Gitr antagonists and methods of using the same

Patent metadata

Field	Value
Publication number	US-2022251227-A1
Application number	US-202217590135-A
Country	US
Kind code	A1
Filing date	Feb 1, 2022
Priority date	Feb 2, 2021
Publication date	Aug 11, 2022
Grant date	—

Abstract

The present disclosure relates to compounds that bind to human GITR, pharmaceutical compositions comprising such compounds, and methods of using such compounds.

First claim

1 . A compound comprising X, an antigen binding fragment that binds human GITR (SEQ ID NO: 20) and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein
i. the HCDR1 comprises SEQ ID NO: 1, ii. the HCDR2 comprises SEQ ID NO: 2 or SEQ ID NO: 7, iii. the HCDR3 comprises SEQ ID NO: 3, iv. the LCDR1 comprises SEQ ID NO: 4, v. the LCDR2 comprises SEQ ID NO: 5, and vi. the LCDR3 comprises SEQ ID NO: 6.

2 . The compound of claim 1 having the formula:
X-L-M or M-L-X,
wherein M is a VHH moiety that binds to human serum albumin; and
wherein L (if present) is a linker.

3 . The compound of claim 2 , wherein the VHH moiety comprises SEQ ID NO: 13, or an amino acid sequence having at least about 90% to about 99% sequence similarity thereto.

4 . The compound of claim 3 , wherein the VHH moiety is fused to the C-terminus of the heavy chain first constant domain (CH1) of the Fab fragment via L.

5 . The compound of claim 4 , wherein X comprises a VL having SEQ ID NO: 10.

6 . The compound of claim 5 , wherein X comprises a VH having SEQ ID NO: 8 or a VH having SEQ ID NO: 9.

7 . The compound of claim 6 , wherein L comprises a peptide linker selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO:23.

8 . The compound of claim 7 , wherein X comprises a light chain (LC) as shown in SEQ ID NO: 16.

9 . The compound of claim 8 , wherein X comprises a HC as shown in SEQ ID NO: 14 or a HC as shown in SEQ ID NO: 15.

10 . A nucleic acid comprising SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19.

11 . A vector comprising the nucleic acid of claim 10 .

12 . A cell comprising the vector of claim 11 .

13 . A process of producing a compound comprising culturing the cell of claim 12 under conditions such that the antibody is expressed and recovering the expressed antibody from the culture medium.

14 . A compound produced by the process of claim 13 .

15 . A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient, diluent or carrier.

16 . A method of treating a GITR associated disorder by inhibiting GITR activities in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

17 . The method of claim 16 , wherein the GITR associated disorder is an autoimmune disorder, allergic disease, asthma, atopic dermatitis (AtD), inflammatory disorder, joint inflammation, arthritis, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), Crohn's disease (CD) or ulcerative colitis (UC).

18 . A method of treating a GITR associated disorder by inhibiting GITR activities in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 15 .

19 . The method of claim 18 , wherein the GITR associated disorder is an autoimmune disorder, allergic disease, asthma, AtD, inflammatory disorder, joint inflammation, arthritis, RA, IBD, CD or UC.

Assignees

• Lilly Co Eli

Inventors

• Verdino Petra
• Cain Paul Francis
• Lacerte Melinda Ann
• Lee Stacey Lynn
• Wortinger Mark Andrew

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• C07K14/765

  Serum albumin, e.g. HSA · CPC title

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title

• C07K2317/569

  Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody® · CPC title