COMPOSITIONS AND METHODS OF TREATING MUSCLE ATROPHY AND MYOTONIC DYSTROPHY
Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle atrophy or myotonic dystrophy.
1 . A conjugate comprising an anti-transferrin receptor antibody or antigen binding fragment thereof conjugated to an oligonucleotide molecule, wherein the oligonucleotide molecule comprises a sequence with at least 16 consecutive nucleotides of SEQ ID NO: 7089.
2 . The conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length antibody, a Fab′ fragment, or a Fab fragment.
3 . The conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is conjugated to the oligonucleotide molecule via a linker.
4 . The conjugate of claim 3 , wherein the linker is a cleavable linker or a non-cleavable linker, wherein the linker is a heterobifunctional linker or a homobifunctional linker, and wherein the linker comprises a maleimide group, a dipeptide moiety, a benzoic acid group or derivatives thereof, a C 1 -C 6 alkyl group, or a combination thereof.
5 . The conjugate of claim 4 , wherein the maleimide group comprises succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sMCC) or sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC).
6 . The conjugate of claim 4 , wherein the dipeptide moiety comprises Val-Cit (valine-citrulline).
7 . The conjugate of claim 4 , wherein the benzoic acid group comprises paraaminobenzoic acid (PABA) or gamma-aminobutyric acid (GABA).
8 . The conjugate of claim 1 , wherein the oligonucleotide molecule comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety.
9 . The conjugate of claim 8 , wherein the at least one 2′ modified nucleotide comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-deoxy, 2′-deoxy-2′-fluoro, or locked nucleic acid (LNA).
10 . The conjugate of claim 8 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.
11 . The conjugate of claim 1 , wherein the oligonucleotide conjugate has an average DAR of 1 to 8.
12 . The conjugate of claim 1 , wherein the oligonucleotide conjugate has an average DAR of 1.
13 . The conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is conjugated to the oligonucleotide molecule through a lysine residue.
14 . A conjugate comprising: (a) a Fab fragment of an anti-transferrin receptor antibody; and (b) an oligonucleotide molecule consisting of 16 nucleotides, wherein the 16 nucleotides correspond to nucleotides 1-16 of SEQ ID No: 7089; wherein the oligonucleotide molecule is conjugated to the Fab fragment through a lysine residue of the Fab fragment via a linker; and wherein the conjugate has an average DAR of 1.