Muscle targeting complexes and formulations for treating facioscapulohumeral muscular dystrophy

A complex comprising a structure of formula (I):

• [R1]n1—R2, wherein each R1 comprises a group of the formula (Ia):
• or a pharmaceutically acceptable salt thereof,
• wherein R3 comprises an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of SEQ ID NO:
• 22 and a structure (5′→3′) of VP-mU*fG*mCmCmAmGmAmAmUmUmUmCmAfCmGmGmAmAmGmAmA*mC*mA, and
• a sense strand comprising a nucleobase sequence of SEQ ID NO:
• 21 and a structure (5′→3′) of mU*mU*mCmUfUmCmCmGfUfGfAmAmAfUmUmCmUmGfG*mC*mA, wherein:
• mA, mC, mG, and mU are 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
• fA, fC, fG, and fU are 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
• “*” between two nucleosides represents a phosphorothioate linkage;
• the absence of “*” between two nucleosides represents a phosphodiester internucleoside linkage;
• and “VP” represents 5′-(E)-Vinylphosphonate;
• wherein R2 comprises a Fab comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:
• 19 and a light chain comprising the amino acid sequence of SEQ ID NO:
• 20;
• wherein R1 is covalently linked at attachment point A to R2;
• wherein n1 is an integer of 1-5 representing the number of instances of R1, and wherein each instance of R1 is covalently linked to a different amino acid residue of the Fab.

A complex comprising a structure of formula (I):

• [R1]n1—R2, wherein each R1 comprises a group of the formula (Ib):
• or a pharmaceutically acceptable salt thereof,
• wherein:
• mA, mC, mG, and mU are 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
• fA, fC, fG, and fU are 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
• “*” between two nucleosides represents a phosphorothioate linkage;
• the absence of “*” between two nucleosides represents a phosphodiester internucleoside linkage;
• and “VP” represents 5′-(E)-Vinylphosphonate;
• wherein R2 comprises a Fab comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:
• 19 and a light chain comprising the amino acid sequence of SEQ ID NO:
• 20;
• wherein R1 is covalently linked at attachment point A to R2;
• wherein n1 is an integer of 1-5 representing the number of instances of R1, and wherein each instance of R1 is covalently linked to a different amino acid residue of the Fab.

A complex comprising a structure of the formula (Id):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• mA, mC, mG, and mU are 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
• fA, fC, fG, and fU are 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
• “*” between two nucleosides represents a phosphorothioate linkage;
• the absence of “*” between two nucleosides represents a phosphodiester internucleoside linkage;
• and “VP” represents 5′-(E)-Vinylphosphonate;
• wherein R2 comprises a Fab comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:
• 19 and a light chain comprising the amino acid sequence of SEQ ID NO:
• 20;
• wherein n1 is an integer of 1-5 representing the number of instances of the group enclosed by square brackets, and wherein each instance of the group enclosed by square brackets is covalently linked to a different amino acid residue of the Fab.