Antibody molecules to dengue virus and uses thereof

• US 9,365,639 B2
• Filed: 10/23/2015
• Issued: 06/14/2016
• 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:
  US14/921,701
• Publication Number:
  US 20160046697A1
• Time in Patent Office: 235 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. 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.