Methods and compositions for treating myotonic dystrophy

Abstract

Aspects of the disclosure relate to methods of reducing fatigue in a subject having myotonic dystrophy type 1 (DM1). Aspects of the disclosure relate to methods of treating one or more symptoms assessable by the MDHI (e.g., a GI symptom, myotonia, upper extremity function impairment, fatigue, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment) in a subject having myotonic dystrophy type 1 (DM1). In some embodiments, the methods comprise administering to the subject a composition comprising complexes (e.g., muscle targeting complexes) comprising an oligonucleotide (e.g., a DMPK- targeting oligonucleotide) covalently linked to an antibody (e.g., anti-TfRl antibody).

Description

METHODS AND COMPOSITIONS FOR TREATING MYOTONIC DYSTROPHYRELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 617,071, filed January 2, 2024, entitled “METHODS AND COMPOSITIONS FOR TREATING FATIGUE”, to U.S. Provisional Application No. 63 / 573,675, filed April 3, 2024, entitled “METHODS AND COMPOSITIONS FOR REDUCING FATIGUE”, and to U.S. Provisional Application No. 63 / 649,428, filed May 19, 2024, entitled “METHODS AND COMPOSITIONS FOR TREATING MYOTONIC DYSTROPHY”, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present application relates to targeting complexes for delivering an effective amount of oligonucleotide molecular pay loads to cells (e.g., muscle cells and / or cells of the central nervous system (CNS)) and uses thereof, particularly uses relating to treatment of disease.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (D082470087WO00-SEQ-CBD.xml; Size: 48,789 bytes; and Date of Creation: December 6, 2024) are herein incorporated by reference in their entirety.BACKGROUND

[0004] Myotonic dystrophy (DM) is a dominantly inherited genetic disease that is characterized by myotonia, muscle loss or degeneration, diminished muscle function, insulin resistance, cardiac arrhythmia, smooth muscle dysfunction, and neurological abnormalities. DM is the most common form of adult-onset muscular dystrophy, with a worldwide incidence of about 1 in 8000 people worldwide. Two types of the disease, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), have been described. DM1, the more common form of the disease, results from a repeat expansion of a CTG trinucleotide repeat in the 3' non-coding region of DMPK on chromosome 19; DM2 results from a repeat expansion of a CCTG tetranucleotide repeat in the first intron of ZNF9 on chromosome 3. In DM1 patients, the repeat expansion of a CTG trinucleotide repeat, which may comprise greater than about 50 to about 3,000 or more total repeats, leads to generation of toxic RNA repeats capable of forming hairpinstructures that bind essential intracellular proteins, e.g., muscleblind-like proteins, with high affinity resulting in protein sequestration and the loss-of-function phenotypes that are characteristic of the disease. Apart from supportive care and treatments to address the symptoms of the disease, no effective therapeutic for DM1 is currently available.SUMMARY

[0005] According to some aspects, the present disclosure provides methods (e.g., methods of delivering oligonucleotides to a subject, methods of administering complexes to a subject, methods of reducing expression or activity of DMPK in a subject, and / or methods of treating myotonic dystrophy (e.g., DM1) in a subject), the method comprising administering to the subject a composition comprising an effective amount of complexes comprising an antitransferrin receptor 1 (TfRl) antibody covalently linked to one or more oligonucleotides. In some embodiments, compositions and methods described herein are effective in alleviating DM1 disease burden and / or symptoms as indicated by the Myotonic Dystrophy Health Index (MDHI). MDHI is a disease-specific, patient-reported outcome measure to estimate the overall disease burden and the impact of key symptomatic themes in DM1 patients. In some embodiments, compositions and methods described herein are effective in treating one or more symptoms of DM1. In some embodiments, compositions and methods described herein are effective in treating fatigue . In some embodiments, the fatigue is muscle fatigue, central fatigue, peripheral fatigue, or combinations thereof. In some embodiments, compositions and methods described herein are effective in treating a GI symptom. In some embodiments, the GI symptom is abdominal pain, coughing while eating, dysphagia, dyspepsia, heartburn, emesis, bloating, diarrhea, constipation, dyschezia, anal incontinence, or a combination thereof. In some embodiments, compositions and methods described herein are effective in treating myotonia. In some embodiments, compositions and methods described herein are effective in treating upper extremity function impairment. In some embodiments, compositions and methods described herein are effective in treating mobility impairment. In some embodiments, compositions and methods described herein are effective in treating impairment in the ability to perform activities. In some embodiments, compositions and methods described herein are effective in treating pain. In some embodiments, compositions and methods described herein are effective in treating vision impairment. In some embodiments, compositions and methods described herein are effective in treating communication impairment). In some embodiments, compositions and methods described herein are effective in treating emotional issues. In some embodiments, compositions and methods described herein are effective in treating cognitive impairment. In some embodiments, compositions and methods described herein are effective in treating socialsatisfaction impairment. In some embodiments, compositions and methods described herein are effective in treating social performance impairment. In some embodiments, compositions and methods described herein are effective in treating breathing impairment. In some embodiments, compositions and methods described herein are effective in treating swallowing impairment. In some embodiments, compositions and methods described herein are effective in treating hearing impairment. In some embodiments, compositions and methods described herein are effective in treating two or more symptoms of DM1 selected from: fatigue, a GI symptom, myotonia, upper extremity function impairment, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment.

[0006] According to some aspects, the present disclosure provides methods of treating fatigue in a subject having myotonic dystrophy, 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 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 oligonucleotides of the complexes comprise the nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21).

[0007] According to some aspects, the present disclosure provides methods of alleviating myotonic dystrophy type 1 (DM1) disease burden and / or symptoms in a subject as indicated by a Myotonic Dystrophy Health Index (MDHI), 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 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 oligonucleotides of the complexes comprise the nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21). In some embodiments, the administering results in improvement of one or more subscales of a Myotonic Dystrophy Health Index (MDHI) selected from: mobility, upper extremity function, ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, emotional issues, cognitive impairment, social satisfaction, myotonia, breathing, swallowing, and hearing, optionally wherein the one or more subscales are patient-reported.

[0008] In some embodiments, the oligonucleotides of the complexes comprise a 5’-X-Y- Z-3’ configuration, wherein X and Z are flanking regions comprising one or more modified nucleosides and Y is a gap region comprising one or more 2’-deoxyribonucleosides.

[0009] 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, in which R3comprises an oligonucleotide comprising a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21) and comprising a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage;R2comprises the 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.

[0010] In some embodiments, each complex comprises a structure of formula (I): [R^ni- R2, wherein: each R1comprises a group of the formula (lb):(lb), or a pharmaceutically acceptable salt thereof, in which +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage, and the oligonucleotide of R1comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21);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 formula (I): [ R11ni - R2, wherein: each R1comprises a group of the formula (Ic):(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.

[0012] In some embodiments, each complex comprises a structure of the formula (Id):(Id), or a pharmaceutically acceptable salt thereof, in which +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21);R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of 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 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.

[0013] In some embodiments, the anti-TfRl antibody is a Fab fragment. 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. In some embodiments, 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.

[0014] In some embodiments, the average value of nl of the complexes of the composition is in the range of 0.7- 1.5. In some embodiments, the average value of nl of the complexes of the composition is 1.1. In some embodiments, the average value of nl of the complexes of the composition is 1.15. In some embodiments, the average value of nl of the complexes of the composition is 1.

[0015] In some embodiments, the effective amount provides to the subject 5 mg to 110 mg of the anti-TfRl antibody of the complexes per kg of the subject. In some embodiments, the effective amount of each administration provides to the subject:(a) 10 mg to 110 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(b) 5 mg to 90 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(c) 10 mg to 20 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 13 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(d) 18 mg to 36 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 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(e) 30 mg to 58 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 40 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(f) 36 mg to 72 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 50 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(g) 55 mg to 110 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 75 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(h) 6 mg to 12 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 8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(i) 11 mg to 22 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 15 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(j) 22 mg to 44 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 30 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(k) 44 mg to 88 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 60 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(l) 20 mg to 43 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) 26 mg to 53 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 37 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

[0016] In some embodiments, the effective amount of each administration provides to the subject 13 mg, 25 mg, 40 mg, 50 mg, or 75 mg of the anti-TfRl antibodies of the complexes per kg of the subject. In some embodiments, the effective amount of each administration provides to the subject 40 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

[0017] In some embodiments, the effective amount of each administration provides to the subject 50 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

[0018] In some embodiments, the effective amount of each administration provides to the subject 1.8 mg, 3.4 mg, 5.4 mg, 6.8 mg, or 10.2 mg of the oligonucleotides of the complexes per kg of the subject.

[0019] In some embodiments, during a period of administration, the composition is administered once every 4 weeks, once every 8 weeks, or once every 12 weeks. In some embodiments, the period of administration is less than 10 years. In some embodiments, the period of administration is the remainder of the subject’s lifetime. 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. In some embodiments, the first period of administration is 8-16 weeks, and / or wherein the second period of administration is 16 weeks to the remainder of the subject’s lifetime.

[0020] In some embodiments, the composition is in the form of an aqueous solution and further comprises tris(hydroxymethyl)aminomethane and sucrose. 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 of 10and the aqueous solution is at a pH of 7.5. In some embodiments, the complexes are present in the composition at a concentration in the range of 10 mg / mL to 50 mg / mL.

[0021] In some embodiments, the administering reduces fatigue in the subject. In some embodiments, wherein the administering reduces fatigue in the subject as reported by the subject following a period of administration. In some embodiments, the fatigue is muscle fatigue, central fatigue, peripheral fatigue, or combinations thereof. In some embodiments, the muscle fatigue is skeletal muscle fatigue.

[0022] In some embodiments, the administering reduces a GI symptom in the subject. In some embodiments, the administering reduces a GI symptom in the subject as reported by the subject following a period of administration. In some embodiments, the GI symptom is abdominal pain, coughing while eating, dysphagia, dyspepsia, heartbum, emesis, bloating, diarrhea, constipation, dyschezia, anal incontinence, and / or a combination thereof.

[0023] In some embodiments, the administering reduces myotonia in the subject. In some embodiments, the administering reduces myotonia in the subject as reported by the subject following a period of administration.

[0024] In some embodiments, the administering reduces upper extremity function impairment in the subject. In some embodiments, the administering reduces upper extremityfunction impairment in the subject as reported by the subject following a period of administration.

[0025] In some embodiments, the administering reduces mobility impairment in the subject. In some embodiments, the administering reduces mobility impairment in the subject as reported by the subject following a period of administration.

[0026] In some embodiments, the administering reduces pain in the subject. In some embodiments, the administering reduces pain in the subject as reported by the subject following a period of administration.

[0027] In some embodiments, the administering reduces communication impairment in the subject. In some embodiments, the administering reduces communication impairment in the subject as reported by the subject following a period of administration.

[0028] In some embodiments, the administering reduces emotional issues in the subject. In some embodiments, the administering reduces emotional issues in the subject as reported by the subject following a period of administration.

[0029] In some embodiments, the administering reduces sleep impairment in the subject. In some embodiments, the administering reduces sleep impairment in the subject as reported by the subject following a period of administration.

[0030] In some embodiments, the administering reduces cognitive impairment in the subject. In some embodiments the administering reduces cognitive impairment in the subject as reported by the subject following a period of administration.

[0031] In some embodiments, the administering reduces social satisfaction impairment in the subject. In some embodiments, the administering reduces social satisfaction impairment in the subject as reported by the subject following a period of administration.

[0032] In some embodiments, the administering reduces social performance impairment in the subject. In some embodiments, the administering reduces social performance impairment in the subject as reported by the subject following a period of administration.

[0033] In some embodiments, the administering reduces vision impairment in the subject. In some embodiments, the administering reduces vision impairment in the subject as reported by the subject following a period of administration.

[0034] In some embodiments, the administering reduces breathing impairment in the subject. In some embodiments, the administering reduces breathing impairment in the subject as reported by the subject following a period of administration.

[0035] In some embodiments, he administering reduces swallowing impairment in the subject. In some embodiments, the administering reduces swallowing impairment in the subject as reported by the subject following a period of administration.

[0036] In some embodiments, the administering reduces hearing impairment in the subject. In some embodiments, the administering reduces hearing impairment in the subject as reported by the subject following a period of administration.

[0037] In some embodiments, the period of administration is 24 weeks. In some embodiments, the period of administration is 48 weeks.

[0038] In some embodiments, the subject is human.

[0039] In some embodiments, the complex is administered systemically. In some embodiments, the complex is administered intravenously. In some embodiments, the complex is administered by infusion.

[0040] In some embodiments, the composition further comprises one or more anti-TfRl antibodies that are not covalently linked to an oligonucleotide.

[0041] In some embodiments, the heavy chain of the antibody comprises an N-terminal pyroglutamate.BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIGs. 1A-1B show DMPK expression the gastrocnemius (FIG. 1A) and tibialis anterior (FIG. IB), respectively, of non-human primates after administration of 10 mg / kg ASO- equivalent of conjugates containing an anti-TfRl Fab covalently linked to a DMPK-targeting ASO. Tissue DMPK levels were measured 4, 8 and 12 weeks after administration of the conjugates and are presented relative to vehicle-treated controls. Data are shown as means ± standard deviation. Statistics were calculated by unpaired t-test (*, P < 0.05).

[0043] FIGs. 2A-2D show DMPK expression the heart (FIG. 2A), diaphragm (FIG. 2B), tibialis anterior (FIG. 2C), or gastrocnemius (FIG. 2D), respectively, of non-human primates after administration of 5 mg / kg (“5”) or 10 mg / kg (“10”) ASO-equivalent of conjugates containing an anti-TfRl Fab covalently linked to a DMPK-targeting ASO. Following administration of either a single 5 mg / kg ASO-equivalent dose or a single 10 mg / kg ASO- equivalent dose to a non-human primate model, tissue DMPK levels were measured after four weeks and are presented relative to vehicle-treated controls (“Vehicle”). Data are shown as means + standard deviation. Statistics were calculated by one-way ANOVA (*, P < 0.05; **, P < 0.01).

[0044] FIGs. 3A-3G show DMPK expression in the heart (FIG. 3 A), diaphragm (FIG. 3B), tibialis anterior (FIG. 3C), gastrocnemius (FIG. 3D), masseter (FIG. 3E), esophagus (FIG. 3F), or duodenum (FIG. 3G) respectively, of non-human primates after administration of either two 5 mg / kg ASO-equivalent doses (“2 x 5”) or two 10 mg / kg ASO-equivalent doses (“2 x 10”)of conjugates containing an anti-TfRl Fab covalently linked to a DMPK-targeting ASO. Following administration of either two 5 mg / kg ASO-equivalent doses or two 10 mg / kg ASO- equivalent doses to a non-human primate model, each four weeks apart, tissue DMPK levels were measured four weeks after the final dose and are presented relative to vehicle-treated controls (“Vehicle”). Data are shown as means + standard deviation. Statistics were calculated by one-way ANOVA followed by an uncorrected Fisher’s Least Significant Difference (LSD) test (*, P < 0.05; **, P < 0.01; ***, P < 0.001).

[0045] FIGs. 4A-4C show quantification of ASO (in nM) within brain tissue of cynomolgus monkeys following administration of ASO not covalently linked to an antibody (“Naked ASO”; downward facing arrows) or an ASO-equivalent dose of anti-TfRl Fab-ASO complexes (upward facing arrows) via intravenous (IV) injection. ASO content over time was measured by hybridization-based ELISA in the cortex (FIG. 4A), deep brain (FIG. 4B) and cerebellum (FIG. 4C). Values are shown as mean + / - standard error (N = 2 monkeys per group).

[0046] FIGs. 5A-5C show ASO distribution in brain tissue of cynomolgus monkeys following administration of ASO not covalently linked to an antibody (“Naked ASO”) or an ASO-equivalent dose of anti-TfRl Fab-ASO complexes via intravenous (IV) or intrathecal (IT) administration. ASO distribution was measured by in situ hybridization, and is shown in the cortex and deep brain areas (FIG. 5A) and cerebellum (FIG. 5B) in monkeys intravenously (IV) administered either the naked ASO or the complexes, and in the cortex and deep brain of monkeys intrathecally (IT) administered naked ASO or IV administered the complexes (FIG. 5C). The deep brain area shown includes the caudate nucleus and putamen.

[0047] FIG. 6 shows Patient Reported Outcomes at day 169 since beginning of treatment indicate efficacy in treating fatigue in DM1 patients at lowest dose tested in the clinical trial (at a dose that delivers 1.8 mg of oligonucleotide per kg of a subject’s weight, administered once every 4 weeks). Improvement in MDHI fatigue subscale suggests that the conjugates are effective in treating muscle and / or CNS symptoms of DM1.

[0048] FIG. 7 shows delivery of ASO to cells in the CNS of cynomolgus monkeys following administration of ASO not covalently linked to an antibody (“Naked ASO”) or an ASO-equivalent dose of anti-TfRl Fab-ASO complexes via intravenously (IV) administration. NeuN, IB Al and GFAP immunofluorescent staining was used to identify neurons, microglia, and astrocytes, respectively, to assess delivery of ASO to the cells. ASO delivery to the cells following IV administration of the complexes or IV administration of naked ASO to the monkeys was visualized. ASO is shown in the neurons, microglia, and astrocytes in monkeys intravenously (IV) administered the complexes. ASO is not shown in the neurons, microglia, and astrocytes in monkeys intravenously (IV) administered the naked ASO.

[0049] Further aspects of the disclosure, including a description of defined terms, are provided below.

[0050] FIG. 8 shows Patient Reported Outcomes at day 169 and day 337 since beginning of treatment indicate efficacy in treating symptoms of DM1. As shown in the left panel, total MDHI score is decreased at day 169 and day 337 in DM1 patients at lowest dose tested in the clinical trial (at a dose that delivers 1.8 mg of oligonucleotide per kg of a subject’s weight, administered once every 4 weeks) and at day 169 at a higher dose (a dose that delivers 3.4 mg of oligonucleotide per kg of a subject’s weight, administered once every 4 weeks). The right panel shows the results at day 169 and 337 for upper extremity function (top), gastrointestinal symptoms (middle), and fatigue (bottom), measured in DM1 patients at lowest dose tested in the clinical trial (at a dose that delivers 1.8 mg of oligonucleotide per kg of a subject’s weight, administered once every 4 weeks) for days 169 and 337 and at a higher dose (a dose that delivers 3.4 mg of oligonucleotide per kg of a subject’s weight, administered once every 4 weeks) at day 169. Improvement in MDHI GI subscale, MDHI Upper Extremity Function subscale, and Fatigue subscale suggests that the conjugates are effective in treating gastrointestinal symptoms of DM1, upper extremity function impairment related to DM1, and fatigue related to DM1. Improvement in MDHI total score suggests that the conjugates are effective in treating DM1 overall.DEFINITIONS

[0051] 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).

[0052] 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).

[0053] 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, anantibody 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 refers to 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 thatcomprises 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 Antibodies and 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).

[0054] 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 antibodieshaving 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.

[0055] 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 et al., 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))

[0056] Complementary: As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleotides or two sets of nucleotides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleotides or two sets of nucleotides. For example, if a base at one position of an oligonucleotide is capable 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.

[0057] 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.

[0058] Disease-associated-repeat: As used herein, the term “disease-associated-repeat” refers to a repeated nucleotide sequence at a genomic location for which the number of units of the repeated nucleotide sequence is correlated with and / or (e.g., and) directly or indirectly contributes to, or causes, genetic disease. Each repeating unit of a disease associated repeat may be 2, 3, 4, 5 or more nucleotides in length. For example, in some embodiments, a disease associated repeat is a dinucleotide repeat. In some embodiments, a disease associated repeat is a trinucleotide repeat. In some embodiments, a disease associated repeat is a tetranucleotide repeat. In some embodiments, a disease associated repeat is a pentanucleotide repeat. In some embodiments, the disease-associated-repeat comprises CAG repeats, CTG repeats, CUG repeats, CGG repeats, CCTG repeats, or a nucleotide complement of any thereof. In some embodiments, a disease-associated-repeat is in a non-coding portion of a gene. However, in some embodiments, a disease-associated-repeat is in a coding region of a gene. In some embodiments, a disease-associated-repeat is expanded from a normal state to a length that directly or indirectlycontributes to, or causes, genetic disease. In some embodiments, a disease-associated-repeat is in RNA (e.g., an RNA transcript). In some embodiments, a disease-associated-repeat is in DNA (e.g., a chromosome, a plasmid). In some embodiments, a disease-associated-repeat is expanded in a chromosome of a germline cell. In some embodiments, a disease-associated-repeat is expanded in a chromosome of a somatic cell. In some embodiments, a disease-associated-repeat is expanded to a number of repeating units that is associated with congenital onset of disease. In some embodiments, a disease-associated-repeat is expanded to a number of repeating units that is associated with childhood onset of disease. In some embodiments, a disease-associated-repeat is expanded to a number of repeating units that is associated with adult onset of disease. In DM1, the DMPK gene comprises a disease-associated repeat of CTG units.

[0059] DMPK: As used herein, the term “DMPK” refers to a gene that encodes myotonin-protein kinase (also known as myotonic dystrophy protein kinase or dystrophia myotonica protein kinase), a serine / threonine protein kinase. Substrates for this enzyme may include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. In some embodiments, DMPK may be a human (Gene ID: 1760), non-human primate (e.g., Gene ID: 456139, Gene ID: 715328, Gene ID: 102125829), or rodent gene (e.g., Gene ID: 13400). In humans, a CTG repeat expansion in the 3' non-coding, untranslated region of DMPK is associated with myotonic dystrophy type I (DM1). In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_001081563.2, NM_004409.4, NM_001081560.2, NM_001081562.2, NM_001288764.1, NM_001288765.1, and NM_001288766.1) have been characterized that encode different protein isoforms.

[0060] DMPK allele: As used herein, the term “DMPK allele” refers to any one of alternative forms (e.g., wild-type or mutant forms) of a DMPK gene. In some embodiments, a DMPK allele may encode for wild-type myotonin-protein kinase that retains its normal and typical functions. In some embodiments, a DMPK allele may comprise one or more disease- associated-repeat expansions. In some embodiments, normal subjects have two DMPK alleles comprising in the range of 5 to 37 repeat units. In some embodiments, the number of CTG repeat units in subjects having DM1 is in the range of about 50 to about 3,000 or more, with higher numbers of repeats leading to an increased severity of disease. In some embodiments, mildly affected DM1 subjects have at least one DMPK allele having in the range of 50 to 150 repeat units. In some embodiments, subjects with classic DM1 have at least one DMPK allele having in the range of 100 to 1,000 or more repeat units. In some embodiments, subjects having DM1 with congenital onset may have at least one DMPK allele comprising more than 2,000 repeat units.

[0061] Fatigue: As used herein, the term “fatigue” refers to a subjective feeling of a lack of physical and / or mental energy that only partially withdraws after rest. In some embodiments, the term “fatigue” refers to a symptom that a subject having myotonic dystrophy (e.g., DM1) experiences. Fatigue can have both central and peripheral origins, and its dual origin may impact therapy development strategies. The Myotonic Dystrophy Health Index (MDHI) is a patient reported outcome measures (PROMs) that has been incorporated into many recent clinical studies and trials and includes separate question banks that assess fatigue, sleep, and cognition. Its fatigue component is thought to focus on muscle fatigue, muscle endurance, and “tiredness” arising from muscle. The sleep and cognitive components have been linked to CNS-based fatigue, including motivation and concentration. Methods of measuring fatigue (e.g., in subjects having DM1) have been described, e.g., in Peric et al., Acta Myol. 2019 Dec; 38(4): 239-244, the entire contents of which are incorporated herein by reference.

[0062] The term “fatigue,” as used herein, encompasses the types of fatigue known or as described herein to be a symptom of myotonic dystrophy (DM1), including, e.g., muscle fatigue, central fatigue, peripheral fatigue. Muscle fatigue refers to a decrease in maximal force or power production in response to contractile activity. Muscle fatigue can originate at different levels of the motor pathway and usually includes central fatigue and / or peripheral fatigue. Central fatigue originates at the central nervous system (CNS), which refers to a deficient drive of motor cortical output attenuating performance or even stopping the activity, whereby inhibitory and excitatory processes are affected (e.g., as described in Ament et al., Sports Med. 2009;39:389- 422). Peripheral fatigue is produced by changes at or distal to the neuromuscular junction and refers to the reduction in the efficacy of the neuromuscular junction and processes beyond the neuromuscular function as metabolic and biochemical changes within the muscle (e.g., as described in in Ament et al., Sports Med. 2009 ;39: 389^ 22 and Korzeniewski et al., Eur. J. Appl. Physiol. 2019;119:2201-2213).

[0063] Framework: 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 subregions (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 occurringimmunoglobulin 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.

[0064] Gastrointestinal (GI) Symptom: As used herein, the term “gastrointestinal symptom” or “GI symptom” refers to one or more symptoms relating to the gastrointestinal tract, including the esophagus, stomach, small intestine (duodenum, jejunum, and / or ileum), large intestine, and anus. In some embodiments, the term “GI symptom” refers to a symptom that a subject having myotonic dystrophy (e.g., DM1) experiences. Gastrointestinal symptoms are often among the first symptom of myotonic dystrophy in a subject. The Myotonic Dystrophy Health Index (MDHI) is a patient reported outcome measures (PROMs) that has been incorporated into many recent clinical studies and trials and includes separate question banks that assess varied symptoms of DM1, including gastrointestinal issues. Its GI component is thought to focus on symptoms arising from a loss of smooth muscle tone and / or neurological abnormalities along the GI tract, such as abdominal pain, coughing while eating, dysphagia, dyspepsia, heartbum, emesis, bloating, diarrhea, constipation, dyschezia, and / or anal incontinence. In some embodiments, a GI symptom is an upper GI symptom (e.g., a symptom related to the esophagus, stomach, and / or duodenum). In some embodiments, a GI symptom is a lower GI symptom (e.g., a symptom related to the jejunum, ileum, large intestine and / or anus).

[0065] The term “GI symptom,” as used herein, encompasses the types of GI symptoms known or as described herein to be a symptom of myotonic dystrophy (DM1), including, e.g., abdominal pain, coughing while eating, dysphagia, dyspepsia, heartbum, emesis, bloating, diarrhea, constipation, dyschezia, and / or anal incontinence. Without intending to be bound by theory, a GI symptom may result from loss of smooth muscle tone along the GI tract and / or neurological abnormalities relating to the GI tract.

[0066] 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 the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0067] Humanized antibody: The term "humanized antibody" refers to antibodies which comprise heavy and light chain variable region sequences from a non-human speciese.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.

[0068] Improve: The terms “improve”, “improving” and “improvement”, as used herein, refer to alleviation of one or more symptoms of a disease being treated, reduction of one or more issues or impairments associated with a disease being treated, and / or improvements in one or more functions (e.g., physiological functions) affected by a disease being treated, such as myotonic dystrophy (e.g., DM1). In some embodiments, the improvements are in symptoms according to one or more subscales of a Myotonic Dystrophy Health Index (MDHI). In some embodiments, the improvements are indicated by a reduction in the MDHI score of one or more subscales as measured from a change from a baseline assessment (e.g., prior to administration of the treatment). In some embodiments, the improvements are patient-reported. In some embodiments, the improvements are in one or more subscales of a Myotonic Dystrophy Health Index (MDHI) selected from: mobility, upper extremity function, ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, emotional issues, cognitive impairment, social satisfaction, myotonia, breathing, swallowing, and hearing. In some embodiments, the term “improve,” “improving,” and “improvement” refers to the demonstration of clinical benefits resulting from the treatment. .

[0069] 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 34for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 forCDR3.

[0070] Myotonic dystrophy (DM): As used herein, the term “Myotonic dystrophy (DM)” refers to a genetic disease caused by mutations in the DMPK gene or CNBP (ZNF9) gene that is characterized by muscle loss, muscle weakening, and muscle function. Two types of the disease, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), have been described. DM1 is associated with an expansion of a CTG trinucleotide repeat in the 3' non-coding region of DMPK. DM2 is associated with an expansion of a CCTG tetranucleotide repeat in the first intron of ZNF9. In both DM1 and DM2, the nucleotide expansions lead to toxic RNA repeats capable of forming hairpin structures that bind critical intracellular proteins, e.g., muscleblind-like proteins, with high affinity. Myotonic dystrophy, the genetic basis for the disease, and related symptoms are described in the art (see, e.g., Thornton, C.A., “Myotonic Dystrophy” Neurol Clin. (2014), 32(3): 705-719.; and Konieczny et al. “Myotonic dystrophy: candidate small molecule therapeutics” Drug Discovery Today (2017), 22:11). In some embodiments, subjects are born with a variation of DM1 called congenital myotonic dystrophy. Symptoms of congenital myotonic dystrophy are present from birth and include weakness of all muscles, breathing problems, clubfeet, developmental delays and intellectual disabilities. DM1 is associated with Online Mendelian Inheritance in Man (OMIM) Entry # 160900. DM2 is associated with OMIM Entry # 602668. Patients having DM1 may also have abnormalities in the parts of the brain that determine the rhythm of sleeping and waking, resulting in excessive daytime sleepiness, fatigue, and / or exhaustion. In some embodiments, patients having DM1 may have one or more of: GI symptoms (including abdominal pain, coughing while eating, dysphagia, dyspepsia, heartburn, emesis, bloating, diarrhea, constipation, dyschezia, and / or anal incontinence), myotonia, upper extremity function impairment, fatigue, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment.

[0071] 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 singlestranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleosides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidinemodifications). 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.

[0072] 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.

[0073] 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, 10'7M, 10'8M, 10'9M, 10'10M, 10'11M, 102M, IO’13M, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, e.g., an epitope of the apical domain of transferrin receptor.

[0074] 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 a disease resulting from a disease-associated-repeat expansion, e.g., in a DMPK allele.

[0075] 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 ID711568 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).

[0076] “Treat”: As used herein, the terms “treat” and “treatment” refer to both therapeutic treatment and measures that can improve symptoms (e.g., reduction of one or more issues or impairments associated with a disease being treated, and / or improvements in one or more functions (e.g., physiological functions) affected by a disease being treated) or provide some benefit (e.g., clinical benefits) to a subject, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progress, development or spread of a disease (e.g., DM1) or symptoms (e.g., fatigue). In some embodiments, a symptom to be treated is mobility impairment. In some embodiments, a symptom to be treated is upper extremity function impairment. In some embodiments, a symptom to be treated is impairment in ability to do activities. In some embodiments, a symptom to be treated is fatigue. In some embodiments, a symptom to be treated is pain. In some embodiments, a symptom to be treated is a gastrointestinal symptom. In some embodiments, a symptom to be treated is vision impairment. In some embodiments, a symptom to be treated is communication impairment. In some embodiments, a symptom to be treated is sleep impairment. In some embodiments, a symptom to be treated is emotional issues. In some embodiments, a symptom to be treated is cognitive impairment. In some embodiments, a symptom to be treated is social satisfaction impairment. In some embodiments, a symptom to be treated is social performance impairment. In some embodiments, a symptom to be treated is myotonia. In some embodiments, a symptom to be treated is breathing impairment. In some embodiments, a symptom to be treated is swallowing impairment. In some embodiments, a symptom to be treated is hearing impairment.

[0077] Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. In some embodiments, “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, “treatment” can also mean delaying progression of disease as compared to the progression of disease if not receiving treatment. Those in need of treatment include those already with a condition, disease or disorder, or those suspected to or susceptible to have a condition, disease or disorder. As such, the term “treat” or “treatment” encompasses prophylactic use of a therapeutic agent. As described herein, the term “treat fatigue” or “treating fatigue” encompasses reducing, preventing, and / or increasing resistance to any type of fatigueknown in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat a GI symptom” or “treating a GI symptom” encompasses reducing, preventing, and / or increasing resistance to any type of GI symptom known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat myotonia” or “treating myotonia” encompasses reducing, preventing, and / or increasing resistance to any type of myotonia known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat upper extremity function impairment” or “treating upper extremity function impairment” encompasses reducing, preventing, and / or increasing resistance to any type of upper extremity function impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat mobility impairment” or “treating mobility impairment” encompasses reducing, preventing, and / or increasing resistance to any type of mobility impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat impairment in the ability to do activities” or “treating impairment in the ability to do activities” encompasses reducing, preventing, and / or increasing resistance to any type of impairment in the ability to do activities known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat pain” or “treating pain” encompasses reducing, preventing, and / or increasing resistance to any type of pain known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat vision impairment” or “treating vision impairment” encompasses reducing, preventing, and / or increasing resistance to any type of vision impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat communication impairment” or “treating communication impairment” encompasses reducing, preventing, and / or increasing resistance to any type of communication impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat sleep impairment” or “treating sleep impairment” encompasses reducing, preventing, and / or increasing resistance to any type of sleep impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat emotional issues” or “treating emotional issues” encompasses reducing, preventing, and / or increasing resistance to any type of emotional issues known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat cognitiveimpairment” or “treating cognitive impairment” encompasses reducing, preventing, and / or increasing resistance to any type of cognitive impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat social satisfaction impairment” or “treating social satisfaction impairment” encompasses reducing, preventing, and / or increasing resistance to any type of social satisfaction impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat social performance impairment” or “treating social performance impairment” encompasses reducing, preventing, and / or increasing resistance to any type of social performance impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat breathing impairment” or “treating breathing impairment” encompasses reducing, preventing, and / or increasing resistance to any type of breathing impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat swallowing impairment” or “treating swallowing impairment” encompasses reducing, preventing, and / or increasing resistance to any type of swallowing impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1). As described herein, the term “treat hearing impairment” or “treating hearing impairment” encompasses reducing, preventing, and / or increasing resistance to any type of hearing impairment known in the art or as described therein in a subject having or susceptible of having myotonic dystrophy (e.g., DM1).

[0078] 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 nucleotides and oligonucleotides comprising the 2’ -modified nucleosides have increased affinity to a targetsequences, relative to an unmodified oligonucleotide. Examples of structures of 2’-modified nucleosides are provided below:2'-O-methoxyethyl 'locked nucleic acid ethylene-bridged (S)-constrained

[0079] In certain embodiments, the internucleoside phosphate groups are as depicted, i.e., deprotonated in salt form. In certain embodiments, the internucleoside 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.).

[0080] Ranges: All ranges provided in the present disclosure are inclusive of the end points.

[0081] 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 the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Cl-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.Complexes

[0082] Provided herein are complexes that comprise a targeting agent, e.g., an antibody, covalently linked to an oligonucleotide. In some embodiments, a complex comprises a muscletargeting antibody covalently linked to one or more oligonucleotides. In some embodiments, the oligonucleotide is an antisense oligonucleotide that targets a DMPK RNA to reduce expression or activity of DMPK (e.g., reduce the level of a mutant or wild-type DMPK RNA, or the activity of a DMPK gene product).

[0083] Complexes 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 oligonucleotide comprising a 5’-X-Y-Z-3’ configuration). A linker comprises at least one covalent bond.

[0084] In some embodiments, complexes described herein comprise a structure of formula (I): [R^ni-R2, in which each R1independently comprises a compound comprising an oligonucleotide (e.g., an oligonucleotide comprising a 5’-X-Y-Z-3’ configuration) 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 acomplex is independently covalently linked to a different amino acid residue (e.g., lysine or cysteine) of R2.

[0085] 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 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.

[0086] In some embodiments, the value of nl of each or any complex (e.g., any complex in any of the compositions or formulations 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 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 thecomposition 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, or 0.9-1.2). 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).

[0087] In some embodiments, compositions are provided (e.g., formulations 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 oligonucleotide comprising a 5’-X-Y-Z-3’ configuration, such as a DMPK-targeting oligonucleotide). In such embodiments, different complex types are characterized by having different 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 DMPK-targeting 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, 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, or 0.9- 1.2). In some embodiments, compositions described herein comprise complexes in which nl is 0.

[0088] In some embodiments, a composition described herein comprises antibody that is not conjugated to an oligonucleotide (e.g., in trace amounts) and antibody conjugated to one or more oligonucleotides. In some embodiments, antibody that is not conjugated to an oligonucleotide may be referred to as a compound of the structure of formula (I): [ R11ni -R2, for which nl is zero. Accordingly, in some embodiments, a composition for administration to a subject in the methods described herein comprises compounds (e.g., complexes) of the structureof 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 of the 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, 010.9-1.2).

[0089] 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). However, 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.

[0090] In some embodiments, complexes provided herein (e.g., in compositions or formulations described herein) comprise a structure of formula (I): | R1|H i-R2, in which each instance of R1independently comprises a group of the formula (la):(la), or a pharmaceutically acceptable salt thereof,

[0091] in which R3comprises an oligonucleotide, e.g., an oligonucleotide comprising a 5’-X-Y-Z-3’ configuration; and R1is covalently linked to R2at attachment point A. In some embodiments, R2comprises an antibody comprising a sequence as set forth in Table 2. Forexample, 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, R2 comprises an antibody that is a Fab fragment. In some embodiments, R3comprises an oligonucleotide comprising a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21). In some embodiments, R3comprises an oligonucleotide comprising a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage. In some embodiments, complexes provided herein (e.g., in compositions or formulations described herein) comprise a structure of formula (I): [R^ni-R2, inwhich each R1comprises a group of the formula (lb):(lb), or a pharmaceutically acceptable salt thereof, wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’-O-methoxyethyl (MOE) modified ribonucleoside, oC represents a 5-methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, * represents a phosphorothioate intemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (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 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 aheavy 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, R2 comprises an antibody that is a Fab fragment.

[0092] In some embodiments, complexes provided herein (e.g., in compositions or formulations described herein) comprise a structure of formula (I): [R^ni- R2, in which each R1comprises a group of the formula (Ic):(Ic), or a pharmaceutically acceptable salt thereof, wherein 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., 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, R2 comprises an antibody that is a Fab fragment.

[0093] In some embodiments, complexes provided herein (e.g., in compositions or formulations described herein) comprise a structure of the formula (Id):(Id), or a pharmaceutically acceptable salt thereof,wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’-O-methoxyethyl (MOE) modified ribonucleoside, oC represents a 5-methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, * represents a phosphorothioate intemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (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, R2 comprises an antibody that is a Fab fragment.

[0094] 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).

[0095] In some embodiments, complexes described herein comprise a structure of formula (A): oligonucleotide(A), wherein y is 0-15 (e.g., 3) and z is 0-15 (e.g., 4), and wherein s 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 oligonucleotide comprising a 5’-X-Y-Z-3’ configuration). 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 IDNOs: 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.Antibodies

[0096] In some embodiments, complexes 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: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANVT KPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFPA ARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREF KLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLV HANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNA ELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCP SDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAW GPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGY LSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWA SKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARA AAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARG DFFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSPKESPFRHVFWGSG SHTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF (SEQ ID NO: 23).

[0097] 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

[0098] 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).

[0099] 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 tothe 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 ID NO: 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). [000100] 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).[000101] 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.[000102] 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.[000103] 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 in addition (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.[000104] 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.[000105] 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.[000106] 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[000107] In some embodiments, an oligonucleotide of the complexes described herein is a single stranded oligonucleotide. In some embodiments, the oligonucleotide is useful fortargeting DMPK (e.g., for reducing expression or activity of a DMPK RNA, such as the level of a mutant or wild-type DMPK RNA). In some embodiments, an oligonucleotide that is useful for targeting DMPK RNAs. (e.g., for reducing expression or activity of a DMPK RNA, such as the level of a mutant or wild- type DMPK RNA). In some embodiments, the oligonucleotide comprises a region of complementarity to a DMPK RNA. In some embodiments, the oligonucleotide is useful for reducing levels of toxic DMPK having disease-associated repeat expansions, e.g., in a subject having or suspected of having myotonic dystrophy. In some embodiments, the oligonucleotide is designed to direct RNAse H mediated degradation of the target DMPK RNA residing in the nucleus of cells, e.g., muscle cells (e.g., myotubes) or cells of the nervous system (e.g., central nervous system (CNS) cells). 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.[000108] In some embodiments, DMPK-targeting oligonucleotides described herein are designed to caused RNase H mediated degradation of DMPK mRNA. It should be appreciated that, in some embodiments, oligonucleotides in one format (e.g., antisense oligonucleotides) may be suitably adapted to another format (e.g., siRNA oligonucleotides) by incorporating functional sequences (e.g., antisense strand sequences) from one format to the other format. [000109] Examples of oligonucleotides useful for targeting DMPK are provided in US Patent Application Publication 20100016215A1, published on January 1, 2010, entitled Compound And Method For Treating Myotonic Dystrophy, US Patent Application Publication 20130237585A1, published July 19, 2010, Modulation Of Dystrophia Myotonica-Protein Kinase (DMPK) Expression', US Patent Application Publication 20150064181A1, published on March 5, 2015, entitled “Antisense Conjugates For Decreasing Expression Of Dmpk”', US Patent Application Publication 20150238627A1, published on August 27, 2015, entitled "Peptide-Einked Morpholino Antisense Oligonucleotides For Treatment Of Myotonic Dystrophy''', and US Patent Application Publication 20160304877A1, published on October 20, 2016, entitled “Compounds And Methods For Modulation Of Dystrophia Myotonica-Protein Kinase (Dmpk) Expression,” the contents of each of which are incorporated herein in their entireties.[000110] In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence set forth as follows, which is an example human DMPK gene sequence (Gene ID 1760; NM_001081560.2):AGGGGGGCTGGACCAAGGGGTGGGGAGAAGGGGAGGAGGCCTCGGCCGGCCGCAGAGAGAAGTGGCCAGAGAGGCCCAGGGGACAGCCAGGGACAGGCAGACATGCAGCCAGGGCTCCAGGGCCTGGACAGGGGCTGCCAGGCCCTGTGACAGGAGGACCCCGAGCCCCCGGCCCGGGGAGGGGCCATGGTGCTGCCTGTCCAACATGTCAGCCGAGGTGCGGCTGAGGCGGCTCCAGCAGCTGGTGTTGGACCCGGGCTTCCTGGGGCTGGAGCCCCTGCTCGACCTTCTCCTGGGCGTCCACCAGGAGCTGGGCGCCTCCGAACTGGCCCAGGACAAGTACGTGGCCGACTTCTTGCAGTGGGCGGAGCCCATCGTGGTGAGGCTTAAGGAGGTCCGACTGCAGAGGGACGACTTCGAGATTCTGAAGGTGATCGGACGCGGGGCGTTCAGCGAGGTAGCGGTAGTGAAGATGAAGCAGACGGGCCAGGTGTATGCCATGAAGATCATGAACAAGTGGGACATGCTGAAGAGGGGCGAGGTGTCGTGCTTCCGTGAGGAGAGGGACGTGTTGGTGAATGGGGACCGGCGGTGGATCACGCAGCTGCACTTCGCCTTCCAGGATGAGAACTACCTGTACCTGGTCATGGAGTATTACGTGGGCGGGGACCTGCTGACACTGCTGAGCAAGTTTGGGGAGCGGATTCCGGCCGAGATGGCGCGCTTCTACCTGGCGGAGATTGTCATGGCCATAGACTCGGTGCACCGGCTTGGCTACGTGCACAGGGACATCAAACCCGACAACATCCTGCTGGACCGCTGTGGCCACATCCGCCTGGCCGACTTCGGCTCTTGCCTCAAGCTGCGGGCAGATGGAACGGTGCGGTCGCTGGTGGCTGTGGGCACCCCAGACTACCTGTCCCCCGAGATCCTGCAGGCTGTGGGCGGTGGGCCTGGGACAGGCAGCTACGGGCCCGAGTGTGACTGGTGGGCGCTGGGTGTATTCGCCTATGAAATGTTCTATGGGCAGACGCCCTTCTACGCGGATTCCACGGCGGAGACCTATGGCAAGATCGTCCACTACAAGGAGCACCTCTCTCTGCCGCTGGTGGACGAAGGGGTCCCTGAGGAGGCTCGAGACTTCATTCAGCGGTTGCTGTGTCCCCCGGAGACACGGCTGGGCCGGGGTGGAGCAGGCGACTTCCGGACACATCCCTTCTTCTTTGGCCTCGACTGGGATGGTCTCCGGGACAGCGTGCCCCCCTTTACACCGGATTTCGAAGGTGCCACCGACACATGCAACTTCGACTTGGTGGAGGACGGGCTCACTGCCATGGAGACACTGTCGGACATTCGGGAAGGTGCGCCGCTAGGGGTCCACCTGCCTTTTGTGGGCTACTCCTACTCCTGCATGGCCCTCAGGGACAGTGAGGTCCCAGGCCCCACACCCATGGAACTGGAGGCCGAGCAGCTGCTTGAGCCACACGTGCAAGCGCCCAGCCTGGAGCCCTCGGTGTCCCCACAGGATGAAACAGCTGAAGTGGCAGTTCCAGCGGCTGTCCCTGCGGCAGAGGCTGAGGCCGAGGTGACGCTGCGGGAGCTCCAGGAAGCCCTGGAGGAGGAGGTGCTCACCCGGCAGAGCCTGAGCCGGGAGATGGAGGCCATCCGCACGGACAACCAGAACTTCGCCAGTCAACTACGCGAGGCAGAGGCTCGGAACCGGGACCTAGAGGCACACGTCCGGCAGTTGCAGGAGCGGATGGAGTTGCTGCAGGCAGAGGGAGCCACAGCTGTCACGGGGGTCCCCAGTCCCCGGGCCACGGATCCACCTTCCCATCTAGATGGCCCCCCGGCCGTGGCTGTGGGCCAGTGCCCGCTGGTGGGGCCAGGCCCCATGCACCGCCGCCACCTGCTGCTCCCTGCCAGGGTCCCTAGGCCTGGCCTATCGGAGGCGCTTTCCCTGCTCCTGTTCGCCGTTGTTCTGTCTCGTGCCGCCGCCCTGGGCTGCATTGGGT TGGTGGCCCACGCCGGCCAACTCACCGCAGTCTGGCGCCGCCCAGGAGCCGCCCGC GCTCCCTGAACCCTAGAACTGTCTTCGACTCCGGGGCCCCGTTGGAAGACTGAGTGCCCGGGGCACGGCACAGAAGCCGCGCCCACCGCCTGCCAGTTCACAACCGCTCCGAG CGTGGGTCTCCGCCCAGCTCCAGTCCTGTGATCCGGGCCCGCCCCCTAGCGGCCGGG GAGGGAGGGGCCGGGTCCGCGGCCGGCGAACGGGGCTCGAAGGGTCCTTGTAGCCGGGAATGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT GCTGCTGCTGGGGGGATCACAGACCATTTCTTTCTTTCGGCCAGGCTGAGGCCCTGA CGTGGATGGGCAAACTGCAGGCCTGGGAAGGCAGCAAGCCGGGCCGTCCGTGTTCCATCCTCCACGCACCCCCACCTATCGTTGGTTCGCAAAGTGCAAAGCTTTCTTGTGCA TGACGCCCTGCTCTGGGGAGCGTCTGGCGCGATCTCTGCCTGCTTACTCGGGAAATT TGCTTTTGCCAAACCCGCTTTTTCGGGGATCCCGCGCCCCCCTCCTCACTTGCGCTGCTCTCGGAGCCCCAGCCGGCTCCGCCCGCTTCGGCGGTTTGGATATTTATTGACCTCG TCCTCCGACTCGCTGACAGGCTACAGGACCCCCAACAACCCCAATCCACGTTTTGGA TGCACTGAGACCCCGACATTCCTCGGTATTTATTGTCTGTCCCCACCTAGGACCCCCACCCCCGACCCTCGCGAATAAAAGGCCCTCCATCTGCCCAAAGCTCTGGA(SEQ ID NO: 24).[000111] In some embodiments, oligonucleotides may comprise a region of complementarity to a sequence set forth as follows, which is an example mouse DMPK gene sequence (Gene ID 13400; NM_001190490.1).GAACTGGCCAGAGAGACCCAAGGGATAGTCAGGGACGGGCAGACATGCAGCTAGG GTTCTGGGGCCTGGACAGGGGCAGCCAGGCCCTGTGACGGGAAGACCCCGAGCTCC GGCCCGGGGAGGGGCCATGGTGTTGCCTGCCCAACATGTCAGCCGAAGTGCGGCTGAGGCAGCTCCAGCAGCTGGTGCTGGACCCAGGCTTCCTGGGACTGGAGCCCCTGCT CGACCTTCTCCTGGGCGTCCACCAGGAGCTGGGTGCCTCTCACCTAGCCCAGGACA AGTATGTGGCCGACTTCTTGCAGTGGGTGGAGCCCATTGCAGCAAGGCTTAAGGAGGTCCGACTGCAGAGGGATGATTTTGAGATTTTGAAGGTGATCGGGCGTGGGGCGTT CAGCGAGGTAGCGGTGGTGAAGATGAAACAGACGGGCCAAGTGTATGCCATGAAG ATTATGAATAAGTGGGACATGCTGAAGAGAGGCGAGGTGTCGTGCTTCCGGGAAGAAAGGGATGTATTAGTGAAAGGGGACCGGCGCTGGATCACACAGCTGCACTTTGCCT TCCAGGATGAGAACTACCTGTACCTGGTCATGGAATACTACGTGGGCGGGGACCTG CTAACGCTGCTGAGCAAGTTTGGGGAGCGGATCCCCGCCGAGATGGCTCGCTTCTACCTGGCCGAGATTGTCATGGCCATAGACTCCGTGCACCGGCTGGGCTACGTGCACA GGGACATCAAACCAGATAACATTCTGCTGGACCGATGTGGGCACATTCGCCTGGCA GACTTCGGCTCCTGCCTCAAACTGCAGCCTGATGGAATGGTGAGGTCGCTGGTGGCTGTGGGCACCCCGGACTACCTGTCTCCTGAGATTCTGCAGGCCGTTGGTGGAGGGCCTGGGGCAGGCAGCTACGGGCCAGAGTGTGACTGGTGGGCACTGGGCGTGTTCGCCTATGAGATGTTCTATGGGCAGACCCCCTTCTACGCGGACTCCACAGCCGAGACATATGCCAAGATTGTGCACTACAGGGAACACTTGTCGCTGCCGCTGGCAGACACAGTTGTCCCCGAGGAAGCTCAGGACCTCATTCGTGGGCTGCTGTGTCCTGCTGAGATAAGGCTAGGTCGAGGTGGGGCAGACTTCGAGGGTGCCACGGACACATGCAATTTCGATGTGGTGGAGGACCGGCTCACTGCCATGGTGAGCGGGGGCGGGGAGACGCTGTCAGACATGCAGGAAGACATGCCCCTTGGGGTGCGCCTGCCCTTCGTGGGCTACTCCTACTGCTGCATGGCCTTCAGAGACAATCAGGTCCCGGACCCCACCCCTATGGAACTAGAGGCCCTGCAGTTGCCTGTGTCAGACTTGCAAGGGCTTGACTTGCAGCCCCCAGTGTCCCCACCGGATCAAGTGGCTGAAGAGGCTGACCTAGTGGCTGTCCCTGCCCCTGTGGCTGAGGCAGAGACCACGGTAACGCTGCAGCAGCTCCAGGAAGCCCTGGAAGAAGAGGTTCTCACCCGGCAGAGCCTGAGCCGCGAGCTGGAGGCCATCCGGACCGCCAACCAGAACTTCTCCAGCCAACTACAGGAGGCCGAGGTCCGAAACCGAGACCTGGAGGCGCATGTTCGGCAGCTACAGGAACGGATGGAGATGCTGCAGGCCCCAGGAGCCGCAGCCATCACGGGGGTCCCCAGTCCCCGGGCCACGGATCCACCTTCCCATCTAGATGGCCCCCCGGCCGTGGCTGTGGGCCAGTGCCCGCTGGTGGGGCCAGGCCCCATGCACCGCCGTCACCTGCTGCTCCCTGCCAGGATCCCTAGGCCTGGCCTATCCGAGGCGCGTTGCCTGCTCCTGTTCGCCGCTGCTCTGGCTGCTGCCGCCACACTGGGCTGCACTGGGTTGGTGGCCTATACCGGCGGTCTCACCCCAGTCTGGTGTTTCCCGGGAGCCACCTTCGCCCCCTGAACCCTAAGACTCCAAGCCATCTTTCATTTAGGCCTCCTAGGAAGGTCGAGCGACCAGGGAGCGACCCAAAGCGTCTCTGTGCCCATCGCGCCCCCCCCCCCCCCCCACCGCTCCGCTCCACACTTCTGTGAGCCTGGGTCCCCACCCAGCTCCGCTCCTGTGATCCAGGCCTGCCACCTGGCGGCCGGGGAGGGAGGAACAGGGCTCGTGCCCAGCACCCCTGGTTCCTGCAGAGCTGGTAGCCACCGCTGCTGCAGCAGCTGGGCATTCGCCGACCTTGCTTTACTCAGCCCCGACGTGGATGGGCAAACTGCTCAGCTCATCCGATTTCACTTTTTCACTCTCCCAGCCATCAGTTACAAGCCATAAGCATGAGCCCCCTATTTCCAGGGACATCCCATTCCCATAGTGATGGATCAGCAAGACCTCTGCCAGCACACACGGAGTCTTTGGCTTCGGACAGCCTCACTCCTGGGGGTTGCTGCAACTCCTTCCCCGTGTACACGTCTGCACTCTAACAACGGAGCCACAGCTGCACTCCCCCCTCCCCCAAAGCAGTGTGGGTATTTATTGATCTTGTTATCTGACTCACTGACAGACTCCGGGACCCACGTTTTAGATGCATTGAGACTCGACATTCCTCGGTATTTATTGTCTGTCCCCACCTACGACCTCCACTCCCGACCCTTGCGAATAAAATACTTCTGGTCTGCCCTAAA (SEQ ID NO: 25).[000112] In some embodiments, an oligonucleotide may comprise a region of complementarity to DMPK gene sequences of multiple species, e.g., selected from human, mouse and non-human species (e.g., cynomolgus monkey).[000113] In some embodiments, the oligonucleotide may comprise a region of complementarity to a mutant form of DMPK, for example, a mutant form as reported in Botta A. et al. “The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients.” J Med Genet. 2008 Oct;45(10):639-46.; and Machuca-Tzili L. et al. “Clinical and molecular aspects of the myotonic dystrophies: a review.” Muscle Nerve. 2005 Jul;32(l):l-18.; the contents of each of which are incorporated herein by reference in their entireties.[000114] In some embodiments, an oligonucleotide provided herein is an antisense oligonucleotide targeting DMPK. In some embodiments, the oligonucleotide targeting DMPK is any one of the antisense oligonucleotides targeting DMPK as described in US Patent Application Publication US20160304877A1, published on October 20, 2016, entitled “Compounds And Methods For Modulation Of Dystrophia Myotonica-Protein Kinase (DMPK) Expression,” incorporated herein by reference). In some embodiments, the DMPK targeting oligonucleotide targets a region of the DMPK gene sequence as set forth in Genbank accession No. NM_001081560.2 (SEQ ID NO: 24) or as set forth in Genbank accession No. NG_009784.1 (SEQ ID NO: 26).[000115] In some embodiments, a DMPK targeting oligonucleotide provided herein comprises a nucleotide sequence comprising a region complementary to a target region that is at least 8 continuous nucleotides (e.g., at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20 or more continuous nucleotides) of SEQ ID NO: 24.[000116] In some embodiments, a DMPK targeting oligonucleotide provided herein is 10- 35 (e.g., 10-35, 10-30, 10-25, 10-20, 10-15, 15-35, 15-30, 15-25, 15-20, 20-35, 20-30, 13-18, 14-17, 15-18, 20-30, 15-17, 27-30, 25-35, or 30-35) nucleotides in length. In some embodiments, a DMPK targeting oligonucleotide provided herein is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length, optionally 15-30, or 16 nucleotides in length. In some embodiments, a DMPK targeting oligonucleotide provided herein is 16 nucleotides in length.[000117] In some embodiments, a DMPK targeting oligonucleotide provided herein comprises a region of complementarity of at least 8 e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) consecutive nucleotides to a DMPK RNA.[000118] In some embodiments, a DMPK targeting oligonucleotide provided herein comprises a region of complementarity of at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) consecutive nucleotides to a DMPK sequence as set forth in SEQ ID NO: 24 or 25.[000119] In some embodiments, a DMPK targeting oligonucleotide provided herein comprises a region of complementarity of at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, or 16) consecutive nucleotides to a target sequence as set forth in SEQ ID NO: 22 (TGACTGGTGGGCGCTG). In some embodiments, an oligonucleotide useful for targeting DMPK comprises at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, or 16) consecutive nucleotides of a sequence as set forth in SEQ ID NO: 21 (CAGCGCCCACCAGUCA). In some embodiments, an oligonucleotide useful for targeting DMPK comprises the nucleotide sequence of SEQ ID NO: 21.[000120] In some embodiments, the DMPK targeting oligonucleotide comprises a 5’-X-Y- Z-3’ configuration. An oligonucleotide comprising a 5’-X-Y-Z-3’ configuration can refer to a chimeric antisense compound in which a gap region having a plurality of nucleosides that support RNase H cleavage is positioned between flanking regions having one or more nucleosides, wherein the nucleosides comprising the gap region are chemically distinct from the nucleoside or nucleosides comprising the flanking regions. In some embodiments, an oligonucleotide described herein (e.g., a DMPK-targeting oligonucleotide described herein) comprises a 5'-X-Y-Z-3' configuration, with X and Z as flanking regions around a gap region Y. In some embodiments, the gap region Y comprises one or more 2’-deoxyribonucleosides. In some embodiments, each nucleoside in the gap region Y is a 2’ -deoxyribonucleoside, and neither the flanking region X nor the flanking region Z contains any 2’ -deoxyribonucleosides. [000121] In some embodiments, the gap region Y comprises a continuous stretch of 6 or more 2’ -deoxyribonucleosides, which are capable of recruiting an RNAse, such as RNAse H. In some embodiments, the oligonucleotide binds to the target nucleic acid, at which point an RNAse is recruited and can then cleave the target nucleic acid. In some embodiments, the flanking regions X and Z each comprise one or more modified nucleosides. In some embodiments, flanking regions X and Z each comprise one or more high-affinity modified nucleosides, e.g., one to six high-affinity modified nucleosides. Examples of high affinity modified nucleosides include, but are not limited to, 2'-modified nucleosides (e.g., 2’ -MOE, 2'- O-Me, 2’-F) or 2’-4’ bicyclic nucleosides (e.g., LNA, cEt, ENA). In some embodiments, the flanking regions X and Z may be of 1-20 nucleotides, 1-8 nucleotides, or 1-5 nucleotides in length. The flanking regions X and Z may be of similar length or of dissimilar lengths. In someembodiments, the gap region Y may comprise a nucleotide sequence of 5-20 nucleotides, 5-15 nucleotides, 5-12 nucleotides, or 6-10 nucleotides in length.[000122] In some embodiments, the gap region Y comprises one or more unmodified intemucleoside linkages. In some embodiments, one or both flanking regions X and Z each independently comprise phosphorothioate intemucleoside linkages (e.g., phosphorothioate intemucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. In some embodiments, the gap region Y and two flanking regions X and Z each independently comprise modified intemucleoside linkages (e.g., phosphorothioate intemucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides.[000123] In some embodiments, the gap region Y in the gapmer is 5-20 nucleosides in length. For example, the gap region Y may be 5-20, 5-15, 5-10, 10-20, 10-15, or 15-20 nucleosides in length. In some embodiments, the gap region Y is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleosides in length. In some embodiments, each nucleoside in the gap region Y is a 2’ -deoxyribonucleoside. In some embodiments, all nucleosides in the gap region Y are 2’ -deoxyribonucleosides. In some embodiments, one or more of the nucleosides in the gap region Y is a modified nucleoside (e.g., a 2’ modified nucleoside such as those described herein). In some embodiments, one or more cytosines in the gap region Y are optionally 5- methyl-cytosines. In some embodiments, each cytosine in the gap region Y is a 5-methyl- cy to sine.[000124] In some embodiments, the flanking region X of the oligonucleotide (X in the 5'- X-Y-Z-3' configuration) and the flanking region Z of the oligonucleotide (Z in the 5'-X-Y-Z-3' configuration) are independently 1-20 nucleosides long. For example, the flanking region X of the oligonucleotide and the flanking region Z of the oligonucleotide may be independently 1-20, 1-15, 1-10, 1-7, 1-5, 1-3, 1-2, 2-5, 2-7, 3-5, 3-7, 5-20, 5-15, 5-10, 10-20, 10-15, or 15-20 nucleosides long. In some embodiments, the flanking region X of the oligonucleotide and the flanking region Z of the oligonucleotide are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleosides long. In some embodiments, the flanking region X of the oligonucleotide and the flanking region Z of the oligonucleotide are of the same length. In some embodiments, the flanking region X of the oligonucleotide and the flanking region Z of the oligonucleotide are of different lengths. In some embodiments, the flanking region X of the oligonucleotide is longer than the flanking region Z of the oligonucleotide. In some embodiments, the flanking region X of the oligonucleotide is shorter than the flanking region Z of the oligonucleotide.[000125] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide) comprises a 5'-X-Y-Z-3' configuration of 5-10-5, 4-12-4, 3-14-3, 2- 16-2, 1-18-1, 3-10-3, 2-10-2, 1-10-1, 2-8-2, 4-6-4, 3-6-3, 2-6-2, 4-7-4, 3-7-3, 2-7-2, 4-8-4, 3-8-3,2-8-2, 1-8-1, 2-9-2, 1-9-1, 2-10-2, 1-10-1, 1-12-1, 1-16-1, 2-15-1, 1-15-2, 1-14-3, 3-14-1, 2-14- 2, 1-13-4, 4-13-1, 2-13-3, 3-13-2, 1-12-5, 5-12-1, 2-12-4, 4-12-2, 3-12-3, 1-11-6, 6-11-1, 2-11-5,5-11-2, 3-11-4, 4-11-3, 1-17-1, 2-16-1, 1-16-2, 1-15-3, 3-15-1, 2-15-2, 1-14-4, 4-14-1, 2-14-3,3-14-2, 1-13-5, 5-13-1, 2-13-4, 4-13-2, 3-13-3, 1-12-6, 6-12-1, 2-12-5, 5-12-2, 3-12-4, 4-12-3,1-11-7, 7-11-1, 2-11-6, 6-11-2, 3-11-5, 5-11-3, 4-11-4, 1-18-1, 1-17-2, 2-17-1, 1-16-3, 1-16-3,2-16-2, 1-15-4, 4-15-1, 2-15-3, 3-15-2, 1-14-5, 5-14-1, 2-14-4, 4-14-2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2, 3-13-4, 4-13-3, 1-12-7, 7-12-1, 2-12-6, 6-12-2, 3-12-5, 5-12-3, 1-11-8, 8-11-1,2-11-7, 7-11-2, 3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-18-1, 1-17-2, 2-17-1, 1-16-3, 3-16-1, 2-16-2,1-15-4, 4-15-1, 2-15-3, 3-15-2, 1-14-5, 2-14-4, 4-14-2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2,3-13-4, 4-13-3, 1-12-7, 7-12-1, 2-12-6, 6-12-2, 3-12-5, 5-12-3, 1-11-8, 8-11-1, 2-11-7, 7-11-2,3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-19-1, 1-18-2, 2-18-1, 1-17-3, 3-17-1, 2-17-2, 1-16-4, 4-16-1,2-16-3, 3-16-2, 1-15-5, 2-15-4, 4-15-2, 3-15-3, 1-14-6, 6-14-1, 2-14-5, 5-14-2, 3-14-4, 4-14-3,1-13-7, 7-13-1, 2-13-6, 6-13-2, 3-13-5, 5-13-3, 4-13-4, 1-12-8, 8-12-1, 2-12-7, 7-12-2, 3-12-6,6-12-3, 4-12-5, 5-12-4, 2-11-8, 8-11-2, 3-11-7, 7-11-3, 4-11-6, 6-11-4, 5-11-5, 1-20-1, 1-19-2,2-19-1, 1-18-3, 3-18-1, 2-18-2, 1-17-4, 4-17-1, 2-17-3, 3-17-2, 1-16-5, 2-16-4, 4-16-2, 3-16-3,1-15-6, 6-15-1, 2-15-5, 5-15-2, 3-15-4, 4-15-3, 1-14-7, 7-14-1, 2-14-6, 6-14-2, 3-14-5, 5-14-3,4-14-4, 1-13-8, 8-13-1, 2-13-7, 7-13-2, 3-13-6, 6-13-3, 4-13-5, 5-13-4, 2-12-8, 8-12-2, 3-12-7,7-12-3, 4-12-6, 6-12-4, 5-12-5, 3-11-8, 8-11-3, 4-11-7, 7-11-4, 5-11-6, 6-11-5, 1-21-1, 1-20-2,2-20-1, 1-20-3, 3-19-1, 2-19-2, 1-18-4, 4-18-1, 2-18-3, 3-18-2, 1-17-5, 2-17-4, 4-17-2, 3-17-3,1-16-6, 6-16-1, 2-16-5, 5-16-2, 3-16-4, 4-16-3, 1-15-7, 7-15-1, 2-15-6, 6-15-2, 3-15-5, 5-15-3,4-15-4, 1-14-8, 8-14-1, 2-14-7, 7-14-2, 3-14-6, 6-14-3, 4-14-5, 5-14-4, 2-13-8, 8-13-2, 3-13-7, 7-13-3, 4-13-6, 6-13-4, 5-13-5, 1-12-10, 10-12-1, 2-12-9, 9-12-2, 3-12-8, 8-12-3, 4-12-7, 7-12-4,5-12-6, 6-12-5, 4-11-8, 8-11-4, 5-11-7, 7-11-5, 6-11-6, 1-22-1, 1-21-2, 2-21-1, 1-21-3, 3-20-1,2-20-2, 1-19-4, 4-19-1, 2-19-3, 3-19-2, 1-18-5, 2-18-4, 4-18-2, 3-18-3, 1-17-6, 6-17-1, 2-17-5,5-17-2, 3-17-4, 4-17-3, 1-16-7, 7-16-1, 2-16-6, 6-16-2, 3-16-5, 5-16-3, 4-16-4, 1-15-8, 8-15-1,2-15-7, 7-15-2, 3-15-6, 6-15-3, 4-15-5, 5-15-4, 2-14-8, 8-14-2, 3-14-7, 7-14-3, 4-14-6, 6-14-4,5-14-5, 3-13-8, 8-13-3, 4-13-7, 7-13-4, 5-13-6, 6-13-5, 4-12-8, 8-12-4, 5-12-7, 7-12-5, 6-12-6,5-11-8, 8-11-5, 6-11-7, or 7-11-6. The numbers indicate the number of nucleosides in X, Y, andZ regions, respectively, in an oligonucleotide comprising the 5’-X-Y-Z-3’ configuration.[000126] In some embodiments, one or more nucleosides in the flanking region X of the oligonucleotide (X in the 5'-X-Y-Z-3' configuration) or the flanking region Z of the oligonucleotide (Z in the 5'-X-Y-Z-3' configuration) are modified nucleosides (e.g., high-affinitymodified nucleosides). In some embodiments, the modified nucleoside (e.g., high-affinity modified nucleosides) is a 2’-modified nucleoside. In some embodiments, the 2’-modified nucleoside is a 2’ -4’ bicyclic nucleoside or a non-bicyclic 2’ -modified nucleoside. In some embodiments, the high-affinity modified nucleoside is a 2’ -4’ bicyclic nucleoside (e.g., LNA, cEt, or ENA) or a non-bicyclic 2’ -modified nucleoside (e.g., 2’ -fluoro (2’-F), 2’-O-methyl (2’- O-Me), 2’-O-methoxyethyl (2’-MOE), 2’-O-aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-O-NMA)).[000127] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises a 5'-X-Y-Z-3' configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6-10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 in X (the 5’-most position is position 1) is a non-bicyclic 2’- modified nucleoside (e.g., 2’-MOE or 2’-O-Me), wherein the rest of the nucleosides in both X and Z are 2’-4’ bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2’deoxyribonucleoside. In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein)comprises a 5'-X-Y-Z-3' configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6- 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 in Z (the 5’-most position is position 1) is a non-bicyclic 2’-modified nucleoside (e.g., 2’-M0E or 2’-0-Me), wherein the rest of the nucleosides in both X and Z are 2’ -4’ bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2’deoxyribonucleoside. In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises a 5'-X-Y-Z-3' configuration, wherein X and Z are independently 2-7 (e.g., 2, 3, 4, 5, 6, or 7) nucleosides in length and Y is 6- 10 (e.g., 6, 7, 8, 9, or 10) nucleosides in length, wherein at least one but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 in X and at least one of positions but not all (e.g., 1, 2, 3, 4, 5, or 6) of positions 1, 2, 3, 4, 5, 6, or 7 in Z (the 5’-most position is position 1) is a non-bicyclic 2’-modified nucleoside (e.g., 2’-M0E or 2’-0-Me), wherein the rest of the nucleosides in both X and Z are 2’ -4’ bicyclic nucleosides (e.g., LNA or cEt), and wherein each nucleoside in Y is a 2 ’ deoxyribonucleo side .[000128] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide) is 10-20 nucleosides (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleosides) in length, comprises a region of complementarity to at least 8 consecutive nucleosides (e.g., at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, atleast 15, or 16 consecutive nucleosides) of SEQ ID NO: 22 (TGACTGGTGGGCGCTG), and comprises a 5’-X-Y-Z-3’ configuration, wherein X comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in X is a 2’-modified nucleoside (e.g., 2’- MOE modified nucleoside, 2’-0-Me modified nucleoside, LNA, cEt, or ENA); Y comprises 6- 10 (e.g., 6, 7, 8, 9, or 10) linked 2’ -deoxyribonucleosides, wherein each cytosine in Y is optionally and independently a 5-methyl-cytosine; and Z comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in Z is a 2’- modified nucleoside (e.g., 2’- MOE modified nucleoside, 2’-O-Me modified nucleoside, LNA, cEt, or ENA).[000129] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises at least 8 consecutive nucleosides (e.g., at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or 16 consecutive nucleosides consecutive nucleosides) of the nucleotide sequence of SEQ ID NO: 21 (CAGCGCCCACCAGUCA), and comprises a 5’-X-Y-Z-3’ configuration, wherein X comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in X is a 2’- modified nucleoside (e.g., 2’ -MOE modified nucleoside, 2’-O-Me modified nucleoside, LNA, cEt, or ENA); Y comprises 6-10 (e.g., 6, 7, 8, 9, or 10) linked 2’ -deoxyribonucleosides, wherein each cytosine in Y is optionally and independently a 5-methyl-cytosine; and Z comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in Z is a 2’-modified nucleoside (e.g., 2’-M0E modified nucleoside, 2’-O-Me modified nucleoside, LNA, cEt, or ENA). In some embodiments, each thymine base (T) of the nucleotide sequence of the antisense oligonucleotide may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.[000130] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises the nucleotide sequence of SEQ ID NO: 21 and comprises a 5’-X-Y-Z-3’ configuration, wherein X comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in X is a 2’-modified nucleoside (e.g., 2’- MOE modified nucleoside, 2’-O-Me modified nucleoside, LNA, cEt, or ENA); Y comprises 6- 10 (e.g., 6, 7, 8, 9, or 10) linked 2’ -deoxyribonucleosides, wherein each cytosine in Y is optionally and independently a 5-methyl-cytosine; and Z comprises 3-5 (e.g., 3, 4, or 5) linked nucleosides, wherein at least one of the nucleosides in Z is a 2’- modified nucleoside (e.g., 2’- MOE modified nucleoside, 2’-O-Me modified nucleoside, LNA, cEt, or ENA). In some embodiments, each thymine base (T) of the nucleotide sequence of the antisense oligonucleotide may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.[000131] In some embodiments, X comprises at least one 2’ -4’ bicyclic nucleoside (e.g., LNA, cEt, or ENA) and at least one non-bicyclic 2’-modified nucleoside e.g., 2’-MOE modified nucleoside or 2’-O-Me modified nucleoside, and / or (e.g., and) Z comprises at least one 2’ -4’ bicyclic nucleoside (e.g., LNA, cEt, or ENA) and at least one non-bicyclic 2’-modified nucleoside (e.g., 2’-MOE modified nucleoside or 2’-O-Me modified nucleoside).[000132] In some embodiments, the 2’ -4’ bicyclic nucleoside is selected from LNA, cEt, and ENA nucleosides. In some embodiments, the non-bicyclic 2’-modified nucleoside is a 2’- MOE modified nucleoside or a 2’-OMe modified nucleoside.[000133] In some embodiments, the nucleosides of the oligonucleotides are joined together by phosphorothioate intemucleoside linkages, phosphodiester internucleoside linkages or a combination thereof. In some embodiments, the oligonucleotide comprises only phosphorothioate internucleoside linkages joining each nucleoside (i.e., the oligonucleotide comprises a fully phosphorothioate backbone). In some embodiments, the oligonucleotide comprises at least one phosphorothioate intemucleoside linkage. In some embodiments, the oligonucleotide comprises a mix of phosphorothioate and phosphodiester internucleoside linkages. In some embodiments, the oligonucleotide comprises only phosphorothioate intemucleoside linkages joining each pair of 2’ -deoxyribonucleosides and a mix of phosphorothioate and phosphodiester intemucleoside linkages joining the remaining nucleosides.[000134] In some embodiments, the oligonucleotide comprises a 5’-X-Y-Z-3’ configuration of LLEE-(D)8-EELL, wherein “E” is a 2’-M0E modified ribonucleoside; “L” is LNA; “D” is a 2’ -deoxy ribonucleoside; and “10” or “8” is the number of 2’- deoxyribonucleosides in Y, and wherein the oligonucleotide comprises phosphorothioate intemucleoside linkages, phosphodiester intemucleoside linkages or a combination thereof. [000135] In some embodiments, each cytidine (e.g., a 2’ -modified cytidine) in X and / or Z of the oligonucleotide is optionally and independently a 5-methyl-cytidine, and / or each uridine (e.g., a 2’ -modified uridine) in X and / or Z is optionally and independently a 5-methyl-uridine. [000136] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises a 5’-X-Y-Z-3’ configuration and comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21). In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’-O-methoxyethyl (MOE) modified ribonucleoside, oCrepresents a 5-methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, * represents a phosphorothioate intemucleoside linkage.[000137] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) comprises a structure of the formula (le):pharmaceutically acceptable salt thereof,.[000138] In some embodiments, an oligonucleotide described herein (e.g., a DMPK targeting oligonucleotide described herein) can be in salt form, e.g., as sodium, potassium, or magnesium salts.[000139] In some embodiments, the 5’ or 3’ nucleoside (e.g., terminal nucleoside) of the 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,-0-, -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.[000140] 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 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. 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.[000141] 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.[000142] 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.[000143] In some embodiments, any one or more of the thymine bases (T’s) in any one of the oligonucleotides provided herein may independently and optionally be uracil bases (U’s), and / or any one or more of the U’s in the oligonucleotides provided herein (e.g., the oligonucleotide as set forth in SEQ ID NO: 21) may independently and optionally be T’s.Compositions[000144] 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) comprisetris(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.[000145] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein comprise complexes (i.e., a plurality of complexes), each of which complex comprises an oligonucleotide (e.g., an oligonucleotide comprising a 5’-X-Y-Z-3’ configuration) covalently linked to an antibody. In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein comprise complexes, in which each complex comprises an oligonucleotide (e.g., an oligonucleotide comprising a 5’-X-Y-Z-3’ configuration) covalently linked to an anti-TfRl antibody, optionally wherein 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.[000146] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein comprise complexes (i.e., a plurality of complexes) comprising a structure of formula (I): [ R11ni -R2, in which each R1independently comprises a compound comprising an oligonucleotide (e.g., an oligonucleotide comprising a 5’- X-Y-Z-3’ configuration) and is covalently linked to R2, wherein R2comprises an antibody (e.g., anti-TfRl antibody), and in which in each complex nl is independently an integer of one or greater representing the number of instances of R1in each complex.[000147] In some embodiments, the value of nl of each complex 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 (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 independently 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.[000148] In some embodiments, a composition for administration to a subject in the methods described herein comprises unconjugated antibody (e.g., in trace amounts) and antibody conjugated to one or more oligonucleotides. In some embodiments, unconjugated antibody 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 the methods 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, or 0.9-1.2).[000149] 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 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, 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 aminoacid residue residing in a CDR region of the antibody are not detectable in the composition using standard detection techniques.[000150] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described 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):(la), or a pharmaceutically acceptable salt thereof, in which R3comprises an oligonucleotide, e.g., an oligonucleotide comprising a 5’-X-Y-Z-3’ configuration; 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., 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 lightchain 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 oligonucleotide comprising a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21). In some embodiments, R3comprises an oligonucleotide comprising a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage. 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, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein further comprise complexes in which nl is 0.[000151] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described 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):(lb), or a pharmaceutically acceptable salt thereof, wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’-O-methoxyethyl (MOE) modified ribonucleoside, oC represents a 5-methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, * represents a phosphorothioateintemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (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 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, 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, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein further comprise complexes in which nl is 0.[000152] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described 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):(Ic), or a pharmaceutically acceptable salt thereof, wherein 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., 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 anantibody 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, 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, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein further comprise complexes in which nl is 0.[000153] In some embodiments, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein comprise complexes that comprise a structure of the formula (Id):(Id), or a pharmaceutically acceptable salt thereof, wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’-O-methoxyethyl (MOE) modified ribonucleoside, oC represents a 5-methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, * represents a phosphorothioate intemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (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 thegroup 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. 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, compositions (e.g., in aqueous solutions) for administration to a subject in the methods described herein further comprise complexes in which nl is 0.[000154] In some embodiments, compositions (e.g., aqueous solutions) for administration to a subject in the methods described herein comprise a structure of formula (A):(A), wherein y is 0-15 (e.g., 3) and z is 0-15 (e.g., 4), and whereinrepresents 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 oligonucleotide comprising a 5’-X-Y-Z-3’ configuration). 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 chaincomprising 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.[000155] In some embodiments, a 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, the route of administration is intravenous or subcutaneous.Methods of Use / Treatment[000156] Complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating a subject having a myotonic dystrophy, e.g., DM1. In some embodiments, complexes comprise a molecular payload that is an oligonucleotide, e.g., an oligonucleotide that facilitates reduced expression or activity of DMPK (e.g., reduced level of a mutant or wild-type DMPK RNA) in a subject (e.g., a subject having DM1).[000157] In some embodiments, oligonucleotides disclosed herein can be delivered to the muscle (e.g., skeletal muscle, cardiac muscle, and / or smooth muscle) using complexes described here (e.g., anti-TfRl antibody complexes comprising the oligonucleotide). In some embodiments, oligonucleotides disclosed herein can be delivered to the CNS using complexes described here (e.g., anti-TfRl antibody complexes comprising the oligonucleotide). In some embodiments, oligonucleotides described herein can be delivered to one or more regions of the brain selected from cortex, deep brain (e.g., thalamus, caudate nucleus and / or putamen regions), and cerebellum using complexes described herein (e.g., anti-TfRl antibody complexes comprising the oligonucleotide). In some embodiments, oligonucleotides described herein can be delivered into one or more cell types of the CNS using complexes described herein (e.g., anti- TfRl antibody complexes comprising the oligonucleotide). In some embodiments, the one or more cell types are neurons or glial cells (e.g., microglia and astrocytes).[000158] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in alleviating one or more symptoms (e.g., neurological symptoms and / or muscle symptoms) of DM1 and / or in alleviating DM1 disease burden. In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in achieving positive outcome for one or more DM1 symptoms (e.g., neurological symptoms and / or muscle symptoms) included in the Myotonic Dystrophy Health Index or MDHI (e.g., as describedherein Heatwole et al., Muscle Nerve. 2014 Jun; 49(6): 906-914; and Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) one or more symptoms assessable by the MDHI in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of one or more symptoms assessable by the MDHI, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience one or more symptoms assessable by the MDHI as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience one or more symptoms assessable by the MDHI. In some embodiments, a subject being treated has reported to have vision impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, the method further comprises receiving indicia of patient-reported improvements in one or more subscales of a Myotonic Dystrophy Health Index (MDHI) selected from: mobility, upper extremity function, ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, emotional issues, cognitive impairment, social satisfaction, myotonia, breathing, swallowing, and hearing. In some embodiments, indicia are provided to a physician. In some embodiments, indicia are received electronically.[000159] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) fatigue in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more)level of fatigue, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience fatigue as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience fatigue.[000160] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) a GI symptom in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of a GI symptom, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience a GI symptom as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience a GI symptom.[000161] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) myotonia in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of myotonia, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linkedto a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience myotonia as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience myotonia.[000162] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) upper extremity function impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of upper extremity function impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience upper extremity function impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience upper extremity function impairment.[000163] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) impairment in the ability to perform activities in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of impairment in the ability to perform activities, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a methoddescribed herein experience impairment in the ability to perform activities as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience impairment in the ability to perform activities.[000164] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) pain in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of pain, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience pain as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience pain.[000165] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) communication impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of communication impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience communication impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience communication impairment.[000166] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) emotional issues in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of emotional issues, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience emotional issues as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience emotional issues.[000167] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) sleep impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of sleep impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience sleep impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience sleep impairment.[000168] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to)cognitive impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of cognitive impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience cognitive impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience cognitive impairment.[000169] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) social satisfaction impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of social satisfaction impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience social satisfaction impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience social satisfaction impairment.[000170] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) social performance impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to amethod described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of social performance impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience social performance impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience social performance impairment. [000171] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) vision impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of vision impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience vision impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience vision impairment.[000172] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) breathing impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of breathing impairment, relative to subject not treated with such complexes. Insome embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience breathing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience breathing impairment.[000173] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) swallowing impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of swallowing impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience swallowing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience swallowing impairment.[000174] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are effective in treating (e.g., reducing, preventing, and / or increasing resistance to) hearing impairment in a subject having DM1. For example, in some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience a reduced (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of hearing impairment, relative to subject not treated with such complexes. In some embodiments, a reduced percentage (e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab)covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience hearing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience hearing impairment.[000175] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to one or more symptoms assessable by the MDHI, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to one or more symptoms assessable by the MDHI as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to one or more symptoms assessable by the MDHI.[000176] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to fatigue, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to fatigue as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to fatigue.[000177] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to GI symptoms, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to GI symptoms as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to GI symptoms.[000178] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to myotonia, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to myotonia as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to myotonia.[000179] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to upper extremity function impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to upper extremity function impairment as a DM1 symptom, relative to the percentage of a cohort ofDM1 subjects not treated with such complexes and experience no increase in resistance to upper extremity function impairment.[000180] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to impairment in the ability to perform activities, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to impairment in the ability to perform activities as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to impairment in the ability to perform activities.[000181] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to pain, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to pain as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to pain.[000182] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to communication impairment, relative to subject not treated with such complexes. In someembodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to communication impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to communication impairment.[000183] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to emotional issues, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to emotional issues as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to emotional issues.[000184] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to sleep impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to sleep impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to sleep impairment.[000185] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to cognitive impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to cognitive impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to cognitive impairment.[000186] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to social satisfaction impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to social satisfaction impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to social satisfaction impairment.[000187] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to social performance impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more)of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to social performance impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to social performance impairment.[000188] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to vision impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to vision impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to vision impairment.[000189] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to breathing impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to breathing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to breathing impairment.[000190] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience anincreased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to swallowing impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to swallowing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to swallowing impairment.[000191] In some embodiments, subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein may experience an increased (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) level of resistance to hearing impairment, relative to subject not treated with such complexes. In some embodiments, an increased percentage (e.g., increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more) of a cohort of DM1 subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein experience resistance to hearing impairment as a DM1 symptom, relative to the percentage of a cohort of DM1 subjects not treated with such complexes and experience no increase in resistance to hearing impairment.[000192] In some embodiments, whether a subject experiences one or more symptoms assessable by the MDHI (e.g., fatigue, GI symptoms, myotonia, upper extremity function impairment, mobility impairment, impairment in the ability to perform activities, pain, communication impairment, emotional issues, sleep impairment, cognitive impairment, social satisfaction impairment, social performance impairment, vision impairment, breathing impairment, swallowing impairment, and / or hearing impairment), or the level of one or more symptoms assessable by the MDHI a subject experiences is based reported by the subject (patient-reported). In some embodiments, the symptom is measured by a MDHI subscale score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score. In some embodiments, patient reported outcomes from subjects treated with complexes comprising an anti-TfRl antibody (e.g.,Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein indicate a more favorable (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more favorable) MDHI subscale score and / or INQoL score.[000193] In some embodiments, whether a subject experiences fatigue (e.g., muscle fatigue, central fatigue, and / or peripheral fatigue), or the level of fatigue a subject experiences is based reported by the subject (patient-reported). In some embodiments, fatigue is measured by a MDHI fatigue score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183— 190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) fatigue score. In some embodiments, patient reported outcomes from subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein indicate a lower (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more lower) MDHI fatigue score and / or INQoL fatigue score. [000194] In some embodiments, whether a subject experiences a GI symptom (e.g., abdominal pain, coughing while eating, dysphagia, dyspepsia, heartbum, emesis, bloating, diarrhea, constipation, dyschezia, and / or anal incontinence), or the level of GI symptom a subject experiences is based reported by the subject (patient-reported). In some embodiments, a GI symptom is measured by a MDHI GI score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score. In some embodiments, patient reported outcomes from subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein indicate a lower (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more lower) MDHI GI score.[000195] In some embodiments, whether a subject experiences myotonia or the level of myotonia a subject experiences is based reported by the subject (patient-reported). In some embodiments, myotonia is measured by a MDHI myotonia score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score. In some embodiments, patient reported outcomes from subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein according to amethod described herein indicate a lower (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more lower) MDHI myotonia score.[000196] In some embodiments, whether a subject experiences upper extremity function impairment or the level of upper extremity function impairment a subject experiences is based reported by the subject (patient-reported). In some embodiments, upper extremity function impairment is measured by a MDHI upper extremity function impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score. In some embodiments, patient reported outcomes from subjects treated with complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein according to a method described herein indicate a lower (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more lower) MDHI score indicating upper extremity function impairment.[000197] In some embodiments, whether a subject experiences mobility impairment or the level of mobility impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, mobility impairment is measured by a MDHI mobility impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183— 190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000198] In some embodiments, whether a subject experiences impairment in the ability to perform activities or the level of impairment in the ability to perform activities a subject experiences is based reported by the subject (patient-reported). In some embodiments, impairment in the ability to perform activities is measured by a MDHI impairment in the ability to perform activities score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000199] In some embodiments, whether a subject experiences pain or the level of pain a subject experiences is based reported by the subject (patient-reported). In some embodiments, pain is measured by a MDHI pain score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000200] In some embodiments, whether a subject experiences communication impairment or the level of communication impairment a subject experiences is based reported by the subject (patient-reported). In some embodiments, communication impairment is measured by a MDHI communication impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000201] In some embodiments, whether a subject experiences emotional issues or the level of emotional issues a subject experiences is based reported by the subject (patient- reported). In some embodiments, emotional issues is measured by a MDHI emotional issues score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000202] In some embodiments, whether a subject experiences sleep impairment or the level of sleep impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, sleep impairment is measured by a MDHI sleep impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000203] In some embodiments, whether a subject experiences cognitive impairment or the level of cognitive impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, cognitive impairment is measured by a MDHI cognitive impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183— 190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000204] In some embodiments, whether a subject experiences social satisfaction impairment or the level of social satisfaction impairment a subject experiences is based reported by the subject (patient-reported). In some embodiments, social satisfaction impairment is measured by a MDHI social satisfaction impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000205] In some embodiments, whether a subject experiences social performance impairment or the level of social performance impairment a subject experiences is based reported by the subject (patient-reported). In some embodiments, social performance impairment is measured by a MDHI social performance impairment score (e.g., as described in Heatwole etal., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000206] In some embodiments, whether a subject experiences vision impairment or the level of vision impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, vision impairment is measured by a MDHI vision impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000207] In some embodiments, whether a subject experiences breathing impairment or the level of breathing impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, breathing impairment is measured by a MDHI breathing impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183— 190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000208] In some embodiments, whether a subject experiences swallowing impairment or the level of swallowing impairment a subject experiences is based reported by the subject (patient-reported). In some embodiments, swallowing impairment is measured by a MDHI swallowing impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183-190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000209] In some embodiments, whether a subject experiences hearing impairment or the level of hearing impairment a subject experiences is based reported by the subject (patient- reported). In some embodiments, hearing impairment is measured by a MDHI hearing impairment score (e.g., as described in Heatwole et al., Muscle Nerve. 2016 Feb; 53(2): 183— 190, the entire contents of each of which are incorporated herein by reference) and / or an Individualized Neuromuscular Quality of Life Questionnaire (INQoL) score.[000210] In some embodiments, therapeutic effects of complexes (e.g., in treating fatigue) comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following an administration of the complexes (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer of the administration.[000211] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating one or more symptoms assessable by the MDHI) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration). In some embodiments, the therapeutic effect is measured by one or more MDHI subscale (e.g., an MDHI subscale assessing fatigue, a GI symptom, myotonia, upper extremity function impairment, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment).[000212] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating fatigue) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks or longer within each administration).[000213] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating a GI symptom, myotonia, upper extremity function impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000214] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating myotonia) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000215] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating upper extremity function impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000216] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating mobility impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000217] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating impairment in the ability to perform activities) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000218] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating pain) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000219] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating communication impairment) is measured, established, and / or reported (e.g., bya subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000220] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating emotional issues) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000221] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating sleep impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000222] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating cognitive impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000223] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating social satisfaction impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, fourweeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000224] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating social performance impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000225] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating vision impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000226] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating breathing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000227] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating swallowing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000228] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times, and therapeutic effects of the complexes (e.g., in treating hearing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) following each of the multiple administrations (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer within each administration).[000229] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating one or more symptoms assessable by the MDHI (e.g., fatigue, a GI symptom, myotonia, upper extremity function impairment, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, hearing impairment and / or a combination thereof) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti- TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating fatigue, a GI symptom, myotonia, upper extremity function impairment, mobility impairment, impairment in the ability to perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends. In some embodiments, the therapeutic effect is assessed by an MDHI subscale (e.g., an MDHI subscale assessing fatigue, a GI symptom, myotonia, upper extremity function impairment, mobility impairment, impairment in the abilityto perform activities, pain, vision impairment, communication impairment, sleep impairment, emotional issues, cognitive impairment, social satisfaction impairment, social performance impairment, breathing impairment, swallowing impairment, and / or hearing impairment).[000230] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating fatigue) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti- TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating fatigue) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000231] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating a GI symptom) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating a GI symptom) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000232] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating myotonia) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti- TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating myotonia) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000233] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating upper extremity function impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating upper extremity function impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000234] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as describedherein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating mobility impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating mobility impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000235] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating impairment in the ability to perform activities) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating impairment in the ability to perform activities) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000236] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), andtherapeutic effects of the complexes (e.g., in treating pain) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti- TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating pain) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000237] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating communication impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating communication impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000238] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating emotional issues) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, twoweeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating emotional issues) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000239] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating sleep impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating sleep impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000240] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating cognitive impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecularpay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating cognitive impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000241] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating social satisfaction impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating social satisfaction impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000242] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating social performance impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeuticeffects of the complexes (e.g., in treating social performance impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000243] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating sleep impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating sleep impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000244] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating vision impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating vision impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment)within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000245] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating breathing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating breathing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000246] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating swallowing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating swallowing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000247] In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular payload (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration (e.g., a period of 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks, or longer), and therapeutic effects of the complexes (e.g., in treating hearing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) after the end of the period of administration (e.g., within one day, one week, two weeks, three weeks, four weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 48 weeks or longer after the end of the period of administration). In some embodiments, complexes comprising an anti-TfRl antibody (e.g., Fab) covalently linked to a molecular pay load (e.g., a DMPK-targeting oligonucleotide) as described herein are administered to a subject multiple times over a period of administration of 24 weeks or 48 weeks, and therapeutic effects of the complexes (e.g., in treating hearing impairment) is measured, established, and / or reported (e.g., by a subject receiving the treatment or a physician administering the treatment) within one day after the end of administration. In some embodiments, additional administration of the complexes may occur after the period of administration ends.[000248] In some embodiments, a subject may be a human subject. In some embodiments, the subject is a neonatal or 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 between 18 and 50 (e.g., 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 human subject 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). In some embodiments, the subject is a human subject that is between 5 and 12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) years old. In some embodiments, the subject is a human subject that is 4-16 (e.g., 4-16, 5-16, 6-16, 7-16, 8-16, 9-16, 10-16, 11-16, 12-16, 13- 16, 14-16, 15-16, 4-15, 5-15, 6-15, 7-15, 8-15, 9-15, 10-15, 11-15, 12-15, 13-15, 14-15, 4-14, 5- 14, 6-14, 7-14, 8-14, 9-14, 10-14, 11-14, 12-14, 13-14, 4-13, 5-13, 6-13, 7-13, 8-13, 9-13, 10-13, 11-13, 12-13, 4-12, 5-12, 6-12, 7-12, 8-12, 9-12, 10-12, 11-12, 4-11, 5-11, 6-11, 7-11, 8-11, 9-16, 10-11, 4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 4-9, 5-9, 6-9, 7-9, 8-9, 4-9, 5-9, 6-9, 7-9, 8-9, 4-8, 5-8, 6-8, 7-8, 4-7, 5-7, 6-7, 4-6, 5-6, or 4-5) years old. In some embodiments, the subject is a human subject that is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 years old. In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have one or more symptoms assessable by the MDHI as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have fatigue as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have a GI symptom as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have myotonia as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have upper extremity function impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have mobility impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have impairment in ability to do activities as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have pain as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have vision impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have communication impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have sleep impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have emotional issues as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have cognitive impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have social satisfaction impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, asubject is a human subject having DM1, and has reported (e.g., patient reported) to have social performance impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have breathing impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have swallowing impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI). In some embodiments, a subject is a human subject having DM1, and has reported (e.g., patient reported) to have hearing impairment as a symptom according to the Myotonic Dystrophy Health Index (MDHI).[000249] In some embodiments, a subject has myotonic dystrophy, such as DM1. In some embodiments, a subject has a DMPK allele, which may optionally contain a disease-associated repeat, e.g., a CTG trinucleotide repeat expansion. In some embodiments, a subject may have a DMPK allele with an expanded disease-associated-repeat that comprises about 2-10 repeat units, about 2-50 repeat units, about 2-100 repeat units, about 50-1,000 repeat units, about 50-500 repeat units, about 50-250 repeat units, about 50-100 repeat units, about 500-10,000 repeat units, about 500-5,000 repeat units, about 500-2,500 repeat units, about 500-1,000 repeat units, or about 1,000-10,000 repeat units. In some embodiments, a subject is suffering from symptoms of DM1, e.g., muscle atrophy, muscle loss, excessive daytime sleepiness or cognitive delay. In some embodiments, a subject is not suffering from symptoms of DM1. In some embodiments, subjects have congenital myotonic dystrophy. In some embodiments, a subject is ambulant. In some embodiments, a subject is non-ambulant.[000250] An aspect of the disclosure includes methods involving treating one or more symptoms assessable by the MDHI in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating fatigue in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating a GI symptom in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating myotonia in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating upper extremity function impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition(e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating mobility impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating impairment in the ability to do activities in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating pain in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating vision impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating communication impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating sleep impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating emotional issues in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating social satisfaction impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating social performance impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating breathing impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating swallowing impairment in a subject having DM1, the methods comprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. An aspect of the disclosure includes methods involving treating hearing impairment in a subject having DM1, the methodscomprising administering to the subject an effective amount of a composition (e.g., aqueous solution) comprising complexes as described herein. In some embodiments, an effective amount of a composition (e.g., aqueous solution) that comprises complexes comprising an anti-TfRl antibody (e.g., Fab) described herein covalently linked to an oligonucleotide (e.g., a DMPK- targeting 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 comprising complexes 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, 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).[000251] In some embodiments, a composition comprising a plurality of complexes described herein 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).[000252] In some embodiments, provided are methods of and / or uses for treating one or more symptoms assessable by the MDHI in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), comprising administering to the subject a composition comprising a complex or plurality of complexes described herein with an effective amount of the complexes. In some embodiments, provided are methods of and / or uses for reducing one or more symptoms assessable by the MDHI in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), the methods comprising contacting cells (e.g., muscle cells, CNS cells, and / or cells of the blood brain barrier) of the subject with the composition comprising a plurality of complexes described herein with an effective amount of the complex(es).In some embodiments, provided are methods of and / or uses for treating fatigue in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), comprising administering to the subject a composition comprising a complex or plurality of complexes described herein with an effective amount of the complexes. In some embodiments, provided are methods of and / or uses for reducing fatigue in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), the methods comprising contacting cells (e.g., muscle cells, CNS cells, and / or cells of the blood brain barrier) of the subject with the composition comprising a plurality ofcomplexes described herein with an effective amount of the complex(es). In some embodiments, provided are methods of and / or uses for treating a GI symptom, myotonia, and / or upper extremity function impairment in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), comprising administering to the subject a composition comprising a complex or plurality of complexes described herein with an effective amount of the complexes. In some embodiments, provided are methods of and / or uses for reducing a GI symptom, myotonia, and / or upper extremity function impairment in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1), the methods comprising contacting cells (e.g., muscle cells, CNS cells, and / or cells of the blood brain barrier) of the subject with the composition comprising a plurality of complexes described herein with an effective amount of the complex(es). In some embodiments, the method comprises administering a lyophilized form (e.g., lyophilized powder) of a composition comprising a plurality of complexes described herein, comprising reconstituting a lyophilized form of the composition in an aqueous solution, and administering the aqueous solution to a subject in need thereof. For example, in some embodiments, a lyophilized form of the composition comprising a complex or plurality of complexes is shipped and / or stored in the lyophilized form, reconstituted in an aqueous solution at a location (e.g., healthcare provider location) for administration, and administered in the reconstituted form (e.g., as an aqueous solution) by injection or intravenously, e.g., by infusion. In some embodiments, the subject has a DMPK allele, which may optionally contain a disease-associated repeat, e.g., a CTG trinucleotide repeat expansion. [000253] In some embodiments, a composition is administered via site-specific 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. [000254] In some embodiments, methods provided herein for treating a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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 determiningregion 3 (CDR-L3) comprising a sequence as set forth in SEQ ID NOs: 6 or 16, wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21), optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage; further 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. In some embodiments, the administering results in improvements in a subject. In some embodiments, the improvements in one or more symptoms assessable by the MDHI in a subject. In some embodiments, the administering results in overall improvements in symptoms provided in the MDHI. In some embodiments, the administration results in overall improvements in symptoms provided in the MDHI in the subject as reported by the subject following a period of administration. In some embodiments, the administration results in overall improvements in symptoms provided in the MDHI in the subject following a period of administration of 24 weeks or 48 weeks.[000255] In some embodiments, methods provided herein for treating fatigue in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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 IDNOs: 6 or 16, wherein the oligonucleotide comprises a nucleobase sequence ofCAGCGCCCACCAGUCA (SEQ ID NO: 21), optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage; further 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. In some embodiments, the administering reduces fatigue in the subject, optionally wherein the administration reduces fatigue in the subject as reported by the subject following a period of administration. In some embodiments, the administration reduces fatigue in the subject following a period of administration of 24 weeks or 48 weeks. In some embodiments, the fatigue is muscle fatigue, optionally skeletal muscle fatigue. In some embodiments, the fatigue is associated with central fatigue, peripheral fatigue, or combinations thereof.[000256] In some embodiments, methods provided herein for treating a GI symptom in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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 comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21),optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage; further 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. In some embodiments, the administering reduces a GI symptom in the subject, optionally wherein the administration reduces a GI symptom in the subject as reported by the subject following a period of administration. In some embodiments, the administration reduces a GI symptom in the subject following a period of administration of 24 weeks or 48 weeks. In some embodiments, the GI symptom is abdominal pain, coughing while eating, dysphagia, dyspepsia, heartburn, emesis, bloating, diarrhea, constipation, dyschezia, anal incontinence, and / or a combination thereof.[000257] In some embodiments, methods provided herein for treating myotonia in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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 comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21), optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein+N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage; further 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. In some embodiments, the administering reduces myotonia in the subject, optionally wherein the administration reduces myotonia in the subject as reported by the subject following a period of administration. In some embodiments, the administration reduces myotonia in the subject following a period of administration of 24 weeks or 48 weeks. [000258] In some embodiments, methods provided herein for treating upper extremity function impairment in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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- 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, 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 comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21), optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage;further 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. In some embodiments, the administering reduces upper extremity function impairment in the subject, optionally wherein the administration reduces upper extremity function impairment in the subject as reported by the subject following a period of administration. In some embodiments, the administration reduces upper extremity function impairment in the subject following a period of administration of 24 weeks or 48 weeks [000259] In some embodiments, methods provided herein for treating mobility impairment in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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 comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21), optionally wherein the oligonucleotide comprises a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage; further 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 sequenceof SEQ ID NO: 20. In some embodiments, the administering reduces mobility impairment in the subject, optionally wherein the administration reduces mobility impairment in the subject as reported by the subject following a period of administration. In some embodiments, the administration reduces mobility impairment in the subject following a period of administration of 24 weeks or 48 weeks.[000260] In some embodiments, methods provided herein for treating impairment in the ability to perform activities in a subject having DM1 and / or having a DMPK allele associated with myotonic dystrophy (e.g., DM1) 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- 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, 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...

Claims

CLAIMSWhat is claimed is:

1. A method of treating fatigue in a subject having myotonic dystrophy, 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, 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 oligonucleotides of the complexes comprise the nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21).

2. A method of alleviating myotonic dystrophy type 1 (DM1) disease burden and / or symptoms in a subject as indicated by a Myotonic Dystrophy Health Index (MDHI), 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, 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 oligonucleotides of the complexes comprise the nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21).

3. The method of claim 2, wherein the administering results in improvement of one or more subscales of a Myotonic Dystrophy Health Index (MDHI) selected from: mobility, upper extremity function, ability to do activities, fatigue, pain, gastrointestinal issues, vision, communication, sleep, emotional issues, cognitive impairment, social satisfaction, myotonia, breathing, swallowing, and hearing, optionally wherein the one or more subscales are patient- reported.

4. The method of any one of claims 1-3, wherein the oligonucleotides of the complexes comprise a 5’-X-Y-Z-3’ configuration, wherein X and Z are flanking regions comprising one or more modified nucleosides and Y is a gap region comprising one or more 2’- deoxyribonucleosides.

5. The method of any one of claims 1-4, wherein 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, in which R3comprises an oligonucleotide comprising a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21) and comprising a structure of +C*+A*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*oG*oU*+C*+A (SEQ ID NO: 21), wherein +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage;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 pointA 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. The method of any one of claims 1-4, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein: each R1comprises a group of the formula (lb):(lb), or a pharmaceutically acceptable salt thereof, in which +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage, and the oligonucleotide of R1comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21);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.

7. The method of any one of claims 1-4, wherein each complex comprises a structure of formula (I): [R^ni-R2, wherein: each R1comprises a group of the formula (Ic):(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.

8. The method of any one of claims 1-4, wherein each complex comprises a structure of the formula (Id):(Id), or a pharmaceutically acceptable salt thereof, in which +N represents an LNA (2’ -4’ methylene bridge) ribonucleoside, dN represents a 2’- deoxyribonucleoside, oN represents a 2’ -MOE modified ribonucleoside, oC represents a 5- methyl-2’-MOE-cytidine, +C represents a 5-methyl-2’-4’-bicyclic-cytidine (2’-4’ methylene bridge), oU represents a 5-methyl-2’-MOE-uridine, and * represents a phosphorothioate intemucleoside linkage, and wherein the oligonucleotide comprises a nucleobase sequence of CAGCGCCCACCAGUCA (SEQ ID NO: 21);R2comprises the anti-TfRl antibody; and in each complex, nl is independently an integer of 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 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.

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

10. The method of any one of claims 1-9, 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.

11. The method of any one of claims 5-10, wherein the average value of nl of the complexes of the composition is in the range of 0.7-1.5, optionally wherein the average value of nl of the complexes of the composition is 1, 1.1, or 1.15.

12. The method of any one of claims 1-11, wherein the effective amount provides to the subject 5 mg to 110 mg of the anti-TfRl antibody of the complexes per kg of the subject.

13. The method of claim 12, wherein the effective amount of each administration provides to the subject:(a) 10 mg to 110 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(b) 5 mg to 90 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(c) 10 mg to 20 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 13 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(d) 18 mg to 36 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 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(e) 30 mg to 58 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 40 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(f) 36 mg to 72 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 50 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(g) 55 mg to 110 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 75 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(h) 6 mg to 12 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 8 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(i) 11 mg to 22 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 15 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(j) 22 mg to 44 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 30 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(k) 44 mg to 88 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 60 mg of the anti-TfRl antibodies of the complexes per kg of the subject;(l) 20 mg to 43 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) 26 mg to 53 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 37 mg of the anti-TfRl antibodies of the complexes per kg of the subject.

14. The method of any one of claims 1-12, wherein the effective amount of each administration provides to the subject 13 mg, 25 mg, 40 mg, 50 mg, or 75 mg of the anti-TfRl antibodies of the complexes per kg of the subject or wherein the effective amount of each administration provides to the subject 1.8 mg, 3.4 mg, 5.4 mg, 6.8 mg, or 10.2 mg of the oligonucleotides of the complexes per kg of the subject.

15. The method of any one of claims 1-14, wherein during a period of administration, the composition is administered once every 4 weeks, once every 8 weeks, or once every 12 weeks, optionally wherein the period of administration is less than 10 years or is the remainder of the subject’s lifetime.

16. The method of any one of claims 1-14, 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, optionally wherein the first period of administration is 8-16 weeks, and / or wherein the second period of administration is 16 weeks to the remainder of the subject’s lifetime.

17. The method of any one of claims 1-16, wherein the composition is in the form of an aqueous solution and further comprises tris(hydroxymethyl)aminomethane and sucrose, optionally 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 10 w / v%, and the aqueous solution is at a pH of 7.5.

18. The method of claim 17, wherein the complexes are present in the composition at a concentration in the range of 10 mg / mL to 50 mg / mL.

19. The method of any one of claims 1-18, wherein(i) the administering reduces fatigue in the subject, optionally wherein the administering reduces fatigue in the subject as reported by the subject following a period of administration, further optionally wherein the fatigue is muscle fatigue, central fatigue, peripheral fatigue, or combinations thereof;(ii) the administering reduces a GI symptom in the subject, optionally wherein the administering reduces a GI symptom in the subject as reported by the subject following a period of administration, further optionally wherein the GI symptom is abdominal pain, coughing while eating, dysphagia, dyspepsia, heartburn, emesis, bloating, diarrhea, constipation, dyschezia, anal incontinence, and / or a combination thereof;(iii) the administering reduces myotonia in the subject, optionally wherein the administering reduces myotonia in the subject as reported by the subject following a period of administration;(iv) the administering reduces upper extremity function impairment in the subject, optionally wherein the administering reduces upper extremity function impairment in the subject as reported by the subject following a period of administration;(v) the administering reduces mobility impairment in the subject, optionally wherein the administering reduces mobility impairment in the subject as reported by the subject following a period of administration;(vii) the administering reduces pain in the subject, optionally wherein the administering reduces pain in the subject as reported by the subject following a period of administration;(viii) reduces communication impairment in the subject, optionally wherein the administering reduces communication impairment in the subject as reported by the subject following a period of administration;(ix) the administering reduces emotional issues in the subject, optionally wherein the administering reduces emotional issues in the subject as reported by the subject following a period of administration;(x) the administering reduces sleep impairment in the subject, optionally wherein the administering reduces sleep impairment in the subject as reported by the subject following a period of administration;(xi) the administering reduces cognitive impairment in the subject, optionally wherein the administering reduces cognitive impairment in the subject as reported by the subject following a period of administration;(xii) the administering reduces social satisfaction impairment in the subject, optionally wherein the administering reduces social satisfaction impairment in the subject as reported by the subject following a period of administration;(xiii) the administering reduces social performance impairment in the subject, optionally wherein the administering reduces social performance impairment in the subject as reported by the subject following a period of administration;(xiv) the administering reduces vision impairment in the subject, optionally wherein the administering reduces vision impairment in the subject as reported by the subject following a period of administration;(xv) the administering reduces breathing impairment in the subject, optionally wherein the administering reduces breathing impairment in the subject as reported by the subject following a period of administration;(xvi) the administering reduces swallowing impairment in the subject, optionally wherein the administering reduces swallowing impairment in the subject as reported by the subject following a period of administration; and / or(xvii) the administering reduces hearing impairment in the subject, optionally wherein the administering reduces hearing impairment in the subject as reported by the subject following a period of administration.

20. The method of claim 19, wherein the period of administration is 24 weeks or 48 weeks.

21. The method of any one of claims 1-20, wherein the subject is human.

22. The method of any one of claims 1-21, wherein the complex is administered systemically, optionally wherein the complex is administered intravenously, further optionally wherein the complex is administered by infusion.

23. The method of any one of claims 1-22, wherein the composition further comprises one or more anti-TfRl antibodies that are not covalently linked to an oligonucleotide.

24. The method of any one of claims 1-23, wherein the heavy chain of the antibody comprises an N-terminal pyroglutamate.

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