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Proc Natl Acad Sci USA. A common solution to group 2 influenza virus neutralization
[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
A common solution to group 2 influenza virus neutralization
Robert H. E. Friesen<SUP>a</SUP>,<SUP>1</SUP>, Peter S. Lee<SUP>b</SUP>,<SUP>c</SUP>,<SUP>1</SUP>, Esther J. M. Stoop<SUP>a</SUP>, Ryan M. B. Hoffman<SUP>b</SUP>, Damian C. Ekiert<SUP>b</SUP>,<SUP>2</SUP>, Gira Bhabha<SUP>b</SUP>,<SUP>3</SUP>, Wenli Yu<SUP>b</SUP>, Jarek Juraszek<SUP>a</SUP>, Wouter Koudstaal<SUP>a</SUP>, Mandy Jongeneelen<SUP>a</SUP>, Hans J. W. M. Korse<SUP>a</SUP>, Carla Ophorst<SUP>a</SUP>, Els C. M. Brinkman-van der Linden<SUP>a</SUP>, Mark Throsby<SUP>a</SUP>,<SUP>4</SUP>, Mark J. Kwakkenbos<SUP>d</SUP>, Arjen Q. Bakker<SUP>d</SUP>, Tim Beaumont<SUP>d</SUP>, Hergen Spits<SUP>d</SUP>, Ted Kwaks<SUP>a</SUP>, Ronald Vogels<SUP>a</SUP>, Andrew B. Ward<SUP>b</SUP>, Jaap Goudsmit<SUP>a</SUP>,<SUP>5</SUP>, and Ian A. Wilson<SUP>b</SUP>,<SUP>c</SUP>,<SUP>5</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 2333 CN, Leiden, The Netherlands; <SUP>b</SUP>Department of Integrative Structural and Computational Biology and <SUP>c</SUP>The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and <SUP>d</SUP>AIMM Therapeutics, 1105 BA, Amsterdam, The Netherlands
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved November 13, 2013 (received for review October 8, 2013)
Published online before print December 11, 2013, doi: 10.1073/pnas.1319058110 / <ABBR>PNAS</ABBR> December 11, 2013
Significance
The HA surface glycoprotein on influenza A viruses mediates viral entry into host cells. HA is highly variable and classified into 18 divergent subtypes, which cluster into two major phylogenetic groups. Antibody CR8043 has heterosubtypic neutralizing activity against group 2 viruses, including H3 viruses that currently circulate in humans. X-ray and EM structures of CR8043 Fab in complex with H3 HAs reveal that the antibody targets a conserved epitope on the HA stem. Compared with CR8020, the only other structurally characterized group 2 neutralizing antibody, CR8043 binds to HA with a different approach angle using different contact residues. The epitopes of both antibodies are very similar, which suggests that this conserved stem epitope has great potential for design of therapeutics and vaccines.
Abstract
The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
antibody recognition ? X-ray crystallography - electron microscopy
Footnotes
<SUP>1</SUP>R.H.E.F. and P.S.L. contributed equally to this work.
<SUP>2</SUP>Present address: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
<SUP>3</SUP>Present address: Department of Molecular Pharmacology, University of California, San Francisco, CA 94143.
<SUP>4</SUP>Present address: Merus B.V., 3584 CH, Utrecht, The Netherlands.
<SUP>5</SUP>To whom correspondence may be addressed. E-mail: J.Goudsmit@crucell.com or Wilson@scripps.edu.
Author contributions: R.H.E.F., P.S.L., D.C.E., G.B., W.K., M.J., E.C.M.B.-v.d.L., M.T., M.J.K., A.Q.B., T.B., H.S., T.K., R.V., A.B.W., J.G., and I.A.W. designed research; P.S.L., R.M.B.H., D.C.E., G.B., W.Y., M.J., H.J.W.M.K., C.O., M.J.K., and A.Q.B. performed research; R.H.E.F., P.S.L., E.J.M.S., R.M.B.H., D.C.E., G.B., J.J., W.K., M.T., M.J.K., A.Q.B., T.K., R.V., A.B.W., J.G., and I.A.W. analyzed data; and R.H.E.F., P.S.L., E.J.M.S., J.J., W.K., A.B.W., J.G., and I.A.W. wrote the paper.
Conflict of interest statement: R.H.E.F., E.J.M.S., J.J., W.K., M.J., H.J.W.M.K., C.O., E.C.M.B.-v.d.L., T.K., R.V., and J.G. are employees of Crucell Holland B.V.. M.J.K., A.Q.B., T.B., and H.S. are employees of AIMM Therapeutics.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structures have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4NM4 and 4NM8). The reconstruction data reported have been deposited in the Electron Microscopy Data Bank, www.emdatabank.org (codes 5793 and 5794).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1319058110/-/DCSupplemental.
Freely available online through the PNAS open access option.
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A common solution to group 2 influenza virus neutralization
Robert H. E. Friesen<SUP>a</SUP>,<SUP>1</SUP>, Peter S. Lee<SUP>b</SUP>,<SUP>c</SUP>,<SUP>1</SUP>, Esther J. M. Stoop<SUP>a</SUP>, Ryan M. B. Hoffman<SUP>b</SUP>, Damian C. Ekiert<SUP>b</SUP>,<SUP>2</SUP>, Gira Bhabha<SUP>b</SUP>,<SUP>3</SUP>, Wenli Yu<SUP>b</SUP>, Jarek Juraszek<SUP>a</SUP>, Wouter Koudstaal<SUP>a</SUP>, Mandy Jongeneelen<SUP>a</SUP>, Hans J. W. M. Korse<SUP>a</SUP>, Carla Ophorst<SUP>a</SUP>, Els C. M. Brinkman-van der Linden<SUP>a</SUP>, Mark Throsby<SUP>a</SUP>,<SUP>4</SUP>, Mark J. Kwakkenbos<SUP>d</SUP>, Arjen Q. Bakker<SUP>d</SUP>, Tim Beaumont<SUP>d</SUP>, Hergen Spits<SUP>d</SUP>, Ted Kwaks<SUP>a</SUP>, Ronald Vogels<SUP>a</SUP>, Andrew B. Ward<SUP>b</SUP>, Jaap Goudsmit<SUP>a</SUP>,<SUP>5</SUP>, and Ian A. Wilson<SUP>b</SUP>,<SUP>c</SUP>,<SUP>5</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 2333 CN, Leiden, The Netherlands; <SUP>b</SUP>Department of Integrative Structural and Computational Biology and <SUP>c</SUP>The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and <SUP>d</SUP>AIMM Therapeutics, 1105 BA, Amsterdam, The Netherlands
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved November 13, 2013 (received for review October 8, 2013)
Published online before print December 11, 2013, doi: 10.1073/pnas.1319058110 / <ABBR>PNAS</ABBR> December 11, 2013
Significance
The HA surface glycoprotein on influenza A viruses mediates viral entry into host cells. HA is highly variable and classified into 18 divergent subtypes, which cluster into two major phylogenetic groups. Antibody CR8043 has heterosubtypic neutralizing activity against group 2 viruses, including H3 viruses that currently circulate in humans. X-ray and EM structures of CR8043 Fab in complex with H3 HAs reveal that the antibody targets a conserved epitope on the HA stem. Compared with CR8020, the only other structurally characterized group 2 neutralizing antibody, CR8043 binds to HA with a different approach angle using different contact residues. The epitopes of both antibodies are very similar, which suggests that this conserved stem epitope has great potential for design of therapeutics and vaccines.
Abstract
The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
antibody recognition ? X-ray crystallography - electron microscopy
Footnotes
<SUP>1</SUP>R.H.E.F. and P.S.L. contributed equally to this work.
<SUP>2</SUP>Present address: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
<SUP>3</SUP>Present address: Department of Molecular Pharmacology, University of California, San Francisco, CA 94143.
<SUP>4</SUP>Present address: Merus B.V., 3584 CH, Utrecht, The Netherlands.
<SUP>5</SUP>To whom correspondence may be addressed. E-mail: J.Goudsmit@crucell.com or Wilson@scripps.edu.
Author contributions: R.H.E.F., P.S.L., D.C.E., G.B., W.K., M.J., E.C.M.B.-v.d.L., M.T., M.J.K., A.Q.B., T.B., H.S., T.K., R.V., A.B.W., J.G., and I.A.W. designed research; P.S.L., R.M.B.H., D.C.E., G.B., W.Y., M.J., H.J.W.M.K., C.O., M.J.K., and A.Q.B. performed research; R.H.E.F., P.S.L., E.J.M.S., R.M.B.H., D.C.E., G.B., J.J., W.K., M.T., M.J.K., A.Q.B., T.K., R.V., A.B.W., J.G., and I.A.W. analyzed data; and R.H.E.F., P.S.L., E.J.M.S., J.J., W.K., A.B.W., J.G., and I.A.W. wrote the paper.
Conflict of interest statement: R.H.E.F., E.J.M.S., J.J., W.K., M.J., H.J.W.M.K., C.O., E.C.M.B.-v.d.L., T.K., R.V., and J.G. are employees of Crucell Holland B.V.. M.J.K., A.Q.B., T.B., and H.S. are employees of AIMM Therapeutics.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and structures have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4NM4 and 4NM8). The reconstruction data reported have been deposited in the Electron Microscopy Data Bank, www.emdatabank.org (codes 5793 and 5794).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1319058110/-/DCSupplemental.
Freely available online through the PNAS open access option.
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