Human Antibodies to Middle East Respiratory Syndrome - Coronavirus Spike Protein

Abstract

The present invention provides monoclonal antibodies that bind to the Middle East Respiratory Syndrome—Coronavirus (MERS-CoV) spike protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to MERS-CoV spike protein. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing MERS-CoV activity, thus providing a means of treating or preventing MERS infection in humans. In some embodiments, the invention provides for a combination of one or more antibodies that bind to the MERS-CoV spike protein for use in treating MERS infection. In certain embodiments, the one or more antibodies bind to distinct non-competing epitopes comprised in the receptor binding domain of the MERS-CoV spike protein.

What is claimed is: 
     
         1 . A composition comprising:
 (a) a first anti-Middle East Respiratory Syndrome-Coronavirus spike protein (MERS-CoV-S) antibody or antigen-binding fragment thereof;   (b) a second anti-MERS-CoV-S antibody or antigen-binding fragment thereof; and   (c) a pharmaceutically acceptable carrier or diluent;   wherein said first anti-MERS-CoV-S antibody does not cross-compete with said second anti-MERS-CoV-S antibody.   
     
     
         2 . The composition of  claim 1 , wherein said first antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) contained within any one of the heavy chain variable region (HCVR) amino acid sequences selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) contained within any one of the light chain variable region (LCVR) amino acid sequences selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450. 
     
     
         3 . The composition of  claim 2 , wherein said first antibody or antigen-binding fragment thereof comprises said HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 from an HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450. 
     
     
         4 . The composition of  claim 2 , wherein said first antibody or antigen-binding fragment thereof comprises an HCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442. 
     
     
         5 . The composition of  claim 4 , wherein said first antibody or antigen-binding fragment thereof comprises an LCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450. 
     
     
         6 . The composition of  claim 5 , wherein said first antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of:
 SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450.   
     
     
         7 . The composition of  claim 2 , wherein said second antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) contained within any one of the heavy chain variable region (HCVR) amino acid sequences selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) contained within any one of the light chain variable region (LCVR) amino acid sequences selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450. 
     
     
         8 . The composition of  claim 7 , wherein said second antibody or antigen-binding fragment thereof comprises said HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 from an HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450. 
     
     
         9 . The composition of  claim 8 , wherein said second antibody or antigen-binding fragment thereof comprises an HCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442. 
     
     
         10 . The composition of  claim 9 , wherein said second antibody or antigen-binding fragment thereof comprises an LCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450. 
     
     
         11 . The composition of  claim 10 , wherein said second antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of:
 SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450.   
     
     
         12 . The composition of  claim 11 , wherein said first antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of:
 SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450 and said second antibody or antigen-binding fragment thereof comprises a different HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450.   
     
     
         13 . The composition of  claim 12 , wherein said first antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid pair of SEQ ID NOs: 218/226 and said second antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid pair of SEQ ID NOs: 66/74. 
     
     
         14 . The composition of any one of  claims 1 - 13 , wherein:
 a) said first antibody or antigen-binding fragment thereof is an antibody;   b) said second antibody or antigen-binding fragment thereof is an antibody; or   c) both.   
     
     
         15 . The composition of  claim 14 , wherein the antibodies of a), or b), or c) are IgG1 antibodies or IgG4 antibodies. 
     
     
         16 . The composition of  claim 14 , wherein the antibodies of a), or b), or c) have one or more of the following characteristics:
 a) is a fully human monoclonal antibody   b) interacts with one or more amino acid residues in the receptor binding domain of the MERS-CoV spike protein selected from amino acid residues 367 to 606 of SEQ ID NO: 457;   c) binds to MERS-CoV spike protein with a dissociation constant (KD) of less than 18.5 nM, as measured in a surface plasmon resonance assay;   d) blocks binding of MERS-CoV spike protein to dipeptidyl peptidase 4 (DPP4) by more than 90%, as measured in a blocking ELISA assay;   e) neutralizes MERS-CoV infectivity of human host cells by more than 90% and with IC 50  less than 4 nM, as measured in a virus-like particle (VLP) neutralization assay; and   f) neutralizes MERS-CoV infectivity wherein the MERS-CoV comprises an isolate of the virus selected from the group consisting of EMC/2012, Jordan-N3/2012, England-Qatar/2012, Al-Hasa_1_2013, Al-Hasa_2_2013, Al-Hasa_3_2013, Al-Hasa_4_2013, Al-Hasa_12, Al-Hasa_15, Al-Hasa_16, Al-Hasa 17, Al-Hasa_18, Al-Hasa_19, Al-Hasa_21, Al-hasa_25, Bisha_1, Buraidah_1, England 1, Hafr-Al-batin_1, Hafr-Al-Batin_2, Hafr-Al-Batin_6, Jeddah_1, KFU-HKU 1, KFU-HKU 13, Munich, Qatar3, Qatar4, Riyadh_1, Riyadh_2, Riyadh_3, Riyadh_3, Riyadh_4, Riyadh_5, Riyadh_9, Riyadh_14, Taif_1, UAE, and Wadi-Ad-Dawasir.