Compositions and methods for treating arenavirus infection
The invention generally provides compositions and methods of treating or preventing an arenavirus infection, using an agent that inhibits binding of an arenavirus glycoprotein 1 (GP1) polypeptide to transferrin receptor 1 (TfR1). The invention also provides methods of designing or identifying therapeutic agents that bind to or target a GP1 receptor-binding site (RBS) to inhibit arenavirus attachment to a cell, and therapeutic agents identified using the methods.
1. An isolated antibody or an antigen-binding fragment thereof that specifically binds to arenavirus glycoprotein 1 (GP1), wherein the antibody or the antigen binding fragment thereof comprises a heavy chain comprising three complementary determining region (CDR) sequences as follows:
CDR H1 sequence
(SEQ ID NO: 1)
GFTFGTSI
CDR H2 sequence
(SEQ ID NO: 2)
ISHDESRK
CDR H3 sequence
(SEQ ID NO: 3)
AKDLSPPYSYAWDIFQYW
and a light chain comprising three CDR sequences as follows:
CDR L1 sequence
(SEQ ID NO: 4)
QSVLYSSRSDNKY
CDR L2 sequence
(SEQ ID NO: 36)
WAS
CDR L3 sequence
(SEQ ID NO: 5)
QQYYSSPPTF;
or
wherein the antibody or the antigen binding fragment thereof comprises a heavy chain comprising three CDR sequences as follows:
CDR H1 sequence
(SEQ ID NO: 6)
GFTFSSA
CDR H2 sequence
(SEQ ID NO: 7)
IWSDGSNE
CDR H3 sequence
(SEQ ID NO: 8)
ATDKTYVSGYTSTWYYFNY
and a light chain comprising three CDR sequences as follows:
CDR L1 sequence
(SEQ ID NO: 9)
QSIDNW
CDR L2 sequence
(SEQ ID NO: 37)
KAS; and
CDR L3 sequence
(SEQ ID NO: 10)
QHRT.
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises the heavy chain sequence
(SEQ ID NO: 11)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSSAMHWVRQAPGKGLE
WVAVIWSDGSNENYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYY
CATDKTYVSGYTSTWYYFNYWGQGTLVTVS
and the light chain sequence
(SEQ ID NO: 12)
DIQMTQSPSTLSASVGDRVTITCRASQSIDNWLAWYQQKPGKAPKLLIY
TASRLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHRTFGQG
TKVEIK
or an antibody comprises the heavy chain sequence
(SEQ ID NO: 13)
QVQLVESGGGVVHPGRSLRLSCAASGFTFGTSIMHWVRQAPGKGM
QWVAQISHDESRKFYSDSVKGRFTVSRDNSKNTLFLEMSSLRIEDTA
VYYCAKDLSPPYSYAWDIFQYWGQGSLVTVS
and the light chain sequence
(SEQ ID NO: 14)
DIVMTQSPESLAVSLGERATINCKSSQSVLYSSRSDNKDYLAWYQQK
PGQSPKLLIYWASTRESGVPERFTGSGSGTDFTLSISSLQAEDVAVY
YCQQYYSSPPTFGGGTKVELK.
3. The isolated antibody or antigen-binding fragment thereof of claim 1 , that inhibits binding of GP1 and a transferrin receptor 1 (TfR1).
4. The isolated antibody or antigen-binding fragment thereof of claim 1 , that binds a TfR1 receptor binding site of GP1.
5. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the TfR1 receptor binding site comprises amino acids 87-235 of JUNV GP1 as shown in FIG. 8A and set forth in SEQ ID NO: 30, or corresponding amino acids of an arenavirus GP1.
6. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the TfR1 receptor binding site comprises one or more of amino acids Serine 111, Aspartate 113, Isoleucine 115, and Lysine 216, amino acids 113-124 (JUNV GP1 loop 3), and amino acids 166-174 (JUNV GP1 loop 3) of JUNV GP1 as shown in FIG. 8A and set forth in SEQ ID NO: 30, or corresponding amino acids of an arenavirus GP1 7-13.
7. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof binds to an arenavirus glycoprotein 1 (GP1) in a subject who is infected or at risk of infection with a New World arenavirus.
8. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof binds to an arenavirus glycoprotein 1 (GP1) of a New World arenavirus selected from Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabiá (SBAV), Chapare virus (CHPV), Tacaribe virus (TCRV), or White Water Arroyo virus (WWAV).
9. A method of inhibiting or preventing binding of a transferrin receptor 1 (TfR1) and an arenavirus glycoprotein 1 (GP1), the method comprising contacting a TfR1 with the isolated antibody or the antigen-binding fragment thereof of claim 1 .
10. A method of treating or preventing a New World arenavirus infection, the method comprising administering to a subject in need thereof the isolated antibody or the antigen-binding fragment thereof of claim 1 .
11. A kit comprising the antibody or antigen-binding fragment thereof of claim 1 .
12. The method of claim 9 , wherein the method is in vivo or in vitro.
13. The method of claim 9 , wherein the antibody or the antigen-binding fragment thereof binds a TfR1 receptor binding site of GP1.
14. The method of claim 13 , wherein the PRI receptor binding site comprises amino acids 87-235 of JUNV GP1 or corresponding amino acids of an arenavirus GP1.
15. The method of claim 13 , wherein the TfR1 receptor binding site comprises one or more of amino acids Serine 111, Aspartate 113, Isoleucine 115, and Lysine 216, amino acids 113-124 (JUNV GP1 loop and amino acids 166-174 (JUNV GP1 loop 3) of JUNV GP1 or corresponding amino acids of an arenavirus GP1.
16. The method of claim 13 , wherein the TfR1 receptor binding site interacts with Tyr211 of TfR1.
17. The method of claim 9 , wherein the arenavirus GP1 is from a New World arenavirus selected from Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SBA Chapare virus (CHPV), Tacaribe virus (TCRV), or White Water Arroyo virus (WWAV).
18. The method of claim 10 , wherein the subject has or is at risk of developing viral hemorrhagic fever.
19. The method of claim 10 , wherein the isolated antibody or the antigen-binding fragment thereof has neutralizing activity against New World arenavirus in the subject.