IP Library › Granted Patent US 12,216,122
Granted Patent B2
US 12,216,122 · App. 16/879,611 · Granted Feb 4, 2025

Compositions and methods relating to detection, inhibition, and imaging of indoleamine 2,3-dioxygenase 1 (IDO1)

Inventors: Heather Dawn Agnew (Culver City, CA); Bert Tsunyin Lai (Culver City, CA); Anders Eliasen (Culver City, CA)
Assignee: Regeneron Pharmaceuticals, Inc.
G01N33/573C07K5/10C07K7/06C12N9/0069G01N33/68C07K2319/70C12Q2521/501C12Y113/11052G01N33/534G01N2333/90241
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Quick Facts
Patent No.
US 12,216,122
App. No.
16/879,611
Granted
Feb 4, 2025
Kind
B2
Abstract

The present application provides stable heterobiligands made up of peptide-based IDO1 ligands and small molecule inhibitors of IDO1 and methods of use of the heterobiligands as detection, imaging, diagnostic, and therapeutic agents. The application further provides methods of manufacturing IDO1 heterobiligands, capture agents, and imaging agents.

Claims (25)

1. A heterobiligand comprising a first ligand having affinity for an epitope on indoleamine 2,3-dioxygenase 1 (IDO1), a linker, and a second ligand, wherein the second ligand comprises a small molecule inhibitor of IDO1, wherein the linker links the first ligand and the second ligand, wherein the heterobiligand specifically binds and inhibits IDO1, wherein IDO1 comprises an active site, and wherein the small molecule inhibitor of IDO1 binds the IDO1 active site, wherein the first ligand comprises an amino acid sequence selected from the group consisting of wyvay (SEQ ID NO:2), wyaay (SEQ ID NO: 8), (F-Phe)n(Me-Trp)(Me-Trp)w (SEQ ID NO:5), (F-Phe)rhl(Me-Trp) (SEQ ID NO: 9), (F-Phe)t(Me-Trp)y(Me-Trp) (SEQ ID NO:10), G(F-Phe)nwk (SEQ ID NO:11), (Me-Trp)ffkf (SEQ ID NO:12), ndn(Me-Trp)w (SEQ ID NO:13), npv(F-Phe)w (SEQ ID NO: 14), ntk(Me-Trp)p (SEQ ID NO:15), n(Me-Trp)p(Me-Trp)f (SEQ ID NO:16), pp(Me-Trp)s(Me-Trp) (SEQ ID NO:17), yyy(Me-Trp)t (SEQ ID NO:18), and yfn(Me-Trp)(Me-Trp) (SEQ ID NO:19); and

wherein the small molecule inhibitor of IDO1 is

wherein X is S, O, or NH, wherein R 1 is —CH 2 —R 2 —, —(CH 2 ) n —R 2 —, absent, —(CH 2 —CH 2 —O) m —CH 2 —CH 2 —R 2 —, or —CH 2 —CH 2 —NH—SO 2 —R 2 —, wherein R 2 is —CO— or —NH—, wherein n is an integer from 2 to 10, wherein m is an integer from 1 to 6.

2. The heterobiligand of claim 1 , wherein the small molecule inhibitor of IDO1 is

wherein X is S, wherein R 1 is —CH 2 —R 2 —, and wherein R 2 is —CO—.

3. The heterobiligand of claim 1 , wherein the small molecule inhibitor of IDO1 is

wherein X is NH, and wherein R 1 is absent.

4. The heterobiligand of claim 1 , wherein the small molecule inhibitor of IDO1 is

wherein X is NH, wherein R 1 is —CH 2 —CH 2 —NH—SO 2 —R 2 —, and wherein R 2 is —NH—.

5. The heterobiligand of claim 1 , wherein the first ligand comprises 5 to 9 amino acids.

6. The heterobiligand of claim 1 , wherein the epitope comprises the amino acid sequence GFWEDPKEFAGGSAGQSSVFQ (SEQ ID NO:1).

7. The heterobiligand of claim 1 , wherein the first ligand comprises a 1,4-substituted-1,2,3-triazole residue (Tz4) or a 1,5-substituted-1,2,3-triazole residue (Tz5).

8. The heterobiligand of claim 1 , wherein the triazole residue is a 1,4-substituted-1,2,3-triazole (Tz4) residue.

9. The heterobiligand of claim 1 , wherein the length of the linker is from about 11 Å to about 38 Å.

10. The heterobiligand of claim 1 , wherein the heterobiligand further comprises a detectable moiety.

11. The heterobiligand of claim 10 , wherein the detectable moiety is selected from the group consisting of biotin, copper-DOTA, biotin-PEG 3 , aminooxyacetate, 19 FB, 18 FB, and FITC-PEG 3 .

12. The heterobiligand of claim 10 , wherein the detectable moiety is selected from the group consisting of 64 Cu DOTA, 68 Ga DOTA, 68 Ga NOTA, 18 F, Al 18 F NOTA, 64 Cu, 68 Ga, 89 Zr, 124 I, 86 Y, 94m Tc, 110m In, 11 C and 76 Br.

13. The heterobiligand of claim 10 , wherein the detectable moiety is 18 F.

14. The heterobiligand of claim 1 , wherein the heterobiligand has the structure:

wherein the sequence X 1 X 2 X 3 X 4 X 5 is selected from the group consisting of wyvay (SEQ ID NO: 2), (F-Phe)n(Me-Trp)(Me-Trp)w (SEQ ID NO:5), (F-Phe)rhl(Me-Trp) (SEQ ID NO:9), (F-Phe)t(Me-Trp)y(Me-Trp) (SEQ ID NO:10), G(F-Phe)nwk (SEQ ID NO:11), (Me-Trp)ffkf (SEQ ID NO: 12), ndn(Me-Trp)w (SEQ ID NO:13), npv(F-Phe)w (SEQ ID NO:14), ntk(Me-Trp)p (SEQ ID NO:15), n(Me-Trp)p (Me-Trp)f (SEQ ID NO:16), pp(Me-Trp)s(Me-Trp) (SEQ ID NO: 17), yyy(Me-Trp)t (SEQ ID NO:18), and yfn(Me-Trp)(Me-Trp) (SEQ ID NO:19), and

wherein the linker is PEG 4 , PEG 6 , PEG 7 , or PEG 8 .

15. The heterobiligand of claim 14 , wherein the heterobiligand has the following structure:

wherein PEG 6 , PEG 7 , or PEG 8 .

16. The heterobiligand of claim 14 , wherein the linker is PEG 4 or PEG 6 .

17. The heterobiligand of claim 14 , wherein the heterobiligand has the structure:

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 26, 2023
From: INDI MOLECULAR, INC.
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 065356/0723 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2020
From: AGNEW, HEATHER DAWN; LAI, BERT TSUNYIN; ELIASEN, ANDERS
To: INDI MOLECULAR, INC.
Reel/Frame 052938/0683 →
Continuity (2)
Provisional Application 62850533 · May 20, 2019
Related Publication 20200371101A1 · Nov 26, 2020
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