Antibodies to SARS coronavirus
The present invention relates to antibodies including human antibodies and antigen-binding portions thereof that specifically bind to human SARS-CoV S protein, and that function to neutralize SARS-CoV. The invention also relates to antibodies that are bispecific, derivatized, single chain antibodies or portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulins derived from human anti-SARS-CoV S protein antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention also relates to methods of using the antibodies and compositions for diagnosis and treatment. The invention also provides gene therapy methods using nucleic acid molecules encoding the heavy and/or light immunoglobulin molecules that comprise the human anti-SARS-CoV S protein antibodies. The invention also relates to transgenic animals or plants comprising nucleic acid molecules of the present invention.
1. An isolated human monoclonal antibody, or antigen-binding portion thereof, that specifically binds SARS-CoV S protein, comprising light chain variable (VL) and heavy chain variable (VH) domains that are at least 99% identical in amino acid sequence to the VL domain shown as SEQ ID NO:60 and the VH domain shown as SEQ ID NO:58, respectively, of the monoclonal antibody 3C7.
2. An isolated human monoclonal antibody, or antigen-binding portion thereof, that specifically binds SARS-CoV S protein, comprising:
(a) a heavy chain variable domain amino acid sequence that comprises the amino acid sequence of SEQ ID NO:58
(b) a light chain variable domain amino acid sequence that comprises the amino acid sequence of SEQ ID NO:60; or
(c) a heavy chain variable domain of (a) and a light chain variable domain of (b).
3. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds human SARS-CoV S protein, comprising:
(a) a heavy chain variable domain that comprises the amino acid sequences of the heavy chain CDR1, CDR2 and CDR3 of the antibody 3C7 shown in SEQ ID NO:58; and
(b) a light chain variable domain that comprises the amino acid sequences of the light chain CDR1, CDR2 and CDR3 of the antibody 3C7 shown in SEQ ID NO:60.
4. An isolated monoclonal antibody that specifically binds SARS-CoV S protein comprising:
(a) a heavy chain of the antibody 3C7 that comprises the amino acid sequence of SEQ ID NO:58;
(b) a light chain of the antibody 3C7 that comprises the amino acid sequence of SEQ ID NO:60; or
(c) a heavy chain of (a) and a light chain of (b).
5. A composition comprising at least one isolated monoclonal antibody, or antigen-binding portion thereof, of claim 1 , 2 , 3 or 4 , and further comprising a pharmaceutically-acceptable carrier.
6. The composition according to claim 5 , further comprising at least one additional therapeutic agent selected from the group consisting of:
(a) one or more antibodies or an antigen binding portion thereof, wherein said antibody is from the group consisting of: 1B5, 1G3, 2E8.1, 2E8.2, 2B10.1, 2B10.2, 2B10.3, 2B10.4, 3A7, 3C7, 3F3, 3H12, 4E2, 4A10, 4D4.1, 4D4.2, 4D4.3, 4G2, 5E1.1.1, 5E1.1.2, 5E1.2, 5E1.3, 5E10.1, 5E10.2, 5E4, 5A5, 5A7, 5C12.1, 5C12.2, 5D1.1, 5D1.2, 5D1.3, 5D1.4, 5D1.5, 5D3, 5D6, 6B1, 6B5, 6B8 , 6C1, and 6C2;
(b) one or more antibodies that specifically bind SARS-CoV S protein of a different SARS-CoV strain;
(c) one or more SARS-CoV neutralizing antibodies, wherein said antibodies do not bind SARS-CoV S protein;
(d) one or more agents that bind a SARS-CoV S protein receptor and blocks binding of S protein to the receptor; and
(e) one or more anti-viral agents.
7. The composition according to claim 5 , further comprising at least two antibodies that specifically bind to different regions of human SARS-CoV S protein selected from the group consisting of: amino acid residues 1-1255 (SEQ ID NO: 94), a region that is at least 80% identical to SEQ ID NO:94, amino acid residues 12-261 (SEQ ID NO: 95), a region that is at least 80% identical to SEQ ID NO:95, amino acid residues 318-510(SEQ ID NO:96), a region that is at least 80% identical to SEQ ID NO:96, amino acid residues 15-680(SEQ ID NO:97), and a region that is at least 80% identical to SEQ ID NO:97.
8. An isolated cell line that produces the antibody, or the antigen-binding portion thereof, of claims 1 , 2 , 3 or 4 .
9. A method for decreasing S protein-mediated SARS-CoV binding to cells, the method comprising the step of contacting the S protein with the composition of claim 5 .
10. The method according to claim 9 , wherein said cells express angiotensin converting enzyme 2 (Ace2).
11. A method for decreasing a SARS-CoV S protein-mediated activity, comprising contacting the S protein with the composition of claim 5 .
12. The method according to claim 11 , wherein the SARS-CoV S protein-mediated activity is selected from: viral attachment to a cell, fusing of viral membrane with a cell, or combinations thereof.
13. The method according to claim 11 , wherein the method is performed in a subject.
14. The antigen-binding portion according to any of claims 1 - 3 or 4 , wherein the antigen-binding portion is selected from the group consisting of Fab, Fab′, F(ab′) 2 , Fd, Fv, dAb, single-chain antibodies (scFv), chimeric antibodies, and diabodies.
15. The isolated human monoclonal antibody or antigen-binding portion according to any of claims 1 - 3 or 4 , wherein said antibody or antigen-binding portion is labeled.