARS-CoV from two nonimmune human antibody libraries. One scFv 80R efficiently neutralized SARS-CoV and inhibited syncytia formation between cells expressing the S protein and those expressing the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2). Mapping of the 80R epitope showed it is located within the N-terminal 261-672 amino acids of S protein and is not glycosylation-dependent. 80R scFv competed with soluble ACE2 for association with the S1 domain and bound S1 with high affinity (equilibrium dissociation constant, Kd=32.3 nM). A human IgG1 form of 80R bound S1 with a 20-fold higher affinity of 1.59 nM comparable to that of ACE2 (Kd=1.70 nM), and neutralized virus 20-fold more efficiently than the 80R scFv. These data suggest that the 80R human monoclonal antibody may be a useful viral entry inhibitor for the emergency prophylaxis and treatment of SARS, and that the ACE2-binding site of S1 could be an attractive target for subunit vaccine and drug development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal
  • Gene Library
  • Giant Cells / immunology
  • Humans
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology
  • Immunoglobulin G / isolation & purification
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Light Chains / chemistry
  • Immunoglobulin Light Chains / genetics
  • Molecular Sequence Data
  • Neutralization Tests
  • Receptors, Virus / immunology*
  • SARS Virus / immunology
  • SARS Virus / pathogenicity*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Severe Acute Respiratory Syndrome / immunology*

Substances

  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Receptors, Virus

Associated data

  • GENBANK/AY530312
  • GENBANK/AY530313
  • GENBANK/AY530314
  • GENBANK/AY530315
  • GENBANK/AY530316
  • GENBANK/AY530317
  • GENBANK/AY530318
  • GENBANK/AY530319
  • GENBANK/AY530320
  • GENBANK/AY530321
  • GENBANK/AY530322
  • GENBANK/AY530323
  • GENBANK/AY530324
  • GENBANK/AY530325
  • GENBANK/AY530326