Antibody molecules to dengue virus and uses thereof
Antibody molecules that specifically bind to dengue virus are disclosed. In certain embodiments, the antibody molecule bind to dengue virus serotypes DV-1, DV-2, DV-3, and DV-4. The antibody molecules can be used to treat, prevent, and/or diagnose dengue virus.
1. A method of neutralizing dengue virus, the method comprising contacting the dengue virus with an antibody molecule capable of binding to the dengue virus, wherein the antibody molecule comprises:
(a) a heavy chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence DVYMS (SEQ ID NO: 3),
a CDR2 comprising the sequence RIDPENGDTKYDPKLQG (SEQ ID NO: 4), and
a CDR3 comprising the sequence GWEGFAY (SEQ ID NO: 5); and
(b) a light chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence RASENVDKYGNSFMH (SEQ ID NO: 6),
a CDR2 comprising the sequence RASELQW (SEQ ID NO: 7), and
a CDR3 comprising the sequence QRSNEVPWT (SEQ ID NO: 8), thereby neutralizing dengue virus.
2. The method of claim 1 , wherein the dengue virus is of serotype DV-1, DV-2, DV-3, and DV-4.
3. A method of inhibiting dengue virus, the method comprising administering to a subject in need thereof an antibody molecule capable of binding to the dengue virus, wherein the antibody molecule comprises:
(a) a heavy chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence DVYMS (SEQ ID NO: 3),
a CDR2 comprising the sequence RIDPENGDTKYDPKLQG (SEQ ID NO: 4), and
a CDR3 comprising the sequence GWEGFAY (SEQ ID NO: 5); and
(b) a light chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence RASENVDKYGNSFMH (SEQ ID NO: 6),
a CDR2 comprising the sequence RASELQW (SEQ ID NO: 7), and
a CDR3 comprising the sequence QRSNEVPWT (SEQ ID NO: 8), thereby inhibiting dengue virus.
4. The method of claim 3 , wherein the antibody molecule neutralizes dengue virus serotypes DV-1, DV-2, DV-3, and DV-4.
5. The method of claim 3 , wherein the subject is infected with dengue virus.
6. The method of claim 3 , wherein the antibody molecule is administered to the subject prior to the subject being exposed to dengue virus.
7. The method of claim 3 , wherein the antibody molecule is administered to the subject prior to onset of one or more manifestations of dengue virus.
8. The method of claim 3 , wherein the antibody molecule comprises a VH FW1 having the sequence QVQLVQSGAEVKKPGASVKVSCKAGFNIK (SEQ ID NO: 11) or a FW1 of the VH amino acid sequence of SEQ ID NO: 36.
9. The method of claim 3 , wherein the antibody molecule comprises a VH FW2 having the sequence WVRQAPGQGLEWMG (SEQ ID NO: 84) or WVRQAPEQGLEWMG (SEQ ID NO: 85).
10. The method of claim 3 , wherein the antibody molecule comprises the VH amino acid sequence of SEQ ID NO: 1.
11. The method of claim 3 , wherein the antibody molecule comprises the VL amino acid sequence of SEQ ID NO: 2.
12. The method of claim 3 , wherein the antibody molecule comprises the VH amino acid sequence of SEQ ID NO: 1 and the VL amino acid sequence of SEQ ID NO: 2.
13. The method of claim 3 , wherein the antibody molecule is a Fab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
14. The method of claim 3 , wherein the antibody molecule comprises a heavy chain constant region chosen from IgG1, IgG2, IgG3, or IgG4.
15. The method of claim 3 , wherein the antibody molecule comprises a light chain constant region chosen from the light chain constant regions of kappa or lambda.
16. The method of claim 3 , wherein the antibody molecule comprises one or more framework regions derived from a human framework germline sequence.
17. The method of claim 3 , wherein the antibody molecule is capable of binding to dengue virus EDIII (E protein domain III).
18. The method of claim 17 , wherein the antibody molecule is capable of binding to dengue virus EDIII with a dissociation constant (K D ) of less than about 30 nM.
19. The method of claim 17 , wherein the antibody molecule is capable of binding to dengue virus serotype DV-4 EDIII with a dissociation constant (K D ) of less than about 10 nM.
20. The method of claim 17 , wherein the antibody molecule is capable of binding to DV-3 or DV-4 EDIII domain with at least a 6-fold greater affinity than an antibody comprising the VH amino acid sequence of SEQ ID NO: 33 and the VL amino acid sequence of SEQ ID NO: 34 or antibody 4E11.
21. The method of claim 3 , wherein the antibody molecule is capable of binding to an EDIII polypeptide from a dengue virus strain chosen from DENV-1/Vietnam/2008, DENV-1/Malaysia/2005, DENV-1/Mexico/2007, DENV-2/Singapore/2008, DENV-2/Venezuela/2007, DENV-2/Peru/1995, DENV-2/Vietnam/2007, DENV-3/Cambodia/2008, DENV-3/Singapore/2009, DENV-3/Nicaragua/2010, DENV-3/Puerto Rico/1977, DENV-4/Venezuela/2008, DENV-4/Singapore/2010, DENV-4/New Caledonia/2009, DENV-4/Brazil/2011, DENV-4/Thailand/1997, or DENV-4/Philippines/1956 (H241), with at least 2-fold greater affinity than an antibody comprising the VH amino acid sequence of SEQ ID NO: 33 and the VL amino acid sequence of SEQ ID NO: 34 or antibody 4E11.
22. The method of claim 3 , wherein the antibody molecule is capable of neutralizing dengue virus in a focus reduction neutralization test.
23. The method of claim 3 , wherein the antibody molecule is capable of neutralizing dengue virus with an IC50 that is at least 2-fold lower than an antibody comprising the VH amino acid sequence of SEQ ID NO: 33 and the VL amino acid sequence of SEQ ID NO: 34 or antibody 4E11 in a focus reduction neutralization test.
24. The method of claim 3 , further comprising administering an anti-viral agent to the subject.
25. The method of claim 24 , wherein the anti-viral agent is chosen from one or more of balapiravir, chloroquine, celgosivir, ivermectin, or Carica folia.
26. The method of claim 24 , wherein the anti-viral agent is an anti-dengue antibody different from the antibody molecule comprising:
(a) a heavy chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence DVYMS (SEQ ID NO: 3),
a CDR2 comprising the sequence RIDPENGDTKYDPKLQG (SEQ ID NO: 4), and
a CDR3 comprising the sequence GWEGFAY (SEQ ID NO: 5); and
(b) a light chain immunoglobulin variable region segment comprising:
a CDR1 comprising the sequence RASENVDKYGNSFMH (SEQ ID NO: 6),
a CDR2 comprising the sequence RASELQW (SEQ ID NO: 7), and
a CDR3 comprising the sequence QRSNEVPWT (SEQ ID NO: 8).
27. The method of claim 24 , wherein the anti-viral agent is chosen from one or more of an alpha-glucosidase I inhibitor, an adenosine nucleoside inhibitor, an inhibitor of NS3 and/or its cofactor NS2B, an RNA-dependent RNA polymerase (RdRp) inhibitor, an inhibitor of host pyrimidine biosynthesis, an inhibitor of viral NS4B protein, or an iminosugar.
28. The method of claim 27 , wherein the alpha-glucosidase I inhibitor is celgosivir, the adenosine nucleoside inhibitor is NITD008, the inhibitor of NS3 and/or its cofactor NS2B is a [5-amino-1-(phenyl)sulfonyl-pyrazol-3-yl] compound, the RNA-dependent RNA polymerase (RdRp) inhibitor is NITD107, the inhibitor of host pyrimidine biosynthesis is an inhibitor of host dihydroorotate dehydrogenase (DHODH) selected from NITD-982 or brequinar, the inhibitor of viral NS4B protein is NITD-618, or the iminosugar is UV-4.
29. The method of claim 3 , further comprising administering a vaccine to the subject.
30. The method of claim 3 , wherein administration is parenteral or intravenous.