Antibody molecules to dengue virus and uses thereof

• US 9,212,217 B2
• Filed: 01/20/2015
• Issued: 12/15/2015
• Est. Priority Date: 02/11/2014
• Status: Active Grant

• Current Assignee: Visterra, Inc. (Otsuka Holdings Company Limited)
• Original Assignee: Visterra, Inc. (Otsuka Holdings Company Limited)
• Inventors: Robinson, Luke, Shriver, Zachary, Myette, James, Babcock, Gregory, Viswanathan, Karthik
• Primary Examiner(s): CHEN, STACY BROWN
• Application Number:
  US14/600,306
• Publication Number:
  US 20150225474A1
• Time in Patent Office: 329 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07K 16/1081 Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: G01N 2333/185 Flaviviruses or Group B arboviruses, e.g. yellow fever virus, japanese encephalitis, tick-borne encephalitis, dengue
• CPC Class Codes: G01N 33/56983 Viruses
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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.