Dosing of muscle targeting complexes for treating facioscapulohumeral muscular dystrophy

Abstract

Aspects of the disclosure relate to methods of reducing expression or activity of DUX4 (e.g., DUX4 protein and / or mRNA) and / or methods of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject. In some embodiments, the methods comprise administering to the subject a composition comprising complexes (e.g., muscle targeting complexes) comprising an oligonucleotide (e.g., an RNAi oligonucleotide such as an siRNA) covalently linked to an antibody (e.g., anti-TfRl antibody).

Description

DOSING OF MUSCLE TARGETING COMPLEXES FOR TREATING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHYRELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 657,745 filed June 7, 2024, entitled “DOSING OF MUSCLE TARGETING COMPLEXES FOR TREATING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY,”; and U.S. Provisional Patent Application No. 63 / 720,846 filed November 15, 2024, entitled “DOSING OF MUSCLE TARGETING COMPLEXES FOR TREATING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY,” the entire contents of which are herein incorporated by reference.FIELD OF THE INVENTION

[0002] The present application relates to targeting complexes for delivering oligonucleotide molecular payloads to cells and uses thereof, particularly uses relating to treatment of disease.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (D082470088WO00-SEQ- CBD.xml; Size: 36,802 bytes; and Date of Creation: May 23, 2025) are herein incorporated by reference in their entirety.BACKGROUND

[0004] Muscular dystrophies (MDs) are a group of diseases characterized by the progressive weakness and loss of muscle mass. These diseases are caused by mutations in genes which encode proteins needed for healthy muscle tissue. Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited type of MD which primarily affects muscles of the face, shoulder blades, and upper arms. Other symptoms of FSHD include abdominal muscle weakness, retinal abnormalities, hearing loss, and joint pain and inflammation. FSHD is the most prevalent of the nine types of MD affecting both adults and children, with a worldwide incidence of about 1 in 8,300 people. FSHD is caused by aberrant production of double homeobox 4 (DUX4), a protein that regulates gene expression. The DUX4 gene, which encodes the DUX4 protein, is located in the D4Z4 repeat region on chromosome 4 and is typically expressed in adult testes and thymus, and in 2-cell stage embryos, after which it isrepressed by hypermethylation of the D4Z4 repeats which surround and compact the DUX4 gene. Two types of FSHD, Type 1 and Type 2 have been described. Type 1, which accounts for about 95% of cases, is associated with deletions of D4Z4 repeats in the subtelomeric region of chromosome 4. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. Two allelic variants of chromosome 4q (4qA and 4qB) exist in the most distal unit of the D4Z4 repeats. 4qA is in cis with a functional polyadenylation consensus site. Contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and stable. Type 2 FSHD, which accounts for about 5% of cases, is associated with mutations of the SMCHD1 gene on chromosome 18. Type 2 FSHD may also be associated with the DNMT3B gene or LRIF1 gene. Besides supportive care and treatments to address the symptoms of the disease, there are no effective therapies for FSHD.SUMMARY

[0005] According to some aspects, the present disclosure provides methods (e.g., methods of delivering oligonucleotides (e.g., RNAi oligonucleotides) to a subject, methods of administering complexes to a subject, methods of reducing expression or activity of DUX4 in a subject, and / or methods of treating Facioscapulohumeral muscular dystrophy (FSHD) (e.g., in a subject), the method comprising administering to the subject a composition comprising an effective amount of complexes comprising an anti-transferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides (e.g., RNAi oligonucleotides). In some embodiments, administration of a composition comprising an effective amount of complexes according to any one of the methods described herein results in preserved muscle function (e.g., in a subject). In some embodiments, administration of a composition comprising an effective amount of complexes according to any one of the methods described herein results in restored muscle function (e.g., in a subject).

[0006] According to some aspects, a method of reducing DUX4 expression in a subject provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising an anti-transferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides, wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject, wherein the antibody comprises: a heavy chain complementarity determining region 1 (CDR-H1)comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, wherein the one or more oligonucleotides of the complexes is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21).

[0007] According to some aspects, a method of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising an anti-transferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides, wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject, wherein the antibody comprises: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, wherein the one or more oligonucleotides of the complexes is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21).

[0008] In some embodiments, each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (la):(la), or a pharmaceutically acceptable salt thereof, wherein R3comprises an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; wherein R2comprises the anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

[0009] In some embodiments, each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (lb):(Ib), or a pharmaceutically acceptable salt thereof, wherein: mA, mC, mG, and mU are 2’-0-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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'- (E)-Vinylphosphonate; and the oligonucleotide of R1is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

[0010] In some embodiments, each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

[0011] In some embodiments, each complex comprises a structure of the formula (Id):(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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5’-(E)-Vinylphosphonate, wherein the oligonucleotide is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21; wherein R2comprises the anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

[0012] According to some aspects, a method of reducing DUX4 expression in a subject provided herein comprises administering to the subject an effective amount of a composition comprising a plurality of complexes, wherein each complex of the plurality of complexes comprises a structure of formula (I): [R^ni-R2, wherein each R1represents a group of:(i) the formula (la):(la), or a pharmaceutically acceptable salt thereof, wherein R3represents an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; wherein R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5;(ii) the formula (lb):(lb), or a pharmaceutically acceptable salt thereof,wherein: mA, mC, mG, and mU are 2’-0-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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'- (E)-Vinylphosphonate; and the oligonucleotide of R1is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2represents an anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5;(iii) the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2represents an anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; or(iv) the formula (Id):(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 intemucleosidelinkage; and “VP” represents 5’-(E)-Vinylphosphonate, wherein the oligonucleotide is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21; wherein R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject.

[0013] According to some aspects, a method of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject provided herein comprises administering to the subject an effective amount of a composition comprising a plurality of complexes, wherein each complex of the plurality of complexes comprises a structure of formula (I): [R^ni-R2, wherein each R1represents a group of:(i) the formula (la):(la), or a pharmaceutically acceptable salt thereof, wherein R3represents an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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’-fluorocytidine, 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 R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5;(ii) the formula (lb):(lb), 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; and the oligonucleotide of R1is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2represents an anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5;(iii) the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2represents an anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; or(iv) the formula (Id):(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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5’-(E)-Vinylphosphonate, wherein the oligonucleotide is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21; wherein R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject.

[0014] In some embodiments, the average value of nl of the complexes of the composition is 1.

[0015] In some embodiments, the anti-TfRl antibody is a Fab fragment.

[0016] In some embodiments, the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 18, optionally wherein the anti-TfRl antibody comprises 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.

[0017] In some embodiments, the VH comprises an N-terminal pyroglutamate.

[0018] In some embodiments, the administration occurs one or more times.

[0019] In some embodiments, the effective amount of each administration provides to the subject:(a) 4 mg to 23 mg of the anti-TfRl antibodies of the complexes per kg of the subject,(b) 9 mg to 20 mg of the anti-TfRl antibodies of the complexes per kg of the subject,(c) 2 mg to 5 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 3.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(d) 3 mg to 7 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 4.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(e) 4 mg to 10 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 6.4 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(f) 7 mg to 14 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 9.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(g) 9 mg to 19 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 12.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(h) 12 mg to 23 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 16.1 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(i) 14 mg to 28 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 19.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(j) 17 mg to 33 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 22.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(k) 19 mg to 37 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 25.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(l) 22 mg to 42 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 29 mg of the anti-TfRl antibodies of the complexes per kg of the subject; or(m) 24 mg to 46 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 32.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

[0020] In some embodiments, the effective amount of each administration provides to the subject:(a) 1 mg to 10 mg of the oligonucleotides of the complexes per kg of the subject;(b) 1.5 mg to 7 mg of the oligonucleotides of the complexes per kg of the subject;(c) 3 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject;(d) 0.6 mg to 2 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 1 mg of the oligonucleotides of the complexes per kg of the subject;(e) 1 mg to 2 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 1.5 mg of the oligonucleotides of the complexes per kg of the subject(f) 1 mg to 3 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 2 mg of the oligonucleotides of the complexes per kg of the subject;(g) 2 mg to 5 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 3 mg of the oligonucleotides of the complexes per kg of the subject;(h) 2 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 4 mg of the oligonucleotides of the complexes per kg of the subject;(i) 3 mg to 7 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 5 mg of the oligonucleotides of the complexes per kg of the subject;(j) 4 mg to 8 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 6 mg of the oligonucleotides of the complexes per kg of the subject;(k) 4 mg to 10 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 7 mg of the oligonucleotides of the complexes per kg of the subject;(l) 5 mg to 11 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 8 mg of the oligonucleotides of the complexes per kg of the subject;(m) 6 mg to 12 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 9 mg of the oligonucleotides of the complexes per kg of the subject; or(n) 6 mg to 13 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 10 mg of the oligonucleotides of the complexes per kg of the subject.

[0021] In some embodiments, the composition is administered during a period of administration, wherein the composition is administered once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks, optionally wherein an initial dose is administered at week 0.

[0022] In some embodiments, the period of administration is selected from the group consisting of: i) less than 1 year; ii) less than 2 years; iii) less than 3 years; iv) less than 5 years; and v) less than 10 years.

[0023] In some embodiments, the period of administration is the remainder of the subject’s lifetime.

[0024] In some embodiments, the composition is administered once every 4 weeks during a first period of administration, and subsequently administered once every 8 weeks during a second period of administration.

[0025] In some embodiments, the first period of administration is 8-12 weeks, and / or wherein the second period of administration is selected from the group consisting of:(i) 8-12 weeks, (ii) longer than 12 weeks, and (iii) the remainder of the subject’s lifetime.

[0026] In some embodiments, the composition is in the form of an aqueous solution and further comprises tris(hydroxymethyl)aminomethane and sucrose.

[0027] In some embodiments, the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of 25 mM, the sucrose is present in the aqueous solution at a concentration ofand the aqueous solution is at a pH of 7.5.

[0028] In some embodiments, the complexes are present in the composition at a concentration in the range of 10 mg / mL to 50 mg / mL.

[0029] In some embodiments, the administering reduces DUX4 expression in a muscle cell of the subject, optionally wherein the administering reduces the amount of DUX4 RNA in the muscle cell, optionally wherein the administering results in reversal of loss of muscle function in the subject.

[0030] In some embodiments, reducing DUX4 expression in the muscle cell comprises reducing the amount of DUX4 protein in the muscle cell.

[0031] In some embodiments, the subject is human.

[0032] In some embodiments, the composition is administered systemically, optionally wherein the composition is administered intravenously, further optionally wherein the complex is administered by infusion.

[0033] In some embodiments, each administration comprises providing the composition to the subject by intravenous infusion over 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 150 minutes, or 180 minutes, optionally wherein the infusion is continuous, optionally wherein the composition is administered to the subject by intravenous infusion at a rate of 0.05 mg to 1.5 mg (0.05 mg to 1.5 mg, 0.05 mg to 1 mg, 0.05 mg to 0.5 mg, 0.05 mg to 0.1 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 mg, 0.5 mg to 1.5 mg, 0.5 mg to 1 mg, or 1 mg to 1.5 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject per minute.

[0034] In some embodiments, the composition further comprises one or more anti- TfRl antibodies that are not covalently linked to an oligonucleotide.

[0035] In some embodiments, the composition is administered to the subject once.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIGs. 1A-1C show dose-dependent inhibition of the DUX4 transcriptome (D4T) in quadriceps (FIG. 1A), gastrocnemius (FIG. IB) and tibialis anterior (FIG. 1C) of hTfRl / iFLExD mice two weeks after a single intravenous 0.5, 1, 2 or 6 mg / kg siRNAequivalent dose of anti-TfRl Fab-siRNA complex, or vehicle. Skeletal muscle was harvested two weeks after dosing and RNA was isolated from the indicated skeletal muscles for quantitative RT-PCR analysis of mouse Wfdc3, Sard, and Serpinb6c mRNA. All were normalized to the housekeeping gene Rpl37A, and the average of the 3 genes for each animal was considered as the composite D4T level. Relative expression was calculated as the percentage of the individual animal’s D4T relative to the mean of the vehicle group. Mean + / - SD are shown from n=5-l l animals / group.

[0037] FIGs. 2A-2C show dose-dependent and durable DUX4 transcriptome knockdown in quadriceps (FIG. 2A), gastrocnemius (FIG. 2B) and tibialis anterior (FIG. 2C) of hTfRl / iFLExD mice after a single intravenous 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex, or vehicle. Skeletal muscle was harvested 2, 4, 8, or 12 weeks after dosing and RNA was isolated from the skeletal muscles for quantitative RT-PCR analysis of mouse Wfdc3, Sard, and Serpinb6c mRNA. All were normalized to the housekeeping gene Rpl37A, and the average of the 3 genes for each animal was considered as the composite D4T level. Relative expression was calculated as the percentage of the individual animal’s D4T relative to the mean of the vehicle group. Mean + / - SD are shown from n=4-12 animals / group.

[0038] FIGs. 3A-3C show reduced myofiber splitting and hypotrophic myofiber formation 8 weeks (FIG. 3A) or 12 weeks (FIG. 3B) after a single intravenous siRNAequivalent dose of anti-TfRl Fab-siRNA complex in hTfRl / iFLExD mice. 8 week old mice were intravenously injected with a single 2 or 6 mg / kg dose of siRNA-equivalent dose of anti- TfRl Fab-siRNA complex or vehicle and quadriceps were isolated 8 or 12 weeks later. Samples from age-matched normal mice and hTfRl / iFLExD mice were collected at baseline for comparison. Muscle samples were cryoembedded in OCT compound (Sakura), cryosectioned, and immunofluorescently stained for laminin expression. FIG. 3A shows representative baseline images demonstrating the extent of fiber splitting in normal mice and hTfRl / iFLExD mice, along with sections from animals treated with a 2 or 6 mg / kg siRNAequivalent dose of anti-TfRl Fab-siRNA complex 8 weeks after dosing. Dashed circles point to appearance of hypotrophic myofibers in the tissue. Scale bar = 50 pm. FIG. 3B shows representative baseline images demonstrating the extent of fiber splitting in normal mice and hTfRl / iFLExD mice, along with sections from animals treated with a 2 or 6 mg / kg siRNAequivalent dose of anti-TfRl Fab-siRNA complex 12 weeks after dosing. Dashed circles point to appearance of hypotrophic myofibers in the tissue. Scale bar = 50 pm. FIG. 3C shows quantification of hypotrophic myofiber reduction 12 weeks after treatment with a 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex in hTfRl / iFLExD mice. Quantification of hypotrophic myofiber in vehicle treated normal mice and hTfRl / iFLExD mice are also shown.

[0039] FIG. 4 shows prevention of loss of muscle function in hTfRl / iFLExD mice treated with anti-TfRl Fab-siRNA complex in a forced treadmill run. hTfRl / iFLExD mice were administered a single intravenous 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex, or vehicle two weeks before boosting DUX4 levels by tamoxifen administration. Two 5 mg / kg doses of tamoxifen were administered intragastrically to allanimals 24 hours apart; day 0 of the experiment was considered to be the day the first dose of tamoxifen was administered. On day -11, all animals were acclimated to the treadmill without forcing them to run and on days -7 and -4, all animals were trained to run the treadmill. After tamoxifen administration, all animals were subjected to a forced treadmill run. Total distance ran was measured for each animal during each session. Data shown are mean + / - SD for n=5-6 animals per group. Normal animals were treated with tamoxifen and the vehicle for anti-TfRl Fab-siRNA complex to control for the effects of tamoxifen.

[0040] FIGs. 5A-5C show preservation of muscle function following treatment with anti-TfRl Fab-siRNA complex is associated with DUX4 transcriptome (D4T) knockdown. After forced treadmill test, animals treated with a 1, 2 or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex and controls were humanely euthanized and the indicated skeletal muscles were collected for DUX4 transcriptome measurement. RNA was isolated for quantitative RT-PCR analysis of mouse Wfdc3, Sard, and Serpinb6c mRNA; all were normalized to the housekeeping gene Rpl37A, and the average of the 3 genes for each animal was considered as the composite D4T level. Relative expression was calculated as the percentage of the individual animal’s D4T relative to the mean of the vehicle group. FIG. 5 A shows D4T scores in quadriceps muscle tissue. FIG. 5B shows D4T scores in gastrocnemius muscle tissue. FIG. 5C shows D4T scores in tibialis anterior muscle tissue. Mean + / - SD are shown from n=5-6 animals / group. Numbers above the bars indicate percent D4T knockdown. One-way ANOVA was used to compare all groups to the induced vehicle group *p<0.05, **p<0.01, ***p < 0.001, ****p < 0.0001.

[0041] FIG. 6 shows that preservation of muscle function following treatment with anti-TfRl Fab-siRNA complex is associated with improved myofiber pathology. Representative images are shown of laminin immunolabeled quadriceps muscle tissue of hTfRl / iFLExD mice treated with a 2 or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab- siRNA complex or vehicle after forced treadmill test. A representative image from a tamoxifen-treated normal mouse is shown for comparison. Dashed circles point to appearance of hypotrophic myofibers in the tissue. Scale bar = 50 pm.

[0042] FIGs. 7A-7B show suppression of DUX4 transcriptome in patient-derived FSHD cell lines treated with anti-TfRl Fab-siRNA complex. FIG. 7A: Patient-derived myoblasts from 3 different individuals with FSHD were induced to differentiate in the presence of 1 pM anti-TfRl Fab-siRNA complex for 7 days prior to RNA isolation. Quantitative RT-PCR was used to measure the expression of MBD3L2, TR1M43, ZSCAN4 mRNA expression relative to RPL13A. Data were quantitated relative to the mean of thevehicle control group on day 7, and the mean of the three genes was calculated for each sample. The mean and SD of 3 independent samples is shown. FIG. 7B: Patient-derived myoblasts were differentiated for 7 days prior to RNA isolation. 1 pM anti-TfRl Fab-siRNA complex was added to the culture media at the start of differentiation (early treatment) or 5 days after differentiation was initiated (late treatment), at a point where the DUX4 transcriptome is active. Vehicle treated cells are included for comparison (Vehicle) and the expression at baseline pre-differentiation is shown (Baseline). Quantitative RT-PCR was used to measure the expression of MBD3L2, TR1M43, ZSCAN4 mRNA expression relative to RPL13A. Data were quantitated relative to the mean of the vehicle control group on day 7, and the mean of the three genes was calculated for each sample. The mean and SD of 3 independent samples is shown.

[0043] FIG. 8 shows prevention and reversal of loss of muscle function in hTfRl / iFLExD mice treated with anti-TfRl Fab-siRNA complex in a forced treadmill run. hTfRl / iFLExD mice were administered a single intravenous 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex, or vehicle by tail vein injection either 2 weeks before, the same day, or 1 week after boosting DUX4 levels by tamoxifen administration. Two 5 mg / kg doses of tamoxifen were administered intragastrically to all animals 24 hours apart; day 0 of the experiment was considered to be the day the first dose of tamoxifen was administered. All animals were trained to run the treadmill prior to tamoxifen administration. After tamoxifen administration, all animals were subjected to a forced treadmill run on experimental days 3, 7, 10, 14, 17, and 20. Total distance ran was measured for each animal during each session. Data shown are mean + / - SD for n=6-7 animals per group. Normal animals were treated with tamoxifen and the vehicle for anti-TfRl Fab-siRNA complex to control for the effects of tamoxifen.

[0044] FIGs. 9A-9B show preservation and reversal of muscle function following treatment with anti-TfRl Fab-siRNA complex is associated with DUX4 transcriptome (D4T) knockdown. After forced treadmill test, animals treated with 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex either 1 week before, the same day, or 1 week after boosting DUX4 levels by tamoxifen administration and controls were humanely euthanized. The indicated skeletal muscles were collected for DUX4 transcriptome measurement. RNA was isolated for quantitative RT-PCR analysis of mouse Wfdc3, Sard, and Serpinb6c mRNA; all were normalized to the housekeeping gene Rpl37A, and the average of the 3 genes for each animal was considered as the composite D4T level. Relative expression was calculated as the percentage of the individual animal’s D4T relative to the mean of the vehicle group. FIG. 9 Ashows D4T scores in quadriceps muscle tissue. FIG. 9B shows D4T scores in tibialis anterior muscle tissue. Mean + / - SD are shown from n=6-7 animals / group.

[0045] FIG. 10 shows dose-dependent reduction of interleukin-6 (116) mRNA expression in FSHD mouse quadriceps following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFLExD mice were administered a 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex by tail vein injection two weeks before tamoxifen-mediated DUX4 induction (+). Mice were trained to run on a treadmill before DUX4 induction (study Day 0). After DUX4 induction, mice were run on a treadmill on four days (study Days 3, 7, 10 and 14). On Day 15, mice were euthanized and the quadriceps were collected. RT-qPCR was performed to measure 116 mRNA levels in the quadriceps samples. Increased 116 mRNA was detected in uninduced hTfRl / iFLExD mice (which have low levels of DUX4 activity, leading to pathological muscle damage without overt loss of muscle function) compared to tamoxifen- treated normal control mice. 116 mRNA expression is increased following DUX4 induction, while anti-TfRl Fab-siRNA complex pre-treatment dose-dependently reduced 116 levels.

[0046] FIG. 11 shows dose-dependent reduction of interferon-y (Ifny mRNA expression in FSHD mouse quadriceps following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFLExD mice were administered a 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex by tail vein injection two weeks before tamoxifen-induced DUX4 induction (+). Mice were trained to run on a treadmill before DUX4 induction (study Day 0). After DUX4 induction, mice were run on a treadmill on four days (study Days 3, 7, 10 and 14). On Day 15, mice were euthanized and the quadriceps were collected. RT-qPCR was performed to measure Ifny mRNA levels in the quadriceps samples. Increased Ifny mRNA was detected in uninduced hTfRl / iFLExD mice (which have low levels of DUX4 activity, leading to pathological muscle damage without overt loss of muscle function) compared to tamoxifen- treated normal control mice. Ifny mRNA expression is increased following DUX4 induction, while anti-TfRl Fab-siRNA complex pre-treatment dose-dependently reduced Ifny levels.

[0047] FIG. 12 shows dose-dependent reduction of galectin-3 (Lgals3) mRNA expression in FSHD mouse quadriceps following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFLExD mice were administered a 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab-siRNA complex by tail vein injection two weeks before tamoxifen-induced DUX4 induction (+). Mice were trained to run on a treadmill before DUX4 induction (study Day 0). After DUX4 induction, mice were run on a treadmill on four days (study Days 3, 7, 10 and 14). On Day 15, mice were euthanized and the quadriceps were collected. RT-qPCR was performed to measure Lgals3 mRNA levels in the quadriceps samples. Increased Lgals3mRNA was detected in uninduced hTfRl / iFFExD mice (which have low levels of DUX4 activity, leading to pathological muscle damage without overt loss of muscle function) compared to tamoxifen-treated normal control mice. Lgals3 mRNA expression is increased following DUX4 induction, while anti-TfRl Fab-siRNA complex pre-treatment dose- dependently reduces Lgals3 levels.

[0048] FIG. 13 shows dose-dependent reduction of Stat5b mRNA expression in FSHD mouse quadriceps following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFFExD mice were administered a dose of 1, 2, or 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab- siRNA complex by tail vein injection two weeks before tamoxifen-induced DUX4 induction (+). Mice were trained to run on a treadmill before DUX4 induction (study Day 0). After DUX4 induction, mice were run on a treadmill on four days (study Days 3, 7, 10 and 14). On Day 15, mice were euthanized and the quadriceps were collected. RT-qPCR was performed to measure Stat5b mRNA levels in the quadriceps samples. Decreased Stat5b mRNA was detected in uninduced and tamoxifen-induced vehicle control hTfRl / iFFExD mice compared to tamoxifen-treated normal control mice. Anti-TfRl Fab-siRNA pre-treatment increases Stat5b levels, although not to the levels observed in normal mice.

[0049] FIGs. 14A-14B show reduction of interleukin-6 (116) in muscles of tamoxifen- induced hTfRl / iFFExD mice following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFFExD mice were administered a 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab- siRNA complex via tail vein injection on Study Days -14 and 0 (prophylactic administration), or Day 7 (therapeutic administration), with Study Day 0 being the first day of tamoxifen- mediated DUX4 induction. Muscle function was measured by assessing run distance in a forced treadmill run. Animals were euthanized on Study Day 21 and the quadriceps and tibialis anterior were collected. RNA was isolated from the tissues and RT-qPCR performed to assess 116 mRNA levels. Efficacious treatment, defined by restoration of the ability to run on a treadmill, was accompanied by reduced tissue 116 mRNA levels. FIG. 14A shows results from the quadriceps. FIG. 14B shows results from the tibialis anterior.

[0050] FIGs. 15A-15B show reduction of interferon-y (Ifng) in muscles of tamoxifen- induced hTfRl / iFFExD mice following treatment with anti-TfRl Fab-siRNA complex. hTfRl / iFFExD mice were administered a 6 mg / kg siRNA-equivalent dose of anti-TfRl Fab- siRNA complex via tail vein injection on Study Days -14 and 0 (prophylactic administration), or Day 7 (therapeutic administration), with Study Day 0 being the first day of tamoxifen- mediated DUX4 induction. Muscle function was measured by assessing run distance in a forced treadmill run. Animals were euthanized on Study Day 21 and the quadriceps and tibialisanterior were collected. RNA was isolated from the tissues and RT-qPCR performed to assess Ifiig mRNA levels. Efficacious treatment, defined by restoration of the ability to run on a treadmill, was accompanied by reduced tissue Ifiig mRNA levels. FIG. 15A shows results from the quadriceps. FIG. 15B shows results from the tibialis anterior.DETAILED DESCRIPTION OF INVENTION

[0051] According to some aspects, the present disclosure provides methods of reducing expression or activity of DUX4 (e.g., DUX4 protein and / or mRNA) and / or methods of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject. In some embodiments, any one of the methods described herein results in preserved muscle function (e.g., in a subject). In some embodiments, any one of the methods described herein results in restored muscle function (e.g., in a subject). In some embodiments, the methods described herein comprise administering to the subject a composition comprising an effective amount of muscle targeting complexes, each complex comprising an anti-transferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides, wherein the effective amount provides to the subject 0.5 mg to 15 mg (e.g., about 0.5 mg to 15 mg, about 1 mg to 8 mg, about 3 mg to 14 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg) of the oligonucleotides of the complexes per kg of the subject. In some embodiments, the effective amount provides to the subject about 3 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, the effective amount provides to the subject about 4 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, the effective amount provides to the subject 2 mg to 50 mg (e.g., 2 mg to 19 mg, 10 mg to 50 mg, about 3.2 mg, about 6.4 mg, about 9.7 mg, about 12.9 mg, about 16.1 mg, about 19.3 mg, about 22.5, about 25.8, about 29.0, about 32.2, about 35.4, about 38.7, about 41.9 mg, about 45.1 mg, or about 48.3 mg) of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, the effective amount provides to the subject about 9.7 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, the effective amount provides to the subject about 12.9 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, the administration is once every 4 weeks to once every 12 weeks (e.g., once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks). In some embodiments, the subject is administered the composition once every 4 weeks during a first period of administration, and subsequently administered the composition once every 8 weeksduring a second period of administration. In some embodiments, the subject is administered the composition once every 6 weeks during a first period of administration, and subsequently administered the composition once every 12 weeks during a second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, the subject has facioscapulohumeral muscular dystrophy (FSHD).

[0052] Further aspects of the disclosure, including a description of defined terms, are provided below.DEFINITIONS

[0053] Administering: As used herein, the terms “administering” or “administration” means to provide a complex to a subject in a manner that is physiologically and / or (e.g., and) pharmacologically useful e.g., to treat a condition in the subject).

[0054] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0055] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., paratope that specifically binds to an antigen. In some embodiments, an antibody is a full- length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, a Fab’ fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment. In some embodiments, an antibody is a nanobody derived from a camelid antibody or a nanobody derived from shark antibody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germline sequence. In another embodiment, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgGl, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgAl, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH), and / or (e.g., and) a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant domain, e.g., an Fc region. An immunoglobulin constant domain refersto a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein can be an alpha (a), delta (A), epsilon (e), gamma (y) or mu (p) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (a), delta (A), epsilon (e), gamma (y) or mu (p ) heavy chain. In a particular embodiment, an antibody described herein comprises a human gamma 1 CHI, CH2, and / or (e.g., and) CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (y) heavy chain constant region, such as any known in the art. Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Pat. No. 5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein. In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecule are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, an antibody is a construct that comprises a polypeptide comprising one or more antigen binding fragments of the disclosure linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Examples of linker polypeptides have been reported (see e.g., Holliger, P, et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2: 1121-1123). Still further, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodiesand Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058).

[0056] CDR: As used herein, the term "CDR" refers to the complementarity determining region within antibody variable sequences. A typical antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or (e.g., and) the contact definition, all of which are well known in the art. See, e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; IMGT®, the international ImMunoGeneTics information system® http: / / www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P, Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P, Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [Epub], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33:D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37:D1006-1012 (2009);Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17: 132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, a CDR may refer to the CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the same amino acid sequence of that CDR as determined by the same method, for example, the IMGT definition.

[0057] There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term "CDR set" as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat etal., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-portions of CDRs may be designated as LI, L2 and L3 or Hl, H2 and H3 where the "L" and the "H" designates the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems. Examples of CDR definition systems are provided in Table 1.Table 1. CDR Definitions1IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999)2Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.Department of Health and Human Services, NIH Publication No. 91-32423Chothia et al., J. Mol. Biol. 196:901-917 (1987))

[0058] Complementary: As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleotides or nucleosides or two sets of nucleotides or nucleosides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleotides or nucleosides or two sets of nucleotides or nucleosides. For example, if a base at one position of an oligonucleotide iscapable of hydrogen bonding with a base at the corresponding position of a target nucleic acid (e.g., an mRNA), then the bases are considered to be complementary to each other at that position. Base pairings may include both canonical Watson-Crick base pairing and non- Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairings, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil-type bases (U), that cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3- nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T.

[0059] Covalently linked: As used herein, the term “covalently linked” refers to a characteristic of two or more molecules being linked together via at least one covalent bond. In some embodiments, two molecules can be covalently linked together by a single bond, e.g., a disulfide bond or disulfide bridge, that serves as a linker between the molecules. However, in some embodiments, two or more molecules can be covalently linked together via a molecule that serves as a linker that joins the two or more molecules together through multiple covalent bonds. In some embodiments, a linker may be a cleavable linker. However, in some embodiments, a linker may be a non-cleavable linker.

[0060] DUX4: As used herein, the term “DUX4” refers to a gene that encodes double homeobox 4, a protein which is generally expressed during fetal development and in the testes of adult males. In some embodiments, DUX4 may be a human (Gene ID: 100288687), nonhuman primate (e.g., Gene ID: 750891, Gene ID: 100405864), or rodent gene (e.g., Gene ID: 306226). In humans, expression of the DUX4 gene outside of fetal development and the testes or thymus is associated with facioscapulohumeral muscular dystrophy. In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001293798.2, NM_001306068.3, NM_001363820.1) have been characterized that encode different protein isoforms.

[0061] Facioscapulohumeral muscular dystrophy (FSHD): As used herein, the term “facioscapulohumeral muscular dystrophy (FSHD)” refers to a genetic disease caused by mutations in the DUX4 gene, SMCHD1 gene, DNMT3B gene, or LRIF1 gene that is characterized by muscle mass loss and muscle atrophy, primarily in the muscles of the face, shoulder blades, and upper arms. Two types of the disease, Type 1 and Type 2, have been described. Type 1 is associated with deletions in D4Z4 repeat regions on chromosome 4 which contains the DUX4 gene. In some embodiments, Type 1 is associated with deletions in D4Z4repeat regions on chromosome 4 allelic variant 4qA which contains the DUX4 gene. Type 2 is associated with mutations in the SMCHD1 gene, DNMT3B gene, or LRIF1 gene (see, e.g. Jia et al., “Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings” Neuromuscul Disord. (2021), 31(11): 1101-1112. Both Type 1 and Type 2 FSHD are characterized by aberrant production of the DUX4 protein after fetal development in skeletal muscle. Facioscapulohumeral dystrophy, the genetic basis for the disease, and related symptoms are described in the art (see, e.g. Campbell, A.E., et al., “Facioscapulohumeral dystrophy: Activating an early embryonic transcriptional program in human skeletal muscle” Human Mol Genet. (2018); and Tawil, R. “Facioscapulohumeral muscular dystrophy” Handbook Clin. Neurol. (2018), 148: 541-548.) FSHD Type 1 is associated with Online Mendelian Inheritance in Man (OMIM) Entry # 158900. FSHD Type 2 is associated with OMIM Entry # 158901.

[0062] F ramework : As used herein, the term "framework" or "framework sequence" refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of light chain and CDR-H1, CDR-H2, and CDR-H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region. Human heavy chain and light chain acceptor sequences are known in the art. In one embodiment, the acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0063] Human antibody: The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site- specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from thegermline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0064] Humanized antibody: The term "humanized antibody" refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and / or (e.g., and) VL sequence has been altered to be more "human-like", i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding nonhuman CDR sequences. In one embodiment, humanized anti-transferrin receptor antibodies and antigen binding portions are provided. Such antibodies may be generated by obtaining murine anti-transferrin receptor monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in Kasaian et al PCT publication No. WO 2005 / 123126 A2.

[0065] Internalizing cell surface receptor: As used herein, the term, “internalizing cell surface receptor” refers to a cell surface receptor that is internalized by cells, e.g., upon external stimulation, e.g., ligand binding to the receptor. In some embodiments, an internalizing cell surface receptor is internalized by endocytosis. In some embodiments, an internalizing cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, an internalizing cell surface receptor is internalized by a clathrin- independent pathway, such as, for example, phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake or constitutive clathrin-independent endocytosis. In some embodiments, the internalizing cell surface receptor comprises an intracellular domain, a transmembrane domain, and / or (e.g., and) an extracellular domain, which may optionally further comprise a ligand-binding domain. In some embodiments, a cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, a ligand may be a muscle-targeting agent or a muscle-targeting antibody. In some embodiments, an internalizing cell surface receptor is a transferrin receptor.

[0066] Kabat numbering: The terms "Kabat numbering", "Kabat definitions and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

[0067] Oligonucleotide: As used herein, the term “oligonucleotide” refers to an oligomeric nucleic acid compound of up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNAs, shRNAs), microRNAs, gapmers, mixmers, phosphorodiamidate morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNAs), etc. Oligonucleotides may be single- stranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleosides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, an oligonucleotide may comprise one or more modified intemucleoside linkage. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation.

[0068] Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0069] Region of complementarity: As used herein, the term “region of complementarity” refers to a nucleotide sequence, e.g., of an oligonucleotide, that is sufficiently complementary to a cognate nucleotide sequence, e.g., of a target nucleic acid, such that the two nucleotide sequences are capable of annealing to one another under physiological conditions (e.g., in a cell). In some embodiments, a region of complementarity is fully complementary to a cognate nucleotide sequence of target nucleic acid. However, in some embodiments, a region of complementarity is partially complementary to a cognate nucleotide sequence of target nucleic acid (e.g., at least 80%, 90%, 95% or 99% complementarity). In some embodiments, a region of complementarity contains 1, 2, 3, or 4 mismatches compared with a cognate nucleotide sequence of a target nucleic acid.

[0070] Specifically binds: As used herein, the term “specifically binds” refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish the binding partner from an appropriate control in a binding assay or other binding context. With respect to an antibody, the term, “specifically binds”, refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or avidity, compared with an appropriate reference antigen or antigens, that enables the antibody to be used to distinguish the specific antigen from others, e.g., to an extent that permits preferential targeting to certain cells, e.g., muscle cells, through binding to the antigen, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a KD for binding the target of at least about 10'4M, 10'5M, 10'6M, IO’7M, 10'8M, 10'9M, 1040M, 1041M, 102M, 103M, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, e.g., an epitope of the apical domain of transferrin receptor.

[0071] Subject: As used herein, the term “subject” refers to a mammal. In some embodiments, a subject is non-human primate, or rodent. In some embodiments, a subject is a human. In some embodiments, a subject is a patient, e.g., a human patient that has or is suspected of having a disease. In some embodiments, the subject is a human patient who has or is suspected of having FSHD.

[0072] Transferrin receptor: As used herein, the term, “transferrin receptor” (also known as TFRC, CD71, p90, TFR, or TFR1) refers to an internalizing cell surface receptor that binds transferrin to facilitate iron uptake by endocytosis. In some embodiments, a transferrin receptor may be of human (NCBI Gene ID 7037), non-human primate (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodent (e.g., NCBI Gene ID 22042) origin. In addition, multiple human transcript variants have been characterized that encoded different isoforms of the receptor (e.g., as annotated under GenBank RefSeq Accession Numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0073] 2’-modified nucleoside: As used herein, the terms “2’ -modified nucleoside” and “2’ -modified ribonucleoside” are used interchangeably and refer to a nucleoside having a sugar moiety modified at the 2’ position. In some embodiments, the 2’ -modified nucleoside is a 2’-4’ bicyclic nucleoside, where the 2’ and 4’ positions of the sugar are bridged (e.g., via a methylene, an ethylene, or a (S)-constrained ethyl bridge). In some embodiments, the 2’- modified nucleoside is a non-bicyclic 2’-modified nucleoside, e.g., where the 2’ position of the sugar moiety is substituted. Non-limiting examples of 2’ -modified nucleosides include: 2’- deoxy, 2’-fluoro (2’-F), 2’-O-methyl (2’-0-Me), 2’-O-methoxyethyl (2’-M0E), 2’-O- aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O- dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), 2’- O-N-methylacetamido (2’-0-NMA), locked nucleic acid (LNA, methylene-bridged nucleic acid), ethylene-bridged nucleic acid (ENA), and (S)-constrained ethyl-bridged nucleic acid (cEt). In some embodiments, the 2’ -modified nucleosides described herein are high-affinity modified nucleosides and oligonucleotides comprising the 2’ -modified nucleosides have increased affinity to a target sequences, relative to an unmodified oligonucleotide. Examples of structures of 2’-modified nucleosides are provided below:2'-O-methoxyethyl 'locked nucleic acid ethylene-bridged (S)-constrainedThese examples are shown with phosphate groups, but any internucleoside linkages are contemplated between 2’-modified nucleosides. In certain embodiments, the intemucleoside phosphate groups are as depicted, i.e., deprotonated in salt form. In certain embodiments, the intemucleoside phosphate groups are protonated. The extent to which the phosphate groups are protonated or deprotonated will vary depending on the chemical environment of the nucleosides (e.g., pH, presence of basic media, etc.).

[0074] Ranges: All ranges provided in the present disclosure are inclusive of the end points.Complexes

[0075] Provided herein are methods of reducing the expression or activity treating facioscapulohumeral muscular dystrophy (FSHD) in a subject comprising administering to the subject an effective amount of muscle targeting complexes, wherein the complexes comprise a targeting agent, e.g., an antibody, covalently linked to an oligonucleotide. In some embodiments, a complex comprises a muscle-targeting antibody (e.g., an anti-TfRl antibody) covalently linked to one or more oligonucleotides. In some embodiments, the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) that targets a DUX4 RNA to reduce expression or activity of DUX4 (e.g., to reduce DUX4 protein and / or mRNA levels).

[0076] Complexes used in a method described herein generally comprise a linker that covalently links an antibody (e.g., an anti-TfRl antibody) described herein to an oligonucleotide (e.g., an RNAi oligonucleotide). A linker comprises at least one covalent bond.

[0077] In some embodiments, complexes used in a method described herein comprise a structure of formula (I): [ R11Ni -R2, in which each R1independently comprises a compound comprising an oligonucleotide (e.g., an RNAi oligonucleotide) and R2comprises an antibody (e.g., an anti-TfRl antibody), and wherein in each complex nl is independently an integer (e.g., one or greater) representing the number of instances of R1in each complex. In some embodiments, each R1independently comprises a group comprising an oligonucleotide. In some embodiments, each R1independently comprises a group that comprises additional elements in addition to an oligonucleotide. In some embodiments, R2comprises an antibody e.g., an anti-TfRl antibody) comprising a heavy chain comprising a heavy chain variable region (VH) and a heavy chain constant region, and a light chain comprising a light chain variable region (VL) and a light chain constant region. In some embodiments, each R1of a complex is independently covalently linked to a different amino acid residue (e.g., lysine or cysteine) of R2.

[0078] In some embodiments, in each complex nl is independently an integer (e.g., one or greater). In some embodiments, the antibody comprises a sequence as set forth in Table 2. For example, in some embodiments, the antibody comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprises a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR- L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprises a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprises a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprises a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain comprising the amino acidsequence of SEQ ID NO: 19 and / or comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibody is a Fab fragment, a full- length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, the antibody is a Fab fragment.

[0079] In some embodiments, the value of nl of each or any complex (e.g., any complex in any of the compositions disclosed herein) is an integer up to the number of amino acid residues in the antibody to which conjugation is desired or targeted (e.g., the number of lysine residues). In some embodiments, in each complex the value of nl is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27. In some embodiments, in each complex the value of nl is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26. In some embodiments, in each complex the value of nl is 1. In some embodiments, in each complex the value of nl is independently in the range of 1-27, 1-26, 1-10, 1-5, or 1-3. In some embodiments, the average value of nl of complexes of the composition is in the range of 1 to 5 (e.g., 1-5, 1-4, 1-3, 3-5, or 1-2). In some embodiments, compositions described herein comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9- 1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is an integer. In some embodiments, the average value of nl of complexes of the composition is a non-integer (e.g., a decimal). In some embodiments, the average value of nl of complexes of the composition is 1. In some embodiments, in each complex type nl is independently an integer of one or greater representing the number of instances of R1in each complex of the complex type, and in which the different complex types of the composition are characterized by having different nl values (e.g., nl values in the range of 1-27, 1-26, 1-25, 1-20, 1-15, 1-10, 1-5, or 1-3).

[0080] In some embodiments, compositions are provided (e.g., compositions comprising tris(hydroxymethyl)aminomethane and / or sucrose, as described herein) that comprise a plurality of different complexes. In some embodiments, the plurality of different complexes comprise a common targeting agent (e.g. an antibody) and a common oligonucleotide (e.g., an RNAi oligonucleotide, such as a DUX4-targeting RNAi oligonucleotide). In such embodiments, different complex types are characterized by havingdifferent numbers of oligonucleotides covalently linked to an antibody. For example, in some embodiments, compositions are provided that comprise a plurality of complexes comprising a structure of formula (I): [ R11Ni -R2, in which each R1independently comprises a compound comprising an oligonucleotide (e.g., a DUX4-targeting RNAi oligonucleotide) and R2comprises an antibody (e.g., anti-TfRl antibody), and in which nl is an integer representing the number of instances of R1in a complex, and in which different complexes of the composition may have different nl values (e.g., nl values in the range of 1-27, 1-26, 1-10, 1-5, or 1-3). In some embodiments, in complexes of a composition nl is independently an integer. In some embodiments, in complexes of a composition nl is 1. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1- 1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1. In some embodiments, compositions described herein comprise complexes in which nl is 0.

[0081] In some embodiments, a composition described herein comprises an antibody that is not conjugated to an oligonucleotide (e.g., in trace amounts) and an antibody conjugated to one or more oligonucleotides. In some embodiments, the antibody that is not conjugated to an oligonucleotide may be referred to as a compound comprising a structure of formula (I): [R^ni-R2, for which nl is zero. Accordingly, in some embodiments, a composition for administration to a subject in a method described herein comprises compounds (e.g., complexes) comprising a structure of formula (I): [ R11ni -R2, for which each R1independently comprises a group comprising an oligonucleotide, R2comprises an antibody and nl is independently an integer of zero or greater that reflects the number of instances of R1in each compound (e.g., complex). In some embodiments, the fraction of compounds comprising a structure of formula (I): [R^ni-R2, in a composition, for which nl is zero, compared with all compounds of that structure in the composition for which nl is one or greater, is less than 10%, less than 5%, less than 1% less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3,1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.

[0082] In some embodiments, each instance of R1in a complex is covalently linked to a different amino acid residue of the antibody. In some embodiments, an amino acid to which R1is covalently linked comprises an 8-amino group (e.g., lysine, arginine). In some embodiments, an amino acid to which R1is covalently linked is a lysine. In some embodiments, an amino acid to which R1is covalently linked is a cysteine. In some embodiments, R1is directly covalently linked to an amino acid residue of the antibody. However, in some embodiments, R1is indirectly covalently linked to an amino acid of the antibody, e.g., covalently linked to a glycosylation site on the amino acid. In some embodiments, R1is not covalently linked to an amino acid residue residing in a CDR region of the antibody.

[0083] In some embodiments, complexes used in a method provided herein comprise a structure of formula (I): [R^ni-R2, in which each instance of R1independently comprises a group of the formula (la):(la), or a pharmaceutically acceptable salt thereof, in which R3comprises an oligonucleotide, e.g., an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof; and R1is covalently linked e.g., indirectly or directly linked, e.g., directly linked) to R2at attachment point A. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR- Hl) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. Insome embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment. In some embodiments, R3comprises an RNAi oligonucleotide (e.g., an siRNA), or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate. In some embodiments, in each complex nl is independently an integer (e.g., one or greater). In some embodiments, in each complex nl is 1.

[0084] In some embodiments, complexes used in a method provided herein comprise a structure of formula (I): [R^ni-R2, in which each R1comprises a group of the formula (lb):(lb), 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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein nl is an integer (e.g., one or greater) representing the number of instances of R1in each complex, and each R1is covalently linked to R2at attachment point A. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR- L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment.

[0085] In some embodiments, complexes used in a method provided herein comprise a structure of formula (I): [R^ni- R2, in which each R1comprises a group of the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R1is covalently linked to R2at attachment point A. In some embodiments, nl is an integer (e.g., one or greater) representing the number of instances of R1in each complex. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g.,at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment.

[0086] In some embodiments, complexes used in a method provided herein comprise a structure of the formula (Id):(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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises an antibody comprising a sequence as set forth in Table 2; wherein nl is an integer (e.g., one or greater) representing the number of instances of the group enclosed by square brackets, wherein each instance of the group enclosed by square brackets is covalently linked to a different amino acid residue of the antibody, optionally wherein each different amino acid residue is a lysine. In some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment.

[0087] Each of formula (la), formula (lb), formula (Ic) and formula (Id), as depicted herein, include one or more phosphorous containing groups (e.g., phosphate group, phosphorothioate group, phosphodiester group) that are protonated. In certain embodiments, the phosphorous containing groups (e.g., phosphate group, phosphorothioate group, phosphodiester group) are as depicted, i.e., protonated. In certain embodiments, the phosphorous containing groups (e.g., phosphate group, phosphorothioate group, phosphodiester group) groups are deprotonated, i.e., in salt form. The extent to which the phosphorous containing groups are protonated or deprotonated will vary depending on the chemical environment of the complexes (e.g., pH, presence of basic media, etc.). For example, in a composition (e.g., formulation) described herein that has a pH of about 7.5, or at a physiological pH, complexes comprising a structure of formula (la), formula (lb), formula (Ic) and formula (Id) may comprise one or more deprotonated phosphorous containing groups (e.g., a phosphate group, a phosphorothioate group, a phosphodiester group).

[0088] In some embodiments, complexes used in a method described herein comprise a structure of formula (A): oligonucleotide(A), or a pharmaceutically acceptable salt thereof, wherein y is 0-15 (e.g., 3), z is 0-15 (e.g., 4), and wherein - A represents an indirect or direct linkage. In some embodiments, the amide shown adjacent the antibody (e.g., anti-TfRl antibody) in the structure (A) results from a reaction with an amine of the antibody, such as a lysine epsilon amine. In some embodiments, a complex described herein comprises an anti-TfRl antibody (e.g., an anti-TfRl Fab) covalently linked via a lysine of the antibody to the 5’ end of an oligonucleotide e.g., an RNAi oligonucleotide). In some embodiments, the antibody comprises a sequence as set forth in Table 2. For example, in some embodiments, the antibody comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprises a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprises a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprises a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequenceat least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprises a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibody is a Fab fragment, a full- length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, the antibody is a Fab fragment.Antibodies

[0089] In some embodiments, complexes used in a method described herein comprise an antibody that binds human transferrin receptor 1 (TfRl). An example human TfRl amino acid sequence, corresponding to NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows:MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANV TKPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDF PAARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQF REFKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTG KLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKF PIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGN MEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVG AQRDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVG ATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQ FLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMD TYKELIE RIPELNKVARAAAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEM GLSLQWLYSARGDFFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSP KESPFRHVFWGSGSHTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANAL SGDVWDIDNEF (SEQ ID NO: 23).

[0090] Table 2 provides examples of sequences of an anti-TfRl antibody useful in the complexes provided herein.Table 2. Examples of anti-TfRl antibody sequences

[0091] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 1 (according to the IMGT definition system), a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 2 (according to the IMGT definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 3 (according to the IMGT definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 4 (according to the IMGT definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the IMGT definition system), and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 6 (according to the IMGT definition system).

[0092] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 7 (according to the Kabat definition system), a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 8 (according to the Kabat definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 9 (according to the Kabat definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ IDNO: 10 (according to the Kabat definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 11 (according to the Kabat definition system), and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 6 (according to the Kabat definition system).

[0093] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain complementarity determining region 1 (CDR-H1) of SEQ ID NO: 12 (according to the Chothia definition system), a heavy chain complementarity determining region 2 (CDR-H2) of SEQ ID NO: 13 (according to the Chothia definition system), a heavy chain complementarity determining region 3 (CDR-H3) of SEQ ID NO: 14 (according to the Chothia definition system), a light chain complementarity determining region 1 (CDR-L1) of SEQ ID NO: 15 (according to the Chothia definition system), a light chain complementarity determining region 2 (CDR-L2) of SEQ ID NO: 5 (according to the Chothia definition system), and a light chain complementarity determining region 3 (CDR-L3) of SEQ ID NO: 16 (according to the Chothia definition system).

[0094] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain variable region (VH) containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) in the framework regions as compared with the VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a light chain variable region (VL) containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) in the framework regions as compared with the VL comprising the amino acid sequence of SEQ ID NO: 18.

[0095] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or in addition (e.g., in addition), in some embodiments, the anti-TfRl antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL comprising the amino acid sequence of SEQ ID NO: 18.

[0096] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 17. Alternatively or inaddition (e.g., in addition), in some embodiments, the anti-TfRl antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 18.

[0097] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising an amino acid sequence least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the amino acid sequence of SEQ ID NO: 19.Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a light chain comprising an amino acid sequence least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfRl antibody of the present disclosure is a Fab that comprises a heavy chain comprising an amino acid sequence least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure is a Fab that comprises a light chain comprising an amino acid sequence least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the amino acid sequence of SEQ ID NO: 20.

[0098] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19.Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-TfRl antibody of the present disclosure is a Fab that comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure is a Fab that comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0099] In some embodiments, the anti-TfRl antibody provided herein may have one or more post-translational modifications. In some embodiments, N-terminal cyclization, also called pyroglutamate formation (pyro-Glu), may occur in the antibody at N-terminal Glutamate (Glu) and / or Glutamine (Gin) residues during production. As such, it should be appreciated that an antibody specified as having a sequence comprising an N-terminal glutamate or glutamine residue encompasses antibodies that have undergone pyroglutamate formation resulting from a post-translational modification. In some embodiments, pyroglutamate formation occurs in a heavy chain sequence. In some embodiments, pyroglutamate formation occurs in a light chain sequence.Oligonucleotides[000100] In some embodiments, the oligonucleotides provided herein are useful for targeting DUX4 (e.g., for reducing expression or activity of DUX4, such as the level of DUX4 protein and / or mRNA). In some embodiments, the oligonucleotides are designed to cause RNAi mediated degradation of DUX4 mRNA. In some embodiments, the oligonucleotide is an RNAi oligonucleotide. In some embodiments, the oligonucleotide provided herein comprises an antisense strand that comprises a region of complementarity to a DUX4 RNA. In some embodiments, the oligonucleotide provided herein further comprises a sense strand that forms a double- stranded oligonucleotide (e.g., siRNA). In some embodiments, the oligonucleotide is designed to have desirable bioavailability and / or serum- stability properties. In some embodiments, the oligonucleotide is designed to have desirable binding affinity properties. In some embodiments, the oligonucleotide is designed to have desirable toxicity profiles. In some embodiments, the oligonucleotide is designed to have low-complement activation and / or cytokine induction properties. In some embodiments, the oligonucleotide is designed to have reduced off-target effects, e.g., compared to other known DUX4-targeting siRNAs.[000101] Examples of oligonucleotides useful for targeting DUX4 are provided in US Patent Number 9,988,628, published on February 2, 2017, entitled “AGENTS USEFUL IN TREATING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY”; US Patent Number 9,469,851, published October 30, 2014, entitled “RECOMBINANT VIRUS PRODUCTS AND METHODS FOR INHIBITING EXPRESSION OF DUX4”; US Patent Application Publication 20120225034, published on September 6, 2012, entitled “AGENTS USEFUL IN TREATING FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY”; PCT Patent Application Publication Number WO 2013 / 120038, published on August 15, 2013, entitled “MORPHOLINO TARGETING DUX4 FOR TREATING FSHD”; Chen et al., “Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics,” Molecular Therapy, 2016, 24:8, 1405-1411.; and Ansseau et al., “Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy (FSHD),” Genes, 2017, 8, 93; the contents of each of which are incorporated herein in their entireties. In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence as set forth as: Human DUX4, corresponding to NCBI sequence NM_001293798.2 (SEQ ID NO: 25) or NCBI Sequence: NM_001306068.3 (SEQ ID NO: 26) as below and / or (e.g., and) Mouse DUX4, corresponding to NCBI sequence NM_001081954.1 (SEQ ID NO: 27), as below. Other non-limiting exemplary human DUX4 RNA include NCBI Sequence: NM_033178, GenBank accessionnumbers FJ439133, AF117653, HM101229, HM101230, HM101232, HM101233, HM101234, HM101235, HM101240, HM101241, HM101242, HM101243, HM101244, HM101245, HM101246, HM101247, HM101248, HM101249, HM101250, HM101251 and HM190160, HM190161, HM190162, HM190163, HM190164, HM190165, HM190166, HM190167, HM190168, HM190169, HM190170, HM190171, HM190172, HM190173, HM190174, HM190175, HM190176, HM190177, HM190178, HM190179, HM190180, HM190181, HM190182, HM190183, HM190184, HM190185, HM190186, HM190187, HM190188, HM190189, HM190190, HM190191, HM190192, HM190193, HM190194, HM190195, HM190196, each of which is incorporated herein by reference. In some embodiments, the oligonucleotide may have a region of complementarity to a hypomethylated, contracted D4Z4 repeat, as in Daxinger, et al., “Genetic and Epigenetic Contributors to FSHD,” published in Curr Opin Genet Dev in 2015, Lim J-W, et al., DICER / AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD Hum Mol Genet. 2015 Sep 1; 24(17): 4817-4828, the contents of each of which are incorporated in their entireties.[000102] In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence set forth as follows, which is an example human DUX4 gene sequence (NM_001293798.2) (SEQ ID NO: 25):ATGGCCCTCCCGACACCCTCGGACAGCACCCTCCCCGCGGAAGCCCGGGGACGAG GACGGCGACGGAGACTCGTTTGGACCCCGAGCCAAAGCGAGGCCCTGCGAGCCTG CTTTGAGCGGAACCCGTACCCGGGCATCGCCACCAGAGAACGGCTGGCCCAGGCC ATCGGCATTCCGGAGCCCAGGGTCCAGATTTGGTTTCAGAATGAGAGGTCACGCC AGCTGAGGCAGCACCGGCGGGAATCTCGGCCCTGGCCCGGGAGACGCGGCCCGCC AGAAGGCCGGCGAAAGCGGACCGCCGTCACCGGATCCCAGACCGCCCTGCTCCTC CGAGCCTTTGAGAAGGATCGCTTTCCAGGCATCGCCGCCCGGGAGGAGCTGGCCA GAGAGACGGGCCTCCCGGAGTCCAGGATTCAGATCTGGTTTCAGAATCGAAGGGC CAGGCACCCGGGACAGGGTGGCAGGGCGCCCGCGCAGGCAGGCGGCCTGTGCAG CGCGGCCCCCGGCGGGGGTCACCCTGCTCCCTCGTGGGTCGCCTTCGCCCACACCG GCGCGTGGGGAACGGGGCTTCCCGCACCCCACGTGCCCTGCGCGCCTGGGGCTCT CCCACAGGGGGCTTTCGTGAGCCAGGCAGCGAGGGCCGCCCCCGCGCTGCAGCCC AGCCAGGCCGCGCCGGCAGAGGGGATCTCCCAACCTGCCCCGGCGCGCGGGGATT TCGCCTACGCCGCCCCGGCTCCTCCGGACGGGGCGCTCTCCCACCCTCAGGCTCCT CGCTGGCCTCCGCACCCGGGCAAAAGCCGGGAGGACCGGGACCCGCAGCGCGAC GGCCTGCCGGGCCCCTGCGCGGTGGCACAGCCTGGGCCCGCTCAAGCGGGGCCGCAGGGCCAAGGGGTGCTTGCGCCACCCACGTCCCAGGGGAGTCCGTGGTGGGGCTG GGGCCGGGGTCCCCAGGTCGCCGGGGCGGCGTGGGAACCCCAAGCCGGGGCAGC TCCACCTCCCCAGCCCGCGCCCCCGGACGCCTCCGCCTCCGCGCGGCAGGGGCAG ATGCAAGGCATCCCGGCGCCCTCCCAGGCGCTCCAGGAGCCGGCGCCCTGGTCTG CACTCCCCTGCGGCCTGCTGCTGGATGAGCTCCTGGCGAGCCCGGAGTTTCTGCAG CAGGCGCAACCTCTCCTAGAAACGGAGGCCCCGGGGGAGCTGGAGGCCTCGGAA GAGGCCGCCTCGCTGGAAGCACCCCTCAGCGAGGAAGAATACCGGGCTCTGCTGG AGGAGCTTTAGGACGCGGGGTCTAGGCCCGGTGAGAGACTCCACACCGCGGAGAA CTGCCATTCTTTCCTGGGCATCCCGGGGATCCCAGAGCCGGCCCAGGTACCAGCAG ACCTGCGCGCAGTGCGCACCCCGGCTGACGTGCAAGGGAGCTCGCTGGCCTCTCT GTGCCCTTGTTCTTCCGTGAAATTCTGGCTGAATGTCTCCCCCCACCTTCCGACGCT GTCTAGGCAAACCTGGATTAGAGTTACATCTCCTGGATGATTAGTTCAGAGATATA TTAAAATGCCCCCTCCCTGTGGATCCTATAG[000103] In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence set forth as follows, which is an example human DUX4 gene sequence (NM_001306068.3) (SEQ ID NO: 26):ATGGCCCTCCCGACACCCTCGGACAGCACCCTCCCCGCGGAAGCCCGGGGACGAG GACGGCGACGGAGACTCGTTTGGACCCCGAGCCAAAGCGAGGCCCTGCGAGCCTG CTTTGAGCGGAACCCGTACCCGGGCATCGCCACCAGAGAACGGCTGGCCCAGGCC ATCGGCATTCCGGAGCCCAGGGTCCAGATTTGGTTTCAGAATGAGAGGTCACGCC AGCTGAGGCAGCACCGGCGGGAATCTCGGCCCTGGCCCGGGAGACGCGGCCCGCC AGAAGGCCGGCGAAAGCGGACCGCCGTCACCGGATCCCAGACCGCCCTGCTCCTC CGAGCCTTTGAGAAGGATCGCTTTCCAGGCATCGCCGCCCGGGAGGAGCTGGCCA GAGAGACGGGCCTCCCGGAGTCCAGGATTCAGATCTGGTTTCAGAATCGAAGGGC CAGGCACCCGGGACAGGGTGGCAGGGCGCCCGCGCAGGCAGGCGGCCTGTGCAG CGCGGCCCCCGGCGGGGGTCACCCTGCTCCCTCGTGGGTCGCCTTCGCCCACACCG GCGCGTGGGGAACGGGGCTTCCCGCACCCCACGTGCCCTGCGCGCCTGGGGCTCT CCCACAGGGGGCTTTCGTGAGCCAGGCAGCGAGGGCCGCCCCCGCGCTGCAGCCC AGCCAGGCCGCGCCGGCAGAGGGGATCTCCCAACCTGCCCCGGCGCGCGGGGATT TCGCCTACGCCGCCCCGGCTCCTCCGGACGGGGCGCTCTCCCACCCTCAGGCTCCT CGGTGGCCTCCGCACCCGGGCAAAAGCCGGGAGGACCGGGACCCGCAGCGCGAC GGCCTGCCGGGCCCCTGCGCGGTGGCACAGCCTGGGCCCGCTCAAGCGGGGCCGC AGGGCCAAGGGGTGCTTGCGCCACCCACGTCCCAGGGGAGTCCGTGGTGGGGCTG GGGCCGGGGTCCCCAGGTCGCCGGGGCGGCGTGGGAACCCCAAGCCGGGGCAGCTCCACCTCCCCAGCCCGCGCCCCCGGACGCCTCCGCCTCCGCGCGGCAGGGGCAG ATGCAAGGCATCCCGGCGCCCTCCCAGGCGCTCCAGGAGCCGGCGCCCTGGTCTG CACTCCCCTGCGGCCTGCTGCTGGATGAGCTCCTGGCGAGCCCGGAGTTTCTGCAG CAGGCGCAACCTCTCCTAGAAACGGAGGCCCCGGGGGAGCTGGAGGCCTCGGAA GAGGCCGCCTCGCTGGAAGCACCCCTCAGCGAGGAAGAATACCGGGCTCTGCTGG AGGAGCTTTAGGACGCGGGGTTGGGACGGGGTCGGGTGGTTCGGGGCAGGGCGGT GGCCTCTCTTTCGCGGGGAACACCTGGCTGGCTACGGAGGGGCGTGTCTCCGCCCC GCCCCCTCCACCGGGCTGACCGGCCTGGGATTCCTGCCTTCTAGGTCTAGGCCCGG TGAGAGACTCCACTCCGCGGAGAACTGCCTTTCTTTCCTGGGCATCCCGGGGATCC CAGAGCCGGCCCAGGTACCAGCAGACCTGCGCGCAGTGCGCACCCCGGCTGACGT GCAAGGGAGCTCGCTGGCCTCTCTGTGCCCTTGTTCTTCCGTGAAATTCTGGCTGA ATGTCTCCCCCCACCTTCCGACGCTGTCTAGGCAAACCTGGATTAGAGTTACATCT CCTGGATGATTAGTTCAGAGATATATTAAAATGCCCCCTCCCTGTGGATCCTATAG[000104] In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence set forth as follows, which is an example mouse DUX4 gene sequence (SEQ ID NO: 27) (NM_001081954.1):ATGGCAGAAGCTGGCAGCCCTGTTGGTGGCAGTGGTGTGGCACGGGAATCCCGGC GGCGCAGGAAGACGGTTTGGCAGGCCTGGCAAGAGCAGGCCCTGCTATCAACTTT CAAGAAGAAGAGATACCTGAGCTTCAAGGAGAGGAAGGAGCTGGCCAAGCGAATGGGGGTCTCAGATTGCCGCATCCGCGTGTGGTTTCAGAACCGCAGGAATCGCAGT GGAGAGGAGGGGCATGCCTCAAAGAGGTCCATCAGAGGCTCCAGGCGGCTAGCCT CGCCACAGCTCCAGGAAGAGCTTGGATCCAGGCCACAGGGTAGAGGCATGCGCTCATCTGGCAGAAGGCCTCGCACTCGACTCACCTCGCTACAGCTCAGGATCCTAGGG CAAGCCTTTGAGAGGAACCCACGACCAGGCTTTGCTACCAGGGAGGAGCTGGCGC GTGACACAGGGTTGCCCGAGGACACGATCCACATATGGTTTCAAAACCGAAGAGC TCGGCGGCGCCACAGGAGGGGCAGGCCCACAGCTCAAGATCAAGACTTGCTGGCGTCACAAGGGTCGGATGGGGCCCCTGCAGGTCCGGAAGGCAGAGAGCGTGAAGGT GCCCAGGAGAACTTGTTGCCACAGGAAGAAGCAGGAAGTACGGGCATGGATACCT CGAGCCCTAGCGACTTGCCCTCCTTCTGCGGAGAGTCCCAGCCTTTCCAAGTGGCACAGCCCCGTGGAGCAGGCCAACAAGAGGCCCCCACTCGAGCAGGCAACGCAGGC TCTCTGGAACCCCTCCTTGATCAGCTGCTGGATGAAGTCCAAGTAGAAGAGCCTGC TCCAGCCCCTCTGAATTTGGATGGAGACCCTGGTGGCAGGGTGCATGAAGGTTCCCAGGAGAGCTTTTGGCCACAGGAAGAAGCAGGAAGTACAGGCATGGATACTTCTAGCCCCAGCGACTCAAACTCCTTCTGCAGAGAGTCCCAGCCTTCCCAAGTGGCACAGC CCTGTGGAGCGGGCCAAGAAGATGCCCGCACTCAAGCAGACAGCACAGGCCCTCT GGAACTCCTCCTCCTTGATCAACTGCTGGACGAAGTCCAAAAGGAAGAGCATGTG CCAGTCCCACTGGATTGGGGTAGAAATCCTGGCAGCAGGGAGCATGAAGGTTCCC AGGACAGCTTACTGCCCCTGGAGGAAGCAGTAAATTCGGGCATGGATACCTCGAT CCCTAGCATCTGGCCAACCTTCTGCAGAGAATCCCAGCCTCCCCAAGTGGCACAGC CCTCTGGACCAGGCCAAGCACAGGCCCCCACTCAAGGTGGGAACACGGACCCCCT GGAGCTCTTCCTCTATCAACTGTTGGATGAAGTCCAAGTAGAAGAGCATGCTCCAG CCCCTCTGAATTGGGATGTAGATCCTGGTGGCAGGGTGCATGAAGGTTCGTGGGA GAGCTTTTGGCCACAGGAAGAAGCAGGAAGTACAGGCCTGGATACTTCAAGCCCC AGCGACTCAAACTCCTTCTTCAGAGAGTCCAAGCCTTCCCAAGTGGCACAGCGCC GTGGAGCGGGCCAAGAAGATGCCCGCACTCAAGCAGACAGCACAGGCCCTCTGG AACTCCTCCTCTTTGATCAACTGCTGGACGAAGTCCAAAAGGAAGAGCATGTGCC AGCCCCACTGGATTGGGGTAGAAATCCTGGCAGCATGGAGCATGAAGGTTCCCAG GACAGCTTACTGCCCCTGGAGGAAGCAGCAAATTCGGGCAGGGATACCTCGATCC CTAGCATCTGGCCAGCCTTCTGCAGAAAATCCCAGCCTCCCCAAGTGGCACAGCCC TCTGGACCAGGCCAAGCACAGGCCCCCATTCAAGGTGGGAACACGGACCCCCTGG AGCTCTTCCTTGATCAACTGCTGACCGAAGTCCAACTTGAGGAGCAGGGGCCTGCC CCTGTGAATGTGGAGGAAACATGGGAGCAAATGGACACAACACCTATCTGCCTCT CACTTCAGAAGAATATCAGACTCTTCTAGATATGCTCTGA[000105] In some embodiments, an oligonucleotide may comprise a region of complementarity to DUX4 sequences of multiple species, e.g., selected from human, mouse and non-human species (e.g., cynomolgus monkey).[000106] In some embodiments, an oligonucleotide provided herein is a double-stranded RNAi oligonucleotide (e.g., siRNA) targeting DUX4. In some embodiments, a DUX4- targeting RNAi oligonucleotide is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, or more base pairs in length. In some embodiments, a DUX4-targeting RNAi oligonucleotide is 8 to 30 base pairs in length, 10 to 15 base pairs in length, 10 to 20 base pairs in length, 15 to 25 base pairs in length, 19 to 21 base pairs in length, 21 to 23 base pairs in length.[000107] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand and a sense strand. In some embodiments, the antisense strand is 18-25 (e.g., 18, 19, 20, 21, 22, 23, 24, or 25) nucleosides in length. In some embodiments, the antisense strand is 23 nucleosides in length.In some embodiments, the sense strand is 18-25 (e.g., 18, 19, 20, 21, 22, 23, 24, or 25) nucleosides in length. In some embodiments, the sense strand is 21 nucleosides in length. [000108] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand comprising a region of complementarity of at least 16 (e.g., 16, 17, 18, 19, 20, or more) consecutive nucleosides to a DUX4 sequence as set forth in SEQ ID NO: 25, 26, and / or 27. In some embodiments, the antisense strand comprises a region of complementarity of at least 16 (e.g., 16, 17, 18, 19, 20, or more) consecutive nucleosides to a target sequence as set forth in SEQ ID NO: 24 or 21. [000109] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that is 18-25 nucleosides (e.g., 18, 19, 20, 21, 22, 23, 24, or 25 nucleosides) in length and comprising a region of complementarity to a target sequence as set forth in SEQ ID NO: 24 (UGUUCUUCCGUGAAAUUCUGGCA), wherein the region of complementarity is at least 16 nucleosides (e.g., 16, 17, 18, 19, 20, 21, or 22 nucleosides) in length. In some embodiments, the antisense strand is 23 nucleosides in length and comprises a region of complementarity to a target sequence as set forth in SEQ ID NO: 24 (UGUUCUUCCGUGAAAUUCUGGCA), wherein the region of complementarity is at least 20 nucleosides (e.g., 20, 21, or 22 nucleosides) in length. In some embodiments, the region of complementarity is fully complementarity with all or a portion of its target sequence. In some embodiments, the region of complementarity includes 1, 2, 3 or more mismatches.[000110] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that comprises at least 15 consecutive nucleosides of (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20) the nucleobase sequence of SEQ ID NO: 22 (UGCCAGAAUUUCACGGAAGAACA). In some embodiments, the oligonucleotide further comprises a sense strand comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, or more) consecutive nucleosides complementary to the antisense strand. In some embodiments, the oligonucleotide further comprises a sense strand that comprises at least 15 consecutive nucleosides of (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20) the nucleobase sequence of SEQ ID NO: 21 (UUCUUCCGUGAAAUUCUGGCA).[000111] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that comprises the nucleobase sequence of SEQ ID NO: 22 (UGCCAGAAUUUCACGGAAGAACA). In someembodiments, the oligonucleotide further comprises a sense strand that comprises the nucleobase sequence of SEQ ID NO: 21 (UUCUUCCGUGAAAUUCUGGCA).[000112] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that comprises the nucleobase sequence of SEQ ID NO: 22 (UGCCAGAAUUUCACGGAAGAACA) and a sense strand that hybridizes to the antisense strand and comprises the nucleobase sequence of SEQ ID NO: 21 (UUCUUCCGUGAAAUUCUGGCA), wherein the antisense strand and / or (e.g., and) the sense strand comprises one or more modified nucleosides (e.g., 2’ -modified nucleosides). In some embodiment, the one or more modified nucleosides are selected from 2’-O-Me and 2’-F modified nucleosides. In some embodiments, the antisense strand further comprises a 5'-(E)-vinylphosphonate.[000113] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that comprises the nucleobase sequence of SEQ ID NO: 22 (UGCCAGAAUUUCACGGAAGAACA) and a sense strand that hybridizes to the antisense strand and comprises the nucleobase sequence of SEQ ID NO: 21 (UUCUUCCGUGAAAUUCUGGCA), wherein each nucleoside in the antisense strand and / or (e.g., and) each nucleoside in the sense strand is a 2’-modified nucleoside selected from 2’-O-Me and 2’-F modified nucleosides. In some embodiments, nucleosides at three consecutive positions of the sense strand are 2’-F modified nucleosides and the nucleosides at three consecutive positions of the antisense strand are 2’-O-Me modified nucleosides. In some embodiments, the antisense strand further comprises a 5'-(E)- viny Ipho sphonate .[000114] In some embodiments, an oligonucleotide described herein is a double stranded RNAi oligonucleotide (e.g., an siRNA) comprising an antisense strand that comprises the nucleobase sequence of SEQ ID NO: 22 (UGCCAGAAUUUCACGGAAGAACA) and a sense strand that hybridizes to the antisense strand and comprises the nucleobase sequence of SEQ ID NO: 21 (UUCUUCCGUGAAAUUCUGGCA), wherein each nucleoside in the antisense strand and each nucleoside in the sense strand is a 2’ -modified nucleoside selected from 2’-O- Me and 2’-F modified nucleosides, wherein the nucleosides at three consecutive positions of the sense strand are 2’-F modified nucleosides and the nucleosides at three consecutive positions of the antisense strand are 2’-O-Me modified nucleosides, and wherein the antisense strand and / or (e.g., and) the sense strand each comprises one or more phosphorothioate intemucleoside linkages. In some embodiments, the antisense strand further comprises a 5'-(E)- viny Ipho sphonate .[000115] In some embodiments, the sense strand does not comprise any phosphorothioate intemucleoside linkages (all the internucleoside linkages in the sense strand are phosphodiester intemucleoside linkages), and the antisense strand comprises 1, 2, or 3 phosphorothioate intemucleoside linkages. In some embodiments, the sense strand comprises 2 phosphorothioate internucleoside linkages, and the antisense strand comprises 4 phosphorothioate internucleoside linkages. In some embodiments, the sense strand comprises 4 phosphorothioate internucleoside linkages, and the antisense strand comprises 4 phosphorothioate internucleoside linkages.[000116] In some embodiments, the antisense strand comprises 2 phosphorothioate intemucleoside linkages, optionally wherein the two intemucleoside linkages at the 3’ end of the antisense strand are phosphorothioate intemucleoside linkages and the rest of the intemucleoside linkages in the antisense strand are phosphodiester intemucleoside linkages. In some embodiments, the antisense strand comprises 4 phosphorothioate intemucleoside linkages, optionally wherein the two intemucleoside linkages at the 3’ end and the two intemucleoside linkage at the 5’ end of the antisense strand are phosphorothioate intemucleoside linkages and the rest of the intemucleoside linkages in the antisense strand are phosphodiester intemucleoside linkages. In some embodiments, the sense strand comprises 2 phosphorothioate intemucleoside linkages, optionally wherein the two intemucleoside linkages at the 5’ end of the sense strand are phosphorothioate intemucleoside linkages and the rest of the intemucleoside linkages in the sense strand are phosphodiester intemucleoside linkages. In some embodiments, the sense strand comprises 4 phosphorothioate intemucleoside linkages. In some embodiments, the two intemucleoside linkages at the 5’ end and the two intemucleoside linkages at the 3’ end of the sense strand are phosphorothioate intemucleoside linkages, and the rest of the intemucleoside linkages in the sense strand are phosphodiester intemucleoside linkages.[000117] In some embodiments, the antisense strand of the oligonucleotide described herein comprises a structure of (5’ to 3’; referred to herein as “MAS7”): mN*fN*mNmNmNmNmNmNmNmNmNmNmNfNmNmNmNmNmNmNmN*mN*mN, wherein “mN” indicates 2’-O-methyl (2’-0-Me) modified nucleoside; “fN” indicates 2’ -fluoro (2’-F) modified nucleoside;represents phosphorothioate intemucleoside linkage; and the absence of between two nucleosides represents phosphodiester intemucleoside linkage. [000118] In some embodiments, the MAS7 structure further comprises a 5’ vinylpho sphonate (e.g., 5'-(E)-vinylphosphonate) modification (5’ to 3’; referred to herein as “VP-MAS7”):VP-mN*fN*mNmNmNmNmNmNmNmNmNmNmNfNmNmNmNmNmNmNmN*mN*mN, wherein “mN” indicates 2’-0-methyl (2’-0-Me) modified nucleoside; “fN” indicates 2’ -fluoro (2’-F) modified nucleoside;represents phosphorothioate internucleoside linkage; the absence of between two nucleosides represents phosphodiester internucleoside linkage; and VP represents 5'-(E)-vinylphosphonate.[000119] In some embodiments, the sense strand of the oligonucleotide described herein comprises a structure of (5’ to 3’; referred to herein as “MS8”): mN*mN*mNmNfNmNmNmNfNfNfNmNmNfNmNmNmNmNfN*mN*mN, wherein “mN” indicates 2’-O-methyl (2’-0-Me) modified nucleoside; “fN” indicates 2’ -fluoro (2’-F) modified nucleoside;represents phosphorothioate internucleoside linkage; and the absence between two nucleosides represents phosphodiester internucleoside linkage.[000120] In some embodiments, the oligonucleotide described herein comprises an antisense strand comprising a structure of (5’ to 3’; VP-MAS7): VP- mN*fN*mNmNmNmNmNmNmNmNmNmNmNfNmNmNmNmNmNmNmN*mN*mN, and a sense strand comprising a structure of (5’ to 3’; MS8): mN*mN*mNmNfNmNmNmNfNfNfNmNmNfNmNmNmNmNfN*mN*mN, wherein “mN” indicates 2’-O-methyl (2’-0-Me) modified nucleoside; “fN” indicates 2’ -fluoro (2’-F) modified nucleoside;represents phosphorothioate internucleoside linkage; and the absence between two nucleosides represents phosphodiester internucleoside linkage; and VP represents 5'-(E)-vinylphosphonate.[000121] In some embodiments, an oligonucleotide described herein (e.g., a DUX4 targeting RNAi oligonucleotide described herein) comprises 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate.[000122] In some embodiments, an oligonucleotide described herein (e.g., a DUX4 targeting RNAi oligonucleotide described herein) comprises a structure of the formula (le), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(le).[000123] In some embodiments, an oligonucleotide described herein (e.g., a DUX4 targeting RNAi oligonucleotide described herein) can be in salt form, e.g., as sodium, potassium, or magnesium salts.[000124] In some embodiments, the 5’ or 3’ nucleoside (e.g., terminal nucleoside) of an oligonucleotide described herein (e.g., a DUX4-targeting RNAi oligonucleotide) is conjugated to an amine group, optionally via a spacer. In some embodiments, the spacer comprises an aliphatic moiety. In some embodiments, the spacer comprises a polyethylene glycol moiety. In some embodiments, a phosphodiester linkage is present between the spacer and the 5’ or 3’ nucleoside of the oligonucleotide. In some embodiments, the 5’ or 3’ nucleoside (e.g., terminal nucleoside) of an oligonucleotide described herein is covalently linked to a spacer that is a 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(RA)-, -S-, -C(=0)-, -C(=0)0-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, - NRAC(=O)O-, -NRAC(=O)N(RA)-, -0C(=0)-, -0C(=0)0-, -OC(=O)N(RA)-, -S(O)2NRA-, - NRAS(O)2-, or a combination thereof; each RAis independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, the spacer is a substituted or unsubstituted alkylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, -O-, -N(RA)-, or -C(=O)N(RA)2, or a combination thereof.[000125] In some embodiments, the 5’ or 3’ nucleoside of the oligonucleotide is conjugated to a compound of the formula -NH2-(CH2)n-, wherein n is an integer from 1 to 12. In some embodiments, n is 6, 7, 8, 9, 10, 11, or 12. In particular embodiments, n is 6. In some embodiments, a phosphodiester linkage is present between the compound of the formula NH2- (CH2)n- and the 5’ or 3’ nucleoside of the oligonucleotide, wherein n is an integer from 1 to 12. In some embodiments, n is 6, 7, 8, 9, 10, 11, or 12. In particular embodiments, n is 6.[000126] In some embodiments, the 5’ nucleoside of the sense strand of the oligonucleotide is conjugated to a compound of the formula -NH2-(CH2)n-, wherein n is an integer from 1 to 12 (e.g., 6). In some embodiments, the 3’ nucleoside of the sense strand of the oligonucleotide is conjugated to a compound of the formula -NH2-(CH2)n-, wherein n is an integer from 1 to 12 (e.g., 6).[000127] In some embodiments, a compound of the formula NH2-(CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2-(CH2)6-OH) and the 5’ phosphate of the oligonucleotide. In some embodiments, a compound of the formula NH2- (CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2- (CH2)6-OH) and the 5’ phosphate of the sense strand of the oligonucleotide. In some embodiments, a compound of the formula NH2-(CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2-(CH2)6-OH) and the 5’ phosphate of the antisense strand of the oligonucleotide.[000128] In some embodiments, a compound of the formula NH2-(CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2-(CH2)6-OH) and the 3’ phosphate of the oligonucleotide. In some embodiments, a compound of the formula NH2- (CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2- (CH2)6-OH) and the 3’ phosphate of the sense strand of an oligonucleotide. In some embodiments, a compound of the formula NH2-(CH2)6- is conjugated to the oligonucleotide via a reaction between 6-amino-l -hexanol (NH2-(CH2)6-OH) and the 3’ phosphate of the antisense strand of the oligonucleotide.[000129] In some embodiments, an oligonucleotide described herein (e.g., a DUX4 targeting RNAi oligonucleotide described herein) conjugated to the formula NH2-(CH2)6- comprises a structure of the formula (If), in which the antisense strand and the sense strand form a double stranded oligonucleotide:Sense StrandAntisense Strand5' end of antisense strand (with vinylphosphonate modification)[000130] In some embodiments, the oligonucleotide is conjugated to a targeting agent, e.g., a muscle targeting agent such as an anti-TfRl antibody, e.g., via an amine group of a lysine of the targeting agent.[000131] In some embodiments, it should be appreciated that methylation of the nucleobase uracil at the C5 position forms thymine. Thus, in some embodiments, a nucleotide or nucleoside having a C5 methylated uracil (or 5-methyl-uracil) may be equivalently identified as a thymine nucleotide or nucleoside.[000132] In some embodiments, any one or more of the thymine bases (T’s) in any one of the oligonucleotides and / or target sequences provided herein may independently and optionally be uracil bases (U’s), and / or any one or more of the U’s in any one of the oligonucleotides or target sequences provided herein (e.g., a DUX4-targeting RNAi oligonucleotide) may independently and optionally be T’s.Compositions[000133] In some embodiments, compositions comprising complexes (z.e., a plurality of complexes) are prepared in a manner suitable for the methods described herein. In some embodiments, compositions comprising muscle-targeting complexes are delivered to a subject in a manner that minimizes degradation, facilitates delivery and / or (e.g., and) uptake, or provides another beneficial property to the complexes in the composition. Accordingly, in some embodiments, compositions comprising complexes (e.g., a plurality of complexes comprising an oligonucleotide covalently linked with a Fab) comprise tris(hydroxymethyl)aminomethane and / or sucrose. In some embodiments, compositions comprising muscle-targeting complexes (e.g., complexes comprising an oligonucleotide covalently linked with a Fab) comprise tris(hydroxymethyl)aminomethane and / or sucrose in aqueous solutions. In some embodiments, compositions comprising a plurality of the complexes, tris(hydroxymethyl)aminomethane, and sucrose can be lyophilized (e.g., for storage). In some embodiments, the lyophilized composition may be reconstituted (e.g., with water) for administration to a subject. In some embodiments, compositions comprising a plurality of the complexes, tris(hydroxymethyl)aminomethane, and sucrose can be frozen (e.g., for storage). In some embodiments, the frozen composition may be thawed prior to administration to a subject, e.g., to produce an aqueous solution. The compositions (e.g., in aqueous solutions, in frozen compositions, or in lyophilized compositions) can be suitably prepared such that when administered to a subject, either into the immediate environment of a target cell or systemically, a sufficient amount of the complexes enter target muscle cells.[000134] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein comprise complexes (z.e., a plurality of complexes), each of which complex comprises an antibody (e.g., anti-TFRl antibody) covalently linked to one or more oligonucleotides (e.g., a DUX4-targeting RNAi oligonucleotide described herein), wherein the antibody comprises a heavy chain comprising a heavy chain variable region (VH) and a heavy chain constant region, and a light chain comprising a light chain variable region (VL) and a light chain constant region. In some embodiments, the antibody of such complexes comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as set forth in Table 2, and further, in some embodiments, wherein the composition further comprises tris(hydroxymethyl)aminomethane and sucrose. In some embodiments, the antibody is an anti-TfRl Fab. Complexes of a composition described herein can comprise any structure provided herein, e.g., a structure of formula (I) (e.g., comprising a group of the formula (la), formula (lb), formula (Ic), formula (Id), or formula (A)).[000135] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein comprise complexes (z.e., a plurality of complexes) wherein each complex comprises a structure of formula (I): [ R1]ni - R2, in which each R1independently comprises a compound comprising an oligonucleotide (e.g., a DUX4- targeting RNAi oligonucleotide described herein) and is covalently linked to R2, wherein R2comprises an antibody (e.g., anti-TfRl antibody) comprising a heavy chain comprising a heavy chain variable region (VH) and a heavy chain constant region, and a light chain comprising a light chain variable region (VL) and a light chain constant region. In some embodiments, each R1of a complex is independently covalently linked to a different amino acid residue (e.g., lysine or cysteine) of R2.[000136] In some embodiments, the value of nl of complexes in the composition is independently and optionally an integer from one up to the number of amino acid residues to which conjugation is desired or targeted (e.g., the number of lysine residues) in the antibody (e.g., an antibody comprised within R2). In some embodiments, the value of nl of each complex in the composition is independently and optionally selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27. In some embodiments, the value of nl of each complex in the composition is independently and optionally selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26. In some embodiments, the value of nl of each complex in the composition is 1. In some embodiments, the value of nl of each complex in the composition isindependently selected and optionally from an integer in the range of 1 to 27, 1 to 26, 1 to 10, 1 to 5, or 1 to 3. In some embodiments, the average value of nl of complexes of the composition is in the range of 1 to 2, 1 to 3, 1 to 5, 1 to 10, 1 to 26, or 1 to 27. In some embodiments, compositions described herein comprise complexes in which the value of nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9- 1.5, 0.9-1.4, 0.9-13, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000137] In some embodiments, a composition for administration to a subject in a method described herein comprises an antibody that is not conjugated to an oligonucleotide (e.g., in trace amounts) and an antibody conjugated to one or more oligonucleotides. In some embodiments, the antibody that is not conjugated to an oligonucleotide may be referred to as a compound comprising a structure of formula (I): [ R11Ni -R2, for which nl is zero. Accordingly, in some embodiments, a composition for administration to a subject in a method described herein comprises compounds (e.g., complexes) comprising a structure of formula (I): [R^ni-R2, for which each R1independently comprises a group comprising an oligonucleotide, R2comprises an antibody and nl is independently an integer of zero or greater that reflects the number of instances of R1in each compound (e.g., complex). In some embodiments, the fraction of compounds comprising a structure of formula (I): [R^ni-R2, in a composition, for which nl is zero, compared with all compounds of that structure in the composition for which nl is one or greater, is less than 10%, less than 5%, less than 1% less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1- 5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1- 1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9- 1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000138] In some embodiments, each instance of R1in a complex herein e.g., a complex of a composition provided herein) is conjugated to a different amino acid residue of the antibody. In some embodiments, each different amino acid comprises an 8-amino group (e.g., lysine, arginine). However, in some embodiments, each different amino acid to which R1is covalently linked is a cysteine. In some embodiments, R1is directly covalently linked to an amino acid residue of the antibody. However, in some embodiments, R1is indirectlycovalently linked to an amino acid of the antibody, e.g., covalently linked to a glycosylation site on the amino acid. In some embodiments, compositions are provided in which complexes for which R1is covalently linked to an amino acid residue residing in a CDR region of the antibody are present in only trace amounts, or in undetectable amount, or not at all. In some embodiments, compositions are provided in which complexes for which R1is covalently linked to an amino acid residue residing in a CDR region of the antibody are not detectable in the composition using standard detection techniques.[000139] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method provided herein comprise complexes that comprise a structure of formula (I): [R^ni-R2, in which each instance of R1in a complex of a composition provided herein independently comprises a group of the formula (la):or a pharmaceutically acceptable salt thereof, in which R3comprises an oligonucleotide, e.g., an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof; and R1is covalently linked to R2at attachment point A. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., atleast 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment. In some embodiments, R3comprises an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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 [000140] 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. In some embodiments, in each complex nl is independently an integer (e.g., an integer in the range of 1-27, 1-26, 1-10, 1-5, or 1-3). In some embodiments, in each complex nl is 1. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5- 1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8- 1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexesof the composition is 1. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method provided herein comprise complexes that comprise a structure of formula (I): [R^ni-R2, in which each instance of R1in a complex of a composition provided herein comprises a group of the formula (lb):(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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'- (E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein nl is an integer (e.g., one or greater) representing the number of instances of R1in each complex, and each R1is covalently linked to R2at attachment point A. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR- L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chaincomplementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab' fragment, a F(ab')2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9- 1.5, 0.9-1.4, 0.9-13, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000141] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method provided herein comprise complexes that comprise a structure of formula (I): [R^ni-R2, in which each instance of R1in a complex of a composition provided herein comprises a group of the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R1is covalently linked to R2at attachment point A. In some embodiments, nl is an integer (e.g., one or greater) representing the number of instances of R1in each complex. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. For example, in some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementaritydetermining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab’ fragment, a F(ab’)2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9- 1.5, 0.9-1.4, 0.9-13, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000142] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method provided herein comprise complexes that comprise a structure of the formula (Id):(Id), or a pharmaceutically acceptable salt thereof,[000143] 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 intemucleoside linkage; and “VP” represents 5’-(E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises an antibody comprising a sequence as set forth in Table 2; wherein nl is an integer (e.g., one or greater) representing the number of instances of the group enclosed by square brackets, wherein each instance of the group enclosed by square brackets is covalently linked to a different amino acid residue of the antibody, optionally wherein each different amino acid residue is a lysine. In some embodiments, R2comprises an antibody comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR- H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, R2comprises an antibody comprising a heavy chain variable region (VH) comprising an aminoacid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprising a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprising a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, R2comprises an antibody comprising a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprising a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, R2comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprising a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, R2comprises an antibody that is a Fab fragment, a full-length IgG, a Fab’ fragment, a F(ab’)2 fragment, an scFv, or an Fv. In some embodiments, R2comprises an antibody that is a Fab fragment. In some embodiments, compositions described herein further comprise complexes in which nl is 0. In some embodiments, the average value of nl of complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7-1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9- 1.5, 0.9-1.4, 0.9-13, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1. In some embodiments, compositions (e.g., aqueous solutions) for administration to a subject in a method herein comprise a structure of formula (A):(A), or a pharmaceutically acceptable salt thereof, wherein y is 0-15 (e.g., 3) and z is 0-15 (e.g., 4), and wherein As represents an indirect or direct linkage. In some embodiments, the amide shown adjacent the antibody (e.g., anti-TfRl antibody) in the structure (A) results from a reaction with an amine of the antibody, such as a lysine epsilon amine. In some embodiments,a complex described herein comprises an anti-TfRl antibody (e.g., an anti-TfRl Fab) covalently linked via a lysine of the antibody to the 5’ end of an oligonucleotide (e.g., an RNAi oligonucleotide). In some embodiments, the antibody comprises a sequence as set forth in Table 2. For example, in some embodiments, the antibody comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprises a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16. In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 17 and / or comprises a light chain variable region (VL) comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 18. In some embodiments, the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and / or comprises a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 19 and / or comprises a light chain comprising an amino acid sequence at least 85% (e.g., at least 95%) identical to SEQ ID NO: 20. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and / or comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibody is a Fab fragment, a full- length IgG, a Fab’ fragment, a F(ab’)2 fragment, an scFv, or an Fv. In some embodiments, the antibody is a Fab fragment.[000144] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein comprise complexes described herein at a concentration of between 1-200 mg of the complex per mL of the composition. In some embodiments, a composition described herein comprises complexes at a concentration of 10- 200 mg / mL (e.g., 10-200 mg / mL, 10-100 mg / mL, 10-50 mg / mL, 10-30 mg / mL, 10-20 mg / mL, 15-200 mg / mL, 15-150 mg / mL, 15-100 mg / mL, 15-45 mg / mL, 20-40 mg / mL, 25-35 mg / mL, 25.5-34.5 mg / mL, 26-34 mg / mL, 27-33 mg / mL, 28-32 mg / mL, 29-31 mg / mL, 29.5-30.5 mg / mL, 10-40 mg / mL, 15-35 mg / mL, 20-30 mg / mL, 21-29 mg / mL, 21.2-28.8 mg / mL, 22-28mg / mL, 23-27 mg / mL, 24-26 mg / mL, 24.5-25.5 mg / mL, 50-200 mg / mL, 100-200 mg / mL, 150-200 mg / mL, 175-200 mg / mL, 20-150 mg / mL, 30-150 mg / mL, 50-150 mg / mL, 100-150 mg / mL, 75-150 mg / mL, or 40-100 mg / mL). In some embodiments, the concentration of complexes in a composition may vary by up to 20% (e.g., + / - up to 20%, + / - up to 15%, + / - up to 10%, or + / - up to 5%) of a set value.[000145] In some embodiments, any one or a plurality of the complexes for use in a method described herein is formulated with tris(hydroxymethyl)aminomethane and sucrose in an aqueous solution. In some embodiments, the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration in the range of 5-50 mM (e.g., 5-40 mM, 5-35 mM, 5-30 mM, 10-50 mM, 15-45 mM, 10-40 mM, 20-40 mM, 20-35 mM, 20-30 mM, 21-29 mM, 22-28 mM, 23-27 mM, 24-26 mM). In some embodiments, the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM). In some embodiments, the sucrose is present in the aqueous solution at a concentration in the range of 2 % to 15 % weight per volume (w / v%), for example,w / v%, 9.5-11% w / v%, or for example, in the range of 9-10 w / v%, 10-11 w / v%, 10-12 w / v%,In some embodiments, the sucrose is present in the aqueous solution at a concentration of approximately 3 VI / N% (e.g., 3 w / v%). In some embodiments, the sucrose is present in the aqueous solution at a concentration of approximately 6 VI / N% (e.g., 6 w / v%). In some embodiments, the sucrose is present in the aqueous solution at a concentration in the range of 7-13In some embodiments, the sucrose is present in the aqueous solution at a concentration of approximately 10 VI / N% (e.g., 10 w / v%). In some embodiments, the aqueous solution has a pH in the range of 6.5 to 8.5, for example, 6.5-6.5, 6.7-6.9, 6.9-7.1, 7.1-7.3, 7.2-7.8, 7.3-7.5, 7.4-7.5, 7.4-7.6, 7.5-7.6; for example, 7.0-8.0, or for example, in the pH range of 7.0-7.3, 7.2-7.8, 7.3-7.5, 7.4-7.6, 7.5-7.6, 7.5-7.7, 7.7-7.9, 7.9-8.0, 8.0-8.2, 8.2-8.4, 8.3-8.4, 8.4-8.5, 8.5-8.6, or 7.3-7.7. In some embodiments, the aqueous solution has a pH in the range of 7.0-8.0 (e.g., 7.0-7.8, 7.1-7.8, 7.2-7.8, 7.3-7.7, 7.3-7.5, 7.3- 7.6, 7.4-7.6, or 7.4-7.8). In some embodiments, the aqueous solution has a pH of approximately 7.5 (e.g., 7.5). In some embodiments, the aqueous solution has a pH in the range of 7.4-7.7. In some embodiments, the aqueous solution has a pH in the range of 7.4-7.6 e.g., 7.5, or about 7.5).[000146] In some embodiments, any one of the compositions for administration to a subject in a method described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration ofapproximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 3 VI / N% (e.g., 3 w / v%), and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000147] In some embodiments, any one of the compositions for administration to a subject in a method described herein described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 3 VI / N% (e.g., 3 w / v%), wherein complexes are present in the aqueous solution at a concentration of approximately 10-200 mg / ml and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000148] In some embodiments, any one of the compositions for administration to a subject in a method described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 6 VI / N% (e.g., 6 w / v%), and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000149] In some embodiments, any one of the compositions for administration to a subject in a method described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 6 VI / N% (e.g., 6 w / v%), wherein complexes are present in the aqueous solution at a concentration of approximately 10-200 mg / ml and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000150] In some embodiments, any one of the compositions for administration to a subject in a method described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 10 VI / N% (e.g., 10 w / v%), and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000151] In some embodiments, any one of the compositions for administration to a subject in a method described herein is an aqueous solution, wherein tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of approximately 25 mM (e.g., 25 mM), wherein sucrose is present in the aqueous solution at a concentration of approximately 10 w / v% (e.g., 10 w / v%), wherein complexes are present in theaqueous solution at a concentration of approximately 10-200 mg / ml and wherein the aqueous solution is at a pH of approximately 7.5 (e.g., 7.5).[000152] In some embodiments, any one or a plurality of the complexes for use in a method described herein is formulated with tris(hydroxymethyl)aminomethane and sucrose in a lyophilized form (e.g., lyophilized powder). In some embodiments, the lyophilized form (e.g., lyophilized powder) is obtained by lyophilization of any one of the aqueous solutions described herein.[000153] In some embodiments, a lyophilized form is a lyophilized cake. In some embodiments, a lyophilized cake comprises a plurality of complexes for use in a method provided herein, tris(hydroxymethyl)aminomethane, and sucrose.[000154] In some embodiments, any one or a plurality of the complexes for use in a method described herein is formulated with tris(hydroxymethyl)aminomethane and sucrose in a frozen form (e.g., a frozen aqueous solid). In some embodiments, the frozen form (e.g., frozen aqueous solid) is obtained by freezing of any one of the aqueous solutions described herein. A frozen form may be frozen to a temperature of less than -20 °C (e.g., less than - 20 °C, less than -30 °C, less than -40 °C, less than -50 °C, less than -60 °C, less than -70 °C, less than -80 °C, or lower).[000155] As described herein, in some embodiments, compositions for administration to a subject in a method described herein are formulated in aqueous solutions that comprise sucrose. In some embodiments, sucrose serves at least in part as a lyoprotectant. In some embodiments, the sucrose is from a plant, e.g., grass, fruit, or vegetable (e.g., root vegetable) source (e.g., beet (e.g., sugar beet, for example, Saccharum spp.)), sugarcane (e.g., Beta vulgaris), dates, sugar maple, sweet sorghum, apples, oranges, carrots, molasses, maple syrup, com sweeteners) or animal product (e.g., honey). In some embodiments, the sucrose is from beet or sugarcane (e.g., beet sucrose, sugarcane sucrose). In some embodiments, a lyoprotectant other than sucrose may be used, e.g., trehalose, mannitol, lactose, polyethylene glycol, or polyvinyl pyrrolidone. However, in some embodiments, a collapse temperature modifier (e.g., dextran, ficoll, or gelatin) may be provided in a composition.[000156] In some embodiments, provided is a product (e.g., lyophilized composition described herein), produced by a process comprising lyophilizing an aqueous solution of a composition (e.g., aqueous form) described herein.[000157] In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g. , intravenous, intradermal, subcutaneous, administration. Typically, theroute of administration is intravenous or subcutaneous. In some embodiments, the route of administration is intravenous.Methods of Use / Treatment / Dosing[000158] Complexes comprising a muscle-targeting agent (e.g., an anti-TfRl antibody) covalently linked to a molecular payload (e.g., an RNAi oligonucleotide) as described herein are effective in treating FSHD. In some embodiments, treating FSHD comprises alleviating one or more symptoms of FSHD in a subject. In some embodiments, one or more symptoms include muscle weakness, muscle mass loss, muscle atrophy, retinal abnormalities, hearing loss, joint pain, and inflammation. In some embodiments, treating FSHD comprises preventing loss of muscle function in a subject. In some embodiments, treating FSHD comprises preserving muscle function in a subject. In some embodiments, treating FSHD comprises restoring muscle function in a subject. In some embodiments, treating FSHD comprises reversing loss of muscle function in a subject. In some embodiments, complexes are effective in treating Type 1 FSHD. In some embodiments, complexes are effective in treating Type 2 FSHD. In some embodiments, FSHD is associated with deletions in D4Z4 repeat regions on chromosome 4 which contain the DUX4 gene. In some embodiments, FSHD is associated with mutations in the SMCHD1 gene. In some embodiments, FSHD is associated with mutations in the DNMT3B gene. In some embodiments, FSHD is associated with mutations in the LRIF1 gene. In some embodiments, a subject may be a human subject, a nonhuman primate subject, a rodent subject, or any suitable mammalian subject. In some embodiments, the subject is a young pediatric human subject (e.g., a human subject that is less than 4 years old, less than 3 years old, less than 2 years old, less than 1 year old, about 11 months old, about 10 months old, about 9 months old, about 8 months old, about 7 months old, about 6 months old, about 5 months old, about 4 months old, about 3 months old, about 2 months old, or about 1 month old). In some embodiments, the subject is a human subject that is between 2 and 60 (e.g., 2-60, 2-50, 2-40, 2-30, 2-20, 2-10) years old. In some embodiments, the subject is a human subject that is between 5 and 30 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) years old. In some embodiments, the subject is a human subject that is at least 10 years old (e.g., at least 10, 20, 30, 40, 50, 60, or 70 years old). In some embodiments, the subject is a human subject that is between 10 and 50 (e.g., 10-50, 10-45, 10-40, 10-35, 10-30, 10-25, 18-50, 18-45, 18-40, 18-35, 18-30, 18-25, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) years old. In some embodiments, the subject is a humansubject that is 60 years old or older (e.g., about 60 years old, about 65 years old, about 70 years old, about 75 years old, or about 80 years old).[000159] In some embodiments, a subject has elevated expression of the DUX4 gene outside of fetal development and the testes. In some embodiments, the subject has facioscapulohumeral muscular dystrophy of Type 1 or Type 2. In some embodiments, the subject having FSHD has mutations in the SMCHD1 gene. In some embodiments, the subject having FSHD has mutations in the DNMT3B gene. In some embodiments, the subject having FSHD has mutations in the LRIF1 gene. In some embodiments, the subject having FSHD has deletion mutations in D4Z4 repeat regions on chromosome 4.[000160] An aspect of the disclosure includes methods involving administering to a subject an effective amount of a pharmaceutical composition (e.g., aqueous solution) comprising complex(es) as described herein. In some embodiments, an effective amount of a pharmaceutical composition (e.g., aqueous solution) that comprises complex(es) comprising an antibody (e.g., Fab) described herein covalently linked to an oligonucleotide (e.g., a DUX4 targeting RNAi oligonucleotide) described herein can be administered to a subject in need of treatment. In some embodiments, a composition (e.g., aqueous solution) is administered systemically. In some embodiments, a pharmaceutical composition (e.g., aqueous solution) comprising complex(es) as described herein may be administered by a suitable route, which may include intravenous administration, e.g., as a bolus or by continuous infusion over a period of time. In some embodiments, a pharmaceutical composition (e.g., aqueous solution) comprising complex(es) as described herein may be administered by a suitable route, which may include subcutaneous administration. In some embodiments, administration may be performed by intravenous, intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra- articular, intrasynovial, or intrathecal routes. In some embodiments, a composition (e.g., aqueous solution) comprising complexes as described herein is administered by infusion (e.g., intravenous infusion).[000161] In some embodiments, a pharmaceutical composition may be in solid form, aqueous form, or a liquid form. In some embodiments, an aqueous or liquid form may be nebulized or lyophilized. In some embodiments, a lyophilized form may be reconstituted with an aqueous or liquid solution (e.g., prior to administration, such as by intravenous infusion). [000162] In some embodiments, provided are methods of and / or uses for treating a subject having aberrant (e.g., increased) expression of DUX4 RNA and / or protein in muscle comprising administering to the subject a composition described herein that comprises an effective amount of complex(es) described herein. In some embodiments, provided aremethods of and / or uses for reducing the expression or activity of DUX4 (e.g., reducing levels of DUX4 RNA and / or protein) in a cell (e.g., a muscle cell), the methods comprising contacting the cell with a composition described herein comprising an effective amount of complex(es) described herein. In some embodiments, the method comprises administering a lyophilized form (e.g., lyophilized powder) of the composition described herein, comprising reconstituting a lyophilized form of the composition in an aqueous solution, and administering the aqueous solution of the composition to a subject in need thereof. For example, in some embodiments, a lyophilized form of the composition is shipped and / or stored in the lyophilized form, reconstituted at a location for administering the aqueous solution of the composition (e.g., healthcare provider location), and administered in the reconstituted form (e.g., as an aqueous solution) by injection or intravenously, e.g., by infusion.[000163] In some embodiments, a pharmaceutical composition is administered via sitespecific or local delivery techniques. Examples of these techniques include implantable depot sources of the complex, local delivery catheters, site specific carriers, direct injection, or direct application.[000164] In some embodiments, in any one the methods described herein, a composition comprising an effective amount of complex(es) described herein is administered to a subject by intravenous infusion. In some embodiments, each administration comprises providing the composition to the subject by intravenous infusion over an infusion period. The length of each infusion periods depends on, e.g., the effective amount of complexes of each administration per kg of the subject’s weight, the subject’s weight, and the rate of infusion. In some embodiments, each administration comprises providing the composition to the subject by intravenous infusion over 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 150 minutes, or 180 minutes. In some embodiments, in any one the methods described herein, a composition comprising an effective amount of complex(es) described herein is administered to a subject by intravenous infusion at a rate of 0.05 mg to 1.5 mg (0.05 mg to 1.5 mg, 0.05 mg to 1 mg, 0.05 mg to 0.5 mg, 0.05 mg to 0.1 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 mg, 0.5 mg to 1.5 mg, 0.5 mg to 1 mg, or 1 mg to 1.5 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject per minute. In some embodiments, the infusion is continuous infusion.[000165] In some aspects, provided herein are methods of reducing expression or activity of DUX4 (e.g., DUX4 protein and / or mRNA) in a subject. In some aspects, provided herein are methods of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject. In some embodiments, the methods of and / or uses described herein (e.g., methods of reducing DUX4expression and / or treating FSHD in a subject) result in prevention of loss of muscle function in the subject. In some embodiments, the methods of and / or uses described herein (e.g., methods of reducing DUX4 expression and / or treating FSHD in a subject), result in preserved muscle function in the subject. In some embodiments, the methods of and / or uses described herein (e.g., methods of reducing DUX4 expression and / or treating FSHD in a subject), result in restored muscle function in the subject. In some embodiments, the methods of and / or uses described herein (e.g., methods of reducing DUX4 expression and / or treating FSHD in a subject), result in reversal of loss of muscle function in the subject. In some embodiments, methods provided herein comprise administering to the subject a composition comprising an effective amount of complexes, each complex comprising an anti-transferrin receptor 1 (TfRl) antibody (e.g., a Fab) covalently linked to one or more oligonucleotides, wherein the antibody comprises: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21), optionally wherein the RNAi oligonucleotide (e.g., siRNA) comprises an antisense strand comprising a structure (5’— >3’) of VP- mU*fG*mCmCmAmGmAmAmUmUmUmCmAfCmGmGmAmAmGmAmA*mC*mA, and a sense strand comprising 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; further optionally, wherein the antibody (e.g., Fab) comprises a VH comprising the amino acidsequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, further optionally wherein the antibody (e.g., Fab) comprises 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.[000166] In some embodiments, methods provided herein comprise administering to the subject a composition comprising an effective amount of complexes, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein each instance of R1comprises a group of the formula (la):(la), or a pharmaceutically acceptable salt thereof, in which R3comprises an RNAi oligonucleotide (e.g., siRNA) or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21), optionally wherein R3comprises an RNAi oligonucleotide (e.g., siRNA) or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises an antisense strand comprising a structure (5’— >3’) of VP- mU*fG*mCmCmAmGmAmAmUmUmUmCmAfCmGmGmAmAmGmAmA*mC*mA, and a sense strand comprising 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 R2comprises an anti-TfRl antibody (e.g., Fab) comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2)comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14; and / or comprising a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5, or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NO: 6 or 16, optionally wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, further optionally wherein the antibody comprises 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 each R1is covalently linked (e.g., indirectly or directly linked, e.g., directly linked) to R2at attachment point A, optionally wherein each R1is covalently linked at attachment point A to a different amino acid residue of the antibody (e.g. Fab) of R2, optionally wherein each different amino acid residue is a lysine; and wherein in each complex nl is independently an integer of one or greater representing the number of instances of R1, optionally wherein the average value of nl of the complexes of the composition is in the range of 1 to 5. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7- 1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9- 2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000167] In some embodiments, methods provided herein comprise administering to the subject a composition comprising an effective amount of complexes, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein each instance of R1comprises a group of the formula (lb):(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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises an anti-TfRl antibody (e.g., Fab) comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, optionally wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, further optionally wherein the antibody comprises 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 each R1is covalently linked to R2at attachment point A, optionally wherein each R1is covalently linked at attachment point A to a different amino acid residue of the antibody (e.g. Fab) of R2, optionally wherein each different amino acid residue is a lysine; and wherein in each complex nl is independently an integer of one or greater representing the number of instances of R1, optionally wherein the average value of nl of the complexes of the composition is in the range of 1 to 5. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7- 1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9- 2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000168] In some embodiments, methods provided herein comprise administering to the subject a composition comprising an effective amount of complexes, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2comprises an anti-TfRl antibody (e.g., Fab) comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, optionally wherein the antibody (e.g., Fab) comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, further optionally wherein the antibody (e.g., Fab) comprises 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 each R1is covalently linked to R2at attachment point A, optionally wherein each R1is covalently linked at attachment point A to a different amino acid residue of the antibody (e.g. Fab) of R2, optionally wherein each different amino acid residue is a lysine; and wherein in each complex nl is independently an integer of one or greater representing the number of instances of R1, optionally wherein the average value of nl of the complexes of the composition is in the range of 1 to 5. In some embodiments, compositions (e.g., in aqueoussolutions) for administration to a subject in a method described herein further comprise complexes that comprise a structure of formula (I): [R^ni-R2, wherein nl is 0. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7- 1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9- 2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000169] In some embodiments, methods provided herein comprise administering to the subject a composition comprising an effective amount of muscle targeting complexes, wherein each complex comprises a group of the formula (Id):(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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'- (E)-Vinylphosphonate; and wherein the oligonucleotide is an RNAi oligonucleotide (e.g., siRNA) comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises an anti-TfRl antibody (e.g., Fab) comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2)comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, optionally wherein the antibody (e.g., Fab) comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, further optionally wherein the antibody (e.g., Fab) comprises 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; and wherein in each complex nl is independently an integer of one or greater, optionally wherein the average value of nl of the complexes of the composition is in the range of 1 to 5, optionally wherein the anti-TfRl antibody (e.g., Fab) covalently linked via different amino acid residue of the antibody (e.g., Fab), optionally wherein each different amino acid residue is a lysine. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in a method described herein further comprise complexes in which nl is 0. As such, in some embodiments, the average value of nl of complexes in a composition disclosed herein is in the range of 0.5 to 5 (e.g., 0.5-5, 1-5, 1-4, 1-3, 3-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1, 0.7- 1.5, 1-1.6, 1-1.5, 1-1.4, 1-1.3, 1-1.2, 1.1-1.5, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.8-1.1, 0.9-3, 0.9- 2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2). In some embodiments, the average value of nl of complexes of the composition is 1.[000170] In some embodiments, in any one of the methods described herein, the composition is in an aqueous solution and further comprises tris(hydroxymethyl)aminomethane and sucrose, wherein the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of 5 mM to 50 mM, the sucrose is present in the aqueous solution at a concentration of 5 VI / N% to In some embodiments, in any one of the methods described herein, the composition is in an aqueous solution and further comprises tris (hydroxymethyl) aminomethane and sucrose, wherein the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of or about 25 mM, the sucrose is present in the aqueous solution at a concentration of or about 10and the composition is at a pH of or about 7.5. In some embodiments, the complexes are present in the composition at a concentration in the range of10 mg / mL to 50 mg / mL (e.g., 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL).[000171] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni -R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)). In some embodiments, in any one of the methods described herein, an effective amount of the complexes provides to the subject an amount of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject, and the amount of oligonucleotides of the complexes provided to the subject per kg of the subject can be derived using the equation (Equation A) below:.. . . . . . , / anti-TfRl antibody amount (mg) \ . oligonucleotide amount (Kmg) = -e— * averaqe value of nl * \ MW of anti-TfRl antibody (^) / a JMW of oligonucleotide (^j), in which “MW” indicates molecular weight (g / mol), and “average value of nl” indicates the average value of nl of the complexes of the composition.[000172] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni -R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)). In some embodiments, in any one of the methods described herein, an effective amount of the complexes provides an amount of the oligonucleotides of the complexes to the subject per kg of the subject, and the amount of the anti-TfRl antibody (e.g., Fab) of the complexes provided to the subject per kg of the subject can be derived using the equation (Equation B) below:in which “MW” indicates molecular weight (g / mol), and “average value of nl” indicates the average value of nl of the complexes of the composition.[000173] It is to be understood that the average value of nl need not be an integer and can be a decimal. In some embodiments, the present disclosure contemplates variation in the average value of nl of up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the average valueof nl of the complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 0.5-4.5, 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 1-5, 1-4.5, 1-4, 1-3.5, 1-3, 1-2.5, 1-2, 1-1.5, 1.5-5,1.5-4.5, 1.5-4, 1.5-3.5, 1.5-3, 1.5-2.5, 1.5-2, 2-5, 2-4.5, 2-4, 2-3.5, 2-3, 2-2.5, 2.5-5, 2.5-4.5,2.5-4, 2.5-3.5, 2.5-3, 3-5, 3-4.5, 3-4, 3-3.5, 3.5-5, 3.5-4.5, 3.5-4, 4-5, 4-4.5 4.5-5, 0.7-2, 0.7- 1.5, 0.7-1.3, 0.7-1.2, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-12, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2), with a variation of up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, a method provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni-R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the average value of nl of the complexes of the composition is in the range of 0.5 to 5 (e.g., 0.5-5, 0.5-4.5, 0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 1-5, 1-4.5, 1-4, 1-3.5, 1-3, 1-2.5, 1-2, 1-1.5, 1.5-5, 1.5-4.5,1.5-4, 1.5-3.5, 1.5-3, 1.5-2.5, 1.5-2, 2-5, 2-4.5, 2-4, 2-3.5, 2-3, 2-2.5, 2.5-5, 2.5-4.5, 2.5-4, 2.5-3.5, 2.5-3, 3-5, 3-4.5, 3-4, 3-3.5, 3.5-5, 3.5-4.5, 3.5-4, 4-5, 4-4.5 4.5-5, 0.7-2, 0.7-1.5, 0.7-1.3, 0.7-1.2, 0.8-2, 0.8-1.5, 0.8-1.3, 0.8-1.2, 0.9-3, 0.9-2, 0.9-1.8, 0.9-1.6, 0.9-1.5, 0.9-1.4, 0.9-1.3, 0.9-1.2, 1, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, or 2), with a variation of up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, a method provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni-R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the average value of nl of the complexes of the composition is about 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, or 1.5, with a variation of up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, a method provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [ R11ni -R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the average value of nl of the complexes of the composition is about 1, with a variation of up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000174] It should be understood that any amount of anti-TfRl antibody (e.g., Fab) provided herein can be represented as an amount of oligonucleotide (e.g., DUX4-targeting oligonucleotide) according to Equation A. As such, it should be understood that descriptionherein relating to providing any amount of anti-TfRl antibody (e.g., Fab) alternatively can be understood as providing oligonucleotide (e.g., DUX4-targeting oligonucleotide) of a corresponding amount according to Equation A. Conversely, any amount of oligonucleoside (e.g., DUX4-targeting oligonucleotide) provided herein can be represented as an amount of anti-TfRl antibody (e.g., Fab) according to Equation B. As such, it should be understood that description herein relating to providing any amount of oligonucleoside (e.g., DUX4-targeting oligonucleotide) alternatively can be understood as providing anti-TfRl antibody (e.g., Fab) of a corresponding amount according to Equation B.[000175] In some embodiments, a method provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni -R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount of complexes provides to the subject an amount of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject, and wherein the amount of oligonucleotides provided to the subject per kg of the subject is derived using Equation A provided herein based on the average value of nl of the complexes of the composition and the amount of anti-TfRl antibody (e.g., Fab) of the complexes provided to the subject per kg of the subject. In some embodiments, the amount of oligonucleotide varies up to 30% from the amount derived from Equation A (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000176] In some embodiments, a method provided herein comprises administering to the subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni -R2as described herein, wherein the composition comprises an amount of the oligonucleotides of the complexes per kg of the subject, and wherein the amount of anti-TfRl antibody (e.g., Fab) provided to the subject per kg of the subject is derived using Equation B provided herein based on the average value of nl of the complexes of the composition and the amount of oligonucleotides of the complexes provided to the subject per kg of the subject. In some embodiments, the amount of anti-TfRl antibody (e.g., Fab) varies up to 45% from the amount derived from Equation B (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). [000177] In some embodiments, for purposes of determining the molecular weight of an oligonucleotide, the oligonucleotide is represented by the following structure, comprising an antisense strand and the sense strand, wherein the antisense strand is annealed to the sense strand:Sense Strand5' end of sense strand (with aminohexyl spacer)Antisense Strand5' end of antisense strand (with vinylphosphonate modification)which corresponds to a molecular weight of 14,893 g / mol[000178] In some embodiments, an anti-TfRl Fab (e.g., an anti-TfRl Fab comprising a heavy chain and a light chain provided in Table 2) of a complex used in a method described herein has a theoretical molecular weight of 47,986 g / mol based on the amino acid sequence. In some embodiments, an anti-TfRl Fab of a complex used in a method described herein comprises a heavy chain comprising an N-terminal pyroglutamate, and has a molecular weight of 47,968 g / mol. For the purposes of calculating the doses provided herein (e.g, the amount of oligonucleotide provided to the subject per kg of the subject derived from Equation A or the amount of anti-TfRl antibody (e.g., Fab) provided to the subject per kg of the subject derived from Equation B), the molecular weight of 47,968 g / mol is used.[000179] Accordingly, in some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni-R2as described herein (e.g., comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount of complexes provides to the subject an amount of the anti-TfRl Fab of the complexes per kg of the subject, and an amount of oligonucleotide per kg of the subject, wherein the amount of oligonucleotide is:.. . . . . . z \ . z-. '.o z \ oligonucleotide amount (mg) = * 1 * 14,893 (^), provided thatthe average value of nl of the complexes of the composition is 1. In some embodiments, the amount of oligonucleotide varies up to 30% from the amount derived from Equation A (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000180] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes comprising a structure of formula (I): [R^ni -R2as described herein, wherein the effective amount of complexes provides to the subject an amount of the oligonucleotides of the complexes per kg of the subject, and an amount of anti-TfRl Fab per kg of the subject, wherein the amount of anti-TfRl Fab is: * 47968 (^), provided that theaverage value of nl of the complexes of the composition is 1. In some embodiments, the amount of anti-TfRl antibody (e.g., Fab) varies up to 45% from the amount derived from Equation B (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to l%).In some embodiments, the administration occurs one or more times. In some embodiments, the subjectis administered a single dose of any one of the compositions comprising an effective amount of the complexes described herein (e.g., complexes comprising a structure of formula (I): [R1]ni- R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)). In some embodiments, the subject is administered multiple doses of any one of the compositions comprising an effective amount of the complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)). In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of the complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once a week to once every 16 weeks. For example, in some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, or once every 16 weeks. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of the complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks to once every 12 weeks (e.g., once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks).[000181] In some embodiments, in any one of the methods described herein a composition is administered to a subject during a period of administration. In some embodiments, a period of administration is 1-24 (e.g., 1-24, 2-24, 3-24, 4-24, 5-24, 6-24, 7-24, 8-24, 9-24, 10-24, 11-24, 12-24, 13-24, 14-24, 15-24, 16-24, 17-24, 18-24, 1-18, 1-12, 1-8, 1- 6, 1-5, 1-4, 1-3, 1-2, 2-18, 2-12, 2-8, 2-6, 2-4, 4-18, 4-12, 4-8, 4-6, 6-18, 6-12, 6-8, 8-18, 8-12, or 12-18) months. In some embodiments, a period of administration is less than 1 month, less than 2 months, less than 3 months, less than 4 months, less than 5 months, less than 6 months, less than 7 months, less than 8 months, less than 9 months, less than 10 months, less than 11 months, less than 12 months, less than 13 months, less than 14 months, less than 15 months, less than 16 months, less than 17 months, or less than 18 months. In some embodiments, a period of administration is 1-20 (e.g., 1-20, 2-20, 3-20, 4-20, 5-20, 6-20, 7-20, 8-20, 9-20, 10- 20, 11-20, 12-20, 13-20, 14-20, 15-20, 16-20, 17-20, 18-20, 19-20, 2-18, 2-12, 2-10, 2-5, 4-18,4-12, 4-8, 6-18, 6-12, or 6-8) years. In some embodiments, a period of administration is less than 1 year, less than 2 years, less than 3 years, less than 4 years, less than 5 years, less than 6 years, less than 7 years, less than 8 years, less than 9 years, less than 10 years, less than 11 years, less than 12 years, less than 13 years, less than 14 years, less than 15 years, less than 16 years, less than 17 years, less than 18 years, less than 19 years, or less than 20 years. In some embodiments, a period of administration is at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 14 years, at least 15 years, at least 16 years, at least 17 years, at least 18 years, at least 19 years, or at least 20 years. In some embodiments, a period of administration is 1-50 years (e.g., 1-50 years, 2-50 years, 3-50 years, 4-50 years, 5-50 years, 6-50 years, 7-50 years, 8-50 years, 9-50 years, 10-50 years, 20-50 years, 30-50 years, 40-50 years, 10-20 years, 10-30 years, 10-40 years, 20-30 years, 20-40 years, or 30-40 years). In some embodiments, a period of administration is the remainder of the subject’s life.[000182] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, or once every 16 weeks for the remainder of the subject’s lifetime. In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks to once every 12 weeks (e.g., once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks) for a period of time (e.g., 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the period of time is for the remainder of the subject’s lifetime. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks (e.g., at week 0, at week 4, at week 8, and so on), for a period of time (e.g., 4 weeks or longer, or the remainder of the subject’s lifetime). In someembodiments, the period of time is for the remainder of the subject’s lifetime. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 6 weeks (e.g., at week 0, at week 6, at week 12, and so on), for a period of time (e.g., 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the period of time is for the remainder of the subject’s lifetime. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 8 weeks (e.g., at week 0, at week 8, at week 16, and so on), for a period of time (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the period of time is for the remainder of the subject’s lifetime. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 12 weeks (e.g., at week 0, at week 12, at week 24, and so on) for a period of time (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the period of time is for the remainder of the subject’s lifetime.[000183] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once a week to once every six weeks (e.g., once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks) during a first period of administration, followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks to once every 16 weeks (e.g., once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, or once every 16 weeks) during a second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, the first period of administration is 2-24 weeks (e.g., 2-24, 2-20, 2-26, 2- 12, 2-8, 2-4, 4-24, 4-20, 4-16, 4-12, 4-8, 4-6, 8-24, 8-20, 8-16, or 8-12 weeks). In someembodiments, the first period of administration is 2, 3, 4, 5, 6 ,7, 8, 9, 10, 11, or 12 weeks. In some embodiments, the first period of administration is 8 weeks. In some embodiments, the first period of administration is 12 weeks. In some embodiments, the second period of administration is 8 weeks or longer (e.g., 8, 12, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96 weeks or longer to the remainder of the subject’s lifetime). In some embodiments, the first period of administration is 8 weeks, and the second period of administration is 8 weeks or longer (e.g., 8, 12, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96 weeks or longer to the remainder of the subject’s lifetime). In some embodiments, the first period of administration is 8 weeks, and the second period of administration is 8 weeks or longer. In some embodiments, the second period of administration is the remainder of the subject’s lifetime. In some embodiments, the first period of administration is 12 weeks, and the second period of administration is 12 weeks or longer (e.g., 12, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96 weeks or longer to the remainder of the subject’s lifetime). In some embodiments, the first period of administration is 12 weeks, and the second period of administration is 12 weeks or longer. In some embodiments, the second period of administration is the remainder of the subject’s lifetime.[000184] In some embodiments, each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration. In some embodiments, each administration during the first period of administration provides the subject with a different amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) from each administration during the second period of administration.[000185] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks during a first period of administration of 4 weeks, 8 weeks, 12 weeks, or 16 weeks (e.g., 8 weeks), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 8 weeks during a second period of administration of 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, 48 weeks, 56 weeks, 64weeks, 72 weeks, 80 weeks, 88 weeks, 96 weeks, 104 weeks, 112 weeks, 120 weeks, 128 weeks, 136 weeks, 144 weeks, 152 weeks, 160 weeks, or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks during a first period of administration of 8 weeks (e.g., initial dose at week 0, second dose at week 4, and third dose at week 8), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 8 weeks (e.g., at week 16, week 24, week 32, and so on) during a second period of administration of 8 weeks or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration.[000186] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks during a first period of administration of 4 weeks, 8 weeks, 12 weeks, or 16 weeks (e.g., 8 weeks), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 8 weeks during a second period of administration of 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, 48 weeks, 56 weeks, 64 weeks, 72 weeks, 80 weeks, 88 weeks, 96 weeks, 104 weeks, 112 weeks, 120 weeks, 128 weeks, 136 weeks, 144 weeks, 152 weeks, 160 weeks, or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration (e.g., the second administration), independently, may provide the subject with a different amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as onecomprising a group of the formula (la), (lb), (Ic), or (Id)) from administrations during the second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 4 weeks during a first period of administration of 8 weeks (e.g., initial dose at week 0, second dose at week 4, and third dose at week 8), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 8 weeks (e.g., at week 16, week 24, week 32, and so on) during a second period of administration of 8 weeks or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration. [000187] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 6 weeks during a first period of administration of 6 weeks, 12 weeks, or 18 weeks (e.g., 12 weeks), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 12 weeks during a second period of administration of 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, 120 weeks, 132 weeks, 144 weeks, 156 weeks, 168 weeks, 180 weeks, or longer or the remainder of the subject’s lifetime, wherein each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 6 weeks during a first period of administration of 12 weeks (e.g., initial dose at week 0, seconddose at week 6, and third dose at week 12), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 12 weeks (e.g., at week 12, week 24, week 36, and so on) during a second period of administration of 12 weeks or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration.[000188] In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 6 weeks during a first period of administration of 6 weeks, 12 weeks, or 18 weeks (e.g., 12 weeks), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 12 weeks during a second period of administration of 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, 120 weeks, 132 weeks, 144 weeks, 156 weeks, 168 weeks, 180 weeks, or longer, or the remainder of the subject’s lifetime, wherein each administration during the first period of administration (e.g., the second administration), independently, may provide the subject with a different amount of complexes (e.g., complexes comprising a structure of formula (I): [R1]^- R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) from administrations during the second period of administration. In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 6 weeks during a first period of administration of 12 weeks (e.g., initial dose at week 0, second dose at week 6, and third dose at week 12), followed by administering to the subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) once every 12 weeks (e.g., at week 12, week 24, week 36, and so on) during a second period of administration of 12 weeks or longer, or the remainder of the subject’s lifetime, wherein eachadministration during the first period of administration provides the subject with a same amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) as each administration during the second period of administration.[000189] In some embodiments, in any one of the methods described herein, additional administrations maybe given to the subject during any period of administration.[000190] In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 1 mg to 100 mg (e.g., 1 mg to 100 mg, 2 mg to 100 mg, 3 mg to 100 mg, 4 mg to 100 mg, 5 mg to 100 mg, 5 mg to 90 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 70 mg, 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 5 mg to 10 mg, 8 mg to 100 mg, 8 mg to 90 mg, 8 mg to 80 mg, 8 mg to 75 mg, 8 mg to 70 mg, 8 mg to 60 mg, 8 mg to 50 mg, 8 mg to 40 mg, 8 mg to 35 mg, 8 mg to 30 mg, 8 mg to 25 mg, 8 mg to 20 mg, 8 mg to 18 mg, 8 mg to 15 mg, 8 mg to 13 mg, 10 mg to 100 mg, 10 mg to 90 mg, 10 mg to 80 mg, 10 mg to 70 mg, 10 mg to 60 mg, 10 mg to 50 mg, 10 mg to 40 mg, 10 mg to 30 mg, 10 mg to 20 mg, 10 mg to 15 mg, 12 mg to 100 mg, 12 mg to 90 mg, 12 mg to 80 mg, 12 mg to 75 mg, 12 mg to 70 mg, 12 mg to 60 mg, 12 mg to 50 mg, 12 mg to 40 mg, 12 mg to 35 mg, 12 mg to 30 mg, 12 mg to 25 mg, 12 mg to 20 mg, 12 mg to 15 mg, 15 mg to 100 mg, 15 mg to 90 mg, 15 mg to 80 mg, 15 mg to 75 mg, 15 mg to 70 mg, 15 mg to 60 mg, 15 mg to 50 mg, 15 mg to 40 mg, 15 mg to 35 mg, 15 mg to 30 mg, 15 mg to 25 mg, 15 mg to 20 mg, 20 mg to 100 mg, 20 mg to 90 mg, 20 mg to 80 mg, 20 mg to 75 mg, 20 mg to 70 mg, 20 mg to 60 mg, 20 mg to 50 mg, 20 mg to 40 mg, 20 mg to 30 mg, 20 mg to 25 mg, 25 mg to 100 mg, 25 mg to 90 mg, 25 mg to 80 mg, 25 mg to 75 mg, 25 mg to 70 mg, 25 mg to 60 mg, 25 mg to 50 mg, 25 mg to 40 mg, 25 mg to 35 mg, or 25 mg to 30 mg) of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 5 mg to 20 mg, 8 mg to 18 mg, 10 mg to 20 mg, 10 mg to 15 mg, 12 mg to 30 mg, 12 mg to 25 mg, 12 mg to 20 mg, or 12 mg to 15 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 3 mg to 23 mg, 3 mg to 20 mg, 3 mg to 19 mg, 3 mg to 16 mg, 4 mg to 23 mg, 4 mg to 20 mg, 4 mg to19 mg, 4 mg to 16 mg, 5 mg to 23 mg, 5 mg to 20 mg, 5 mg to 19 mg, 5 mg to 16 mg, 6 mg to 23 mg, 6 mg to 20 mg, 6 mg to 19 mg, 6 mg to 16 mg, 9 mg to 23 mg, 9 mg to 20 mg, 9 mg to 19 mg, or 9 mg to 16 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 4 mg to 23 mg, of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 9 mg to 20 mg, of the anti- TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, or about 48 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3.2 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 4.8 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 5.3 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 6.4 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 7.6 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 9.7 mg of the anti- TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 10.5 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 12.9 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [ R11ni - R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 16.1 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 19.3 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 22.5 mg of the anti- TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 25.8 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure offormula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 29.0 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni- R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 32.2 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000191] In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 0.1 mg to 31 mg (e.g., 0.1 mg to 31 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.5 mg to 31 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg, 0.5 mg to 5 mg, 1 mg to 31 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 9 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 2 mg to 31 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2 mg to 12 mg, 2 mg to 10 mg, 2 mg to 9 mg, 2 mg to 8 mg, 2 mg to 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to 3 mg, 3 mg to 31 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg, 3 mg to 12 mg, 3 mg to 10 mg, 3 mg to 9 mg, 3 mg to 8 mg, 3 mg to 7 mg, 3 mg to 6 mg, 3 mg to 5 mg, 3 mg to 4 mg, 3.5 mg to 31 mg, 3.5 mg to 25 mg, 3.5 mg to 20 mg, 3.5 mg to 15 mg, 3.5 mg to 12 mg, 3.5 mg to 10 mg, 3.5 mg to 9 mg, 3.5 mg to 8 mg, 3.5 mg to 7 mg, 3.5 mg to 6 mg, 3.5 mg to 5 mg, 3.5 mg to 4 mg, 4 mg to 31 mg, 4 mg to 25 mg, 4 mg to 20 mg, 4 mg to 15 mg, 4 mg to 12 mg, 4 mg to 10 mg, 4 mg to 9 mg, 4 mg to 8 mg, 4 mg to 7 mg, 4 mg to 6 mg, 4 mg to 5 mg, 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 12 mg, 5 mg to 10 mg, 5 mg to 9 mg, 5 mg to 8 mg, 5 mg to 7 mg, 5 mg to 6 mg, 6 mg to 20 mg, 6 mg to 15 mg, 6 mg to 12 mg, 6 mg to 10 mg, 6 mg to 9 mg, 6 mg to 8 mg, 6 mg to 7 mg, 7 mg to 20 mg, 7 mg to 15 mg, 7 mg to 12 mg, 7 mg to 10 mg, 7 mg to 9 mg, 7 mg to 8 mg, 8 mg to 20 mg, 8 mg to 15 mg, 8 mg to 12 mg, 8 mg to 10 mg, 8 mg to 9 mg, 9 mg to 20 mg, 9 mg to 15 mg, 9 mg to 12 mg, 9 mg to 10 mg, 10 mg to 20 mg, 10 mg to 15 mg, 10 mg to 12 mg, 12 mg to 20 mg, 12 mg to 15 mg, or 15 mg to 20 mg) of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising agroup of the formula (la), (lb), (Ic), or (Id)) provides to the subject 0.5 mg to 10 mg, 0.5 mg to 5 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 5 mg, 2 mg to 8 mg, 2 mg to 6 mg, 3 mg to 8 mg, 3 mg to 5 mg, or 4 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 1 mg to 7 mg, 1 mg to 6 mg, 1 mg to 5 mg, 1.5 mg to 7 mg, 1.5 mg to 6 mg, 1.5 mg to 5 mg, 2 mg to 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, 3 mg to 7 mg, 3 mg to 6 mg, 3 mg to 5 mg, or 3 mg to 4 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 1.5 mg to 7 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject 3 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 0.5 mg, about 0.8 mg, about 1 mg, about 1.2 mg, about 1.5 mg, about 1.6 mg, about 1.8 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.5 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.3 mg, about 3.5 mg, about 3.8 mg, about 4 mg, about 4.2 mg, about 4.5 mg, about 4.8 mg, about 5 mg, about 5.2 mg, about 5.5 mg, about 5.8 mg, about 6 mg, about 6.2 mg, about 6.5 mg, about 6.8 mg, about 7 mg, about 7.2 mg, about 7.5 mg, about 7.8 mg, about 8 mg, about 8.2 mg, about 8.5 mg, about 8.8 mg, about 9 mg, about 9.2 mg, about 9.5 mg, about 9.8 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, or about 20 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexescomprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1.5 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1.6 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 2 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 2.4 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3.3 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 4 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni- R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 5 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 6 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb),(Ic), or (Id)) provides to the subject about 7 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 8 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 9 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 10 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 0.9 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1.2 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1.6 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 1.9 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 2.2 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 2.5 mg of the oligonucleotides of the complexes per kg of the subject. Insome embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 2.8 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3.1 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3.4 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 3.7 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 4.0 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 5.0 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 5.3 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 5.9 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 6.2 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount ofcomplexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 7.1 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 8.1 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 9.0 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, in any one of the methods described herein, the effective amount of complexes (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)) provides to the subject about 9.9 mg of the oligonucleotides of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of oligonucleotides, the values can vary by up to 30% (e.g., ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000192] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 2 mg to 50 mg (e.g., 2 mg to 50 mg, 3 mg to 45 mg, 3 mg to 40 mg, 3 mg to 35 mg, 3 mg to 30 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg, 3 mg to 10 mg, 6 mg to 45 mg, 6 mg to 40 mg, 6 mg to 35 mg, 6 mg to 30 mg, 6 mg to 25 mg, 6 mg to 20 mg, 6 mg to 15 mg, 6 mg to 10 mg, 8 mg to 45 mg, 8 mg to 40 mg, 8 mg to 35 mg, 8 mg to 30 mg, 8 mg to 25 mg, 8 mg to 20 mg, 8 mg to 15 mg, 8 mg to 10 mg, 10 mg to 45 mg, 10 mg to 40 mg,10 mg to 30 mg, 10 mg to 20 mg, 10 mg to 15 mg, 12 mg to 45 mg, 12 mg to 40 mg, 12 mg to 30 mg, 12 mg to 20 mg, 12 mg to 15 mg, 15 mg to 45 mg, 15 mg to 40 mg, 15 mg to 30 mg, 15 mg to 20 mg, 20 mg to 45 mg, 20 mg to 40 mg, 20 mg to 30 mg, 30 mg to 45 mg, or 30 mg to 40 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 2 mg to 5 mg, 4 mg to 10 mg, 9 mg to 19 mg, 14 mg to 28 mg, 19 mg to 37 mg or 24 mg to 46 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising aneffective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg, about 10 mg, about 13 mg, about 16 mg, about 19 mg, about 20 mg, about 23 mg, about 26 mg, about 29 mg, about 32 mg, about 35 mg, about 39 mg, about 42 mg, about 45 mg, or about 48 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 3.2 mg, about 4.8 mg, about 5.3 mg, about 6.4 mg, about 7.6 mg, about 9.7 mg, about 10.5 mg, about 12.9 mg, about 16.1 mg, about 19.3 mg, about 22.5 mg, about 25.8 mg, about 29 mg, about 32.2 mg, about 35.4 mg, about 38.7 mg, about 41.9 mg, about 45.1 mg, or about 48.3 of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 3.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 4.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 5.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 6.4 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 7.6 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 9.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 10.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 12.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 16.1 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 19.3 mg of the anti-TfRl antibodies of the- I l l - complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 22.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 25.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 29.0 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 32.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 35.4 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 38.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 41.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 45.1 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 48.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000193] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 3.2 mg to 45.1 mg (e.g., 3.2 mg to 45.1 mg, 3.2 mg to 41.9 mg, 3.2 mg to 35.4 mg, 3.2 mg to 29 mg, 3.2 mg to 25.8 mg, 3.2 mg to 19.3 mg, 3.2 mg to 16.1 mg, 3.2 mg to 9.7 mg, 6.4 mg to 45.1 mg, 6.4 mg to 38.7 mg, 6.4 mg to 35.4 mg, 6.4 mg to 29 mg, 6.4 mg to 25.8 mg, 6.4 mg to 19.3 mg, 6.4 mg to 16.1 mg, 6.4 mg to 9.7 mg, 9.7 mg to 38.7 mg, 9.7 mg to 29 mg, 9.7 mg to 19.3 mg, 9.7 mg to 16.1 mg, 12.9 mg to 45.1 mg, 12.9 mg to 38.7 mg, 12.9 mg to 29 mg, 12.9 mg to 19.3 mg, 12.9 mg to 16.1 mg, 16.1 mg to 45.1 mg, 16.1 mg to38.7 mg, 16.1 mg to 29 mg, 16.1 mg to 19.3 mg, 19.3 mg to 45.1 mg, 19.3 mg to 38.7 mg, 19.3 mg to 29 mg, 29 mg to 45.1 mg, or 29 mg to 38.7 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 3.2 mg, 4.8 mg, 5.3 mg, 6.4 mg, 7.6 mg, about 9.7 mg, 10.5 mg, about 12.9 mg, about 16.1 mg, about 19.3 mg, about 22.5 mg, about25.8 mg, about 29.0 mg, about 32.2 mg, about 35.4 mg, about 38.7 mg, about 41.9 mg, about 45.1 mg, or about 48.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 13 mg, about 16 mg, about 19 mg, about 20 mg, about 23 mg, about 26 mg, about 29 mg, about 32 mg, about 35 mg, about 39 mg, about 42 mg, or about 45 mg, or about 48 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject 6.4 mg to 19.3 mg (e.g., 6.4 mg to 19.3 mg, 6.4 mg to 16.1 mg, 6.4 mg to 12.9 mg, 6.4 mg to 9.7 mg, 9.7 mg to 19.3 mg, 9.7 mg to 16.1 mg, 9.7 mg to 12.9 mg, or 12.9 mg to 19.3 mg) of theanti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 6.4 mg, 7.6 mg, about 9.7 mg, 10.5 mg, about 12.9 mg, about 16.1 mg, or about 19.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 9.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 10.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount (e.g., of each administration) provides to the subject about 12.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000194] In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000195] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g.,complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 2 mg to 5 mg (e.g., 2 mg to 5 mg, 2 mg to 4 mg, 3 mg to 5 mg, or 3 mg to 4 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 3.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000196] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 3 mg to 7 mg (e.g., 3 mg to 7 mg, 3 mg to 6 mg, 3 mg to 5 mg, or 3 mg to 4 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In someembodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 4.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000197] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 4 mg to 8 mg (e.g., 4 mg to 8 mg, 4 mg to 7 mg, 4 mg to 6 mg, 5 mg to 8 mg, 5 mg to 7 mg, or 5 mg to 6 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration)provides to the subject about 5.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000198] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 4 mg to 10 mg (e.g., 4 mg to 10 mg, 4 mg to 9 mg, 4 mg to 8 mg, 4 mg to 7 mg, 5 mg to 9 mg, 5 mg to 8 mg, 5 mg to 7 mg, 5 mg to 6 mg, 6 mg to 9 mg, 6 mg to 8 mg, or 6 mg to 7 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 6.4 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such 12 weeks or longer, or as the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000199] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 5 mg to 11 mg (e.g., 5 mg to 11 mg, 5 mg to 10 mg, 5 mg to 9 mg, 5 mg to 8 mg, 6 mg to 11 mg, 6 mg to 10 mg, 6 mg to 8 mg, 7 mg to 11 mg, 7 mg to 10 mg, 7 mg to 9 mg or 7 mg to 8 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 7.6 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In someembodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000200] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 7 mg to 14 mg (e.g., 7 mg to 14 mg, 7 mg to 12 mg, 7 mg to 11 mg, 8 mg to 14 mg, 8 mg to 12 mg, 8 mg to 10 mg, 9 mg to 14 mg, 9 mg to 12 mg, or 9 mg to 11 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 9.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or theremainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000201] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 8 mg to 16 mg (e.g., 8 mg to 16 mg, 8 mg to 14 mg, 8 mg to 12 mg, 9 mg to 16 mg, 9 mg to 14 mg, 9 mg to 12 mg, 10 mg to 16 mg, 10 mg to 14 mg, 10 mg to 12 mg, or 10 mg to 11 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 10.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000202] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 9 mg to 19 mg (e.g., 9 mg to 19 mg, 9 mg to 15 mg, 10 mg to 19 mg, 10 mg to 15 mg, 10 mg to 13 mg, 12 mg to 19 mg, 12 mg to 15 mg, 12 mg to 14 mg, or 12 mg to 13 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 12.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%).[000203] In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during afirst period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject 12 mg to 23 mg (e.g., 12 mg to 23 mg, 12 mg to 20 mg, 12 mg to 18 mg, 14 mg to 23 mg, 14 mg to 20 mg, 14 mg to 18 mg, 15 mg to 23 mg, 15 mg to 20 mg, 15 mg to 18 mg, or 15 mg to 17 mg) of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic), or (Id)), wherein the effective amount (e.g., of each administration) provides to the subject about 16.1 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, with respect to any of the preceding amounts of anti-TfRl antibody (e.g., Fab), the values can vary by up to 45% (e.g., ± up to 45%, ± up to 40%, ± up to 35%, ± up to 30%, ± up to 25%, ± up to 20%, ± up to 15%, ± up to 10%, ± up to 5%, ± up to 3 %, or ± up to 1%). In some embodiments, the composition is administered once every 4 weeks (e.g., for a period of time such as 4 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks (e.g., for a period of time such as 6 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 8 weeks (e.g., for a period of time such as 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 12 weeks (e.g., for a period of time such as 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 4 weeks during a first period of administration (e.g., 4 weeks, 8 weeks, or 12 weeks), and subsequently administered once every 8 weeks during a second period of administration (e.g., 8 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the composition is administered once every 6 weeks during a first period of administration (e.g., 6 weeks, 12 weeks, or 18 weeks), and subsequently administered once every 12 weeks during a second period of administration (e.g., 12 weeks or longer, or the remainder of the subject’s lifetime). In some embodiments, the initial dose is administered at week 0.[000204] In some embodiments, a method described herein comprises administering to a subject a composition comprising an effective amount of complexes described herein (e.g., complexes comprising a structure of formula (I): [R^ni-R2such as one comprising a group of the formula (la), (lb), (Ic...

Claims

1. CLAIMSWhat is claimed is:

1. A method of reducing DUX4 expression and / or treating facioscapulohumeral muscular dystrophy (FSHD) in a subject, comprising administering to the subject a composition comprising an effective amount of complexes comprising an anti-transferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides, wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject, wherein the antibody comprises: a heavy chain complementarity determining region 1 (CDR-H1) comprising a sequence as set forth in SEQ ID NOs: 1, 7, or 12, a heavy chain complementarity determining region 2 (CDR-H2) comprising a sequence as set forth in SEQ ID NOs: 2, 8, or 13, a heavy chain complementarity determining region 3 (CDR-H3) comprising a sequence as set forth in SEQ ID NOs: 3, 9, or 14, a light chain complementarity determining region 1 (CDR-L1) comprising a sequence as set forth in SEQ ID NOs: 4, 10, or 15, a light chain complementarity determining region 2 (CDR-L2) comprising a sequence as set forth in SEQ ID NOs: 5 or 11, and a light chain complementarity determining region 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, wherein the one or more oligonucleotides of the complexes is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21).

2. The method of claim 1, wherein each complex comprises a structure of formula (I):[R^ni-R2, wherein each R1comprises a group of the formula (la):or a pharmaceutically acceptable salt thereof,wherein R3comprises an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; wherein R2comprises the anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

3. The method of claim 1, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (lb):(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; and the oligonucleotide of R1is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

4. The method of claim 1, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein each R1comprises a group of the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

5. The method of claim 1, wherein each complex comprises 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 intemucleoside linkage; and “VP” represents 5’-(E)-Vinylphosphonate, wherein the oligonucleotide is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21; wherein R2comprises the anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5.

6. A method of reducing DUX4 expression and / or treating facioscapulohumeral muscular dystrophy (FSHD) in a subject, comprising administering to the subject an effective amount of a composition comprising a plurality of complexes, wherein each complex of the plurality of complexes comprises a structure of formula (I): [ R11Ni -R2, wherein each R1represents a group of:(i) the formula (la):or a pharmaceutically acceptable salt thereof, wherein R3represents an RNAi oligonucleotide or a pharmaceutically acceptable salt thereof, wherein the RNA oligonucleotide comprises an antisense strand comprising a nucleobase sequence of SEQ ID NO: 22 and a structure (5’— >3’) of VP- mU*fG*mCmCmAmGmAmAmUmUmUmCmAfCmGmGmAmAmGmAmA*mC*m A, 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-methylguanosine, 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 ofbetween two nucleosides represents a phosphodiester internucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; wherein R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5;(ii) the formula (lb):(lb), 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 intemucleoside linkage; and “VP” represents 5'-(E)-Vinylphosphonate; and the oligonucleotide of R1is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21); wherein R2represents an anti-TfRl antibody; and in each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked viaattachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; (iii) the formula (Ic), in which the antisense strand and the sense strand form a double stranded oligonucleotide:(Ic), or a pharmaceutically acceptable salt thereof, wherein R2represents an anti-TfRl antibody; andin each complex, nl is independently an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; or (iv) the formula (Id):(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 ofbetween two nucleosides represents a phosphodiester intemucleoside linkage; and “VP” represents 5’-(E)-Vinylphosphonate, wherein the oligonucleotide is an RNAi oligonucleotide comprising an antisense strand comprising a nucleobase sequence of UGCCAGAAUUUCACGGAAGAACA (SEQ ID NO: 22) and a sense strand comprising a nucleobase sequence of UUCUUCCGUGAAAUUCUGGCA (SEQ ID NO: 21; wherein R2represents an anti-TfRl antibody; and in each complex, nl is an integer of one or greater representing the number of instances of R1, wherein each instance of R1is covalently linked via attachment point A to a different lysine of the anti-TfRl antibody, optionally wherein the average value of nl of the complexes of the composition is in the range of 0.5-5; wherein the effective amount provides to the subject 2 mg to 50 mg of the anti-TfRl antibody of the complexes per kg of the subject.

7. The method of any one of claims 1-6, wherein the average value of nl of the complexes of the composition is 1.

8. The method of any one of claims 1-7, wherein the anti-TfRl antibody is a Fab fragment.

9. The method of any one of claims 1-8, wherein the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 18, optionally wherein the anti-TfRl antibody comprises 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.

10. The method of claim 9, wherein the VH comprises an N-terminal pyroglutamate.

11. The method of any one of claims 1-10, wherein the administration occurs one or more times.

12. The method of claim 11, wherein the effective amount of each administration provides to the subject:(a) 4 mg to 23 mg of the anti-TfRl antibodies of the complexes per kg of the subject,(b) 9 mg to 20 mg of the anti-TfRl antibodies of the complexes per kg of the subject,(c) 2 mg to 5 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 3.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(d) 3 mg to 7 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 4.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(e) 4 mg to 10 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 6.4 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(f) 7 mg to 14 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 9.7 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(g) 9 mg to 19 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 12.9 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(h) 12 mg to 23 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 16.1 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(i) 14 mg to 28 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 19.3 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(j) 17 mg to 33 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 22.5 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(k) 19 mg to 37 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 25.8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(l) 22 mg to 42 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 29 mg of the anti-TfRl antibodies of the complexes per kg of the subject; or(m) 24 mg to 46 mg of the anti-TfRl antibodies of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 32.2 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

13. The method of claim 11, wherein the effective amount of each administration provides to the subject:(a) 1 mg to 10 mg of the oligonucleotides of the complexes per kg of the subject;(b) 1.5 mg to 7 mg of the oligonucleotides of the complexes per kg of the subject;(c) 3 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject;(d) 0.6 mg to 2 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 1 mg of the oligonucleotides of the complexes per kg of the subject;(e) 1 mg to 2 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 1.5 mg of the oligonucleotides of the complexes per kg of the subject(f) 1 mg to 3 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 2 mg of the oligonucleotides of the complexes per kg of the subject;(g) 2 mg to 5 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 3 mg of the oligonucleotides of the complexes per kg of the subject;(h) 2 mg to 6 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 4 mg of the oligonucleotides of the complexes per kg of the subject;(i) 3 mg to 7 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 5 mg of the oligonucleotides of the complexes per kg of the subject;(j) 4 mg to 8 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 6 mg of the oligonucleotides of the complexes per kg of the subject;(k) 4 mg to 10 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 7 mg of the oligonucleotides of the complexes per kg of the subject;(l) 5 mg to 11 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 8 mg of the oligonucleotides of the complexes per kg of the subject;(m) 6 mg to 12 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 9 mg of the oligonucleotides of the complexes per kg of the subject; or(n) 6 mg to 13 mg of the oligonucleotides of the complexes per kg of the subject, optionally wherein the effective amount of each administration provides to the subject 10 mg of the oligonucleotides of the complexes per kg of the subject.

14. The method of any one of claims 1-13, wherein the composition is administered during a period of administration, wherein the composition is administered once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks, optionally wherein an initial dose is administered at week 0.

15. The method of claim 14, wherein the period of administration is selected from the group consisting of: i) less than 1 year; ii) less than 2 years; iii) less than 3 years; iv) less than 5 years; and v) less than 10 years.

16. The method of claim 14, wherein the period of administration is the remainder of the subject’s lifetime.

17. The method of any one of claims 1-16, wherein the composition is administered once every 4 weeks during a first period of administration, and subsequently administered once every 8 weeks during a second period of administration.

18. The method of claim 15, wherein the first period of administration is 8-12 weeks, and / or wherein the second period of administration is selected from the group consisting of:(i) 8-12 weeks,(ii) longer than 12 weeks, and(iii) the remainder of the subject’s lifetime.

19. The method of any one of claims 1-18, wherein the composition is in the form of an aqueous solution and further comprises tris(hydroxymethyl)aminomethane and sucrose.

20. The method of claim 19, wherein the tris(hydroxymethyl)aminomethane is present in the aqueous solution at a concentration of 25 mM, the sucrose is present in the aqueous solution at a concentration of 10and the aqueous solution is at a pH of 7.5.

21. The method of claim 19 or claim 20, wherein the complexes are present in the composition at a concentration in the range of 10 mg / mL to 50 mg / mL.

22. The method of any one of claims 1-21, wherein the administering reduces DUX4 expression in a muscle cell of the subject, optionally wherein the administering reduces theamount of DUX4 RNA in the muscle cell, optionally wherein the administering results in reversal of loss of muscle function in the subject.

23. The method of claim 22, wherein reducing DUX4 expression in the muscle cell comprises reducing the amount of DUX4 protein in the muscle cell.

24. The method of any one of claims 1-23, wherein the subject is human.

25. The method of any one of claims 1-24, wherein the composition is administered systemically, optionally wherein the composition is administered intravenously, further optionally wherein the complex is administered by infusion.

26. The method of any one of claims 1-25, wherein each administration comprises providing the composition to the subject by intravenous infusion over 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 150 minutes, or 180 minutes, optionally wherein the infusion is continuous, optionally wherein the composition is administered to the subject by intravenous infusion at a rate of 0.05 mg to 1.5 mg (0.05 mg to 1.5 mg, 0.05 mg to 1 mg, 0.05 mg to 0.5 mg, 0.05 mg to 0.1 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 mg, 0.5 mg to 1.5 mg, 0.5 mg to 1 mg, or 1 mg to 1.5 mg of the anti-TfRl antibody (e.g., Fab) of the complexes per kg of the subject per minute.

27. The method of any one of claims 1-26, wherein the composition further comprises one or more anti-TfRl antibodies that are not covalently linked to an oligonucleotide.

28. The method of any one of claims 1-27, wherein the composition is administered to the subject once.

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