MUSCLE TARGETING COMPLEXES AND FORMULATIONS FOR TREATING DYSTROPHINOPATHIES
Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes (e.g., wherein each complex is of the exemplary formula shown below) comprising a phosphorodiamidate morpholino oligomer (e.g., useful for targeting DMD) covalently linked to an antibody (e.g., anti-TfR1 antibody). In some embodiments, the complexes are formulated with histidine (e.g., L-histidine) and sucrose at a specified pH (e.g., about 5.0 to 7.0). Also provided are uses of these formulations for treating a subject having a mutated DMD allele associated with Duchenne Muscular Dystrophy. (Formula I)
1 . A formulation comprising complexes that comprise a phosphorodiamidate morpholino oligomer (PMO) covalently linked to an anti-transferrin receptor 1 (TfR1) antibody, wherein the complexes are formulated with histidine and sucrose.
2 . A formulation comprising complexes comprising a structure of formula: [R 1 ] n1 —R 2 , wherein
each R 1 independently comprises a group of the formula (Ia):
wherein:
R 2 comprises an antibody, and
R 3 comprises a phosphorodiamidate morpholino oligomer (PMO);
wherein R 1 is covalently linked to R 2 at attachment point A; and
wherein n1 is an integer of one or greater representing the number of instances of R 1 , wherein each instance of R 1 is covalently linked to a different amino acid residue of the antibody;
wherein the complexes are formulated with histidine and sucrose.
3 . (canceled)
4 . The formulation of any claim 2 , wherein the formulation is in a lyophilized form, an aqueous solution, or a frozen solid form.
5 . The formulation of claim 4 , wherein the formulation is in an aqueous solution and wherein the histidine is present in the aqueous solution at a concentration in the range of 10 mM to 50 mM.
6 . The formulation of claim 4 , wherein the formulation is in an aqueous solution and wherein the sucrose is present in the aqueous solution at a concentration in the range of 5% to 15% weight per volume (w/v %).
7 . The formulation of claim 4 , wherein the formulation is in an aqueous solution and wherein the aqueous solution has a pH in the range of 5.0 to 7.0.
8 . The formulation of claim 4 , wherein the formulation is in an aqueous solution and wherein the histidine is present in the aqueous solution at a concentration of 25 mM and/or the sucrose is present in the aqueous solution at a concentration of 10 w/v % and/or the aqueous solution is at a pH of 6.0.
9 . The formulation of claim 2 , wherein the antibody is a Fab fragment, a full-length IgG, a Fab′ fragment, a F(ab′) 2 fragment, an scFv, or an Fv.
10 - 12 . (canceled)
13 . The formulation of claim 2 , wherein the PMO comprises a nucleobase sequence that is 15-35 nucleotides in length.
14 - 17 . (canceled)
18 . The formulation of claim 2 , wherein the complexes are present in the formulation at a concentration in the range of 10 mg/mL to 50 mg/mL.
19 . A method of promoting expression or activity of a dystrophin protein in a subject, the method comprising administering to the subject the formulation of claim 2 .
20 . The method of claim 19 , wherein the dystrophin protein is a truncated dystrophin protein.
21 . A method of treating a subject having a mutated DMD allele associated with Duchenne Muscular Dystrophy, the method comprising administering to the subject the formulation of claim 2 .
22 . The method of claim 21 , wherein the mutated DMD allele comprises a mutation amenable to exon 51 skipping.
23 . The method of claim 21 , wherein the mutated DMD allele comprises a frameshift mutation in exon 51.
24 . A complex comprising a structure of formula (I): [R 1 ] n1 —R 2 , wherein
each R 1 comprises a group of the formula (Ia):
wherein R 3 comprises a phosphorodiamidate morpholino oligomer (PMO);
wherein R 2 comprises a Fab,
wherein R 1 is covalently linked to R 2 at attachment point A; and wherein n1 is independently an integer of one or greater representing the number of instances of R 1 in each complex, wherein each instance of R 1 is covalently linked to a different amino acid residue of the Fab.
25 - 27 . (canceled)