Antibody-STING agonist conjugates and their use in immunotherapy

Patent metadata

Field	Value
Publication number	US-11033635-B2
Application number	US-202016933845-A
Country	US
Kind code	B2
Filing date	Jul 20, 2020
Priority date	Jul 19, 2019
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

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. An antibody-drug conjugate (ADC) having the structure of Formula la:
Ab-[-L-D] n   (Formula Ia)

wherein:
“D” represents a cyclic di-nucleotide (CDN) 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 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;
“Ab” represents an antibody or binding fragment thereof which binds a target antigen;
“L” represents, independently for each occurrence, a linker linking one or more occurrences of D to Ab;
“n” represents the number of occurrences of D linked to Ab via the linker (L);
and wherein the CDN (D) is covalently bound to linker (L) at the amino, or C 1-6 alkylamino group at the R 1 position of the CDN.

2. The ADC of claim 1 , wherein D is a CDN having the structure of Formula IIm:

wherein
R 1 is ethyl substituted with an amino or C 1-6 alkylamino group; and
R P , independently for each occurrence, is hydroxyl or thiol;

or a pharmaceutically acceptable salt thereof.

3. The ADC of claim 2 , wherein the ADC is derived from a structure of Formula IIn:

or a pharmaceutically acceptable salt thereof.

4. The ADC of claim 1 , wherein the ADC has the structure of Formula III:

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

6. The ADC of claim 1 , wherein the ADC is derived from a CDN with the following structure:

or a pharmaceutically acceptable salt thereof.

7. The ADC of claim 1 , wherein L comprises a cleavable linker that is an acid-cleavable linker.

8. The ADC of claim 1 , wherein L comprises a cleavable linker that is a reducible linker.

9. The ADC of claim 8 , wherein the reducible linker is a disulfide linker.

10. The ADC of claim 1 , wherein L comprises a cleavable linker that is an enzyme-cleavable linker.

11. The ADC of claim 10 , wherein the enzyme-cleavable linker is selected from a polypeptide, tetrapeptide, dipeptide, and a β-glucuronide linker.

12. The ADC of claim 10 , wherein the enzyme cleavable linker is cleavable by a lysosomal enzyme that is a cathepsin.

13. The ADC of claim 1 , wherein L is coupled to Ab via a maleimide group, an activated disulfide, an active ester, a haloformate, an acid halide, an alkyl halide, or a benzyl halide.

14. The ADC of claim 1 , having a covalent linkage formed between L and Ab with a thiol group or primary amino group on Ab.

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

16. The ADC of claim 1 , wherein n is 1, 2, 3, 4, 5, 6, 7, or 8.

17. The ADC of claim 1 , wherein Ab is an antibody that binds to PD-L1, to an antigen that is a Growth Factor Receptor (GFR), to CD47, to an antigen preferentially expressed or overexpressed in cancer cells, or to an antigen derived from a microbe that infects human cells.

18. A pharmaceutical composition comprising the ADC of claim 1 and a pharmaceutically acceptable carrier.

19. A compound, wherein the compound is of Formula IIk:

wherein
W, X, Y, and Z are independently CH or N;
R 1 is ethyl substituted with 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, CC 1-6 alkyl, C 1-6 hydroxyalkoxy, —OC(O)C 1-6 alkyl, —N(H)C(O)C 1-6 alkyl, -N(Ci 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.

20. The compound of claim 19 , wherein R P , independently for each occurrence, is hydroxyl or thiol.

21. The compound of claim 19 , wherein Y and W are both CH.

22. The compound of claim 19 , wherein X and Z are both N.

23. The compound of claim 19 , wherein R 1 is ethyl substituted with an amino group.

24. The compound of claim 19 , wherein R 1 is ethyl substituted with a C 1-6 alkylamino group.

25. The compound of claim 19 , wherein both occurrences of R P are hydroxyl.

26. The compound of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The ADC of claim 5 , wherein both occurrences of R P are hydroxyl.

28. A pharmaceutical composition comprising the ADC of claim 6 and a pharmaceutically acceptable carrier.

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