Antibodies that bind ebola glycoprotein and uses thereof

Abstract

Isolated monoclonal antibodies which bind to Ebola virus glycoprotein and related antibody-based compositions and molecules are disclosed. Also disclosed are therapeutic and diagnostic methods for using the antibodies.

1 . A method for treating Ebola virus infection comprising administering to a subject in need thereof a composition comprising an effective amount of an isolated monoclonal antibody, or antigen binding portion thereof, which binds to Ebola virus glycoprotein, wherein the monoclonal antibody is selected from the group consisting of:
 (a) a monoclonal antibody comprising a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 39 and 14;   (b) a monoclonal antibody comprising a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 32 and 37; and   (c) a monoclonal antibody comprising a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 15 and 17;   and a pharmaceutically effective carrier.   
     
     
         2 . The method of  claim 1 , wherein the monoclonal antibody comprises a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 39 and 14 
     
     
         3 . The method of  claim 1 , wherein the monoclonal antibody comprises a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 32 and 37 
     
     
         4 . The method of  claim 1 , wherein the monoclonal antibody comprises a variable heavy chain and a variable light chain set forth in SEQ ID NOs: 15 and 17. 
     
     
         5 . A method for treating Ebola virus infection comprising administering to a subject in need thereof a composition comprising an effective amount of an isolated monoclonal antibody, or antigen binding portion thereof, which binds to Ebola virus glycoprotein, comprising:
 (a) a heavy chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 83, 84, and 85, respectively, and variable region framework residues selected from the group consisting of 44H, 48H, 70H, 72H, or a combination thereof (Kabat numbering convention) from the heavy chain variable region set forth in SEQ ID NO: 96, wherein the remainder of the heavy chain is from a human immunoglobulin; and   (b) a light chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 87, 88, and 89 respectively, wherein the remainder of the light chain is from a human immunoglobulin; or   (c) a heavy chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 74, 75, and 76, respectively, and variable region framework residues selected from the group consisting of 49H, 50H, or a combination thereof (Kabat numbering convention) from the heavy chain variable region set forth in SEQ ID NO: 94, wherein the remainder of the heavy chain is from a human immunoglobulin; and   (d) a light chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 80, 81, and 82, respectively, and variable region framework residues selected from the group consisting of 3L, 43L, 45L, 70L, 71L, 100L, or a combination thereof (Kabat numbering convention) from the light chain variable region set forth in SEQ ID NO: 95, wherein the remainder of the light chain is from a human immunoglobulin; or   (e) a heavy chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 45, 46, and 47, respectively, wherein the remainder of the heavy chain is from a human immunoglobulin; and   (f) a light chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 48, 50, and 51, respectively, wherein the remainder of the light chain is from a human immunoglobulin;   and a pharmaceutically effective carrier.   
     
     
         6 . A method for treating Ebola virus infection comprising administering to a subject in need thereof a composition comprising an effective amount of an isolated monoclonal antibody, or antigen binding portion thereof, which binds to Ebola virus glycoprotein, and comprises a heavy chain variable region and light chain variable region comprising an amino acid sequence at least 90% identical to the amino acid sequences selected from the group consisting of:
 (a) SEQ ID NOs: 15 and 17, respectively;   (b) SEQ ID NOs: 32 and 37, respectively; and   (c) SEQ IS NOs: 39 and 14, respectively;   
       wherein the monoclonal antibody is a neutralizing antibody and specifically binds to Ebola virus glycoprotein with an EC50 of 200 pM or less, as measured by ELISA;
 and a pharmaceutically effective carrier. 
 
     
     
         7 . The method of  claim 1 , wherein the monoclonal antibody exhibits at least one of the following properties:
 (a) binds to Ebola virus glycoprotein with an EC 50  of 200 pM or less, as measured by ELISA;   (b) binds to a conformational epitope on Ebola virus glycoprotein (SEQ ID NO: 91);   (c) binds within the region V505-C511 of Ebola virus glycoprotein (SEQ ID NO: 91);   (d) binds within the region N550-E564 of Ebola virus glycoprotein (SEQ ID NO: 91);   (e) binds within the region T270-P279 of Ebola virus glycoprotein (SEQ ID NO: 91);   (f) binds within the region Y394-R404 of Ebola virus glycoprotein (SEQ ID NO: 91); and   (g) engages immune components such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).   
     
     
         8 . The method of  claim 1 , wherein the monoclonal antibody binds to a conformational epitope on Ebola virus glycoprotein (SEQ ID NO: 91) that spans V505-C511 and N550-E564. 
     
     
         9 . The method of  claim 1 , wherein the monoclonal antibody binds to a conformational epitope on Ebola virus glycoprotein (SEQ ID NO: 91) that spans T270-P279 and Y394-R409. 
     
     
         10 . The method of  claim 1 , wherein the monoclonal antibody has neutralizing activity against the Zaire Ebola Virus. 
     
     
         11 . The method of  claim 1 , wherein the monoclonal antibody specifically binds to Ebola virus glycoprotein with an EC 50  of 200 pM or less, as measured by ELISA. 
     
     
         12 . The method of  claim 1 , wherein the monoclonal antibody is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, an IgD, and an IgE antibody. 
     
     
         13 . The method of  claim 12 , wherein the antibody is an IgG1 antibody. 
     
     
         14 . The method of  claim 5 , wherein the monoclonal antibody is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, an IgD, and an IgE antibody. 
     
     
         15 . The method of  claim 14 , wherein the antibody is an IgG1 antibody. 
     
     
         16 . The method of  claim 1 , further comprising administering a therapeutic agent. 
     
     
         17 . The method of  claim 16 , wherein the therapeutic agent is interferon alpha. 
     
     
         18 . The method of  claim 5 , further comprising administering a therapeutic agent. 
     
     
         19 . The method of  claim 18 , wherein the therapeutic agent is interferon alpha. 
     
     
         20 . A method for treating Ebola virus infection comprising administering to a subject in need thereof a composition comprising an effective amount of an isolated monoclonal antibody, or antigen binding portion thereof, which binds to Ebola virus glycoprotein, comprising:
 (a) a heavy chain and a light chain, wherein:
 (i) the heavy chain comprises CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 83, 84, and 85, respectively, and variable region framework residues selected from the group consisting of 44H, 48H, 70H, 72H, or a combination thereof (Kabat numbering convention) from the heavy chain variable region set forth in SEQ ID NO: 96, wherein the remainder of the heavy chain is from a human immunoglobulin; and 
 (ii) the light chain comprises CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 87, 88, and 89 respectively, wherein the remainder of the light chain is from a human immunoglobulin; or 
   (b) a heavy chain and light chain, wherein:
 (i) the heavy chain comprises CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 74, 75, and 76, respectively, and variable region framework residues selected from the group consisting of 49H, 50H, or a combination thereof (Kabat numbering convention) from the heavy chain variable region set forth in SEQ ID NO: 94, wherein the remainder of the heavy chain is from a human immunoglobulin; and 
 (ii) the light chain comprises CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 80, 81, and 82, respectively, and variable region framework residues selected from the group consisting of 3L, 43L, 45L, 70L, 71L, 100L, or a combination thereof (Kabat numbering convention) from the light chain variable region set forth in SEQ ID NO: 95, wherein the remainder of the light chain is from a human immunoglobulin; and wherein the monoclonal antibody binds to a conformational epitope on Ebola virus glycoprotein (SEQ ID NO: 91) comprising an amino acid sequence that spans V505-C511 and N550-E564; 
 and a pharmaceutically effective carrier. 
   
     
     
         21 . The method of  claim 20 , wherein the heavy and light chains set forth in (a) comprise a variable heavy chain and a variable light chain selected from the group consisting of:
 (i) SEQ ID NOs: 11 and 12, respectively;   (ii) SEQ ID NOs: 11 and 36, respectively;   (iii) SEQ IS NOs: 11 and 37, respectively;   (iv) SEQ ID NOs: 32 and 12, respectively;   (v) SEQ ID NOs: 32 and 36, respectively;   (vi) SEQ ID NOs: 32 and 37, respectively;   (vii) SEQ ID NOs: 33 and 12, respectively;   (viii) SEQ ID NOs: 33 and 36, respectively; and   (ix) SEQ ID NOs: 33 and 37, respectively.   
     
     
         22 . The method of  claim 20 , wherein the heavy and light chains set forth in (b) comprise a variable heavy chain and a variable light chain selected from the group consisting of:
 (i) SEQ ID NOs: 13 and 14, respectively;   (ii) SEQ ID NOs: 13 and 42, respectively;   (iii) SEQ ID NOs: 13 and 43, respectively;   (iv) SEQ ID NOs: 38 and 14, respectively;   (v) SEQ ID NOs: 38 and 42, respectively;   (vi) SEQ ID NOs: 38 and 43, respectively;   (vii) SEQ ID NOs: 39 and 42, respectively;   (viii) SEQ ID NOs: 39 and 43, respectively;   (ix) SEQ ID NOs: 40 and 14, respectively;   (x) SEQ ID NOs: 40 and 42, respectively; and   (xi) SEQ ID NOs: 40 and 43, respectively.   
     
     
         23 . A method for treating Ebola virus infection comprising administering to a subject in need thereof a composition comprising an effective amount of both isolated monoclonal antibodies of  claim 20  (a) and (b), or antigen binding portion thereof, which binds to Ebola virus glycoprotein, and an isolated monoclonal antibody or antigen binding portion thereof, which binds to Ebola virus glycoprotein, comprising:
 (a) a heavy chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 45, 46, and 47, respectively, wherein the remainder of the heavy chain is from a human immunoglobulin; and 
 (b) a light chain comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 48, 50, and 51, respectively, wherein the remainder of the light chain is from a human immunoglobulin.