IP Library › Patent Application 18265065

Patent Application

App. No. 18/265,065

ANTIBODY-OLIGONUCLEOTIDE COMPLEXES AND USES THEREOF

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Patent No.: US None
App. No.: 18/265,065

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Abstract

Provided herein are oligonucleotide-antibody complexes, methods of preparing the complexes, and methods of using the complexes (e.g., treating muscle diseases). In particular, provided are compounds of Formula (I) and various methods for the preparation of the compounds. Also provided are pharmaceutical compositions comprising compounds of Formula (I) and methods of treating muscle disease in a subject by administering a compound or composition described herein.

Claims (138)

1 . A method of preparing a compound of Formula (I):

or a salt thereof, the method comprising coupling a targeting agent (Q) with a compound of Formula (II):

or a salt thereof, to provide a compound of Formula (I), wherein:

T is

or —S—;

T 1 is

S═C═N—, or

R 3 is a leaving group;

R 4 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group;

L 1 is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, —O—, —N(R A )—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NR A —, —NR A C(═O)—, —NR A C(═O)R A —, —C(═O)R A —, —NR A C(═O)O—, —NR A C(═O)N(R A )—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R A )—, —S(O) 2 NR A —, —NR A S(O) 2 —, or a combination thereof;

A is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A is absent and L 1 is bonded directly to the triazole ring;

L 2 is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, —O—, —N(R A )—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NR A —, —NR A C(═O)—, —NR A C(═O)R A —, —C(═O)R A —, —NR A C(═O)O—, —NR A C(═O)N(R A )—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R A )—, —S(O) 2 NR A —, —NR A S(O) 2 —, or a combination thereof;

X is a cleavable moiety;

R 1 is substituted or unsubstituted arylene, or substituted or unsubstituted alkylene, or a combination thereof;

X 1 is a bond or a peptide;

L 3 is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, —O—, —N(R A )—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NR A —, —NR A C(═O)—, —NR A C(═O)R A —, —C(═O)R A —, —NR A C(═O)O—, —NR A C(═O)N(R A )—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R A )—, —S(O) 2 NR A —, —NR A S(O) 2 —, or a combination thereof;

each R A is independently hydrogen or substituted or unsubstituted alkyl; and

R is a molecular payload.

2 . The method of claim 1 , further comprising reacting a compound of Formula (III):

or a salt thereof, with a compound of Formula (IV):

or a salt thereof, to provide a compound of Formula (II);

wherein A 1 is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A 1 is absent and L 1 is bonded directly to one terminus of the alkyne.

3 . The method of claim 2 , further comprising reacting a compound of Formula (V):

or a salt thereof, with a compound of Formula (VI):

or a salt thereof, to provide a compound of Formula (IV), wherein:

R 5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

4 . The method of claim 3 , further comprising reacting a compound of Formula (VII):

or a salt thereof, with a compound of Formula (VIII):

or a salt thereof, to provide a compound of Formula (V), wherein:

R 5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

5 . The method of claim 4 , further comprising reacting a compound of Formula (IX):

or a salt thereof, with a compound of Formula (X):

N 3 -L 2 -LG (X);

or a salt thereof, to provide a compound of Formula (VII), wherein:

LG is a leaving group.

6 . The method of claim 1 , wherein the compound of Formula (I) is of Formula (I-c):

or a salt thereof, and the compound of Formula (II) is of Formula (I-c):

or a salt thereof, wherein:

each occurrence of Z is independently an amino acid;

each occurrence of Y is independently an amino acid; and

each m is independently 1, 2, or 3.

7 . The method of claim 1 , further comprising purifying the compound of Formula (II).

8 . A method of preparing a compound of Formula (I):

or a salt thereof, the method comprising reacting a compound of Formula (IV):

or a salt thereof, with a compound of Formula (B):

or a salt thereof, to provide a compound of Formula (I), wherein:

Q is targeting agent;

T is

or —S—;

A is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A is absent and L 1 is bonded directly to the triazole ring;

A 1 is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A 1 is absent and L 1 is bonded directly to one terminus of the alkyne;

X is a cleavable moiety;

R 1 is substituted or unsubstituted arylene, or substituted or unsubstituted alkylene, or a combination thereof;

X 1 is a bond or a peptide;

each R A is independently hydrogen or substituted or unsubstituted alkyl; and

R is a molecular payload.

9 . The method of claim 8 , further comprising coupling a targeting agent (Q) with a compound of Formula (III):

or a salt thereof, to provide a compound of Formula (B), wherein:

T is

S═C═N—, or

R 3 is a leaving group; and

10 . The method of claim 9 , further comprising reacting a compound of Formula (V):

or a salt thereof, with a compound of Formula (VI):

or a salt thereof, to provide a compound of Formula (IV), wherein:

R 5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

11 . The method of any claim 10 , further comprising reacting a compound of Formula (VII):

or a salt thereof, with a compound of Formula (VIII):

or a salt thereof, to provide a compound of Formula (V), wherein:

R 5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

12 . The method of claim 11 , further comprising reacting a compound of Formula (IX):

or a salt thereof, with a compound of Formula (X):

N 3 -L 2 -LG (X);

or a salt thereof, to provide a compound of Formula (VII), or a salt thereof, wherein:

LG is a leaving group.

13 . The method of claim 8 , wherein the compound of Formula (I) is of Formula (I-c):

or a salt thereof, the compound of Formula (IV) is of Formula (IV-a):

or a salt thereof, and the compound of Formula (B) is of Formula (B-a):

or a salt thereof, wherein:

each occurrence of Z is independently an amino acid;

each occurrence of Y is independently an amino acid; and

each m is independently 1, 2, or 3.

14 . A method of preparing a compound of Formula (I):

or a salt thereof, the method comprising reacting a targeting agent (Q); a compound of Formula (IV):

or a salt thereof; and a compound of Formula (III):

or a salt thereof; to provide a compound of Formula (I), or a salt thereof, wherein:

T is

or —S—;

T 1 is

S═C═N—, or

R 3 is a leaving group (e.g., halogen, tosylate, mesylate, or triflate);

A is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A is absent and L 1 is bonded directly to the triazole ring;

A 1 is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A 1 is absent and L 1 is bonded directly to one terminus of the alkyne;

X is a cleavable moiety;

R 1 is substituted or unsubstituted arylene, or substituted or unsubstituted alkylene, or a combination thereof;

X 1 is a bond or a peptide;

each R A is independently hydrogen or substituted or unsubstituted alkyl; and

R is a molecular payload.

15 . The method of claim 14 , wherein the compound of Formula (I) is of Formula (I-c):

or a salt thereof, the compound of Formula (IV) is of Formula (IV-b):

or a salt thereof, and the compound of Formula (III) is of Formula (III-a):

or a salt thereof, wherein:

each occurrence of Z is independently an amino acid;

each occurrence of Y is independently an amino acid; and

each m is independently 1, 2, or 3.

16 . The method of claim 1 , wherein

Q is an antibody; and R is an oligonucleotide.

17 . The method of claim 1 , wherein

Q is an anti-TfR antibody; and R is a phosphorodiamidate morpholino oligomer (PMO).

18 . A compound of Formula (I):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotopically enriched derivative thereof, wherein:

Q is a targeting agent;

T is

or —S—;

A is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, or A is absent and L 1 is bonded directly to the triazole ring;

X is a cleavable moiety;

R 1 is substituted or unsubstituted arylene, or substituted or unsubstituted alkylene, or a combination thereof;

X 1 is a bond or a peptide;

each R A is independently hydrogen or substituted or unsubstituted alkyl; and

R is a molecular payload.

19 . The compound of claim 18 , wherein the compound is of Formula (I-c):

or a salt thereof, wherein:

each occurrence of Z is independently an amino acid;

each occurrence of Y is independently an amino acid; and

each m is independently 1, 2, or 3.

20 . The compound of claim 18 , wherein:

Q is an antibody; and R is an oligonucleotide.

21 . (canceled)

Assignments (2)

SECURITY INTEREST Recorded Jun 27, 2025

From: DYNE THERAPEUTICS, INC.

To: HERCULES CAPITAL, INC., AS AGENT

Reel/Frame 071777/0300 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2023

From: HILDERBRAND, SCOTT; NAJIM, JOHN; QIU, QIFENG; VIEIRA, BENJAMIN; WEEDEN, TIMOTHY; SPRING, SEAN

To: DYNE THERAPEUTICS, INC.

Reel/Frame 064630/0739 →