Granted Patent B2

US 11,434,486 · App. 15/760,667 · Granted Sep 6, 2022

Inventors: Gabor Butora (Cambridge, MA); Andrew W. Fraley (Arlington, MA); Edward John Miracco (Cambridge, MA); Jennifer Nelson (Brookline, MA); Amy Rhoden Smith (Watertown, MA); Matthew Stanton (Marlton, NJ)

Assignee: ModernaTX, Inc.

C12N15/113C12N15/111C12N2310/317C12N2310/321C12N2310/3231C12N2310/3233C12N2310/351C12N2320/51

Abstract

Claims (60)

1. A compound, or a pharmaceutically acceptable salt thereof, comprising:

a) a first polynucleotide; and

b) a nucleotide, a second polynucleotide, targeting moiety, small molecule, polypeptide, or polymer,

wherein the first polynucleotide is conjugated to the nucleotide, second polynucleotide, targeting moiety, small molecule, polypeptide, or polymer via a linker comprising the structure of Formula I:

wherein B is a nucleobase, hydrogen, halo, hydroxy, thiol, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted amino, azido, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 12 heterocycle;

X 1 is O, S, NR U , or C(R U ) 2 , wherein each R U is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;

X 2 is —O—, —NR N1 —, —NR N1 NR N1 —, a bond, optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted C 2 -C 10 heterocyclylene, optionally substituted C 6 -C 12 arylene, optionally substituted C 2 -C 100 polyethylene glycolene, or optionally substituted C 1 -C 30 heteroalkylene, wherein R N1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 6 -C 10 aryl;

m is 1, 2, 3, 4, or 5;

each L is, independently, an unbranched or branched linker; and

R 1 and R 2 are each, independently, hydroxyl, or C 1 -C 6 alkoxy.

2. The compound of claim 1 , wherein said compound comprises the structure of Formula II:

wherein A 1 is said first polynucleotide and comprises:

(a) at least one 5′-cap structure;

each C 1 independently comprises said second polynucleotide, a targeting moiety, a small molecule, a polypeptide, or a polymer;

L 1 is an unbranched linker;

L 2 is a branched linker;

n is 0, 1, 2, or 3;

o is 0 or 1;

p is 1, 2, 3, 4, or 5;

X 2 —O—, —NR N1 —, —NR N1 NR N1 —, a bond, optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted C 2 -C 10 heterocyclylene, optionally substituted C 6 -C 12 arylene, optionally substituted C 2 -C 100 polyethylene glycolene, or optionally substituted C 1 -C 30 heteroalkylene, wherein RN N1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 6 -C 10 aryl;

Y 1 is O, S, Se, optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene;

each Y 2 and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted C 1 -C 6 alkylene, or optionally substituted C 1 -C 6 heteroalkylene, wherein RN N1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 6 -C 10 aryl; and

each Y 4 is, independently, H, hydroxy, protected hydroxy, halo, thiol, boranyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, or optionally substituted amino.

3. The compound of claim 2 , wherein A 1 is said first polynucleotide and comprises, in the 5′-to-3′ direction:

(b) a 5′-untranslated region (UTR);

(c) a coding region; and

(d) a 3′-UTR.

4. The compound of claim 2 , wherein said compound comprises the structure of Formula III:

wherein q is 0, 1, 2, 3, 4, or 5.

5. The compound of claim 2 , wherein said compound comprises the structure of Formula IV:

6. The compound of claim 5 , wherein said compound comprises the structure of Formula V:

wherein r and s are each, independently, 1, 2, 3, 4, or 5.

7. The compound of claim 2 , wherein the compound comprises the structure of Formula XXII:

8. The compound of claim 2 , wherein L 1 comprises the structure of Formula VI:

wherein a, b, c, e, f, and g are each, independently, 0 or 1;

d is 0, 1, 2, or 3;

each of R 3 , R 5 , R 7 , and R 9 , is, independently, selected from optionally substituted C 1 -C 6 alkylene, optionally substituted C 1 -C 6 heteroalkylene, optionally substituted C 2 -C 100 polyethylene glycolene, O, S, Se, and NR 10 ;

R 4 and R 8 are each, independently, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

each R 6 is optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted C 2 -C 10 heterocyclylene, optionally substituted C 6 -C 10 arylene, optionally substituted C 2 -C 100 polyethylene glycolene, or optionally substituted C 1 -C 10 heteroalkylene, or a bond linking (R 3 ) a —(R 4 ) b —(R 5 ) c to (R 7 ) e —(R 8 ) f —(R 9 ) g ; and

R 10 is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted C 2 -C 6 heterocyclyl, optionally substituted C 6 -C 12 aryl, or optionally substituted C 1 -C 7 heteroalkyl.

9. The compound of claim 2 , wherein said compound comprises the structure of Formula VII:

10. The compound of claim 2 , wherein said compound has the structure of Formula VIII:

11. The compound of claim 2 , wherein said compound comprises the structure of Formula IX:

12. The compound of claim 2 , wherein said compound comprises the structure of Formula X:

13. The compound of claim 2 , wherein the compound comprises the structure of Formula XI:

or a salt thereof

wherein t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

u is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

14. The compound of claim 2 , wherein the compound comprises the structure of Formula XII:

or a salt thereof,

wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

15. The compound of claim 2 , wherein the compound comprises the structure of Formula XXIII:

16. The compound of claim 2 , wherein C 1 comprises said second polynucleotide.

17. The compound of claim 16 , wherein said second polynucleotide comprises a plurality of adenosines.

18. The compound of claim 17 , wherein all of the nucleosides of said second polynucleotide are adenosines.

19. The compound of claim 16 , wherein said second polynucleotide comprises at least one alternative nucleoside.

20. The compound of claim 19 , wherein said alternative nucleoside is L-adenosine, 2′-O-methyl-adenosine, alpha-thio-2′-O-methyl-adenosine, 2′-fluoro-adenosine, arabino-adenosine, hexitol-adenosine, LNA-adenosine, PNA-adenosine, or inverted thymidine.

21. The compound of claim 2 , wherein C 1 comprises a targeting moiety.

22. The compound of claim 3 , wherein at least one of said coding region, said 5′-UTR, said 3′-UTR, and said 5′-cap structure of A comprises at least one alternative nucleoside.

23. The compound of claim 22 , wherein said alternative nucleoside is a 5-substituted uridine, a 1-substituted pseudouridine, or a 5-substituted cytidine.

Assignments (6)