Arenavirus monoclonal antibodies and uses

Abstract

Disclosed herein are compositions comprising arenavirus monoclonal antibodies, as well as therapeutic, diagnostic, and preventative methods using the novel antibodies. Preventative methods include preparation of vaccines, as well as factors (e.g. small molecules, peptides) that inhibit Old World arenavirus infectivity, including LASV and LCMV. In some embodiments, the antibodies provide pan-arenavirus protection against a number of arenavirus types and strains. Diagnostic and therapeutic antibodies including neutralizing antibodies for the prevention and treatment of infection by LASV and other arenaviruses are also disclosed, as well as new tools and methods for the design, production, and use of arenavirus monoclonal antibodies, including expression in engineered bacterial- and mammalian-based systems.

What is claimed is: 
     
         1 . An antigen-binding composition comprising a neutralizing antibody or neutralizing antigen-binding antibody fragment thereof specific to glycoprotein 1 (GP1), glycoprotein 2 (GP2), glycoprotein precursor (GPC), or full-length glycoprotein (GP) of Lassa virus (LASV), wherein the antibody or antibody fragment comprises a heavy chain variable region (V H ) and a light chain variable region (V L ), the V H  and V L  each comprising complementarity determining regions CDR1, CDR2 and CDR3 selected from the group consisting of:
 (a) a V H  CDR1 of SEQ ID NO: 71, a V H  CDR2 of SEQ ID NO: 72, a V H  CDR3 of SEQ ID NO: 73, a V L  CDR1 of SEQ ID NO: 117, a V L  CDR2 of sequence Trp Ala Ser, and a V L  CDR3 of SEQ ID NO: 118;   (b) a V H  CDR1 of SEQ ID NO: 74, a V H  CDR2 of SEQ ID NO: 75, a V H  CDR3 of SEQ ID NO: 76, a V L  CDR1 of SEQ ID NO: 119, a V L  CDR2 of sequence Glu Val Lys, and a V L  CDR3 of SEQ ID NO: 120;   (c) a V H  CDR1 of SEQ ID NO: 77, a V H  CDR2 of SEQ ID NO: 78, a V H  CDR3 of SEQ ID NO: 79, a V L  CDR1 of SEQ ID NO: 121, a V L  CDR2 of sequence Asp Ala Ser, and a V L  CDR3 of SEQ ID NO: 122;   (d) a V H  CDR1 of SEQ ID NO: 80, a V H  CDR2 of SEQ ID NO: 81, a V H  CDR3 of SEQ ID NO: 82, a V L  CDR1 of SEQ ID NO: 123, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 124;   (e) a V H  CDR1 of SEQ ID NO: 83, a V H  CDR2 of SEQ ID NO: 84, a V H  CDR3 of SEQ ID NO: 85, a V L  CDR1 of SEQ ID NO: 125, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 126;   (f) a V H  CDR1 of SEQ ID NO: 86, a V H  CDR2 of SEQ ID NO: 87, a V H  CDR3 of SEQ ID NO: 88, a V L  CDR1 of SEQ ID NO: 127, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 128;   (g) a V H  CDR1 of SEQ ID NO: 89, a V H  CDR2 of SEQ ID NO: 90, a V H  CDR3 of SEQ ID NO: 91, a V L  CDR1 of SEQ ID NO: 129, a V L  CDR2 of sequence Glu Val Arg, and a V L  CDR3 of SEQ ID NO: 130;   (h) a V H  CDR1 of SEQ ID NO: 92, a V H  CDR2 of SEQ ID NO: 93, a V H  CDR3 of SEQ ID NO: 94, a V L  CDR1 of SEQ ID NO: 131, a V L  CDR2 of sequence Glu Val Ser, and a V L  CDR3 of SEQ ID NO: 132;   (i) a V H  CDR1 of SEQ ID NO: 95, a V H  CDR2 of SEQ ID NO: 96, a V H  CDR3 of SEQ ID NO: 97, a V L  CDR1 of SEQ ID NO: 133, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 134;   (j) a V H  CDR1 of SEQ ID NO: 101, a V H  CDR2 of SEQ ID NO: 102, a V H  CDR3 of SEQ ID NO: 103, a V L  CDR1 of SEQ ID NO: 137, a V L  CDR2 of sequence Gln Ala Ser, and a V L  CDR3 of SEQ ID NO: 138;   (k) a V H  CDR1 of SEQ ID NO: 104, a V H  CDR2 of SEQ ID NO: 105, a V H  CDR3 of SEQ ID NO: 106, a V L  CDR1 of SEQ ID NO: 139, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 140;   (l) a V H  CDR1 of SEQ ID NO: 107, a V H  CDR2 of SEQ ID NO: 108, a V H  CDR3 of SEQ ID NO: 109, a V L  CDR1 of SEQ ID NO: 141, a V L  CDR2 of sequence Gly Ala Tyr, and a V L  CDR3 of SEQ ID NO: 142; and   (m) a V H  CDR1 of SEQ ID NO: 110, a V H  CDR2 of SEQ ID NO: 111, a V H  CDR3 of SEQ ID NO: 112, a V L  CDR1 of SEQ ID NO: 143, a V L  CDR2 of sequence Ala Ala Val, and a V L  CDR3 of SEQ ID NO: 144.   
     
     
         2 . The composition of  claim 1 , wherein the composition comprises two or more of said antibodies or antigen-binding antibody fragments. 
     
     
         3 . The composition of  claim 1 , wherein the composition comprises:
 (1) an antibody or antigen-binding antibody fragment comprising a V H  CDR1 of SEQ ID NO: 83, a V H  CDR2 of SEQ ID NO: 84, a V H  CDR3 of SEQ ID NO: 85, a V L  CDR1 of SEQ ID NO: 125, a V L  CDR2 of sequence Gly Ala Ser, and a V L  CDR3 of SEQ ID NO: 126; or   (2) an antibody or antigen-binding antibody fragment comprising a V H  CDR1 of SEQ ID NO: 92, a V H  CDR2 of SEQ ID NO: 93, a V H  CDR3 of SEQ ID NO: 94, a V L  CDR1 of SEQ ID NO: 131, a V L  CDR2 of sequence Glu Val Ser, and a V L  CDR3 of SEQ ID NO: 132.   
     
     
         4 . The composition of  claim 1 , wherein the antibody is selected from the group consisting of a monoclonal antibody, and a recombinantly produced antibody. 
     
     
         5 . The composition of  claim 1 , wherein the antibody comprises a human monoclonal antibody. 
     
     
         6 . The composition of  claim 1 , wherein the antigen-binding antibody fragment is selected from the group consisting of a Fab, a Fab′, and a F(ab′) 2  fragment. 
     
     
         7 . A nucleic acid having a sequence that encodes for a V H  of the antibody or the antibody fragment of the composition of  claim 1 . 
     
     
         8 . The nucleic acid of  claim 7 , wherein the nucleic acid includes a nucleic acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. 
     
     
         9 . A nucleic acid having a sequence that encodes for a V L  of the antibody or the antibody fragment of the composition of  claim 1 . 
     
     
         10 . The nucleic acid of  claim 9 , wherein the nucleic acid includes a nucleic acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 15, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32. 
     
     
         11 . An expression vector that contains the nucleic acid sequence of  claim 7 . 
     
     
         12 . An antigen-binding composition comprising a neutralizing antibody or neutralizing antigen-binding antibody fragment thereof specific to glycoprotein 1 (GP1), glycoprotein 2 (GP2), glycoprotein precursor (GPC), or full-length glycoprotein (GP) of Lassa virus (LASV), wherein the antibody or antibody fragment comprises a heavy chain variable region (V H ) and a light chain variable region (V L ) selected from the group consisting of:
 (a) a V H  of SEQ ID NO: 35 and a V L  of SEQ ID NO: 51;   (b) a V H  of SEQ ID NO: 36 and a V L  of SEQ ID NO: 52;   (c) a V H  of SEQ ID NO: 37 and a V L  of SEQ ID NO: 53;   (d) a V H  of SEQ ID NO: 38 and a V L  of SEQ ID NO: 54;   (e) a V H  of SEQ ID NO: 39 and a V L  of SEQ ID NO: 55;   (f) a V H  of SEQ ID NO: 40 and a V L  of SEQ ID NO: 56;   (g) a V H  of SEQ ID NO: 41 and a V L  of SEQ ID NO: 57;   (h) a V H  of SEQ ID NO: 42 and a V L  of SEQ ID NO: 58;   (i) a V H  of SEQ ID NO: 43 and a V L  of SEQ ID NO: 59;   (j) a V H  of SEQ ID NO: 45 and a V L  of SEQ ID NO: 61;   (k) a V H  of SEQ ID NO: 46 and a V L  of SEQ ID NO: 62;   (l) a V H  of SEQ ID NO: 47 and a V L  of SEQ ID NO: 63; and   (m) a V H  of SEQ ID NO: 48 and a V L  of SEQ ID NO: 64.   
     
     
         13 . The composition of  claim 12 , wherein the composition comprises two or more of said antibodies or antigen-binding antibody fragments. 
     
     
         14 . The composition of  claim 12 , wherein the composition comprises:
 (1) an antibody or antigen-binding antibody fragment comprising a V H  of SEQ ID NO: 39 and a V L  of SEQ ID NO: 55; or   (2) an antibody or antigen-binding antibody fragment comprising a V H  of SEQ ID NO: 42 and a V L  of SEQ ID NO: 58.   
     
     
         15 . The composition of  claim 12 , wherein the antibody is selected from the group consisting of a monoclonal antibody, and a recombinantly produced antibody. 
     
     
         16 . The composition of  claim 12 , wherein the antibody comprises a human monoclonal antibody. 
     
     
         17 . The composition of  claim 12 , wherein the antigen-binding antibody fragment is selected from the group consisting of a Fab, a Fab′, and a F(ab′) 2  fragment. 
     
     
         18 . A nucleic acid having a sequence that encodes for a V H  of the antibody or the antibody fragment of the composition of  claim 12 . 
     
     
         19 . A nucleic acid having a sequence that encodes for a V L  of the antibody or the antibody fragment of the composition of  claim 12 . 
     
     
         20 . A vaccine for preventing or treating infection of a patient by Lassa virus comprising the antibody or antibody fragment of the composition of  claim 1 . 
     
     
         21 . The vaccine of  claim 22 , which is cross-protective against infection by a lymphocytic choriomeningitis virus. 
     
     
         22 . A pharmaceutical composition for treating or preventing infection by a Lassa virus or a lymphocytic choriomeningitis virus comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         23 . A diagnostic kit for detecting infection of a subject by Lassa virus or other arenaviridae comprising at least one antibody or antibody fragment of the composition of  claim 1  bound to a detectable labelling group. 
     
     
         24 . An antibody or antibody fragment of the composition of  claim 1  bound to a detectable labelling group. 
     
     
         25 . A method of detecting infection by a Lassa virus or a lymphocytic choriomeningitis virus comprising contacting a biological sample from a subject with at least one antibody or antibody fragment of the composition of  claim 1  bound to a detectable labelling group; and detecting a complex between the antibody or antibody fragment and a Lassa virus or other arenaviridae present in the sample. 
     
     
         26 . A method of treating a Lassa virus infection in a subject comprising administering the antibody or antibody fragment of the composition of  claim 1  to the subject. 
     
     
         27 . A method of treating a lymphocytic choriomeningitis virus infection in a subject comprising administering the antibody or antibody fragment of the composition of  claim 1  to the subject.