Full spectrum anti-dengue antibody

• US 10,519,220 B2
• Filed: 01/11/2018
• Issued: 12/31/2019
• 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:
  US15/868,328
• Publication Number:
  US 20180237504A1
• Time in Patent Office: 719 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 16/1081 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 that:

(a) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E5A (SEQ ID NO.

     29) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E5A (SEQ ID NO.

     30); and

(b) its heavy chain comprises one or more of the following mutations relative to 4E5A;

VH_S26_del; and

VH_G27_del or

VH_G27A.

2. The antibody agent of claim 1, wherein the antibody agent:

(a) competes with 4E5A for binding to an epitope within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), SEQ ID NO. 19 (EDIII-DV3), SEQ ID NO. 20 (EDIII-DV4);

(b) shows enhanced affinity for the epitope within SEQ ID NO. 20 (EDIII-DV4) relative to that shown by 4E5A; and

/or

(c) shows comparable affinity to that shown by 4E5A for the epitopes within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), and SEQ ID NO. 19 (EDIII-DV3).

3. A pharmaceutical composition comprising the antibody agent of claim 1 and at least one pharmaceutically acceptable carrier or excipient.

4. The method of claim 1, wherein:

the heavy chain comprises mutation VH_S26_del relative to 4E5A.

5. A method of treating a subject, the method comprising a step of:

administering to a subject suffering from or susceptible to Dengue virus an antibody agent that;

(a) has a heavy chain variable region that shows at least 95% substantial sequence homology with that of heavy chain variable region of 4E5A (SEQ ID NO.

     29) and a light chain variable region that shows at least 95% substantial sequence homology with that of light chain variable region of 4E5A (SEQ ID NO.

     30); and

(b) its heavy chain comprises one or more of the following mutations relative to 4E5A;

VH_S26_del; and

VH_G27_del or

VH_G27A.

6. The method of claim 5, wherein the antibody agent:

(a) competes with 4E5A for binding to an epitope within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), SEQ ID NO. 19 (EDIII-DV3), SEQ ID NO. 20 (EDIII-DV4);

(b) shows enhanced affinity for the epitope within SEQ ID NO. 20 (EDIII-DV4) relative to that shown by 4E5A; and

/or

(c) shows comparable affinity to that shown by 4E5A for the epitopes within each of SEQ ID NO. 17 (EDIII-DV1), SEQ ID NO. 18 (EDIII-DV2), and SEQ ID NO. 19 (EDIII-DV3).

7. A method of claim 5, wherein the step of administering comprises administering a pharmaceutical composition comprising:

the antibody agent; and

at least one pharmaceutically acceptable carrier or excipient, wherein the antibody agent is formulated for administration by a route selected from the group consisting of oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, subcutaneous (SQ), intraventricular, transdermal, interdermal, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical, mucosal, intranasal, buccal, enteral, vitreal, sublingual, intratracheal instillation, bronchial instillation, oral spray, nasal spray, aerosol, or through a portal vein catheter.

8. A method of claim 7, wherein:

the pharmaceutical composition is formulated for IV administration; and

the step of administering involves administration by intravenous infusion.

9. A method of claim 7, wherein:

the pharmaceutical composition is formulated for IM administration; and

the step of administration is by intramuscular injection.

10. A method of claim 7, wherein:

the pharmaceutical composition is formulated for SQ administration;

and the step of administration is by subcutaneous injection.

11. A method of claim 5, wherein:

the heavy chain comprises mutation VH_S26_del relative to 4E5A.