Granted Patent B2

US 12,234,290 · App. 17/187,669 · Granted Feb 25, 2025

Inventors: Andrew John Geall (Carlsbad, CA); Venkata Ramana Doppalapudi (San Diego, CA); David Sai-Ho Chu (La Jolla, CA); Michael Caramian Cochran (La Jolla, CA); Rachel Elizabeth Johns (San Diego, CA); Palani Balu (Cupertino, CA); Rob Burke (Encinitas, CA); Beatrice Diana Darimont (San Diego, CA)

Assignee: AVIDITY BIOSCIENCES, INC.

C07K16/2863A61K31/7088A61K31/713A61K47/60A61K47/6807A61K47/6851A61K47/6889A61K48/0033A61K48/005A61K48/0075A61P35/00A61P35/02C07K16/2851C07K16/30C07K16/3061C12N15/113C12N15/1135C12N15/1138C12N15/88A61K2039/505C07K2317/21C07K2317/24C07K2317/55C07K2317/569C07K2317/622C12N2310/14C12N2310/315C12N2310/321C12N2310/3231C12N2310/332C12N2310/3513C12N2310/3515C12N2320/32

Abstract

Claims (32)

1. A method of treating a disease or disorder in a patient in need thereof, comprising administering to said patient a composition comprising a molecule of Formula (I):

A-X 1 —B—X 2 —C  Formula I

wherein,

A is an antibody or antigen binding fragment thereof;

B consists of a double-stranded polynucleotide consisting of a passenger strand and a guide strand;

C is a polymer;

X 1 is a bond or first non-polymeric linker; and

X 2 is a bond or second non-polymeric linker;

wherein the double-stranded polynucleotide comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety; and

wherein A and C are attached in the same strand, but not attached to B at the same terminus.

2. The method of claim 1 , wherein the disease or disorder is a cancer.

3. The method of claim 2 , wherein the cancer is a solid tumor or a hematologic malignancy.

4. The method of claim 2 , wherein the cancer is selected from a KRAS-associated cancer, an EGFR-associated cancer, an androgen receptor (AR)-associated cancer, a beta-catenin associated cancer, a PIK3C-associated cancer, and a MYC-associated cancer.

5. The method of claim 2 , wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma multiforme, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and thyroid cancer.

6. The method of claim 3 , wherein the hematologic malignancy is selected from acute myeloid leukemia, CLL, DLBCL, and multiple myeloma.

7. The method of claim 1 , wherein the at least one 2′ modified nucleotide comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2-O-aminopropyl, 2′-deoxy, 2′-deoxy-2′-fluoro, 2-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide.

8. The method of claim 1 , wherein the at least one 2′ modified nucleotide comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA).

9. The method of claim 1 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.

10. The method of claim 1 , wherein the at least one inverted abasic moiety is at least one terminus.

11. The method of claim 1 , wherein the passenger strand or guide strand comprises at least one modification.

12. The method of claim 1 , wherein the passenger strand and the guide strands are RNA molecules.

13. The method of claim 1 , wherein the passenger strand comprises a sequence selected from SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, and 2117.

14. The method of claim 1 , wherein the guide strand comprises a sequence selected from SEQ ID NOs: 16-75, 452-1955, 1956-1962, 1967-2002, 2013-2032, 2082-2109, and 2117.

15. The method of claim 1 , wherein X 1 and X 2 are independently a bond.

16. The method of claim 1 , wherein X 1 and X 2 are independently a C 1 -C 6 alkyl group.

17. The method of claim 1 , wherein X 1 is a homobifunctional linker or a heterobifunctional linker, optionally conjugated to a C 1 -C 6 alkyl group.

18. The method of claim 1 , wherein X 2 is a homobifunctional linker or a heterobifunctional linker.

19. The method of claim 1 , wherein the antibody or antigen binding fragment thereof comprises a humanized antibody or antigen binding fragment thereof, chimeric antibody or antigen binding fragment thereof, monoclonal antibody or antigen binding fragment thereof, monovalent Fab′, divalent Fab2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single-domain antibody (sdAb), or camelid antibody or antigen binding fragment thereof.

20. The method of claim 1 , wherein C is polyethylene glycol.

21. The method of claim 20 , wherein C has a molecular weight of about 1000 Da, 2000 Da, or 5000 Da.

22. The method of claim 1 , wherein A-X 1 is conjugated to the 5′ end of the passenger strand or guide strand and X 2 —C is conjugated to the 3′ end of B, or X 2 —C is conjugated to the 5′ end of B and A-X 1 is conjugated to the 3′ end of the passenger strand or guide strand.

23. The method of claim 1 , wherein X 2 —C is conjugated to the 5′ end of the passenger strand or guide strand and A-X 1 is conjugated to the 3′ end of the passenger strand or guide strand.

Assignments (3)

Continuity (3)

References Cited (400)