Antibody-sting agonist conjugates and their use in immunotherapy

Patent metadata

Field	Value
Publication number	US-11213592-B2
Application number	US-202117317864-A
Country	US
Kind code	B2
Filing date	May 11, 2021
Priority date	Jul 19, 2019
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

The present disclosure relates to, among other things, antibody-drug conjugates comprising a STING agonist cyclic di-nucleotide conjugated to an antibody, preparation methods therefor, and uses therefor.

First claim

The invention claimed is:

1. A compound of the formula L-CDN, wherein
L is a linker that includes a site capable of coupling to a complementary site on an antibody or antigen-binding fragment;
CDN is a cyclic dinucleotide having the structure of Formula IIk:

wherein
W, X, Y, and Z are independently CH or N;
R 1 is C 2-4 alkyl substituted with a thiol, amino, an amino or C 1-6 alkylamino group;
R P is, independently for each occurrence, hydroxyl, thiol, C 1-6 alkyl, —BH 3 − , or —NR′R″, wherein R′ and R″ are, independently for each occurrence, hydrogen or C 1-6 alkyl optionally substituted with one or more groups selected from halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, —OC(O)C 1-6 alkyl, —N(H)C(O)C 1-6 alkyl, —N(C 1-3 alkyl)C(O)C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, and azido; or R′ and R″ on the same nitrogen together form a C 3-5 heterocyclic ring;

or a pharmaceutically acceptable salt thereof; and

CDN is coupled to L at the amino or C 1-6 alkylamino group of R 1 .

2. The compound of claim 1 , wherein CDN is coupled to L via an amide, a carbamate, or a urea group.

3. The compound of claim 2 , wherein the compound has the structure of Formula IXb:

wherein R L represents the remainder of the linker L.

4. The compound of claim 1 , wherein R P , independently for each occurrence, is hydroxyl or thiol.

5. The compound of claim 1 , wherein Y and W are both CH.

6. The compound of claim 1 , wherein X and Z are both N.

7. The compound of claim 1 , wherein R 1 is ethyl substituted with an amino group.

8. The compound of claim 1 , wherein R 1 is ethyl substituted with a C 1-6 alkylamino group.

9. The compound of claim 8 , wherein R 1 is ethyl substituted with a methylamino group.

10. The compound of claim 1 , wherein at least one occurrence of R P is hydroxyl.

11. The compound of claim 10 , wherein both occurrences of R P are hydroxyl.

12. The compound of claim 10 , wherein one occurrence of R P is hydroxyl and the other is thiol.

13. The compound of claim 1 , wherein at least one occurrence of R P is thiol.

14. The compound of claim 13 , wherein both occurrences of R P are thiol.

15. The compound of claim 1 , wherein the CDN has the following structure:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 2 , wherein CDN is coupled to L via a carbamate group.

17. The compound of claim 16 , wherein the compound has the following structure:

18. The compound of claim 16 , wherein the CDN has the following structure:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 2 , wherein the compound has the structure of Formula IXa:

wherein R L represents the remainder of the linker L.

20. The compound of claim 2 , wherein CDN is coupled to L via an amide group.

21. The compound of claim 20 , wherein the CDN has the following structure:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 2 , wherein the compound has the structure of Formula IXc:

wherein R L represents the remainder of the linker L.

23. The compound of claim 2 , wherein CDN is coupled to L via a urea group.

24. The compound of claim 23 , wherein the CDN has the following structure:

or a pharmaceutically acceptable salt thereof.

25. A compound of the formula L-CDN, wherein
L is a linker that includes a site capable of coupling to a complementary site on an antibody or antigen-binding fragment;
CDN is a cyclic dinucleotide having the structure of Formula IIk:

wherein
W, X, Y, and Z are independently CH or N;
R 1 is C 2-4 alkyl substituted with an amino group;
R P is, independently for each occurrence, hydroxyl or thiol;

or a pharmaceutically acceptable salt thereof; and

CDN is coupled to L at the amino group of R 1 via an amide, a carbamate, or a urea group.

26. The compound of claim 25 , wherein R 1 is ethyl substituted with an amino group.

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

• Chen Zhijian
• Shi Heping
• Wei Qi
• Chen Chuo
• Sun Lijun
• Qiu Jian
• Wu youtong

Classifications

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• A61K47/6807 Primary

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title