Full spectrum anti-dengue antibody

• US 9,902,764 B2
• Filed: 02/11/2015
• Issued: 02/27/2018
• Est. Priority Date: 02/11/2014
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Sasisekharan, Ram, Tharakaraman, Kannan
• Primary Examiner(s): LI, BAO Q
• Application Number:
  US14/620,144
• Publication Number:
  US 20150368321A1
• Time in Patent Office: 1,112 Days
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/10 from RNA viruses
• CPC Class Codes: C07K 16/1081 Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• 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

The present invention provides, among other things, antibody agents (e.g., antibodies, and/or antigen-binding fragments thereof) that bind to DV epitopes, as well as compositions containing them and methods of designing, providing, formulating, using, identifying and/or characterizing them. In some embodiments, provided antibody agents show significant binding to a plurality of DV serotypes. In some embodiments, provided antibody agents show significant binding to all four DV serotypes. Such antibody agents are useful, for example, in the prophylaxis, treatment, diagnosis, and/or study of DV.

Claims

1. An antibody agent comprising at least one antibody, which at least one antibody comprises two heavy chains and two light chains, wherein:

the heavy chain CDRs are identical to reference CDRs found between residues 27 and 33, residues 53 and 58, and residues 100 and 106 of SEQ ID NO;

29 except that at least one of the heavy chain CDRs differs by a single amino acid substitution relative to its reference CDR; and

the light chain CDRs are identical to reference CDRs found between residues 24 and 38, residues 54 and 60, and residues 93 and 101 of SEQ ID NO;

30, or at least one of the light chain CDRs differs by a single amino acid substitution relative to its reference CDR, wherein the antibody agent;

(i) competes with reference antibody 4E5A for binding to Dengue Virus;

or

(ii) binds to an epitope that is or comprises an amino acid sequence within;

SEQ ID NO;

17 (EDIII-DV1), SEQ ID NO;

18 (EDIII-DV2), SEQ ID NO.;

19 (EDIIIDV3), SEQ ID NO;

20 (EDIII-DV4), or combinations thereof.

2. The antibody agent according to claim 1, wherein the antibody agent is an IgG.

3. The antibody agent according to claim 1, wherein the antibody agent is a monoclonal antibody.

4. A pharmaceutical composition comprising:

one or more antibody agents according to claim 1; and

a pharmaceutically acceptable carrier or excipient.

5. The pharmaceutical composition of claim 4, further comprising at least one additional antiviral agent.

6. A kit comprising:

the at least one antibody agent according to claim 1;

a syringe, needle, or applicator for administration of the at least one antibody or fragment thereof to a subject; and

instructions for use.

7. The antibody agent according to claim 1, wherein the antibody agent is selected from the group consisting of:

a mouse antibody, humanized antibody, a human antibody, and a chimeric antibody.

8. The antibody agent according to claim 1, wherein the antibody agent is selected from the group consisting of:

a purified antibody and an isolated antibody.

9. The antibody agent according to claim 1, wherein the antibody agent is a polyclonal antibody.

10. A vaccine composition comprising the antibody agent of claim 1.

11. The antibody agent according to claim 1, wherein the heavy chain CDRs include one of the following residues:

55Glu or

55Asp.

12. The antibody agent according to claim 1, wherein the light chain CDRs include one or more of the following residues:

31Lys;

57Glu or 57Ser;

59Gln or 59Ans; and

60Trp, 60Tyr, or 60Arg.

13. The antibody agent according to claim 1, wherein the heavy chain has a deletion of Ala25 relative to SEQ ID NO:

29.

14. The antibody agent according to claim 1, wherein the heavy chain has a deletion of Ser26 relative to SEQ ID NO:

29.

15. The antibody agent according to claim 1, wherein the heavy chain has a deletion of Gly27 relative to SEQ ID NO:

29.

16. The antibody agent according to claim 1, wherein the heavy chain has one or more of the following residues:

27Ala or 27Pro, and

106Arg.

17. A cell line expressing an antibody agent according to claim 1.

19. A method of treating a subject in need thereof, comprising administering the antibody agent according to claim 1.

20. A method of treating a subject in need thereof, comprising administering a pharmaceutical composition according to claim 4.

21. A method of manufacturing a pharmaceutical composition, the method comprising steps of:

providing the antibody agent according to claim 1; and

formulating the antibody agent with at least one pharmaceutically acceptable carrier or excipient,

so that a pharmaceutical composition is generated.

22. A method of detecting dengue virus, the method comprising steps of:

contacting an environmental sample with the antibody agent of claim 1; and

detecting dengue virus by detecting binding of the antibody to the sample.

23. The method of claim 22, wherein the environmental sample is or comprises one or more of soil, water and flora.

24. A diagnostic method comprising steps of:

contacting a patient sample with the antibody agent of claim 1; and

diagnosing the patient as suffering from infection with dengue virus by detecting binding of the antibody to the sample.

25. The method of claim 24, wherein the sample from a patient is selected from the group consisting of blood, serum/plasma, peripheral blood mononuclear cells/peripheral blood lymphocytes (PBMC/PBL), sputum, urine, feces, throat swabs, dermal lesion swabs, cerebrospinal fluids, cervical smears, pus samples, food matrices, and tissues from various parts of the body such as brain, spleen, and liver.

26. A method comprising administering the vaccine composition of claim 10 to a subject who is suffering from or susceptible to dengue virus infection.

18. An antibody agent comprising an antigen-binding fragment of an antibody that comprises two heavy chains and two light chains, wherein:

the heavy chain CDRs are identical to reference CDRs found between residues 27 and 33, residues 53 and 58, and residues 100 and 106 of SEQ ID NO;

29 except that at least one of the heavy chain CDRs differs by a single amino acid substitution relative to its reference CDR; and

the light chain CDRs are identical to reference CDRs found between residues 24 and 38, residues 54 and 60, and residues 93 and 101 of SEQ ID NO;

30, or at least one of the light chain CDRs differs by a single amino acid substitution relative to its reference CDR,

wherein;

the antigen-binding fragment comprises the heavy chain CDRs and the light chain CDRs; and

the antibody agent;

(i) competes with reference antibody 4E5A for binding to Dengue Virus;

or

(ii) binds to an epitope that is or comprises an amino acid sequence within;

SEQ ID NO;

17 (EDIII-DV1), SEQ ID NO;

18 (EDIII-DV2), SEQ ID NO.;

19 (EDIIIDV3), SEQ ID NO;

20 (EDIII-DV4), or combinations thereof.