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. An isolated antibody molecule capable of binding dengue virus, 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).
2. The antibody molecule of claim 1 , which comprises a VH FW1 having the sequence QVQLVQSGAEVKKPGASVKVSCKAGFNIK (SEQ ID NO: 11).
3. The antibody molecule of claim 1 , which comprises a VH FW2 having the sequence WVRQAPGQGLEWMG (SEQ ID NO: 84) or WVRQAPEQGLEWMG (SEQ ID NO: 85).
4. The antibody molecule of claim 1 , which comprises a VH FW1 comprising a deletion of position 26 relative to SEQ ID NO: 33.
5. The antibody molecule of claim 1 , which is capable of binding to dengue virus EDIII (E protein domain III).
6. The antibody molecule of claim 1 , which comprises the VH amino acid sequence of SEQ ID NO: 1.
7. The antibody molecule of claim 1 , which comprises the VL amino acid sequence of SEQ ID NO: 2.
8. The antibody molecule of claim 1 , which is a Fab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
9. The antibody molecule of claim 1 , which comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, and IgG4.
10. The antibody molecule of claim 1 , which comprises a light chain constant region chosen from the light chain constant regions of kappa or lambda.
11. The antibody molecule of claim 1 , which is a humanized antibody molecule.
12. The antibody molecule of claim 1 , which contains one or more framework regions derived from a human framework germline sequence.
13. The antibody molecule of claim 1 , which is capable of binding to dengue virus EDIII with a dissociation constant (K D ) of less than about 30 nM.
14. The antibody molecule of claim 1 , which is capable of binding to dengue virus serotype DV-4 EDIII with a dissociation constant (K D ) of less than about 10 nM.
15. The antibody molecule of claim 1 , which is capable of binding to DV-3 or DV-4 EDIII domain with at least a 6-fold greater affinity than antibody A11 or antibody 4E11.
16. The antibody molecule of claim 1 , which is capable of binding to a dengue virus strain selected from DENV-4 BC2, DENV-4-Sing, DENV-4 NC, DENV-4 Phil, DENV-3 Sing, DENV-3 Nic, DENV-3 H87, DENV-2 Peru, DENV-2 Sing, DENV-2 NGC, DENV-1 Hawaii/1944, DENV-2 New Guinea/1944 (NGC), DENV-3 Philippines/1956 (H87), DENV-4 Mexico/1997 (BC287/97), and DENV-4 H241, with at least 2-fold greater affinity than antibody A11 or antibody 4E11.
17. The antibody molecule of claim 1 , which is capable of neutralizing dengue virus in a focus reduction neutralization test.
18. The antibody molecule of claim 1 , which is capable of neutralizing dengue virus with an IC50 that is at least 2-fold lower than antibody A11 or antibody 4E11 in a focus reduction neutralization test.
19. A pharmaceutical composition comprising the antibody molecule of claim 1 and a pharmaceutically acceptable carrier, excipient, or stabilizer.
20. A kit comprising a container having disposed therein the antibody molecule of claim 1 ; a pharmaceutically acceptable carrier, excipient, or stabilizer; and optionally a delivery device.
21. The antibody molecule of claim 1 , which comprises the VH amino acid sequence of SEQ ID NO: 1 and the VL amino acid sequence of SEQ ID NO: 2.