Complexes and uses thereof for treating pompe disease

Abstract

Aspects of the disclosure relate to complexes comprising an anti-TfR1 antibody covalently linked (e.g., via a linker such as a peptide linker) to a lysosomal enzyme (e.g., an acid alpha glucosidase enzyme), and methods of making and using the fusion complexes to treat a lysosomal storage disease (e.g., Pompe disease).

Description

COMPLEXES AND USES THEREOF FOR TREATING POMPE DISEASERELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 662,632 filed June 21, 2024, entitled “COMPLEXES AND USE THEREOF FOR TREATING POMPE DISEASE,”; and U.S. Provisional Patent Application No. 63 / 752,103 filed January 31, 2025, entitled “COMPLEXES AND USES THEREOF FOR TREATING POMPE DISEASE,” the entire contents of which are herein incorporated by reference.FIELD OF THE INVENTION

[0002] The present application relates to complexes for delivering molecular payloads (e.g., enzymes such as lysosomal enzymes) to cells and uses thereof, particularly uses relating to treatment of disease.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (D082470089WO00-SEQ- CBD.xml; Size: 231,598 bytes; and Date of Creation: June 10, 2025) is herein incorporated by reference in its entirety.BACKGROUND

[0004] Lysosomal storage diseases are a group of inherited diseases caused by deficiencies in lysosomal hydrolases or transmembrane proteins. These diseases are often characterized by the progressive accumulation of various undigested substrates and a dysregulation of cellular trafficking pathways.

[0005] Pompe disease (PD) is an autosomal recessive lysosomal storage disease characterized by the build-up of glycogen in muscle cells, which leads to progressive muscle weakness, reduced muscle tone (hypotonia), cardiac enlargement (e.g., cardiomyopathy, cardiomegaly), cardiac failure, and difficulty breathing. Glycogen build-up also occurs in the central nervous system (CNS) and leads to behavioral and cognitive deficits. Pompe disease results from mutations in the GAA gene which encodes the enzyme acid alpha glucosidase (GAA). Symptoms are often present at birth in severe cases, although onset may occur throughout life. Pompe disease affects approximately 1 in 40,000 people in the United States. Current standard of care (SOC) treatment for Pompe disease is enzyme replacement therapy involving administration of recombinant, human GAA protein (rhGAA). However, althoughrhGAA increases survival, efficacy of rhGAA replacement therapy in skeletal muscle and the CNS manifestations is insufficient and continued glycogen accumulation in the CNS of Pompe patients remains unaddressed by the SOC.SUMMARY

[0006] According to some aspects, the present disclosure provides complexes comprising a targeting agent covalently linked to an enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)), compositions comprising such complexes, and methods of their use. In some embodiments, a targeting agent of the complexes described herein effectively delivers the enzyme into the central nervous system (CNS) and / or muscle, or across the blood brain barrier (BBB) of a subject. In some embodiments, a targeting agent of the complexes described herein comprises an anti-transferrin receptor 1 (TfRl) antibody that is demonstrated to be able to transport the enzyme across the blood-brain barrier (e.g., via receptor mediated transcytosis), resulting in delivery of the molecular payloads to cells of the CNS, and to be able to deliver the enzyme into muscle (e.g., via receptor mediated endocytosis or transcytosis). In some embodiments, the anti-TfRl antibody of the complexes described herein is a Fab comprising a heavy chain and a light chain. In some embodiments, in a complex described herein, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) is covalently linked at the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., anti-TfRl Fab). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein breaks down glycogen in the CNS and / or muscle, thereby treating a lysosomal storage disease (e.g., Pompe disease). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein reduces and / or normalizes lysosome size in the CNS and / or muscle, thereby treating a lysosomal storage disease by preventing lysosomal rupturing (e.g., Pompe disease). In some embodiments, a subject having a lysosomal storage disease (e.g., Pompe disease) has at least one mutant GAA allele that leads to functional impairment of GAA and accumulation of glycogen in lysosomes of cells of the subject.

[0007] The present disclosure, in some aspects, provides complexes comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor type 1 (TfRl) antibody covalently linked at the C-terminus to a lysosomal enzyme, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variableregion (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDR-H3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2.

[0008] In some embodiments, the lysosomal enzyme is an acid alpha-glucosidase (GAA).

[0009] In some embodiments, the GAA comprises the amino acid sequence of any one of SEQ ID NOs: 161-170.

[0010] In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme.

[0011] In some embodiments, the complex comprises a single lysosomal enzyme (e.g., GAA), i.e., DAR of 1.

[0012] In some aspects, the present disclosure provides complexes comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked to an acid alpha-glucosidase (GAA) comprising the amino acid sequence of any one of SEQ ID NOs: 161-170, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDR- H3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2.

[0013] In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the GAA.

[0014] In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the GAA.

[0015] In some embodiments, the VH and the VL are selected from any of the anti- TfRl antibodies listed in Table 3.

[0016] In some embodiments, the anti-TfRl antibody is a Fab, optionally wherein the heavy chain of the anti-TfRl antibody and the light chain of the anti-TfRl antibody are selected from any one of the anti-TfRl Fabs listed in Table 5.

[0017] In some embodiments, (i) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 27, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 28, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 29, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the CDR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and a CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32; (ii) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 33, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 34, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 35, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 36, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32; or (iii) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 38, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 39, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 40, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 41, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 42.

[0018] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 76 and the VL comprises the amino acid sequence of SEQ ID NO: 75.

[0019] In some embodiments, the anti-TfRl antibody is a Fab, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90.

[0020] In some embodiments, the first polypeptide comprises an N-terminal pyroglutamate.

[0021]

[0022] In some embodiments, the first polypeptide and / or the second polypeptide further comprises a signal peptide at the N-terminus.

[0023] In some embodiments, the GAA is not glycosylated.

[0024] In some embodiments, the GAA is glycosylated.

[0025] In some embodiments, the GAA comprises one or more glycans selected from O-linked glycans, N-linked glycans, or combinations thereof, optionally wherein the GAA comprises 1-20 glycans.

[0026] In some embodiments, the one or more glycans are linked to one or more amino acids of the GAA selected from amino acids corresponding to N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161, and combinations thereof.

[0027] In some embodiments, each glycan comprises a mannose, a glucose, an N- acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, or combinations thereof.

[0028] In some embodiments, the GAA is covalently linked to the anti-TfRl antibody via a linker, optionally wherein the linker is a peptide linker.

[0029] In some embodiments, the linker comprises the amino acid sequence of (GGGGS)n (SEQ ID NO: 106), (EAAAK)n (SEQ ID NO: 130), or PAPAP (SEQ ID NO: 131), wherein n is an integer of 1-10, optionally wherein n=3.

[0030] In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NOs: 171, 173, 175, 177, 179, 181, 184-193, 195, or 101, and the second polypeptide comprises the amino acid sequence of SEQ ID NOs: 90, 172, 174, 176, 178, 180, 182, 183, 194, or 196.

[0031] In some embodiments, in a complex described herein:(a) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(b) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 171 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(c) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 171 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 172;(d) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 173 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(e) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 173 and the second polypeptide comprises the amino acid sequence of SEQ ID NO; 174;(f) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 175 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(g) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 175 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 176;(h) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 177 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 177 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 178;(j) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(k) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 180;(l) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 184 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(m) the first polypeptide comprises the amino acid sequence of SEQ ID NO:185 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 186 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(o) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 187 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(p) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 188 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(q) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 189 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(r) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 190 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(s) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 191 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(t) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 192 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(u) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 193 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90;(v) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 101 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 194;(w) the first polypeptide comprises the amino acid sequence of SEQ ID NO:195 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90; or(x) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 101 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 196.

[0032] In some embodiments, in a complex described herein, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179 and the second polypeptide comprises the amino acid sequence of SEQ ID NOL 90.

[0033] In some embodiments, in a complex described herein, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 171 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90.

[0034] Other aspects of the present disclosure provide compositions comprising complexes described herein.

[0035] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0036] In some embodiments, the GAA or the complexes of the composition are not glycosylated, glycosylated, or combinations thereof.

[0037] Nucleic acid or a set of nucleic acids encoding any one of the complexes described herein are also provided. Also provided are vectors or a set of vectors comprising the nucleic acid or the set of nucleic acids described herein.

[0038] Cells comprising the nucleic acid or the set of nucleic acids described herein, or the vector or the set of vectors described herein are also provided. In some embodiments, a cell comprises a nucleic acid or a set of nucleic acids encoding a first polypeptide and a second polypeptide described herein, wherein the first polypeptide and / or (e.g., and) the second polypeptide comprise a signal peptide (e.g., N-terminal signal peptide). In some embodiments, the signal peptide comprises the amino acid sequence of MGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, the signal peptide comprises the amino acid sequence of MRVPAQLLGLLLLWLPGARC (SEQ ID NO: 211). In some embodiments, the first polypeptide comprises an N-terminal signal peptide, wherein the signal peptide comprises the amino acid sequence MGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, the second polypeptide comprises an N-terminal signal peptide, wherein the signal peptide comprises the amino acid sequence MRVPAQLLGLLLLWLPGARC (SEQ ID NO: 211). Other aspects of the present disclosure provide methods of producing the complexes described herein, comprising culturing the cell described herein under conditions suitable for the expression of the complex.

[0039] In some embodiments, the method further comprises isolating the complex.

[0040] Further provided herein are methods of delivering a lysosomal enzyme to a cell, comprising contacting any one of the complexes or compositions described herein with the cell.

[0041] In some embodiments, the cell is a muscle cell.

[0042] In some embodiments, the cell is a cell of the nervous system.

[0043] In some embodiments, the nervous system is central nervous system (CNS) or peripheral nervous system (PNS).

[0044] In some embodiments, the cell is a cell of the blood brain barrier.

[0045] In some embodiments, the cell is in vitro.

[0046] In some embodiments, the cell is in a subject.

[0047] In some embodiments, the subject is human.

[0048] Further provided herein are methods of delivering a lysosomal enzyme to a subject, comprising administering any one of the complexes or compositions described herein to the subject.

[0049] In some embodiments, the lysosomal enzyme is delivered to the muscle and / or the central nervous system of the subject. In some embodiments, the lysosomal enzyme is delivered to skeletal muscle and / or cardiac muscle of the subject.

[0050] In some embodiments, the subject has a lysosomal storage disease.

[0051] Also provided herein are methods of treating a lysosomal storage disease in a subject, comprising administering any one of the complexes or compositions described herein to the subject.

[0052] In some embodiments, the lysosomal enzyme is GAA.

[0053] In some embodiments, the lysosomal storage disease is Pompe disease.

[0054] In some embodiments, the subject is human.

[0055] In some embodiments, the complex is administered via intravenous injection or intravenous infusion.

[0056] In some embodiments, the complex is administered once every two weeks, once every four weeks, or once every eight weeks.

[0057] In some embodiments, the complex reduces glycogen level in the subject. In some embodiments, the complex reduces glycogen level in muscle and / or CNS of the subject.

[0058] In some embodiments, wherein the complex reduces and / or normalizes lysosome size in the subject. In some embodiments, the complex reduces and / or normalizes lysosome size muscle and / or CNS cells of the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG. 1 shows the acid alpha-glucosidase (GAA) activities of complexes described herein by measuring the conversion of 4-Methylumbelliferyl-P-D-Glucopyranoside(4-MU-Glu) to 4-Methylumbelliferone (4-MU). Activities of Complex 1, Complex 3, Complex 5, Complex 9, Complex 13, Complex 21, Complex 22, Complex 23, Complex 24, or Complex 25 relative to recombinant human GAA (naked GAA) are shown. The numbering of the tested complexes corresponds to those in Table 9.

[0060] FIGS. 2A-2C show GAA enzyme activity in the heart (FIG. 2A), tibialis anterior (FIG. 2B), and quadriceps (FIG. 2C) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0061] FIGS. 3A-3C show glycogen levels in the heart (FIG. 3A), tibialis anterior (FIG. 3B), and quadriceps (FIG. 3C) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0062] FIG. 4 shows lysosomal staining in muscle (heart and tibialis anterior (i.e., TA)) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heart and tibialis anterior tissues were harvested and stained with LAMP1 (lysosomes) and DAPI (nuclei). The numbering of the tested complexes corresponds to those in Table 9.

[0063] FIGS. 5A-5C show GAA enzyme activity in the cerebral cortex (FIG. 5A), cerebellum (FIG. 5B), and spinal cord (FIG. 5C) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0064] FIGS. 6A-6C show glycogen levels in the cerebral cortex (FIG. 6A), cerebellum (FIG. 6B), and spinal cord (FIG. 6C) after Q1W administration of Complex 1,Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0065] FIG. 7 shows the reduced lysosomal enlargement in the central nervous system (CNS) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Brains were harvested and brain sections were stained with LAMP1 (lysosomes). The numbering of the tested complexes corresponds to those in Table 9. “Ctx” stands for cerebral cortex and “Cb” stands for cerebellum.

[0066] FIGS. 8A-8B show glycogen in the cerebral cortex and cerebellum (FIG. 8A) and corpus callosum, hippocampus, brain stem, and spinal cord (FIG. 8B) after Q1W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg. Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. Brain tissues were harvested and labeled with hematoxylin-eosin (H&E) stain and periodic acid Schiff (PAS) stain. The numbering of the tested complexes corresponds to those in Table 9.

[0067] FIGS. 9A-9D show GAA enzyme activity in the heart (FIG. 9A), tibialis anterior (FIG. 9B), diaphragm (FIG. 9C), and quadriceps (FIG. 9D) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0068] FIGS. 10A-10D show glycogen levels in the heart (FIG. 10A), tibialis anterior (FIG. 10B), diaphragm (FIG. 10C), and quadriceps (FIG. 10D) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, andnaked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0069] FIGS. 11A-11D show GAA protein in the heart (FIG. 11A), tibialis anterior (FIG. 11B), diaphragm (FIG. 11C), and quadriceps (FIG. 11D) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0070] FIGS. 12A-12B show GAA enzyme activity in the cerebral cortex (FIG. 12A) and cerebellum (FIG. 12B) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0071] FIGS. 13A-13C show glycogen levels in the cerebral cortex (FIG. 13A), cerebellum (FIG. 13B), and spinal cord (FIG. 13C) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0072] FIGS. 14A-14B show GAA protein in the cerebral cortex (FIG. 14A) and cerebellum (FIG. 14B) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg.Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0073] FIGS. 15A-15B show glycogen in the hippocampus / corpus callosum (FIG.15A) and the cerebral cortex and cerebellum (FIG. 15B) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of fourdoses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls.Brain tissues were harvested and labeled with PAS stain and fast green stain. The numbering of the tested complexes corresponds to those in Table 9.

[0074] FIG. 16 shows the lysosomal staining in the central nervous system (CNS) after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg. CNS tissues were harvested and stained with LAMP1 (lysosomes). The numbering of the tested complexes corresponds to those in Table 9. “Ctx” stands for cerebral cortex and “Cb” stands for cerebellum.

[0075] FIG. 17 shows reduced neurofilament light-chain (Nf-L) levels in serum after Q2W administration of Complex 1, Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1, Complex 9, and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg or 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0076] FIGS. 18A-18E show GAA enzyme activity in the heart (FIG. 18A), tibialis anterior (FIG. 18B), quadriceps (FIG. 18C), gastrocnemius (FIG. 18D), and diaphragm (FIG. 18E) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0077] FIGS. 19A-19F show glycogen levels in the heart (FIG. 19A), tibialis anterior (FIG. 19B), quadriceps (FIG. 19C), soleus (FIG. 19D), diaphragm (FIG. 19E), and gastrocnemius (FIG. 19F) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex land Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0078] FIGS. 20A-20C show GAA protein in the heart (FIG. 20A), quadriceps (FIG. 20B), and tibialis anterior (FIG. 20C) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0079] FIGS. 21A-21C show GAA enzyme activity in the cerebral cortex (FIG. 21A), cerebellum (FIG. 21B), and spinal cord (FIG. 21C) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0080] FIGS. 22A-22C show glycogen in the cerebral cortex (FIG. 22A), cerebellum (FIG. 22B), and spinal cord (FIG. 22C) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0081] FIGS. 23A-23B show GAA protein in the cerebral cortex (FIG. 23A) and cerebellum (FIG. 23B) after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0082] FIG. 24 shows neurofilament light-chain (Nf-L) levels in serum after Q2W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0083] FIGS. 25A-25E show GAA enzyme activity in the heart (FIG. 25A), tibialis anterior (FIG. 25B), quadriceps (FIG. 25C), gastrocnemius (FIG. 25D), and diaphragm (FIG. 25E) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0084] FIGS. 26A-FIG. 26F show glycogen levels in the heart (FIG. 26A), tibialis anterior (FIG. 26B), quadriceps (FIG. 26C), soleus (FIG. 26D), diaphragm (FIG. 26E), and gastrocnemius (FIG. 26F) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0085] FIGS. 27A-27C show GAA protein in the heart (FIG. 27A), quadriceps (FIG. 27B), and tibialis anterior (FIG. 27C) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex land Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0086] FIG. 28 shows glycogen in the heart and quadriceps after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex land Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Brain tissues were harvested and labeled with PAS stain and fast green stain. The numbering of the tested complexes corresponds to those in Table 9.

[0087] FIG. 29 shows lysosomal staining in the heart and quadriceps after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Heart andquadriceps were harvested and stained with LAMP1 (lysosomes) and Laminin. The numbering of the tested complexes corresponds to those in Table 9.

[0088] FIGS. 30A-30C show GAA enzyme activity in the cerebral cortex (FIG. 30A), cerebellum (FIG. 30B), and spinal cord (FIG. 30C) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0089] FIGS. 31A-31C show glycogen levels in the cerebral cortex (FIG. 31A), cerebellum (FIG. 31B), and spinal cord (FIG. 31C) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex land Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0090] FIGS. 32A-32B show GAA protein in the cerebral cortex (FIG. 32A) and cerebellum (FIG. 32B) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex land Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0091] FIG. 33 shows glycogen in the cerebral cortex and cerebellum after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Brain tissues were harvested and labeled with PAS stain and fast green stain. The numbering of the tested complexes corresponds to those in Table 9.

[0092] FIG. 34 shows lysosomal enlargement in the cerebral cortex (Ctx) and cerebellum (Cb) after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated withvehicle controls. Brains were harvested and brain sections were stained with LAMP1 (lysosomes). The numbering of the tested complexes corresponds to those in Table 9.

[0093] FIG. 35 shows neurofilament light-chain (Nf-L) levels in serum after Q4W administration of Complex 1, Complex 9, or vehicle to homozygous hTfRl / 6Neomice using a total of two doses. Vehicle was included as a control. Complex 1 and Complex 9 were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complexes corresponds to those in Table 9.

[0094] FIGS. 36A-36E show GAA enzyme activity in the heart (FIG. 36A), diaphragm (FIG. 36B), quadriceps (FIG. 36C), tibialis anterior (FIG. 36D) and gastrocnemius (FIG. 36E) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to those in Table 9.

[0095] FIGS. 37A-37B show GAA protein in the heart (FIG. 37A) and quadriceps (FIG. 37B) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to the numbering in Table 9.

[0096] FIGS. 38A-38E show glycogen levels in the heart (FIG. 38A), diaphragm (FIG. 38B), quadriceps (FIG. 38C), tibialis anterior (FIG. 38D) and soleus (FIG. 38E) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to those in Table 9.

[0097] FIG. 39 shows glycogen in the heart and quadriceps after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5mg / kg inheart and 20 mg / kg in quadriceps. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Heart and quadricep tissues were harvested and labeled with PAS stain and fast green stain. The numbering of the tested complex corresponds to the numbering in Table 9.

[0098] FIG. 40 shows lysosomal staining in the heart and quadriceps after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Heart and quadriceps were harvested, and tissue sections were stained with LAMP1 (lysosomes). The numbering of the tested complex corresponds to the numbering in Table 9.

[0099] FIGS. 41A-41C show GAA enzyme activity in the cerebral cortex (FIG. 41A), cerebellum (FIG. 41B), and spinal cord (FIG. 41C) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg.Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to the numbering in Table 9.[000100] FIGS. 42A-42B show GAA protein expression in the cerebral cortex (FIG. 42A) and cerebellum (FIG. 42B) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to the numbering in Table 9.[000101] FIGS. 43A-43C show glycogen levels in the cerebral cortex (FIG. 43A), cerebellum (FIG. 43B), and spinal cord (FIG. 43C) after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to the numbering in Table 9.[000102] FIG. 44 shows glycogen in the cerebral cortex and cerebellum after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using atotal of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls.Brain tissues were harvested and stained with PAS stain and fast green stain. The numbering of the tested complex corresponds to the numbering in Table 9.[000103] FIG. 45 shows lysosomal staining in the central nervous system after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Brains were harvested and brain sections were stained with LAMP1 (lysosomes). The numbering of the tested complex corresponds to the numbering in Table 9.[000104] FIG. 46 shows neurofilament light-chain (Nf-L) levels in serum after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 5 mg / kg and 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. The numbering of the tested complex corresponds to the numbering in Table 9.[000105] FIG. 47 shows neuroinflammation in the cerebral cortex after Q2W administration of Complex 1, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 1 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Cerebral cortex tissues were harvested and immunohistochemically stained with GFAP (glial fibrillary acidic protein; astrocytes) and IB Al (ionized calcium-binding adapter molecule 1; microglia) as markers for neuroinflammation. The numbering of the tested complex corresponds to the numbering in Table 9.[000106] FIGs. 48A-48F show glycogen levels in the heart (FIG. 48A), diaphragm (FIG. 48B), tibialis anterior (FIG. 48C), quadriceps (FIG. 48D), cerebral cortex (FIG. 48E), and cerebellum (FIG. 48F) after a single administration of Complex 9 or vehicle to homozygous hTfRl / 6Neomice. Vehicle was included as a control. Complex 9 was administered to mice via intravenous (IV) infusions at an enzyme equivalent dose of 20 mg / kg. Mice were dosed on day 0; analyzed on days 14, 28, 42, and 56. Data are means +SD; n = 3-4. Complex 9 is as described in Table 9.[000107] FIG. 49 shows neurofilament light-chain (Nf-L) levels in serum after a single administration of Complex 9 or vehicle to homozygous hTfRl / 6Neomice. Vehicle was included as a control. Complex 9 was administered to mice via intravenous (IV) infusions at an enzyme equivalent dose of 20 mg / kg. Mice were dosed on day 0; analyzed on days 14, 28, 42, and 56. Data are means +SD; n = 3-4. Complex 9 is as described in Table 9.[000108] FIGs. 50A-50F show GAA enzyme activity in the heart (FIG. 50A), diaphragm (FIG. 50B), tibialis anterior (FIG. 50C), quadriceps (FIG. 50D), cerebral cortex (FIG. 50E), and cerebellum (FIG. 50F) after a single administration of Complex 9 or vehicle to homozygous hTfRl / 6Neomice. Vehicle was included as a control. Complex 9 was administered to mice via intravenous (IV) infusions at an enzyme equivalent dose of 20 mg / kg. Mice were dosed on day 0; analyzed on days 14, 28, 42, and 56. Data are means +SD; n = 3-4. Complex 9 is as described in Table 9.[000109] FIGS. 51A-51D show GAA enzyme activity in the Heart (FIG. 51A), Quadriceps (FIG. 51B), Diaphragm (FIG. 51C), and Cerebral cortex (FIG. 51D) after Q2W administration of Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 9 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Complex 9 is as described in Table 9.[000110] FIGS. 52A-52D show glycogen levels in the Heart (FIG. 52A), Quadriceps (FIG. 52B), Diaphragm (FIG. 52C), and Cerebral cortex (FIG. 52D) after Q2W administration of Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 9 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Complex 9 is as described in Table 9.[000111] FIG. 53 shows neurofilament light-chain (Nf-L) levels in serum after Q2W administration of Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of four doses. Naked GAA and vehicle were included as controls. Complex 9 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Complex 9 is as described in Table 9.[000112] FIG. 54 shows glycogen in the heart and quadriceps after Q2W administration of Complex 9, naked GAA, or vehicle to homozygous hTfRl / 6Neomice using a total of fourdoses. Naked GAA and vehicle were included as controls. Complex 9 and naked GAA were administered to mice via intravenous (IV) infusions at enzyme equivalent doses of and 20 mg / kg. Heterozygous hTfRl / 6Neo(control) mice were also treated with vehicle controls. Heart and quadricep tissues were harvested and labeled with PAS stain and Richardson’s stain. Complex 9 is as described in Table 9.DETAILED DESCRIPTION[000113] According to some aspects, the present disclosure provides complexes comprising a targeting agent covalently linked to an enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)), compositions comprising such complexes, and methods of their use. In some embodiments, a targeting agent of the complexes described herein effectively delivers the enzyme into the central nervous system (CNS) and / or muscle, or across the blood brain barrier (BBB) of a subject. In some embodiments, a targeting agent of the complexes described herein comprises an anti-transferrin receptor 1 (TfRl) antibody that is demonstrated to be able to transport the enzyme across the blood-brain barrier (e.g., via receptor mediated transcytosis), resulting in delivery of the molecular payloads to cells of the CNS, and to be able to deliver the enzyme into muscle (e.g., via receptor mediated endocytosis or transcytosis). In some embodiments, the anti-TfRl antibody of the complexes described herein is a Fab comprising a heavy chain and a light chain. In some embodiments, in a complex described herein, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) is covalently linked at the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., anti-TfRl Fab). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein breaks down glycogen in the CNS and / or muscle (e.g., skeletal and / or cardiac muscle), thereby treating a lysosomal storage disease (e.g., Pompe disease). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein reduces and / or normalizes lysosome size in the CNS and / or muscle (e.g., skeletal and / or cardiac muscle), thereby treating a lysosomal storage disease by preventing lysosomal rupturing (e.g., Pompe disease). In some embodiments, a subject having a lysosomal storage disease (e.g., Pompe disease) has at least one mutant GAA allele that leads to functional impairment of GAA and accumulation of glycogen in lysosomes of cells of the subject.Further aspects of the disclosure, including a description of defined terms, are provided below.I. Definitions[000114] 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).[000115] 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 aspects, 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).[000116] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., paratope that specifically binds to an antigen. In some embodiments, an antibody is a full- length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, a Fab’ fragment, a F(ab’)2 fragment, a Fv fragment or a scFv fragment. In some embodiments, an antibody is a nanobody derived from a camelid antibody or a nanobody derived from shark antibody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germline sequence. In another aspect, 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 aspect, 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 constantregion 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 molecule(s). 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- acetylgluco s amine unit, an N- acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, an antibody is a construct that comprises a polypeptide comprising one or more antigen binding fragments of the disclosure linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Examples of linker polypeptides have been reported (see e.g., Holliger, P, et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). Still further, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human 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).[000117] 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® www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P, Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P, Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [Epub], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33:D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37:D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17: 132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, a CDR may refer to the CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the same amino acid sequence of that CDR as determined by the same method, for example, the IMGT definition.[000118] 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 otherCDR 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))[000119] CDR-grafted antibody: The term “CDR-grafted antibody” refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and / or (e.g., and) VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.[000120] Chimeric antibody: The term “chimeric antibody” refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.[000121] Complementary: As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleosides or two sets of nucleosides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleosides or two sets of nucleosides. 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 basepairings, 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.[000122] Conservative amino acid substitution: As used herein, a “conservative amino acid substitution” refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for altering polypeptide sequence known to one of ordinary skill in the art such as are found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions made amongst amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.[000123] 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.[000124] Cross-reactive: As used herein and in the context of a targeting agent (e.g., antibody), the term “cross-reactive,” refers to a property of the agent being capable of specifically binding to more than one antigen of a similar type or class (e.g., antigens of multiple homologs, paralogs, or orthologs) with similar affinity or avidity. For example, in some embodiments, an antibody that is cross-reactive against human and non-human primate antigens of a similar type or class (e.g., a human transferrin receptor and non-human primate transferrin receptor) is capable of binding to the human antigen and non-human primate antigens with a similar affinity or avidity. In some embodiments, an antibody is cross -reactive against a human antigen and a rodent antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a rodent antigen and a non-human primate antigen of asimilar type or class. In some embodiments, an antibody is cross -reactive against a human antigen, a non-human primate antigen, and a rodent antigen of a similar type or class.[000125] 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 sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region. Human heavy chain and light chain acceptor sequences are known in the art. In one aspect, the acceptor sequences known in the art may be used in the antibodies disclosed herein.[000126] Acid alpha glucosidase (GAA): As used herein, the term “acid alpha glucosidase” or GAA refers to a protein encoded by the GAA gene, and fragments and variants thereof (e.g., functional fragments and variants thereof). The enzyme acid alpha glucosidase (GAA) breaks down glycogen in lysosomes. Genes that encode acid alpha glucosidase are known. In some embodiments, a GAA gene may be a human (Gene ID: 2548), non-human primate (e.g., Gene ID: 712054, Gene ID: 454940), or rodent gene (e.g., Gene ID: 14387, Gene ID: 367562). In addition, multiple transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000152.4, NM_001079803.2, and NM_001079804.2) have been characterized that encode different protein isoforms. In humans, expression of a mutant GAA protein that is defective in breaking down glycogen results in Pompe disease.[000127] GAA allele: As used herein, the term "GAA allele" refers to any one of alternative forms (e.g., wild-type or mutant forms) of a GAA gene. In some embodiments, a GAA allele may encode for wild-type acid alpha-glucosidase that retains its normal and typical functions. In some embodiments, a GAA allele may comprise one or more mutations associated with Pompe disease, such as, for example, is disclosed in Moravej, et al. "A New Mutation Causing Severe Infantile-Onset Pompe Disease Responsive to Enzyme Replacement Therapy," Iran J Med Sci, 2018; and van der Wai E., et al, "GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells" Mai Ther Nucleic Acids.2017 Jun l6; 7: 101-115; the entire contents of each of which are hereby incorporated by reference.[000128] 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.[000129] Humanized antibody: The term “humanized antibody” refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and / or (e.g., and) VL sequence has been altered to be more “human-like”, i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one aspect, humanized anti-TfRl antibodies and antigen binding portions are provided. Such antibodies may be generated by obtaining murine anti-TfRl 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.[000130] Internalizing cell surface receptor: As used herein, the term, “internalizing cell surface receptor” refers to a cell surface receptor that is internalized by cells, e.g., upon external stimulation, e.g., ligand binding to the receptor. In some embodiments, an internalizing cell surface receptor is internalized by endocytosis. In some embodiments, an internalizing cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, an internalizing cell surface receptor is internalized by a clathrin- independent pathway, such as, for example, phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake or constitutive clathrin-independent endocytosis. In some embodiments, the internalizing cell surface receptor comprises an intracellular domain, a transmembrane domain, and / or (e.g., and) an extracellular domain, which may optionally further comprise a ligand-binding domain. In some embodiments, a cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, a ligand may be a muscle and / or (e.g., and)CNS-targeting agent or a muscle and / or (e.g., and) CNS-targeting antibody. In some embodiments, an internalizing cell surface receptor is a transferrin receptor.[000131] Isolated antibody: An “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities e.g., an isolated antibody that specifically binds transferrin receptor is substantially free of antibodies that specifically bind antigens other than transferrin receptor). An isolated antibody that specifically binds transferrin receptor complex may, however, have cross-reactivity to other antigens, such as transferrin receptor molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and / or (e.g., and) chemicals.[000132] Kabat numbering: The terms “Kabat numbering”, “Kabat definitions and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.[000133] Lysosomal storage disease: As used herein, the term “lysosomal storage disease,” refers to a group of inherited metabolic diseases caused by enzyme deficiencies within lysosomes resulting in the accumulation of undegraded enzyme substrate. The substrate accumulation in lysosomes leads to a broad spectrum of clinical manifestations depending on the specific substrate and the site of accumulation. Examples of lysosomal storage diseases include Pompe disease, Gaucher disease, Fabry disease, mucopolysaccharidoses, mucolipidoses, Niemann-Pick disorder and neuronal ceroid lipofuscinoses.[000134] Molecular payload: As used herein, the term “molecular payload” refers to a molecule or species that functions to modulate a biological outcome. In some embodiments, a molecular payload is linked to, or otherwise associated with a muscle and / or (e.g., and) CNS- targeting agent. In some embodiments, the molecular payload comprises or is a small molecule, a protein, a peptide, a nucleic acid, or an oligonucleotide.[000135] Pompe disease (PD): As used herein the term "Pompe disease (PD)" refers to a genetic disease caused by a mutation in a GAA gene and associated with muscle weakness, difficulty breathing, hypotonia, and in extreme cases, cardiac enlargement leading to cardiac failure and CNS symptoms including behavioral and cognitive deficits. Three categories of PD have been described, arising from when symptoms manifest. Infantile onset PD includes both classical infantile-onset PD and non-classical infantile-onset PD. Classical infantile-onset PD begins within a few months of birth, with patients experience muscle weakness that may lead to respiratory failure, hypotonia, enlarged liver, central nervous system manifestations, and heart defects (e.g., cardiomyopathy, cardiomegaly). If untreated, classical infantile PD generally leads to death within the first year of life. Non-classical infantile PD usually manifests around 1 year of age and is characterized by delayed motor skills and progressive muscle weakness. This weakness leads to serious breathing problems and may lead to respiratory failure, and most patients with non-classical infantile PD die in early childhood. Late-onset PD may not manifest until late childhood, adolescence, or adulthood and is usually less severe than infantile PD. Most patients with late-onset PD experience progressive muscle weakness, which can lead to breathing problems and respiratory failure. Pompe disease (PD) is associated with OMIM Entry #232300. Pompe Disease, the genetic basis for the disease, and related symptoms are described in the art (see, e.g. Lim, et al., "Pompe disease: from pathophysiology to therapy and back again" Frontiers in Aging: Neuroscience. (2014); and Ferreira, et al. "Lysosomal storage diseases" Transl Sci Rare Dis. (2017), 5: 1-71.)[000136] Recombinant antibody: The term “recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more details in this disclosure), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H. R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W. E., (2002) Clin. Biochem. 35:425- 445; Gavilondo J. V., and Larrick J. W. (2002) BioTechniques 29: 128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann S-A., and Green L. L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulinsequences. In certain aspects, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. One aspect of the disclosure provides fully human antibodies capable of binding human transferrin receptor which can be generated using techniques well known in the art, such as, but not limited to, using human Ig phage libraries such as those disclosed in Jermutus et al., PCT publication No. WO 2005 / 007699 A2.[000137] 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.[000138] 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, IO0M, 1041M, 1042M, 103M, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, e.g., an epitope of the apical domain of transferrin receptor.[000139] 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 ahuman. In some embodiments, a subject is a patient, e.g., a human patient that has or is suspected of having a disease.[000140] Transferrin receptor: As used herein, the term, “transferrin receptor” (also known as TFRC, CD71, p90, TfRl) refers to an internalizing cell surface receptor that binds transferrin to facilitate iron uptake by endocytosis. In some embodiments, a gene encoding a transferrin receptor may be of human (NCBI Gene ID 7037), non-human primate (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodent (e.g., NCBI Gene ID 22042) origin. In addition, multiple human transcript variants have been characterized that encoded different isoforms of the receptor (e.g., as annotated under GenBank RefSeq Accession Numbers: NP-001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).II. Complexes[000141] According to some aspects, the present disclosure provides complexes comprising a targeting agent covalently linked to an enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)), compositions comprising such complexes, and methods of their use. In some embodiments, a targeting agent of the complexes described herein effectively delivers the enzyme into the central nervous system (CNS) and / or muscle, and / or across the blood bran barrier (BBB) of a subject. In some embodiments, a targeting agent of the complexes described herein comprises an anti-transferrin receptor 1 (TfRl) antibody that is demonstrated to be able to transport the enzyme across the blood-brain barrier (e.g., via receptor mediated transcytosis), resulting in delivery of the molecular payloads to cells of the CNS, and to be able to deliver the enzyme into muscle (e.g., via receptor mediated endocytosis or transcytosis). In some embodiments, the anti-TfRl antibody of the complexes described herein is a Fab comprising a heavy chain and a light chain. In some embodiments, in a complex described herein, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) is covalently linked to the heavy chain or light chain of the anti-TfRl antibody (e.g., anti-TfRl Fab). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein breaks down glycogen in the CNS and / or muscle (e.g., skeletal muscle and / or cardiac muscle), thereby treating a lysosomal storage disease (e.g., Pompe disease). In some embodiments, the enzyme (e.g., a lysosomal enzyme such as an acid alpha glucosidase (GAA)) of the complexes described herein reduces and / or normalizes lysosome size in the CNS and / or muscle (e.g., skeletal muscle and / or cardiac muscle), thereby treating a lysosomal storage disease by preventing lysosomal rupturing (e.g., Pompe disease). In some embodiments, a subject havinga lysosomal storage disease (e.g., Pompe disease) has at least one mutant GAA allele that leads to functional impairment of GAA and accumulation of glycogen in lysosomes of cells of the subject.[000142] In some embodiments, in a complex described herein, a lysosomal enzyme (e.g., an acid alpha glucosidase) may be linked to the N-terminus and / or C-terminus of the heavy chain and / or light chain of the anti-TfRl antibody (e.g., anti-TfRl Fab). In some embodiments, the lysosomal enzyme (e.g., an acid alpha glucosidase) is linked to the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., anti-TfRl Fab). In some embodiments, a complex described herein comprises 1, 2, 3, or 4 lysosomal enzymes (e.g., an acid alpha glucosidase). In some embodiments, a complex described herein comprises 1 single lysosomal enzymes (e.g., an acid alpha glucosidase). In some embodiments, a complex described herein comprises 2 lysosomal enzymes (e.g., an acid alpha glucosidase), for example, one linked to the N or C- terminus of the heavy chain or light chain of the anti-TfRl antibody (e.g., anti-TfRl Fab).[000143] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody. In some embodiments, the lysosomal enzyme is an acid alpha glucosidase. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., acid alpha glucosidase).[000144] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody. In some embodiments, the lysosomal enzyme is an acid alpha glucosidase. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., acid alpha glucosidase).[000145] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody, and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N-terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., acid alpha glucosidase).[000146] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody, and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C-terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., acid alpha glucosidase).[000147] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N- terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase.[000148] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C- terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase.[000149] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C- terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase.[000150] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to a lysosomal enzyme (e.g., to the C- terminus of a lysosomal enzyme), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to a lysosomal enzyme (e.g., to the N-terminus of a lysosomal enzyme). In some embodiments, the lysosomal enzyme is an acid alpha glucosidase.[000151] In some embodiments, in a complex each lysosomal enzyme (e.g., an acid alpha glucosidase) is covalently linked to the anti-TfRl antibody (e.g., anti-TfRl Fab) via a linker (e.g., a peptide linker). In some embodiments, the linker (e.g., peptide linker) is non-cleavable. [000152] Details of anti-TfRl antibodies (e.g., anti-TfRl) and lysosomal enzymes (e.g., acid alpha glucosidase) of the complexes described herein are provided below.Antibodies[000153] Some aspects of the disclosure are based on the recognition that agents binding to transferrin receptor, e.g., anti-transferrin-receptor antibodies, are capable of targeting muscle and / or (e.g., and) CNS cells. Transferrin receptors are internalizing cell surface receptors that transport transferrin across the cellular membrane and participate in the regulation and homeostasis of intracellular iron levels. Some aspects of the disclosure provide transferrin receptor binding proteins, which are capable of binding to transferrin receptor. Accordingly, aspects of the disclosure provide binding proteins (e.g., antibodies) that bind to transferrin receptor. In some embodiments, binding proteins that bind to transferrin receptor are internalized, along with any bound molecular payload, into a muscle and / or (e.g., and) a CNS cell. As used herein, an antibody that binds to a transferrin receptor may be referred to interchangeably as a transferrin receptor antibody, an anti-transferrin receptor antibody, or an anti-TfRl antibody. Antibodies that bind, e.g. specifically bind, to a transferrin receptor may be internalized into the cell, e.g. through receptor-mediated endocytosis, upon binding to a transferrin receptor.[000154] It should be appreciated that anti-TfRl antibodies may be produced, synthesized, and / or (e.g., and) derivatized using several known methodologies, e.g. library design using phage display. Exemplary methodologies have been characterized in the art and are incorporated by reference (Diez, P. et al. “High-throughput phage-display screening in array format”, Enzyme and microbial technology, 2015, 79, 34-41.; Christoph M. H. and Stanley, J.R. “Antibody Phage Display: Technique and Applications” J Invest Dermatol. 2014, 134:2.; Engleman, Edgar (Ed.) “Human Hybridomas and Monoclonal Antibodies.” 1985, Springer.). In other aspects, an anti-TfRl antibody has been previously characterized or disclosed. Antibodies that specifically bind to transferrin receptor are known in the art (see, e.g. US Patent. No. 4,364,934, filed 12 / 4 / 1979, “Monoclonal antibody to a human early thymocyte antigen and methods for preparing same”; US Patent No. 8,409,573, fded6 / 14 / 2006, “Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells”; US Patent No. 9,708,406, fded 5 / 20 / 2014, “Anti-Transferrin receptor antibodies and methods of use”; US 9,611,323, fded 12 / 19 / 2014, “Low affinity blood brain barrier receptor antibodies and uses therefor”; WO 2015 / 098989, filed 12 / 24 / 2014, “Novel anti-Transferrin receptor antibody that passes through blood-brain barrier”; Schneider C. et al. “Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9.” J Biol Chem. 1982, 257:14, 8516-8522.; Lee et al. “Targeting Rat AntiMouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse” 2000, J Pharmacol. Exp. Then, 292: 1048-1052).[000155] In some embodiments, the anti-TfRl antibody described herein binds to transferrin receptor with high specificity and affinity. In some embodiments, the anti-TfRl antibody described herein specifically binds to any extracellular epitope of a transferrin receptor or an epitope that becomes exposed to an antibody. In some embodiments, anti-TfRl antibodies provided herein bind specifically to transferrin receptor from human, non-human primates, mouse, rat, etc. In some embodiments, anti-TfRl antibodies provided herein bind to human transferrin receptor. In some embodiments, the anti-TfRl antibody described herein binds to an amino acid segment of a human or non-human primate transferrin receptor, as provided in SEQ ID NOs: 105-108. In some embodiments, the anti-TfRl antibody described herein binds to an amino acid segment corresponding to amino acids 90-96 of a human transferrin receptor as set forth in SEQ ID NO: 105, which is not in the apical domain of the transferrin receptor. In some embodiments, the humanized anti-TfRl antibodies described herein binds to TfRl but does not bind to TfR2.[000156] In some embodiments, the anti-TfRl antibodies described herein (e.g., anti- TfRl clone 8 in Table 2 below) bind an epitope in TfRl, wherein the epitope comprises residues in amino acids 214-241 and / or amino acids 354-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope comprising residues in amino acids 214-241 and amino acids 354-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope comprising one or more of residues Y222, T227, K231, H234, T367, S368, S370, T376, and S378 of human TfRl as set forth in SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope comprising residues Y222, T227, K231, H234, T367, S368, S370, T376, and S378 of human TfRl as set forth in SEQ ID NO: 105.[000157] In some embodiments, the anti-TfRl antibody described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope in TfRl, wherein the epitope comprisesresidues in amino acids 258-291 and / or amino acids 358-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies (e.g., 3M12 in Table 2 below and its variants) described herein bind an epitope comprising residues in amino acids amino acids 258-291 and amino acids 358-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope comprising one or more of residues K261, S273, Y282, T362, S368, S370, and K371 of human TfRl as set forth in SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope comprising residues K261, S273, Y282, T362, S368, S370, and K371 of human TfRl as set forth in SEQ ID NO: 105.[000158] An example human transferrin receptor amino acid sequence, corresponding toNCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows:MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANV TKPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFP AARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFRE FKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKL VHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIV NAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNME GDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQ RDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATE WLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLY QDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPEL NKVARAAAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQ WLYSARGDFFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSPKESPFR HVFWGSGSHTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSGDVW DIDNEF (SEQ ID NO: 105)[000159] An example non-human primate transferrin receptor amino acid sequence, corresponding to NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) is as follows:MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLGVDEEENTDNNTKANG TKPKRCGGNICYGTIAVIIFFLIGFMIGYLGYCKGVEPKTECERLAGTESPAREEPEEDFP AAPRLYWDDLKRKLSEKLDTTDFTSTIKLLNENLYVPREAGSQKDENLALYIENQFREF KLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAATVTGKLV HANFGTKKDFEDLDSPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVKADLSFFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGNMEG DCPSDWKTDSTCKMVTSENKSVKLTVSNVLKETKILNIFGVIKGFVEPDHYVVVGAQR DAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEW LEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHPVTGRSLYQD SNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERIPELN KVARAAAEVAGQFVIKLTHDTELNLDYERYNSQLLLFLRDLNQYRADVKEMGLSLQW LYSARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDRVMRVEYYFLSPYVSPKESPFRH VFWGSGSHTLSALLESLKLRRQNNSAFNETLFRNQLALATWTIQGAANALSGDVWDI DNEF (SEQ ID NO: 107).[000160] An example mouse transferrin receptor amino acid sequence, corresponding toNCBI sequence NP_001344227.1 (transferrin receptor protein 1, Mus musculus) is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAADEEENADNNMKASV RKPKRFNGRLCFAAIALVIFFLIGFMSGYLGYCKRVEQKEECVKLAETEETDKSETMET EDVPTSSRLYWADLKTLLSEKLNSIEFADTIKQLSQNTYTPREAGSQKDESLAYYIENQF HEFKFSKVWRDEHYVKIQVKSSIGQNMVTIVQSNGNLDPVESPEGYVAFSKPTEVSGK LVHANFGTKKDFEELSYSVNGSLVIVRAGEITFAEKVANAQSFNAIGVLIYMDKNKFPV VEADLALFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGKM EGSCPARWNIDSSCKLELSQNQNVKLIVKNVLKERRILNIFGVIKGYEEPDRYVVVGAQ RDALGAGVAAKSSVGTGLLLKLAQVFSDMISKDGFRPSRSIIFASWTAGDFGAVGATE WLEGYLSSLHLKAFTYINLDKVVLGTSNFKVSASPLLYTLMGKIMQDVKHPVDGKSL YRDSNWISKVEKLSFDNAAYPFLAYSGIPAVSFCFCEDADYPYLGTRLDTYEALTQKVP QLNQMVRTAAEVAGQLIIKLTHDVELNLDYEMYNSKLLSFMKDLNQFKTDIRDMGLS LQWLYSARGDYFRATSRLTTDFHNAEKTNRFVMREINDRIMKVEYHFLSPYVSPRESPF RHIFWGSGSHTLSALVENLKLRQKNITAFNETLFRNQLALATWTIQGVANALSGDIWNI DNEF (SEQ ID NO: 108).[000161] In some embodiments, an anti-TfRl antibody binds to an amino acid segment of the receptor as follows:FVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFE DLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLG TGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTC RMVTSESKNVKLTVSNVLKE (SEQ ID NO: 109) and does not inhibit the binding interactions between transferrin receptors and transferrin and / or (e.g., and) human hemochromatosis protein (also known as HFE). In some embodiments, the anti-TfRl antibody described herein does not bind an epitope in SEQ ID NO: 109.[000162] Appropriate methodologies may be used to obtain and / or (e.g., and) produce antibodies, antibody fragments, or antigen-binding agents, e.g., through the use of recombinant DNA protocols. In some embodiments, an antibody may also be produced through the generation of hybridomas (see, e.g., Kohler, G and Milstein, C. “Continuous cultures of fused cells secreting antibody of predefined specificity” Nature, 1975, 256: 495-497). The antigen- of-interest may be used as the immunogen in any form or entity, e.g., recombinant or a naturally occurring form or entity. Hybridomas are screened using standard methods, e.g., ELISA screening, to find at least one hybridoma that produces an antibody that targets a particular antigen. Antibodies may also be produced through screening of protein expression libraries that express antibodies, e.g., phage display libraries. Phage display library design may also be used, in some embodiments, (see, e.g. U.S. Patent No 5,223,409, filed 3 / 1 / 1991, “Directed evolution of novel binding proteins”; WO 1992 / 18619, fded 4 / 10 / 1992, “Heterodimeric receptor libraries using phagemids”; WO 1991 / 17271, fded 5 / 1 / 1991, “Recombinant library screening methods”; WO 1992 / 20791, fded 5 / 15 / 1992, “Methods for producing members of specific binding pairs”; WO 1992 / 15679, fded 2 / 28 / 1992, and “Improved epitope displaying phage”). In some embodiments, an antigen-of-interest may be used to immunize a non-human animal, e.g., a rodent or a goat. In some embodiments, an antibody is then obtained from the non-human animal, and may be optionally modified using a number of methodologies, e.g., using recombinant DNA techniques. Additional examples of antibody production and methodologies are known in the art (see, e.g. Harlow et al. “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory, 1988.).[000163] 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 molecules 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, there are about 1-10, about 1-5, about 5-10, about 1- 4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody isfully or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or inside a cell, which may optionally be deficient in an enzyme in the N- or O- glycosylation pathway, e.g. a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application Publication WO20 14065661, published on May 1, 2014, entitled, ''Modif ied antibody, antibody-conjugate and process for the preparation thereof’ .[000164] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VL domain and / or (e.g., and) a VH domain of any one of the anti-TfRl antibodies selected from any one of Tables 2-7, and comprises a constant region comprising the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art, e.g., see Kabat E A et al., (1991) supra.[000165] In some embodiments, agents binding to transferrin receptor, e.g., anti-TfRl antibodies, are capable of targeting muscle cell, CNS cells, and / or cells of the blood brain barrier, and / or (e.g., and) mediate the transportation of an agent across the blood brain barrier. Transferrin receptors are internalizing cell surface receptors that transport transferrin across the cellular membrane and participate in the regulation and homeostasis of intracellular iron levels. Some aspects of the disclosure provide transferrin receptor binding proteins, which are capable of binding to transferrin receptor. Antibodies that bind, e.g. specifically bind, to a transferrin receptor may be internalized into the cell, e.g. through receptor-mediated endocytosis, upon binding to a transferrin receptor.[000166] In some embodiments, an anti-TFRl antibody specifically binds a TfRl (e.g., a human or non-human primate TfRl) with binding affinity (e.g., as indicated by Kd) of at least about 10'4M, 10'5M, 10'6M, 10'7M, 10'8M, 10'9M, IO’10M, 10’11M, IO’12M, 10’13M, or less. In some embodiments, the anti-TfRl antibodies described herein bind to TfRl with a KD of sub-nanomolar range. In some embodiments, the anti-TfRl antibodies described herein selectively bind to transferrin receptor 1 (TfRl) but do not bind to transferrin receptor 2 (TfR2). In some embodiments, the anti-TfRl antibodies described herein bind to human TfRl and cyno TfRl (e.g., with a Kd of 10'7M, 10'8M, 10'9M, IO’10M, 10’11M, IO’12M, 10'13M, or less), but do not bind to a mouse TfRl. The affinity and binding kinetics of the anti-TfRl antibody can be tested using any suitable method including but not limited to biosensor technology (e.g., OCTET or BIACORE). In some embodiments, binding of any one of theanti-TfRl antibody described herein does not complete with or inhibit transferrin binding to the TfRl. In some embodiments, binding of any one of the anti-TfRl antibodies described herein does not complete with or inhibit HFE-beta-2-microglobulin binding to the TfRl. [000167] Non-limiting examples of anti-TfRl antibodies are provided in Table 2.Table 2. Examples of Anti-TfRl Antibodies[000168] In some embodiments, the anti-TfRl antibody of the present disclosure is a variant of any one of the anti-TfRl antibodies provided in Table 2. In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 in any one of the anti-TfRl antibodies provided in Table 2, and comprises a humanized heavy chain variable region and / or (e.g., and) a humanized light chain variable region.[000169] Examples of amino acid sequences of the anti-TfRl antibodies described herein are provided in Table 3.Table 3. Variable Regions of Anti-TfRl Antibodies[000170] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of any one of the anti-TfRl antibodies provided in Table 3 and comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid variations in the framework regions as compared with the respective VH provided in Table 3. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of any one of the anti-TfRl antibodies provided in Table 3 and comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid variations in the framework regions as compared with the respective VL provided in Table 3.[000171] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of any one of the anti-TfRl antibodies provided in Table 3 and comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical in the framework regions as compared with the respective VH provided in Table 3. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of any one of the anti-TfRl antibodies provided in Table 3 and comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical in the framework regions as compared with the respective VL provided in Table 3.[000172] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 69 and a VL comprising the amino acid sequence of SEQ ID NO: 70.[000173] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VL comprising the amino acid sequence of SEQ ID NO: 70.[000174] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 72 and a VL comprising the amino acid sequence of SEQ ID NO: 70.[000175] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 73 and a VL comprising the amino acid sequence of SEQ ID NO: 74.[000176] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 73 and a VL comprising the amino acid sequence of SEQ ID NO: 75.[000177] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 74.[000178] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 75.[000179] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77 and a VL comprising the amino acid sequence of SEQ ID NO: 78.[000180] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 80.[000181] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77 and a VL comprising the amino acid sequence of SEQ ID NO: 80.[000182] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 154 and a VL comprising the amino acid sequence of SEQ ID NO: 155.[000183] In some embodiments, the anti-TfRl antibody described herein is a full-length IgG, which can include a heavy constant region and a light constant region from a human antibody. In some embodiments, the heavy chain of any of the anti-TfRl antibodies as described herein may comprise a heavy chain constant region (CH) or a portion thereof (e.g., CHI, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, e.g., human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (a gamma heavy chain), e.g., IgGl, IgG2, or IgG4. An example of a human IgGl constant region is given below:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 81).[000184] In some embodiments, the heavy chain of any of the anti-TfRl antibodies described herein comprises a mutant human IgGl constant region. For example, the introduction of LALA mutations (a mutant derived from mAb bl2 that has been mutated to replace the lower hinge residues Leu234 Leu235 with Ala234 and Ala235) in the CH2 domain of human IgGl is known to reduce Fey receptor binding (Bruhns, P, et al . (2009) and Xu, D. et al. (2000)). The mutant human IgGl constant region is provided below (mutations bonded and underlined):ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 82).[000185] In some embodiments, the light chain of any of the anti-TfRl antibodies described herein may further comprise a light chain constant region (CL), which can be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below: RTVAAPSVEIEPPSDEQLKSGTASVVCLLNNEYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC (SEQ ID NO: 83).[000186] Other antibody heavy and light chain constant regions are well known in the art, e.g., those provided in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php., both of which are incorporated by reference herein.[000187] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 81 or SEQ ID NO: 82. In some embodiments, the anti- TfRl antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that contains 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) as compared with SEQ ID NO: 81 or SEQ ID NO: 82. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 81. In some embodiments, the anti-TfRl antibody described herein comprises heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 82.[000188] In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least99% identical to SEQ ID NO: 83. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region contains 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) as compared with SEQ ID NO: 83. In some embodiments, the anti- TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region set forth in SEQ ID NO: 83. [000189] Examples of IgG heavy chain and light chain amino acid sequences of the anti- TfRl antibodies described are provided in Table 4 below.Table 4. Heavy chain and light chain sequences of examples of anti-TfRl IgGs[000190] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain 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) as compared with the heavy chain as set forth in any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a light chain 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) as compared with the light chain as set forth in any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.[000191] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 85, 89, 90, 93, 95 and 157.[000192] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000193] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000194] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000195] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.[000196] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.[000197] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.[000198] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.[000199] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 92 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.[000200] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.[000201] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 92 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.[000202] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 156 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.[000203] In some embodiments, the anti-TfRl antibody is a Fab fragment, Fab’ fragment, or F(ab’)2 fragment of an intact antibody (full-length antibody). Antigen binding fragment of an intact antibody (full-length antibody) can be prepared via routine methods (e.g., recombinantly or by digesting the heavy chain constant region of a full length IgG using an enzyme such as papain). For example, F(ab’)2 fragments can be produced by pepsin or papain digestion of an antibody molecule, and Fab fragments that can be generated by reducing the disulfide bridges of F(ab’)2 fragments. In some embodiments, a heavy chain constant region in a Fab’ fragment of the anti-TfRl antibody described herein comprises the amino acid sequence of:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 96).[000204] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 96. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that contains 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) as compared with SEQ ID NO: 96. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprisingany one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 96.[000205] In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 83. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region contains 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) as compared with SEQ ID NO: 83. In some embodiments, the anti- TfRl antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region set forth in SEQ ID NO: 83. [000206] Examples of Fab heavy chain and light chain amino acid sequences of the anti- TfRl antibodies described are provided in Table 5 below.Table 5. Heavy chain and light chain sequences of examples of anti-TfRl Tabs[000207] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain 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) as compared with the heavy chain as set forth in any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a light chain 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) as compared with the light chain as set forth in any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.[000208] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.[000209] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 97 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000210] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 98 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000211] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 99 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.[000212] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 100 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.[000213] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 100 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.[000214] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 101 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.[000215] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 101 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.[000216] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.[000217] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 103 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.[000218] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.[000219] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 158 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.[000220] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 159 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.Other known anti-TfRl antibodies[000221] Any other appropriate anti-TfRl antibodies known in the art may be used as the muscle and / or (e.g., and) CNS-targeting agent in the complexes disclosed herein. Examples of known anti-TfRl antibodies, including associated references and binding epitopes, are listed in Table 6. In some embodiments, the anti-TfRl antibody comprises the complementarity determining regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) of any of the anti-TfRl antibodies provided herein, e.g., anti-TfRl antibodies listed in Table 6.Table 6 - List of anti-TfRl antibody clones, including associated references and binding epitope information.[000222] In some embodiments, anti-TfRl antibodies of the present disclosure include one or more of the CDR-H (e.g., CDR-H1, CDR-H2, and CDR-H3) amino acid sequences from any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti- TfRl antibodies include the CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti-TfRl antibodiesinclude the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfRl antibodies selected from Table 6.[000223] In some embodiments, anti-TfRl antibodies of the disclosure include any antibody that includes a heavy chain variable domain and / or (e.g., and) a light chain variable domain of any anti-TfRl antibody, such as any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti-TfRl antibodies of the disclosure include any antibody that includes the heavy chain variable and light chain variable pairs of any anti-TfRl antibody, such as any one of the anti-TfRl antibodies selected from Table 6.[000224] Aspects of the disclosure provide anti-TfRl antibodies having a heavy chain variable (VH) and / or (e.g., and) a light chain variable (VL) domain amino acid sequence homologous to any of those described herein. In some embodiments, the anti-TfRl antibody comprises a heavy chain variable sequence or a light chain variable sequence that is at least 75% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the heavy chain variable sequence and / or any light chain variable sequence of any anti-TfRl antibody, such as any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, the homologous heavy chain variable and / or (e.g., and) a light chain variable amino acid sequences do not vary within any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within a heavy chain variable and / or (e.g., and) a light chain variable sequence excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-TfRl antibodies provided herein comprise a heavy chain variable sequence and a light chain variable sequence that comprises a framework sequence that is at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequence of any anti-TfRl antibody, such as any one of the anti- TfRl antibodies selected from Table 6.[000225] An example of a transferrin receptor antibody that may be used in accordance with the present disclosure is described in International Application Publication WO 2016 / 081643, incorporated herein by reference. The amino acid sequences of this antibody are provided in Table 7.Table 7. Heavy chain and light chain CDRs of an example of a known anti-TfRl antibody[000226] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 7. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 7.[000227] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-L3, which contains no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the CDR-L3 as shown in Table 7. In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-L3 containing one amino acid variation as compared with the CDR-L3 as shown in Table 7. In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 126) according to the Kabat and Chothia definition system) or QHFAGTPL (SEQ ID NO: 127) according to the Contact definition system). In some embodiments, the anti-TfRl antibody of the present disclosure comprises a CDR-H1, a CDR- H2, a CDR-H3, a CDR-L1 and a CDR-L2 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 7, and comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 126) according to the Kabat and Chothia definition system) or QHFAGTPL (SEQ ID NO: 127) according to the Contact definition system).[000228] In some embodiments, the anti-TfRl antibody of the present disclosure comprises heavy chain CDRs that collectively are at least 80% (e.g., 80%, 85%, 90%, 95%, or 98%) identical to the heavy chain CDRs as shown in Table 7. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises light chain CDRs that collectively are at least 80% (e.g., 80%, 85%, 90%, 95%, or 98%) identical to the light chain CDRs as shown in Table 7.[000229] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 124. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 125.[000230] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 128. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 129.[000231] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a 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) as compared with the VH as set forth in SEQ ID NO: 128. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody of the present disclosure comprises a VL containing no more than 15 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VL as set forth in SEQ ID NO: 129.[000232] In some embodiments, the anti-TfRl antibody of the present disclosure is a full- length IgGl antibody, which can include a heavy constant region and a light constant region from a human antibody. In some embodiments, the heavy chain of any of the anti-TfRl antibodies as described herein may comprises a heavy chain constant region (CH) or a portion thereof (e.g., CHI, CH2, CH3, or a combination thereof). The heavy chain constant region can of any suitable origin, e.g., human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (a gamma heavy chain), e.g., IgGl, IgG2, or IgG4. An example of human IgGl constant region is given below:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 81) [000233] In some embodiments, the light chain of any of the anti-TfRl antibodies described herein may further comprise a light chain constant region (CL), which can be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 83)[000234] In some embodiments, the anti-TfRl antibody described herein is a chimeric antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 132. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 133.[000235] In some embodiments, the anti-TfRl antibody described herein is a fully human antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:134. Alternatively or in addition (e.g., in addition), the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 135.[000236] In some embodiments, the anti-TfRl antibody is an antigen binding fragment (Fab) of an intact antibody (full-length antibody). In some embodiments, the anti-TfRl Fab described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 136. Alternatively or in addition (e.g., in addition), the anti-TfRl Fab described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the anti-TfRl Fab described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137. Alternatively or in addition (e.g., in addition), the anti-TfRl Fab described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 135.[000237] The anti-TfRl antibodies described herein can be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (such as Fab, Fab’, F(ab’)2, Fv), single chain antibodies, bi-specific antibodies, or nanobodies. In some embodiments, the anti-TfRl antibody described herein is a scFv. In some embodiments, the anti-TfRl antibody described herein is a scFv-Fab (e.g., scFv fused to a portion of a constant region). In some embodiments, the anti-TfRl antibody described herein is an scFv fused to a constant region (e.g., human IgGl constant region as set forth in SEQ ID NO: 81).[000238] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are not likely to be involved in interacting with a target antigen (e.g., transferrin receptor), for example, as determined based on a crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an anti-TfRl antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or (e.g., and) antigen-dependent cellular cytotoxicity.[000239] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U.S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI domain can be altered to, e.g., facilitate assembly of the light and heavy chains, orto alter (e.g., increase or decrease) the stability of the antibody or to facilitate linker conjugation.[000240] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a muscle and / or (e.g., and) CNS-targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.[000241] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the anti-TfRl antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Pat. Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.[000242] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the halflife of the anti-TfRl antibody in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibodies can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgGl) and / or (e.g., and) the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the constant region of the IgGl of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, aserine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U.S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as “YTE mutant” has been shown to display fourfold increased half-life as compared to wildtype versions of the same antibody (see Dall’Acqua W F et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat. [000243] In some embodiments, one, two or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the anti-TfRl antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating antibody thereby increasing tumor localization. See, e.g., U.S. Pat. Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R E et al., (2001) J Biol Chem 276: 6591-604).[000244] In some embodiments, one or more amino in the constant region of an anti- TfRl antibody described herein can be replaced with a different amino acid residue such that the antibody has altered Clq binding and / or (e.g., and) reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N- terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or (e.g., and) to increase the affinity of the antibody for an Fey receptor. This approach is described further in International Publication No. WO 00 / 42072.[000245] In some embodiments, the heavy and / or (e.g., and) light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example,CDR-grafted, chimeric, humanized, or composite human antibodies or antigen-binding fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibodies derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will maintain the ability to specifically bind transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to transferrin receptor relative to the original antibody from which it is derived.[000246] In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing ‘Adair’ mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline resulting in an IgGl-like hinge sequence. Accordingly, any of the antibodies may include a stabilizing ‘Adair’ mutation.[000247] 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 molecules 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, there are about 1-10, about 1-5, about 5-10, about 1- 4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody is fully or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or inside a cell, which may optionally be deficient in an enzyme in the N- or O- glycosylation pathway, e.g. a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application PublicationWO20 14065661, published on May 1, 2014, entitled, ''Modified antibody, antibody-conjugate and process for the preparation thereof’ .[000248] In some embodiments, any one of the anti-TfRl antibodies described herein may comprise a signal peptide in the heavy and / or (e.g., and) light chain sequence (e.g., a N- terminal signal peptide). In some embodiments, the anti-TfRl antibody described herein comprises any one of the VH and VL sequences, any one of the IgG heavy chain and light chain sequences, or any one of the F(ab’) heavy chain and light chain sequences described herein, and further comprises a signal peptide (e.g., a N-terminal signal peptide). In some embodiments, the signal peptide comprises the amino acid sequence of MGWSCIILFLVATATGVHS (SEQ ID NO: 104). In some embodiments, the signal peptide comprises the amino acid sequence of MGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, the signal peptide comprises the amino acid sequence of MRVPAQLLGLLLLWLPGARC (SEQ ID NO: 211). In some embodiments, any one of the heavy chain sequences described herein comprises a signal peptide (e.g., a N-terminal signal peptide), wherein the signal peptide comprises the amino acid sequenceMGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, any one of the light chain sequences described herein comprises a signal peptide (e.g., a N-terminal signal peptide), wherein the signal peptide comprises the amino acid sequenceMRVPAQLLGLLLLWLPGARC (SEQ ID NO: 211). In some embodiments, alternative signal peptides can be used such as those known by persons of ordinary skill in the art (see e.g., Mammalian Signal Peptide Database found at signalpeptide.de).[000249] In some embodiments, an 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.Antibody Features / Alterations[000250] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are not likelyto be involved in interacting with a target antigen (e.g., transferrin receptor), for example, as determined based on a crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a muscle and / or (e.g., and) CNS-targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or (e.g., and) antigen-dependent cellular cytotoxicity.[000251] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U.S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI domain can be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody or to facilitate linker conjugation.[000252] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a muscle and / or (e.g., and) CNS-targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.[000253] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Pat. Nos. 5,869,046, 6,121,022,6,277,375, and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.[000254] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the halflife of the anti-transferrin receptor antibody in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibodies can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgGl) and / or (e.g., and) the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the constant region of the IgGl of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U.S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as “YTE mutant” has been shown to display fourfold increased half-life as compared to wildtype versions of the same antibody (see Dall’Acqua W F et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat.[000255] In some embodiments, one, two or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the anti-transferrin receptor antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating antibody thereby increasing tumor localization. See, e.g., U.S. Pat. Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R L et al., (2001) J Biol Chem 276: 6591-604).[000256] In some embodiments, one or more amino in the constant region of a muscle and / or (e.g., and) CNS-targeting antibody described herein can be replaced with a different amino acid residue such that the antibody has altered Clq binding and / or (e.g., and) reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or (e.g., and) to increase the affinity of the antibody for an Fey receptor. This approach is described further in International Publication No. WO 00 / 42072.[000257] In some embodiments, the heavy and / or (e.g., and) light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or composite human antibodies or antigen-binding fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibodies derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will maintain the ability to specifically bind transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to transferrin receptor relative to the original antibody from which it is derived.[000258] In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing ‘Adair’ mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline resulting in an IgGl-like hinge sequence. Accordingly, any of the antibodies may include a stabilizing ‘Adair’ mutation.[000259] As provided herein, antibodies of this disclosure may optionally comprise constant regions or parts thereof. For example, a VL domain may be attached at its C-terminal end to a light chain constant domain like CK or Ck. Similarly, a VH domain or portion thereof may be attached to all or part of a heavy chain like IgA, IgD, IgE, IgG, and IgM, and anyisotype subclass. Antibodies may include suitable constant regions (see, for example, Kabat et al., Sequences of Proteins of Immunological Interest, No. 91-3242, National Institutes of Health Publications, Bethesda, Md. (1991)). Therefore, antibodies within the scope of this may disclosure include VH and VL domains, or an antigen binding portion thereof, combined with any suitable constant regions.Molecular Payloads[000260] Molecular payloads of the complexes described herein comprise enzymes (e.g., lysosomal enzymes such as an acid alpha glucosidase). In some embodiments, complexes provided herein are useful for targeting enzymes (e.g., lysosomal enzymes such as an acid alpha glucosidase) to the lysosomes of cells (e.g., muscle cells, CNS cells, and / or cells of the blood brain barrier). In some embodiments, a molecular pay load of complexes described herein comprises an acid alpha glucosidase capable of reducing levels of glycogen in muscle and / or (e.g., and) CNS, thereby treating a symptom of Pompe disease, including muscle atrophy, inflammation, and decreased differentiation potential, CNS inflammation, and muscle and CNS oxidative stress. In some embodiments, the complexes are designed to have desirable bioavailability and / or serum-stability properties. In some embodiments, the complexes are designed to have desirable binding affinity properties. In some embodiments, the complexes are designed to have desirable toxicity and / or immunogenicity profiles.[000261] An example of human wild-type acid alpha glucosidase sequence, corresponding to NCBI sequence XP_005257251.1 (lysosomal alpha-glucosidase isoform X) is as follows:MGVRHPPCSHRLLAVCALVSLATAALLGHILLHDFLLVPRELSGSSPVLEETHPAHQQ GASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQG LQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMME TENREHFTIKDPANRRYEVPEETPHVHSRAPSPEYSVEFSEEPFGVIVRRQEDGRVEEN TTVAPEFFADQFEQESTSEPSQYITGEAEHESPEMESTSWTRITEWNRDEAPTPGANE YGSHPFYEAEEDGGSAHGVFEENSNAMDVVEQPSPAESWRSTGGIEDVYIFEGPEPKS VVQQYEDVVGYPFMPPYWGEGFHECRWGYSSTAITRQVVENMTRAHFPEDVQWND EDYMDSRRDFTFNKDGFRDFPAMVQEEHQGGRRYMMIVDPAISSSGPAGSYRPYDEG ERRGVFITNETGQPEIGKVWPGSTAFPDFTNPTAEAWWEDMVAEFHDQVPFDGMWID MNEPSNFIRGSEDGCPNNEEENPPYVPGVVGGTEQAATICASSHQFESTHYNEHNE YGETEAIASHRAEVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQEASSVPEIE QFNEEGVPEVGADVCGFEGNTSEEECVRWTQEGAFYPFMRNHNSEESEPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLW GEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPVEALGSLPPPPAAPREPAIHSEGQW VTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDG ESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNG VPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC (SEQ ID NO: 160)[000262] In some embodiments, a molecular payload of a complex described herein comprises the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160). In some embodiments, a molecular payload of a complex described herein comprises a functional fragment or variant of a human acid alpha glucosidase (e.g., a functional fragment or variant as of the acid alpha glucosidase set forth in SEQ ID NO: 160). In some embodiments, a molecular payload of a complex described herein comprises a functional fragment of a human acid alpha glucosidase that is truncated at the N-terminus relative to the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160).[000263] In some embodiments, a molecular payload of a complex described herein comprises a functional fragment of a human acid alpha glucosidase that is truncated at the C- terminus relative to the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160). In some embodiments, a molecular payload of a complex described herein comprises a functional fragment of a human acid alpha glucosidase that is truncated at the N- terminus and at the C-terminus relative to the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160).[000264] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160.[000265] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 122-822 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160.[000266] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 204-782 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160.[000267] In some embodiments, a molecular payload of a complex described herein comprises a functional variant of a human acid alpha glucosidase that comprises one or more mutations (e.g., amino acid substitutions) relative to the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160). In some embodiments, a molecular payload of a complex described herein comprises a functional variant of a human acid alphaglucosidase that comprises one or more mutations (e.g., amino acid substitutions) relative to the human wild-type acid alpha glucosidase (e.g., as set forth in SEQ ID NO: 160), wherein the one or more mutations (e.g., amino acid substitutions) are at one or more amino acid positions involved in glycosylation of the acid alpha glucosidase.[000268] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising one or more mutations (e.g., amino acid substitutions) at positions corresponding to N652, N887, and / or N925 in SEQ ID NO: 160. [000269] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) at a position corresponding to N652 in SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) at a position corresponding to N887 in SEQ ID NO: 160. In some embodiments, a molecular pay load of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) at a position corresponding to N925 in SEQ ID NO: 160.[000270] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) at a positions corresponding to N652 and N887 in SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) at a positions corresponding to N652 and N925 in SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) at a positions corresponding to N887 and N925 in SEQ ID NO: 160.[000271] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) at a positions corresponding to N652, N887, and N925 in SEQ ID NO: 160.[000272] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising one or more mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the one or more mutations are selected from N652Q, N652E, N887Q, N887E, N925Q, N925E, and combinations thereof.[000273] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N652Q or N652E.[000274] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N887Q or N887E.[000275] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N925Q or N925E.[000276] In some embodiments, a molecular pay load of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N887Q.[000277] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E and N887Q.[000278] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N887E.[000279] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E and N887E.[000280] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N925Q.[000281] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N925E.[000282] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E and N925Q.[000283] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E and N925E.[000284] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N887Q and N925Q.[000285] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N887Q and N925E.[000286] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N887E and N925Q.[000287] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N887E and N925E.[000288] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887Q, and N925Q.[000289] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887E, and N925Q.[000290] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887Q, and N925E.[000291] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887E, and N925E.[000292] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887Q, and N925Q.[000293] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887E, and N925Q.[000294] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887Q, and N925E.[000295] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887E, and N925E.[000296] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises one or more mutations (e.g., amino acid substitutions) at positions corresponding to N652, N887, and / or N925 in SEQ ID NO: 160.[000297] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises one or more mutations (e.g., amino acid substitutions) relative to SEQ ID NO: 160, wherein the one or more mutations are selected from N652Q, N652E, N887Q, N887E, N925Q, N925E, and combinations thereof.[000298] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N652Q or N652E.[000299] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N887Q or N887E.[000300] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N925Q or N925E.[000301] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N887Q.[000302] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g.,amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E and N887Q.[000303] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N887E.[000304] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E and N887E.[000305] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N925Q.[000306] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q and N925E.[000307] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E and N925Q.[000308] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E and N925E.[000309] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wild-type acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N887Q and N925Q.[000310] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N887Q and N925E.[000311] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N887E and N925Q.[000312] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N887E and N925E.[000313] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887Q, and N925Q.[000314] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887E, and N925Q.[000315] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887Q, and N925E.[000316] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652Q, N887E, and N925E.[000317] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887Q, and N925Q.[000318] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887E, and N925Q.[000319] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887Q, and N925E.[000320] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 70-952 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises mutations (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutations are N652E, N887E, and N925E.[000321] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 122-822 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) at a position corresponding to N652 in SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 122-822 of a human wild-type acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N652Q or N652E.[000322] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 204-782 of a human wildtype acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) at a position corresponding to N652 in SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase corresponding to amino acids 204-782 of a human wild-type acid alpha glucosidase as set forth in SEQ ID NO: 160, and comprises a mutation (e.g., amino acid substitution) relative to SEQ ID NO: 160, wherein the mutation is N652Q or N652E.[000323] Non-limiting examples of acid alpha glucosidase polypeptides that are suitable as the molecular payload of complexes described herein are provided in Table 8.Table 8 Non-limiting examples of acid alpha glucosidase amino acid sequences[000324] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in any one of SEQ ID NOs: 160-170.[000325] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 161. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 161. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 161.[000326] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 162, and comprises a N652Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 162. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 162.[000327] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 163, and comprises a N925Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 163. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 163.[000328] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 164, and comprises a N887Q mutation and a N925Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 164. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 164.[000329] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 165, and comprises a N652Q, a N877Q, and a N925Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 165. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 165.[000330] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 166. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 166. Insome embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 166. [000331] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 167, and comprises a N652Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 167. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 167.[000332] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 168. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 168. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 168. [000333] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 169, and comprises a N652Q mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising the amino acid sequence as set forth in SEQ ID NO: 169. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 169.[000334] In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence as set forth in SEQ ID NO: 170, and comprises a N652E mutation relative to SEQ ID NO: 160. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase comprising theamino acid sequence as set forth in SEQ ID NO: 170. In some embodiments, a molecular payload of a complex described herein comprises an acid alpha glucosidase consisting of the amino acid sequence as set forth in SEQ ID NO: 170.[000335] In some embodiments, in any one of the complexes described herein, the acid alpha glucosidase is not glycosylated.[000336] In some embodiments, in any one of the complexes described herein, the acid alpha glucosidase is glycosylated (e.g., N-linked glycosylation and / or O-linked glycosylation). In some embodiments, in any one of the complexes described herein, the acid alpha glucosidase comprises one or more (e.g., 1-50, 5-50, 5-45, 5-40, 5-35, 5-30, 5-25, 5-20, 5-15, 5-10, 10-5-, 10-45, 10-40, 10-30, 10-25, 10-20, 10-15, 15-50, 15-45, 15-40, 14-35, 15-30, 15- 25, 15-20, 20-50, 20-45, 20-40, 20-35, 20-30, 20-25, 25-50, 25-45, 25-40, 25-35, 25-30, 30-50, 30-45, 30-40, 30-35, 35-50, 35-45, 35-40, 40-50, 40-45, or 45-50) glycans. For example, in some embodiments, in any one of the complexes described herein, the acid alpha glucosidase comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 glycans. In some embodiments, the one or more glycans are selected from a mannose, a glucose, an N- acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof.[000337] In some embodiments, an acid alpha glucosidase comprises one or more (e.g., 1-50, 5-50, 5-45, 5-40, 5-35, 5-30, 5-25, 5-20, 5-15, 5-10, 10-5-, 10-45, 10-40, 10-30, 10-25, 10-20, 10-15, 15-50, 15-45, 15-40, 14-35, 15-30, 15-25, 15-20, 20-50, 20-45, 20-40, 20-35, 20- 30, 20-25, 25-50, 25-45, 25-40, 25-35, 25-30, 30-50, 30-45, 30-40, 30-35, 35-50, 35-45, 35-40, 40-50, 40-45, or 45-50) glycans linked to one or more amino acids of the acid alpha glucosidase selected from amino acids corresponding to N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161, and combinations thereof. In some embodiments, the one or more glycans are selected from a mannose, a glucose, an N-acetylglucosamine, an N- acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof.[000338] In some embodiments, in any one of the complexes described herein, the acid alpha glucosidase comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 glycans, linked to one or more amino acids of the GAA selected from amino acids corresponding to N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161, and combinations thereof. In some embodiments, the one or more glycans are selected from a mannose, a glucose, an N-acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof.[000339] It is to be understood that one or more glycans (e.g., those selected from a mannose, a glucose, an N-acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof) may be linked to one amino acid (e.g., an amino acid selected from N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161). For example, multiple glycans (e.g., those selected from a mannose, a glucose, an N- acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof) may form a higher order glycan structure that is linked to one amino acid (e.g., an amino acid selected from N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161). In some embodiments, in any one of the complexes described herein, a GAA polypeptide may comprise one or more of such higher order glycan structures at one or more amino acids (e.g., one or more amino acid selected from N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161).Linkers[000340] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000341] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker. In some embodiments, in any one of the complexes described herein, a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000342] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker. In some embodiments, in any one of the complexes described herein, a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked at the N-terminus to the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti- TfRl Fab) via a linker.[000343] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the N-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker. In some embodiments, in any one of the complexes described herein, a molecularpay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked at the C-terminus to the N-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti- TfRl Fab) via a linker.[000344] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker. In some embodiments, in any one of the complexes described herein, a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked at the N-terminus to the C-terminus of the light chain of the anti-TfRl antibody (e.g., an anti- TfRl Fab) via a linker.[000345] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the N-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker. In some embodiments, in any one of the complexes described herein, a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked at the C-terminus to the N-terminus of the light chain of the anti-TfRl antibody (e.g., an anti- TfRl Fab) via a linker.[000346] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker, and a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000347] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the N-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker, and a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000348] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the C-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker, and a molecular pay load (e.g., a lysosomal enzyme such as an acid alphaglucosidase) is covalently linked to the N-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000349] In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the N-terminus of the heavy chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker, and a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the N-terminus of the light chain of the anti-TfRl antibody (e.g., an anti-TfRl Fab) via a linker.[000350] In some embodiments, in any one of the complexes described herein, a linker comprises at least one covalent bond. In some embodiments, a linker may be a single bond, e.g., a disulfide bond or disulfide bridge. In some embodiments, a linker may comprise multiple covalent bonds and / or multiple chemical moieties. In some embodiments, a linker is a cleavable linker. In some embodiments, a linker is a non-cleavable linker. A linker is typically stable in vitro and in vivo, and may be stable in certain cellular environments. Additionally, typically a linker does not negatively impact the functional properties of either the anti-TfRl antibody or the molecular payload. Examples and methods of synthesis of linkers are known in the art (see, e.g. Kline, T. et al. “Methods to Make Homogenous Antibody Drug Conjugates.” Pharmaceutical Research, 2015, 32:11, 3480-3493.; Jain, N. et al. “Current ADC Linker Chemistry” Pharm Res. 2015, 32:11, 3526-3540.; McCombs, J.R. and Owen, S.C. “Antibody Drug Conjugates: Design and Selection of Linker, Pay load and Conjugation Chemistry” AAPS J. 2015, 17:2, 339-351.).[000351] In some embodiments, a linker comprises two different reactive species that allow for attachment to both the anti-TfRl antibody and a molecular pay load. In some embodiments, the two different reactive species may be a nucleophile and / or an electrophile. In some embodiments, a linker contains two different electrophiles or nucleophiles that are specific for two different nucleophiles or electrophiles. In some embodiments, a linker is covalently linked to an anti-TfRl antibody via conjugation to a lysine residue or a cysteine residue of the anti-TfRl antibody. In some embodiments, a linker is covalently linked to a cysteine residue of an anti-TfRl antibody via a maleimide-containing linker, wherein optionally the maleimide-containing linker comprises a maleimidocaproyl or maleimidomethyl cyclohexane- 1 -carboxylate group. In some embodiments, a linker is covalently linked to a cysteine residue of an anti-TfRl antibody or thiol functionalized molecular pay load via a 3- arylpropionitrile functional group. In some embodiments, a linker is covalently linked to a lysine residue of an anti-TfRl antibody. In some embodiments, a linker is covalently linked toan anti-TfRl antibody and / or a molecular payload, independently, via an amide bond, a carbamate bond, a hydrazide, a triazole, a thioether, and / or a disulfide bond.[000352] In some embodiments, a linker is a peptide linker. In some embodiments, a peptide linker comprises various amino acids selected from glycine (G), serine (S), alanine (A), lysine (K), glutamic acid (E), and proline (P). In some embodiments, a peptide linker comprises a serine and a glycine. In some embodiments, a peptide linker comprises an alanine and a proline. In some embodiments, a peptide linker comprises an alanine, a glutamic acid, and a lysine.[000353] Any suitable peptide linkers known in the art and / or described herein may be used in a complex described herein to covalently link an anti-TfRl antibody (e.g., anti-TfRl Fab) to a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase). In some embodiments, in any one of the complexes described herein, a molecular pay load (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the heavy chain of an anti-TfRl antibody (e.g., anti-TfRl Fab), thereby forming one polypeptide chain. In some embodiments, in any one of the complexes described herein, a molecular payload (e.g., a lysosomal enzyme such as an acid alpha glucosidase) is covalently linked to the light chain of an anti-TfRl antibody (e.g., anti-TfRl Fab), thereby forming one polypeptide chain.[000354] In some embodiments, a linker comprises the amino acid sequence of (GGGGS)n (SEQ ID NO: 106), wherein n is an integer of 1-10. In some embodiments, a linker comprises the amino acid sequence of GGGGS (SEQ ID NO: 197). In some embodiments, a linker comprises the amino acid sequence of (GGGGS (SEQ ID NO: 198). In some embodiments, a linker comprises the amino acid sequence of (GGGGS)3 (SEQ ID NO: 199).[000355] In some embodiments, a linker comprises the amino acid sequence of (GGGS)n (SEQ ID NO: 200), wherein n is an integer of 1-10. In some embodiments, a linker comprises the amino acid sequence of (GGS)n (SEQ ID NO: 201), wherein n is an integer of 1-10. In some embodiments, a linker comprises the amino acid sequence of (GS)n (SEQ ID NO: 202), wherein n is an integer of 1-20.[000356] In some embodiments, a linker comprises the amino acid sequence of (PAPAP)n (SEQ ID NO: 203), wherein n is an integer of 1-10. In some embodiments, a linker comprises the amino acid sequence of PAPAP (SEQ ID NO: 131). In some embodiments, a linker comprises the amino acid sequence of (PAPAP)2 (SEQ ID NO: 204).[000357] In some embodiments, a linker comprises the amino acid sequence of (EAAAK)n (SEQ ID NO: 130), wherein n is an integer of 1-10. In some embodiments, a linkercomprises the amino acid sequence of EAAAK (SEQ ID NO: 205). In some embodiments, a linker comprises the amino acid sequence of (EAAAIQ2 (SEQ ID NO: 206). In some embodiments, a linker comprises the amino acid sequence of (EAAAIQ3 (SEQ ID NO: 207). [000358] In some embodiments, a linker comprises the amino acid sequence of EXAAAK (SEQ ID NO: 205). In some embodiments, “x” is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more.[000359] In some embodiments, in a complex described herein that comprise more than one molecular pay load, different linkers (e.g., those selected from the linkers such as peptide linkers described herein or known in the art) may be used to covalently link each molecular pay load to the anti-TfRl antibody.[000360] In some embodiments, in a complex described herein that comprise more than one molecular pay load, each molecular pay load is covalently linked to the anti-TfRl antibody via the same linker (e.g., any one of the linkers such as peptide linkers described herein or known in the art).Complexes[000361] Further provided herein are non-limiting examples of complexes comprising any one of the anti-TfRl antibodies (e.g., anti-TfRl Fabs) described herein covalently linked to any of the molecular payloads (e.g., a lysosomal enzyme such as an acid alpha glucosidase) described herein. In some embodiments, the anti-TfRl antibody (e.g., any one of the anti-TfRl antibodies provided in Tables 2-7) is covalently linked to a molecular payload (e.g., an acid alpha glucosidase provided in Table 8) via a linker (e.g., a peptide linker).[000362] In some embodiments, in a complex described herein, a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8) may be linked to the N-terminus and / or C- terminus of the heavy chain and / or light chain of the anti-TfRl antibody (e.g., anti-TfRl any one of the anti-TfRl antibodies provided in Tables 2-7). In some embodiments, a complex described herein comprises 1, 2, 3, or 4 lysosomal enzymes (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, a complex described herein comprises 1 single lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, a complex described herein comprises 2 lysosomal enzymes (e.g., an acid alpha glucosidase provided in Table 8), for example, one linked to the N- or C-terminus of the heavy chain or light chain of the anti-TfRl antibody (e.g., any one of the anti-TfRl antibodies provided in Tables 2-7).[000363] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000364] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody. In some embodiments, a complex comprises a single lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000365] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody, and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, a complex comprises a single lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000366] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody, and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, a complex comprises a single lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000367] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., e.g., an acid alpha glucosidase provided in Table 8). In someembodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000368] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000369] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000370] In some embodiments, a complex described herein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti- TfRl antibody covalently linked at the N-terminus to the C-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8), and the second polypeptide comprises a light chain of the anti-TfRl antibody covalently linked at the C-terminus to the N-terminus of a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8). In some embodiments, the anti-TfRl antibody is any one of the anti-TfRl antibodies provided in Tables 2-7.[000371] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) at the C-terminus to a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8, comprising the amino acid sequence of any one of SEQ ID NOs: 161-170), and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determiningregion 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDR-H3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 27, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 28, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 29, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the CDR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and a CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 33, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 34, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 35, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 36, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 38, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 39, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 40, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 41, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3. [000372] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) at the C-terminus to a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8, comprising the amino acid sequence of any one of SEQ ID NOs: 161-170), and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH), and the light chain of the anti-TfRl antibody comprises a light chain variable region (VL), wherein the VH and VL are selected from any one of the anti-TfRl antibodies listed in Table 3. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminusof the lysosomal enzyme. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 76 and the VL comprises the amino acid sequence of SEQ ID NO: 75. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000373] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) at the C-terminus to a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8, comprising the amino acid sequence of any one of SEQ ID NOs: 161-170), and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody and the light chain of the anti-TfRl antibody are selected from any one of the anti-TfRl antibodies listed in Table 4. In some embodiments, the heavy chain of the anti- TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 91 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000374] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) at the C-terminus to a lysosomal enzyme (e.g., an acid alpha glucosidase provided in Table 8, comprising the amino acid sequence of any one of SEQ ID NOs: 161-170), and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the anti-TfRl antibody is a Fab, and the heavy chain of the anti-TfRl antibody and the light chain of the anti-TfRl antibody are selected from any one of the anti-TfRl antibodies listed in Table 5. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the anti-TfRl antibody is a Fab, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, the linker is a peptide linker comprisingthe amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000375] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) to an acid alpha glucosidase comprising the amino acid sequence of any one of SEQ ID NOs: 161- 170), and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDR-H3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR- Ll), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 27, the CDR- H2 comprises the amino acid sequence of SEQ ID NO: 28, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 29, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the CDR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and a CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 33, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 34, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 35, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 36, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 38, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 39, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 40, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 41, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000376] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) to an acid alpha glucosidase comprising the amino acid sequence of any one of SEQ ID NOs: 161- 170, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH), and the light chain of the anti-TfRl antibody comprises a light chain variable region (VL), wherein the VH and VL are selected from any one of the anti-TfRl antibodies listed in Table 3. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 76 and the VL comprises the amino acid sequence of SEQ ID NO: 75. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000377] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) to an acid alpha glucosidase comprising the amino acid sequence of any one of SEQ ID NOs: 161- 170, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody and the light chain of the anti-TfRl antibody are selected from any one of the anti-TfRl antibodies listed in Table 4. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 91 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3. [000378] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked (e.g., via a linker such as a peptide linker) to an acid alpha glucosidase comprising the amino acid sequence of any one of SEQ ID NOs: 161- 170, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the anti-TfRl antibody is a Fab, and the heavy chain of the anti-TfRl antibody and the light chain of the anti-TfRl antibody are selected from any one of the anti-TfRl antibodies listed in Table5. In some embodiments, the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme. In some embodiments, the anti-TfRl antibody is a Fab, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, the linker is a peptide linker comprising the amino acid sequence of (GGGGS)n (SEQ ID NO: 208), (EAAAK)n (SEQ ID NO: 209), or PAPAP (SEQ ID NO: 131), wherein n is 1, 2, or 3.[000379] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked at the C-terminus via a peptide linker to the N- terminus of a peptide linker to an acid alpha glucosidase, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101, the light chain of the anti- TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90, and the acid alpha glucosidase comprises the amino acid sequence of SEQ ID NO: 161. In some embodiments, the peptide linker comprises the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 199). In some embodiments, the complex has one single acid alpha glucosidase. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 171, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90.[000380] In some embodiments, a complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked at the C-terminus via a peptide linker to the N- terminus of an acid alpha glucosidase, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101, the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90, and the acid alpha glucosidase comprises the amino acid sequence of SEQ ID NO: 161. In some embodiments, the peptide linker comprises the amino acid sequence of PAPAP (SEQ ID NO: 131). In some embodiments, the complex has one single acid alpha glucosidase. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90.[000381] Non-limiting examples of complexes comprising any one of the anti-TfRl antibodies (e.g., anti-TfRl Fabs) provided herein covalently linked to a molecular payload described herein are provided in Table 9.Table 9. Non-limiting examples of complexes* The GAA SEQ ID NO corresponds to the GAA SEQ ID NOs in Table 9; mutation positions are relative to the position in the wild-type human GAA protein (SEQ ID NO: 160).# Mutations in the GAA portion relative to wild-type human GAA protein (SEQ ID NO: 160) are bolded and underlined.[000382] In some embodiments, a complex described herein comprises:(a) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(b) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 171 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(c) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 171 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 172;(d) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 173 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(e) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 173 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO; 174;(f) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 175 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(g) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to comprises the amino acid sequence of SEQ ID NO: 175 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 176;(h) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 177 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(i) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 177 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 178;(j) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(k) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 180;(l) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 184 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(m) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 185 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(n) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 186 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(o) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 187 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(p) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least99%) identical to the amino acid sequence of SEQ ID NO: 188 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(q) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 189 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(r) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 190 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(s) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 191 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(t) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 192 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(u) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 193 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(v) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 101 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 194;(w) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 195 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 90;(x) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 101 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 196;(y) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 181 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 182; or(z) a first polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 181 and a second polypeptide comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%) identical to the amino acid sequence of SEQ ID NO: 183.[000383] In some embodiments, complex described herein comprises:(a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(b) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 171 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(c) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 171 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 172;(d) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 173 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(e) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 173 and a second polypeptide comprising the amino acid sequence of SEQ ID NO; 174;(f) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 175 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(g) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 175 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 176;(h) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 177 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(i) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 177 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 178;(j) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(k) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 179 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 180;(l) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 184 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(m) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 185 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(n) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 186 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(o) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 187 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(p) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 188 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(q) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 189 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(r) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 190 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(s) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 191 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(t) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 192 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(u) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 193 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(v) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 101 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 194;(w) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 195 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90;(x) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 101 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 196;(y) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 181 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 182; or(z) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 181 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 183.[000384] In some embodiments, a complex described herein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 179, and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90.[000385] In some embodiments, a complex described herein comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 171, and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90.[000386] In some embodiments, in any one of the complexes described herein, the first polypeptide and / or the second polypeptide further comprises a signal peptide at the N- terminus. Any know signal peptides suitable for eukaryotic protein expression may be used. In some embodiments, the signal peptide comprises the amino acid sequence of MGWSCIILFLVATATGVHS (SEQ ID NO: 104). In some embodiments, the signal peptide comprises the amino acid sequence of MGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, the signal peptide comprises the amino acid sequence of MRVPAQLLGLLLLWLPGARC (SEQ ID NO: 211). In some embodiments, the first polypeptide further comprises an N-terminal signal peptide, wherein the signal peptide comprises the amino acid sequence MGWSLILLFLVAVATRVHS (SEQ ID NO: 210). In some embodiments, the second polypeptide further comprises an N-terminal signal peptide,wherein the signal peptide comprises the amino acid sequence MRVPAQEEGEEEEWEPGARC (SEQ ID NO: 211).[000387] In some embodiments, in any one of the complexes described herein, the acid alpha glucosidase is glycosylated (e.g., N-linked glycosylation and / or O-linked glycosylation), e.g., comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 glycans, linked to one or more amino acids of the acid alpha glucosidase selected from amino acids corresponding to N71, N164, N321, N401, N583, N813, N856 of SEQ ID NO: 161, and combinations thereof. In some embodiments, the one or more glycans are selected from a mannose, a glucose, an N-acetylglucosamine, an N-acetylgalactosamine, a galactose, a fucose, a phospholipid, and combinations thereof.[000388] In some embodiments, a complex 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 of a complex at N-terminal Glutamate (Glu) and / or Glutamine (Gin) residues during production. As such, it should be appreciated that a complex 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 the first polypeptide of a complex. In some embodiments, pyroglutamate formation occurs in the second polypeptide of a complex.[000389] In some embodiments, in any one of the complexes described herein, the heavy chain of the anti-TfRl antibody (e.g., anti-TfRl Fab) comprises a N-terminal pyroglutamate (e.g., the N-terminal glutamate (Q) of the heavy chain undergoes N-terminal cyclization, forming an N-terminal pyroglutamate). In some embodiments, in any one of the complexes described herein (e.g., Complexes 1-25 provided in Table 9), when the first polypeptide comprises the heavy chain of the anti-TfRl antibody (e.g., anti-TfRl Fab) covalently linked to an acid alpha glucosidase (i.e., when the N-terminal glutamate (Q) of the heavy chain is the N- terminal amino acid of the first polypeptide), the first polypeptide comprises a N-terminal pyroglutamate (e.g., formed by N-terminal cyclization of the N-terminal glutamate (Q)).Nucleic Acids, Vectors, Cells, and Recombinant Production[000390] Any one of the complexes described herein may be produced via, e.g., recombinant technology. Expression of recombinant proteins may be achieved by artificially combining genetic material from multiple sources to produce recombinant DNA (rDNA) molecules that can comprise sequences that may not otherwise be found in the genome. DNA sequences can be modified or altered to enhance protein stability, functionality, orpharmacokinetic properties to produce protein variants that may possess improved therapeutic efficacy, reduced immunogenicity, or prolonged half-life in the body.[000391] In some embodiments, a complex described herein is prepared by recombinant technology as exemplified below. Nucleic acids (e.g., a single nucleic acid, or a set of nucleic acids) encoding the first polypeptide and the second polypeptide as described herein can be cloned into one expression vector, each nucleotide sequence being in operable linkage to a suitable promoter. In one example, each of the nucleotide sequences encoding the first polypeptide and the second polypeptide is in operable linkage to a distinct promoter. Alternatively, the nucleotide sequences encoding the first polypeptide and the second polypeptide can be in operable linkage with a single promoter, such that both polypeptides are expressed from the same promoter. When necessary, an internal ribosomal entry site (IRES) can be inserted between the first polypeptide and the second polypeptide encoding sequences. [000392] In some examples, the nucleotide sequences encoding the two polypeptides of a complex described herein are cloned into one single vector or into two vectors, which can be introduced into the same or different cells. When the two polypeptides are expressed in different cells, each of them can be isolated from the host cells expressing such and the isolated first polypeptide and the second polypeptide can be mixed and incubated under suitable conditions allowing for the formation of the complex.[000393] Generally, a nucleic acid sequence encoding one or both polypeptides of a complex can be cloned into a suitable expression vector in operable linkage with a suitable promoter using methods known in the art. For example, the nucleotide sequence and vector can be contacted, under suitable conditions, with a restriction enzyme to create complementary ends on each molecule that can pair with each other and be joined together with a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the termini of a gene. These synthetic linkers contain nucleic acid sequences that correspond to a particular restriction site in the vector. The selection of expression vectors / promoter would depend on the type of host cells for use in producing the antibodies.[000394] A variety of promoters can be used for expression of the antibodies described herein, including, but not limited to, cytomegalovirus (CMV) intermediate early promoter, a viral LTR such as the Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, the simian virus 40 (SV40) early promoter, E. coli lac UV promoter, and the herpes simplex tk virus promoter. [000395] Regulatable promoters can also be used. Such regulatable promoters include those using the lac repressor from E. coli as a transcription modulator to regulate transcription from lac operator bearing mammalian cell promoters [Brown, M. et al., Cell, 49:603-612(1987)], those using the tetracycline repressor (tetR) [Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-555115 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P., et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)]. Other systems include FK506 dimer, VP 16 or p65 using astradiol, RU486, diphenol murislerone, or rapamycin. Inducible systems are available from Invitrogen, Clontech and Ariad, among others.[000396] Regulatable promoters that include a repressor with the operon can be used. In one embodiment, the lac repressor from E. coli can function as a transcriptional modulator to regulate transcription from lac operator-bearing mammalian cell promoters [M. Brown et al., Cell, 49:603-612 (1987)]; Gossen and Bujard (1992); [M. Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551(1992)] combined the tetracycline repressor (tetR) with the transcription activator (VP 16) to create a tetR-mammalian cell transcription activator fusion protein, tTa (tetR- VP 16), with the tetO bearing minimal promoter derived from the human cytomegalovirus (hCMV) promoter to create a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline inducible switch is used. The tetracycline repressor (tetR) alone, rather than the tetR-mammalian cell transcription factor fusion derivatives can function as potent trans-modulator to regulate gene expression in mammalian cells when the tetracycline operator is properly positioned downstream for the TATA element of the CMVIE promoter (Yao et al., Human Gene Therapy). One particular advantage of this tetracycline inducible switch is that it does not require the use of a tetracycline repressor-mammalian cells transactivator or repressor fusion protein, which in some instances can be toxic to cells (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551(1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)), to achieve its regulatable effects.[000397] Additionally, the vector can contain, for example, some or all of the following: a selectable marker gene, such as the neomycin gene for selection of stable or transient transfectants in mammalian cells; enhancer / promoter sequences from the immediate early gene of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; SV40 polyoma origins of replication and ColEl for proper episomal replication; internal ribosome binding sites (IRESes), versatile multiple cloning sites; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for producing vectors containing transgenes are well known and available in the art. Examples of polyadenylation signals useful to practice the methods described herein include, but are not limited to, human collagen I polyadenylationsignal, human collagen II polyadenylation signal, and SV40 polyadenylation signal.[000398] One or more vectors (e.g., expression vectors) comprising nucleic acids encoding any of the complexes may be introduced into suitable host cells for producing the antibodies. The host cells can be cultured under suitable conditions for expression of the polypeptides or complexes thereof. Such polypeptides or complexes thereof can be recovered by the cultured cells (e.g., from the cells or the culture supernatant) via a conventional method, e.g., affinity purification. If necessary, polypeptides of the complexes can be incubated under suitable conditions for a suitable period of time allowing for production of the complexes.[000399] In some embodiments, methods for preparing a complex described herein involve a recombinant expression vector that encodes both the first polypeptide and the second polypeptide of a complex as also described herein. The recombinant expression vector can be introduced into a suitable host cell (e.g., a CHO cell) by a conventional method, e.g., calcium phosphate mediated transfection. Positive transformant host cells can be selected and cultured under suitable conditions allowing for the expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or from the culture medium. When necessary, the two chains recovered from the host cells can be incubated under suitable conditions allowing for the formation of the antibody.[000400] In one example, two recombinant expression vectors are provided, one encoding the first polypeptide of a complex and the other encoding the second polypeptide of a complex. Both of the two recombinant expression vectors can be introduced into a suitable host cell (e.g., CHO cell) by a conventional method, e.g., calcium phosphate-mediated transfection.[000401] Alternatively, each of the expression vectors can be introduced into a suitable host cells. Positive transformants can be selected and cultured under suitable conditions allowing for the expression of the polypeptides of the complex. When the two expression vectors are introduced into the same host cells, the antibody produced therein can be recovered from the host cells or from the culture medium. If necessary, the polypeptides can be recovered from the host cells or from the culture medium and then incubated under suitable conditions allowing for formation of the complex. When the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cells or from the corresponding culture media. The two polypeptides can then be incubated under suitable conditions for formation of the complex.[000402] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recovery of the complexes from the culture medium, e.g., by affinity chromatography.[000403] In some embodiments, a transient recombinant protein production system is used. In some embodiments, a stable transgenic recombinant protein production system is used. A transient recombinant protein expression system can deliver the recombinant protein in as little as 24 hours post-transfection, allowing production of recombinant proteins in a short time frame. Advantages of transient recombinant protein production include relatively high expression levels of the recombinant protein. However, since a transient recombinant protein production system is not incorporated into the genome of a cell, the amount of recombinant protein produced will be reduced over time due to a dilution of the components of the transient protein expression system with each cell generation. In some aspects, a stable recombinant protein expression system is used, where the nucleic acids encoding the polypeptides comprising a complex described herein are integrated into the genome of a cell producing the recombinant proteins. Methods of producing a cell line stably expressing one or more recombinant proteins are known in the art and can be readily employed by a person of skill in the art based on the disclosures provided herein.Formulations[000404] Complexes provided herein may be formulated in any suitable manner. Generally, complexes provided herein are formulated in a manner suitable for pharmaceutical use. For example, complexes can be delivered to a subject using a formulation that minimizes degradation, facilitates delivery and / or (e.g., and) uptake, or provides another beneficial property to the complexes in the formulation. In some embodiments, provided herein are compositions comprising complexes and pharmaceutically acceptable carriers. Such compositions can be suitably formulated 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. In some embodiments, complexes are formulated in buffer solutions such as phosphate-buffered saline solutions, liposomes, micellar structures, and capsids.[000405] It should be appreciated that, in some embodiments, compositions may include separately one or more components of complexes provided herein (e.g., muscle- and / or CNS- targeting agents, linkers, molecular payloads, or precursor molecules of any one of them). [000406] In some embodiments, complexes are formulated in water or in an aqueous solution (e.g., water with pH adjustments). In some embodiments, complexes are formulated in basic buffered aqueous solutions (e.g., PBS). In some embodiments, formulations as disclosed herein comprise an excipient. In some embodiments, an excipient confers to acomposition improved stability, improved absorption, improved solubility and / or (e.g., and) therapeutic enhancement of the active ingredient, e.g., a complex described herein. In some embodiments, an excipient is a buffering agent (e.g., sodium citrate, sodium phosphate, a tris base, or sodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum, dimethyl sulfoxide, or mineral oil).[000407] In some embodiments, a complex or component thereof is lyophilized for extending its shelf-life and then made into a solution before use (e.g., administration to a subject). Accordingly, an excipient in a composition comprising a complex, or component thereof, described herein may be a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol, or polyvinyl pyrolidone), or a collapse temperature modifier (e.g., dextran, ficoll, or gelatin). [000408] In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, administration. Typically, the route of administration is intravenous or subcutaneous.[000409] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In some embodiments, formulations include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the complexes in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.[000410] In some embodiments, a composition may contain at least about 0.1% of the complex, or component thereof, or more, although the percentage of the active ingredient(s) may be between about 1 % and about 80% or more of the weight or volume of the total composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.Methods of Use / Treatment[000411] Complexes as described herein (e.g., those provided in Table 9, such as Complex 9 and Complex 1) are effective in treating a subject having a lysosomal storage disease (e.g., Pompe disease). In some embodiments, a subject has infantile-onset Pompe disease (IOPD). In some embodiments, a subject has late-onset Pompe disease (LOPD). In some embodiments, a subject may be a human subject, a non-human primate subject, a rodent subject, or any suitable mammalian subject. In some embodiments, a subject has elevated levels of glycogen in lysosomes of cells. In some embodiments, a complex as described herein when targeted to a muscle cell and / or CNS cell of a subject reduces glycogen content in lysosomes of muscle and / or (e.g., and) CNS cells.[000412] An aspect of the disclosure includes methods involving administering to a subject an effective amount of a complex as described herein. In some embodiments, an effective amount of a pharmaceutical composition that comprises a complex as described herein can be administered to a subject in need of treatment (e.g., a subject having a lysosomal storage such as Pompe disease (e.g., IOPD or LOPD)). In some embodiments, a pharmaceutical composition comprising a complex 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, intravenous administration may be performed by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarticular, intrasynovial, or intrathecal routes. In some embodiments, a pharmaceutical composition may be in solid form, aqueous form, or a liquid form. In some embodiments, an aqueous or liquid form may be nebulized or lyophilized. In some embodiments, a nebulized or lyophilized form may be reconstituted with an aqueous or liquid solution.[000413] Compositions for intravenous administration may contain various carriers such as vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injection, water soluble antibodies can be administered by the drip method, whereby a pharmaceutical formulation containing the fusion complex and a physiologically acceptable excipients is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer’s solution or other suitable excipients. Intramuscular preparations, e.g., a sterile formulation of a suitable soluble salt form of the antibody, can be dissolved and administered in a pharmaceutical excipient such as Water-for- Injection, 0.9% saline, or 5% glucose solution.[000414] In some embodiments, a pharmaceutical composition that comprises a complex described herein is administered via site-specific or local delivery techniques. Examples ofthese techniques include implantable depot sources of the complex, local delivery catheters, site specific carriers, direct injection, or direct application.[000415] In some embodiments, a pharmaceutical composition that comprises a complex comprising a muscle- and / or CNS-targeting agent covalently linked to a molecular payload is administered at an effective concentration that confers therapeutic effect on a subject. Effective amounts vary, as recognized by those skilled in the art, depending on the severity of the disease, unique characteristics of the subject being treated, e.g., age, physical conditions, health, or weight, the duration of the treatment, the nature of any concurrent therapies, the route of administration and related factors. These related factors are known to those in the art and may be addressed with no more than routine experimentation. In some embodiments, an effective concentration is the maximum dose that is considered to be safe for the patient. In some embodiments, an effective concentration will be the lowest possible concentration that provides maximum efficacy.[000416] Empirical considerations, e.g., the half-life of the complex in a subject, generally will contribute to determination of the concentration of pharmaceutical composition that is used for treatment. The frequency of administration may be empirically determined and adjusted to maximize the efficacy of the treatment.[000417] Generally, for administration of any of the complexes described herein, an initial candidate dosage may be about 1 to 100 mg / kg, or more, depending on the factors described above, e.g., safety or efficacy. In some embodiments, a treatment will be administered once. In some embodiments, a treatment will be administered daily, weekly, once every two weeks, monthly, once every two months, or at any time interval that provide maximum efficacy while minimizing safety risks to the subject. In some embodiments, a method provided herein comprises administering any one of the complexes described herein once every two weeks, once every four weeks, or once every eight weeks. Generally, the efficacy and the treatment and safety risks may be monitored throughout the course of treatment.[000418] The efficacy of treatment may be assessed using any suitable methods. In some embodiments, the efficacy of treatment may be assessed by evaluation of observation of symptoms associated with Pompe disease including muscle mass loss and muscle atrophy, and behavioral and cognitive deficits.[000419] In some embodiments, a pharmaceutical composition that comprises a complex described herein is administered to a subject at an effective concentration sufficient to reduce the glycogen content in a target cell, e.g., a muscle cell and / or a CNS cell by at least 10%, atleast 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% relative to a control, e.g. level of glycogen in a target cell prior to treatment.[000420] In some embodiments, a pharmaceutical composition that comprises a complex described herein is administered to a subject at an effective concentration sufficient to reduce and / or normalize lysosome size in a target cell, e.g., a muscle cell and / or a CNS cell 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 at least 95% relative to a control, e.g. size of a lysosome in a target cell prior to treatment.[000421] In some embodiments, a single dose or administration of a pharmaceutical composition that comprises a complex described herein to a subject is sufficient to inhibit accumulation of glycogen for at least 1-5, 1-10, 5-15, 10-20, 15-30, 20-40, 25-50, or more days. In some embodiments, a single dose or administration of a pharmaceutical composition that comprises a complex comprising a muscle- and / or CNS-targeting agent covalently linked to a molecular payload described herein to a subject is sufficient to inhibit accumulation of glycogen in a target cell for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, a single dose or administration of a pharmaceutical composition that comprises a complex c described herein to a subject is sufficient to inhibit accumulation of glycogen in a target cell for at least 1, 2, 3, 4, 5, or 6 months.[000422] In some embodiments, a pharmaceutical composition may comprise more than one complex comprising a muscle- and / or CNS-targeting agent covalently linked to a molecular payload. In some embodiments, a pharmaceutical composition may further comprise any other suitable therapeutic agent for treatment of a subject, e.g. a human subject having a lysosomal storage disease (e.g., Pompe disease). In some embodiments, the other therapeutic agents may enhance or supplement the effectiveness of the complexes described herein. In some embodiments, the other therapeutic agents may function to treat a different symptom or disease than the complexes described herein.EXAMPLESExample 1: Preparation of Complexes[000423] To enhance the uptake of acid alpha glucosidase (GAA) polypeptide in muscle and enable delivery to the central nervous system, complexes of anti-TfRl Fab covalently linked to a GAA polypeptide via a peptide linker were engineered. The peptide linker andGAA polypeptide were covalently linked to the C- or N-terminus of a heavy chain of an anti- TfRl Fab and / or to the C- or N-terminus of a light chain of an anti-TfRl Fab.[000424] Complexes were designed using the full sequence for an anti-TfRl Fab (heavy chain sequence as set forth in SEQ ID NO: 101, light chain sequence as set forth in SEQ ID NO: 90). with several candidate sequences of human acid alpha glucosidase (GAA). In these fusion proteins, a peptide linker was added in between the Fab and GAA portions of the sequence. For all constructs, a signal peptide MGWSCIILFLVATATGVHS (SEQ ID NO: 104) was added to the N-terminal end of each fusion chain sequence to facilitate secretion of the protein. Protein sequences were used to generate codon-optimized DNA sequences for each fusion chain sequence for the expression host cell line.[000425] Transfection plasmids were prepared for each chain of the complexes, one including the light chain of the Fab (in some cases containing GAA as well) and another plasmid containing the heavy chain of the Fab (in some cases containing GAA as well). To express the complexes, light chain and heavy chain plasmids for each sequence were cotransfected into Chinese hamster ovary (CHO) cells. Transfected cell culture supernatants were harvested and clarified prior to purification.[000426] GAA complexes were purified from cell supernatants using affinity chromatography. Complexes were loaded onto a CaptureSelect CHI -XL Affinity Matrix+ column equilibrated with 20 mM Tris and eluted using 50 mM Sodium Acetate, pH 4.0. In some instances, an additional purification step was performed using a HiLoad Superdex 200 pg SEC column. Protein titer was assessed by measuring recovered protein concentrations using UV absorbance at A280. Protein purity was assessed using analytical SEC. Samples were injected on a TOSOH TSKgel G3000SWxl SEC column and a mobile phase consisting of 0.1 mol / L Na2SO4 in 0.1 mol / L Phosphate Buffer, pH 6.7. Purity was determined by assessing the relative peak area of the GAA complex monomer peak with respect to aggregates and other components.[000427] Protein titers and purity results for complexes are shown in Table 10.Table 10. Expression and Purification of Complexes* Complex No. corresponds to the Complex No. in Table 9.[000428] A complex with a single GAA polypeptide comprising the amino acid sequence of SEQ ID NO: 161 (corresponding to amino acids 70-952 of SEQ ID NO: 160) linked to the C-terminus of an anti-TfRl antibody (heavy chain sequence as set forth in SEQ ID NO: 101, light chain sequence as set forth in SEQ ID NO: 90) heavy chain with a (GGGGS)3 (SEQ ID NO: 199) linker demonstrated high titer expression with some aggregation that could be mitigated using formulation (Complex 1). Similarly, a complex with a single GAA polypeptide comprising amino acids 70-952 linked to the C-terminus of an anti-TfRl antibody (heavy chain sequence as set forth in SEQ ID NO: 101, light chain sequence as set forth in SEQ ID NO: 90) heavy chain with a PAPAP (SEQ ID NO: 131) linker demonstrated high titer expression and high purity (Complex 9).[000429] Complexes with a single GAA polypeptide comprising amino acids 70-952 linked to the C-terminus of an anti-TfRl antibody heavy chain with a (GGGGS (SEQ ID NO: 198), GGGGS (SEQ ID NO: 197), (EAAAK)3(SEQ ID NO: 207), or PAPAP (SEQ ID NO: 131) linker demonstrated lower but acceptable titers and purity (Complexes 3, 5, and 7).[000430] Complexes with two GAA polypeptides comprising amino acids 70-952 linked to the C-termini of an anti-TfRl antibody heavy and light chain with a (GGGGS)3 (SEQ IDNO: 199), (GGGGS (SEQ ID NO: 198), GGGGS (SEQ ID NO: 197), PAPAP (SEQ ID NO: 131), or (EAAAK)a (SEQ ID NO: 207) linker demonstrated reduced protein titers but acceptable purity (Complexes 2, 4, 6, 8, and 10).[000431] Complexes comprising anti-TfRl Fab and either one or two GAA polypeptides comprising amino acids 70-952 linked to the C-termini of the heavy and / or light chain with a (GGGGS)3 (SEQ ID NO: 199) linker demonstrated reduced expression and purity (Complexes 11 and 12).[000432] Complexes with a single truncated GAA polypeptide (comprising amino acids 122-882 or 204-782) did not express successfully (Complexes 17-20).[000433] Complexes with mutations that change the glycosylation of GAA (glycan mutations) (e.g., a GAA polypeptide comprising amino acids 70-952 and a N to Q substitution at positions 652, 887, and / or 925) linked to an anti-TfRl Fab with a (GGGGS)3 (SEQ ID NO: 199) linker demonstrated low expression and purity (Complexes 13-16). Glycan mutants with PAPAP (SEQ ID NO: 131) linkers also demonstrated reduced titers compared to similar complexes with wild- type GAA (Complexes 21 and 22 compared to Complex 9).[000434] Linking the GAA comprising amino acids 70-952 with a PAPAP (SEQ ID NO: 131) linker to the C-terminus of the light chain, the N-terminus of the heavy chain or the N- terminus of the heavy chain of an anti-TfRl Fab also resulted in poor expression (Complexes 23-25).Example 2: In vitro GAA enzyme activity[000435] GAA enzyme activity of the complexes described in Example 1 was measured by the conversion of 4-Methylumbelliferyl-P-D-Glucopyranoside (4-MU-Glu) to 4- Methylumbelliferone (4-MU), which can be quantified (Ex / Em = 360 / 465). 4-MU and the small molecule substrate 4-MU-Glu were dissolved in DMSO. 4-MU was subsequently used to generate a standard curve in 0.025M acetate buffer (pH=4.0). All test articles used in the assay were diluted in formulation buffer. To measure the enzymatic activity of the fusion constructs, 10 pL fusion was mixed with 20 pL of 4-MU-Glu substrate. This mixture was incubated at 37°C with shaking in the dark for 90 minutes. The reaction was stopped by the addition of 0.5M bicarbonate buffer (pH=11.0). Subsequently, the fluorescence was measured on a SpectraMax plate reader.[000436] High GAA enzyme activity was observed in Complexes 1, 9, 23, 24, and 25 with lower enzyme activity in Complexes 3, 5, 13, 21, and 22 (FIG. 1). The complexes with highest protein expression and GAA enzyme activity, Complexes 1 and 9, were further testedin vivo due to their high level of expression and purity, and the high GAA enzyme activities observed for these complexes in vitro.Example 3: Intravenous infusions of transiently expressed GAA Complexes in a mouse model[000437] To determine efficacy of transiently expressed Complex 1 or Complex 9 in vivo, heterozygous and homozygous mice were generated by breeding transgenic mice expressing human transferrin receptor 1 (hTfRl) with the 6Neomouse (B6;129-GaatmlRabn / J; JAX:004154) model of Pompe disease to generate the hTfRl / 6Neomouse.[000438] Heterozygous hTfRl / 6Neomice received intravenous (IV) infusions of vehicle control. Homozygous hTfRl / 6Neomice received IV infusions of vehicle control, naked GAA, Complex 1, or Complex 9. hTfRl / 6Neomice were treated with four weekly doses (e.g., on study day 0, 7, 14, and 21) or four doses administered every two weeks (Q2W) (e.g., on study days 0, 14, 28, and 42). Complex 1 and Complex 9 were administered at enzyme equivalent doses of 5 or 20 mg / kg. Following scheduled euthanasia on day 28 or day 49, respectively, blood was collected and processed to serum, and tissues from the heart, quadriceps, tibialis anterior, spinal cord, and brain were collected in 2 mL tubes and were either flash frozen in liquid nitrogen (LN2), OCT embedded, or fixed in 10% neutral buffered formalin (NBF). The term “naked GAA” used herein (e.g., in the Examples and figures) refers to a fragment of the human acid alpha glucosidase corresponding to amino acids 70-952 of SEQ ID NO: 160. The naked GAA may be glycosylated or not glycosylated, or may have the same or different glycosylation than the GAA present in a complex. “Naked” means that the acid alpha glucosidase fragment is not covalently linked or an anti-TfRl antibody (e.g., an anti-TfRl antibody described herein).Assessing GAA enzyme activity[000439] The heart, tibialis anterior, quadriceps, spinal cord, cerebral cortex, and cerebellum were weighed and transferred to water. Tissues were subsequently homogenized in water on a Precellys bead mill homogenizer. Homogenates were boiled and subsequently centrifuged to remove insoluble material. Tissue supernatants were combined with 2mM 4- MU-Glu in 0.025M acetate buffer, pH=4.0 and were incubated at 37°C for 90 minutes protected from light with shaking. Subsequently, 0.5M bicarbonate buffer, pH=l l was addedto all wells to terminate the reaction. The output was immediately measured at 360 / 465 nm on a Spectramax M5 plate reader.Assessing Glycogen Levels[000440] Tissues were weighed and transferred to water. Tissues were subsequently homogenized in water on a PreCellys bead mill homogenizer (Bertin Instruments). Homogenates were boiled and subsequently centrifuged to remove insoluble material. Supernatants were incubated with reaction mixture according to the manufacturer’s instructions (Abeam). Subsequently, absorbance at 450 nm was quantified on a SpectraMax M5 plate reader (Molecular devices).[000441] Four weekly doses (Q1W) of transiently expressed Complex 1 or Complex 9 resulted in an increase of GAA enzyme activity (FIGS. 2A-2C) and dose-dependent glycogen reduction (FIGS. 3A-3C) in the heart, tibialis anterior, and quadriceps of hTfRl / 6Neohomozygous mice. Four weekly doses of transiently expressed Complex 1 or Complex 9 also resulted in increased GAA enzyme activity (FIGS. 5A-5C) and reduced glycogen (FIGS. 6A- 6C and FIGS. 8A-8B) in the central nervous system (e.g., cerebral cortex, cerebellum, corpus callosum, hippocampus, brain stem, and spinal cord) of hTfRl / 6Neohomozygous mice. When dosed every two weeks, transiently expressed Complex 1 or Complex 9 also demonstrated a dose dependent increase of GAA enzyme activity (FIGS. 9A-9D) and dose dependent glycogen reduction (FIGS. 10A-10D) in heart, tibialis anterior, diaphragm, and quadriceps. Further, exposure to transiently expressed Complexes 1 or 9 administered every two weeks resulted in increased GAA enzyme activity in the cerebral cortex and cerebellum (FIGS. 12A- 12B) and reduced glycogen in the hippocampus / corpus callosum, cerebral cortex, cerebellum, and spinal cord (FIGS. 13A-13C and FIGS. 15A-15B). These results demonstrate that IV infusion of transiently expressed Complex 1 or Complex 9 restored GAA enzyme activity and reduced glycogen in the muscles and central nervous system of hTfRl / 6Neohomozygous mice.Assessing lysosomal enlargement[000442] Paraffin embedded tissues were deparaffinized in Xylenes followed by dehydration in ethanol and rehydration in water. High temperature antigen retrieval followed by blocking in 5%BSA / 0.04% Triton X-100 in PBS for 30 minutes was performed prior to antibody incubations. Primary antibody (i.e., LAMP1) was diluted in 5%BSA / 0.04% Triton X- 100 / PBS and incubated at 4°C overnight. Following a series of washes in PBS, the slides were incubated in secondary for 1 hour at room temperature. Slides were subsequently washed,mounted in DAPI Fluoromount G, and stored at 4°C prior to imaging on a Zeiss Axioscan 7 and analysis with Zeiss Zen microscopy software.[000443] Lysosomal enlargement in the muscles (FIG. 4) and central nervous system (FIG. 7) was reduced in hTfRl / 6Neohomozygous mice treated with four weekly doses of transiently expressed Complex 1 or Complex 9, relative to vehicle and naked GAA controls. Similarly, four doses of transiently expressed Complex 1 or Complex 9 administered every two weeks reduced lysosomal enlargement in the central nervous system of hTfRl / 6Neohomozygous mice (FIG. 16). These results confirmed the reduction of lysosomal size across multiple organ systems following exposure to transiently expressed Complex 1 or Complex 9 administered weekly or every two weeks to hTfRl / 6Neohomozygous mice.GAA protein levels in tissue[000444] Frozen tissues were weighed and homogenized in homogenization tubes using a PreCellys tissue homogenizer. Homogenates were centrifuged for 15 minutes at 15,000 rpm. Supernatants were recovered and total protein was quantified using the Pierce Rapid Gold BCA protein assay kit. Supernatants were heat treated at 95°C in reducing Laemmli SDS sample buffer. Samples were electrophoresed and proteins transferred to nitrocellulose membranes. Membranes were blocked with Odyssey. Blots were incubated in anti-human GAA and anti-Mouse GAPDH in Odyssey TBS Antibody Diluent overnight at 4°C with rocking. Subsequently, the blots were washed in 0.01% TBS-T and incubated with secondary IR antibodies in Odyssey TBS Antibody Diluent. Western blot membranes were washed in 0.01% TBS-T and visualized using the Odyssey CLx Imaging System.[000445] GAA protein was observed in the muscle (FIGS. 11A-1 ID) and central nervous system (FIGS. 14A-14B) of hTfRl / 6Neohomozygous mice by western blots following four IV infusions of transiently expressed Complexes 1 or 9 administered every two weeks.Neurofilament light chain assessment[000446] Serum samples were collected for neurofilament light chain (NF-L) assessment. Briefly, maximum attainable blood volume was collected via cardiac puncture. After collection, the blood was clotted, and the clot was removed by centrifuging. Immediately after centrifugation, the liquid component was transferred to two clean tubes with equal volumes in each tube using a pipette. Serum NF-L was analyzed using the Quanterix NF-L light™ assay kit according to the manufacturer’s instructions.[000447] Four doses of transiently expressed Complex 1 or Complex 9 administered every two weeks reduced serum NF-L, a marker of axonal injury in hTfRl / 6Neohomozygous mice (FIG. 17). The results demonstrate that Complex 1 and Complex 9 are effective in alleviate CNS symptoms of Pompe disease.Example 4: Activities of stably expressed Complexes 1 and 9 in a mouse model[000448] To determine efficacy of stably expressed Complex 1 and Complex 9 in vivo, homozygous and heterozygous mice hTfRl / 6Neomice were generated as described in Example 3. Complex 1 and Complex 9 were expressed and purified from cell lines that stably express the complexes.[000449] Heterozygous hTfRl / 6Neomice received intravenous (IV) infusions of vehicle control. Homozygous hTfRl / 6Neomice received IV infusions of vehicle control, naked GAA, Complex 1, or Complex 9. hTfRl / 6Neomice were treated with two doses administered every two weeks (e.g., on study day 0 and 14), four doses administered every two weeks (e.g., on study days 0, 14, 28, and 42), or two monthly doses (e.g., on study days 0 and 28). Complex 1, Complex 9, and naked GAA were administered at an enzyme equivalent doses of 5 or 20 mg / kg. Following scheduled euthanasia on day 28 or day 56, respectively, blood was collected and processed to serum, and tissues from the heart, quadriceps, tibialis anterior, spinal cord, and brain were collected in 2 mL tubes and were either flash frozen in liquid nitrogen (LN2), OCT embedded, or fixed in 10% neutral buffered formalin (NBF).Assessing GAA enzyme activity[000450] The heart, tibialis anterior, quadriceps, spinal cord, cerebral cortex, and cerebellum tissues were prepared as previously described in Example 3. Tissue supernatants were combined with 2mM 4-MU-Glu in 0.025M acetate buffer, pH=4.0 and were incubated at 37°C for 90 minutes protected from light with shaking. Subsequently, 0.5M bicarbonate buffer, pH=l 1 was added to all wells to terminate the reaction. The output was immediately measured at 360 / 465 nm on a Spectramax M5 plate reader.Assessing Glycogen Levels[000451] Tissues were weighed and transferred to water. Tissues were subsequently homogenized in water on a PreCellys bead mill homogenizer (Bertin Instruments).Homogenates were boiled and subsequently centrifuged to remove insoluble material. Supernatants were incubated with reaction mixture according to the manufacturer’sinstructions (Abeam). Subsequently, absorbance at 450 nm was quantified on a SpectraMax M5 plate reader (Molecular devices).[000452] Two doses of stably expressed Complex 1 or Complex 9 administered every two weeks resulted in increased GAA enzyme activity (FIGS. 18A-18E) in the heart, tibialis anterior, quadriceps, gastrocnemius, and diaphragm and reduced glycogen levels (FIGS. 19A- 19F) in the heart, tibialis anterior, quadriceps soleus, diaphragm, and gastrocnemius of hTfRl / 6Neohomozygous mice. Two doses of stably expressed Complex 1 or Complex 9 administered every two weeks also resulted in increased GAA enzyme activity (FIGS. 21A- 21C) and reduced glycogen levels (FIGS. 22A-22C) in the cerebral cortex, cerebellum, and spinal cord of hTfRl / 6Neohomozygous mice.[000453] Four doses of stably expressed Complex 1 administered every two weeks resulted in increased GAA enzyme activity in the heart, diaphragm, quadriceps, tibialis anterior, and gastrocnemius (FIGS. 36A-36E) of hTfRl / 6Neohomozygous mice. Reduced glycogen levels were also observed in the heart, diaphragm, quadriceps, tibialis anterior, and soleus of hTfRl / 6Neohomozygous mice following four doses of stably expressed Complex 1 administered every two weeks (FIGS. 38A-38E and FIG. 39).[000454] Additionally, four doses of stably expressed Complex 1 administered every two weeks resulted in increased GAA enzyme activity (FIGS. 41A-41C) and reduced glycogen levels (FIGS. 43A-43C and FIG. 44) in the cerebral cortex, cerebellum, and spinal cord of hTfRl / 6Neohomozygous mice.[000455] Four doses of stably expressed Complex 9 administered every two weeks resulted in increased GAA enzyme activity in the heart, diaphragm, quadriceps, and cerebral cortex (FIGS. 51A-51D) of hTfRl / 6Neohomozygous mice. Reduced glycogen levels were also observed in the heart, diaphragm, quadriceps, and cerebral cortex of hTfRl / 6Neohomozygous mice following four doses of stably expressed Complex 9 administered every two weeks (FIGS. 52A-52D and FIG. 54).[000456] Two monthly doses of stably expressed Complex 1 or Complex 9 resulted in increased GAA enzyme activity (FIGS. 25A and 25E) in the heart and diaphragm at day 56, while GAA enzyme activity in the (FIGS. 25B-25D) tibialis anterior, quadriceps, and gastrocnemius was comparable to vehicle treated hTfRl / 6Neohomozygous mice at day 56. Two monthly doses of stably expressed Complex 1 or Complex 9 reduced glycogen levels (FIG. 26A, 26C and FIG. 28) in the heart, and quadriceps, as well as (FIGS. 26B, 26D-26F) the tibialis anterior soleus, diaphragm, and gastrocnemius at day 56. GAA enzyme activity (FIGS.30A-30C) at day 56 after 2 monthly doses of stably expressed Complex 1 or Complex 9 was comparable to vehicle treated hTfRl / 6Neohomozygous mice in the cerebral cortex, cerebellum, and spinal cord. Two monthly doses of stably expressed Complex 1 or Complex 9 reduced glycogen levels (FIGS. 31A-31C and FIG. 33) in cerebral cortex, cerebellum, and spinal cord of the mice.[000457] These results demonstrate that IV infusion (every other week or monthly) of stably expressed Complex 1 or Complex 9 restored GAA enzyme activity and reduced glycogen in the muscles and central nervous system of hTfRl / 6Neohomozygous mice.Assessing lysosomal enlargement[000458] Lysosomal enlargement was assessed as described in Example 3. Four doses of stably expressed Complex 1 administered every two weeks reduced lysosomal enlargement in the heart and quadriceps (FIG. 40) and in the cerebral cortex and cerebellum (FIG. 45) of hTfRl / 6Neohomozygous mice. Two monthly doses of stably expressed Complex 1 or Complex 9 reduced lysosomal enlargement in the heart and quadriceps (FIG. 29) and in the central nervous system (FIG. 34) of hTfRl / 6Neohomozygous mice. These results confirmed the reduction of lysosomal size across multiple organ systems following weekly or every other week administration of stably expressed Complex 1 or Complex 9 in hTfRl / 6Neohomozygous mice.GAA protein levels in tissue[000459] GAA protein in the muscles and central nervous system of tissues harvested from hTfRl / 6Neohomozygous mice was assessed as described in Example 3.[000460] GAA protein was observed in the muscle (FIGS. 20A-20C) and central nervous system (FIGS. 23A-23B) of hTfRl / 6Neohomozygous mice by western blots following two IV infusions of stably expressed Complexes 1 or 9 administered two weeks apart. GAA protein was also observed in the heart and quadriceps (FIGS. 37A-37B) and cerebral cortex and cerebellum (FIGS. 42A-42B) of hTfRl / 6Neohomozygous mice by western blots following four IV infusions of stably expressed Complex 1 administered every two weeks. GAA protein was also observed in the cerebral cortex and cerebellum (FIGS. 32A-32B) of hTfRl / 6Neohomozygous mice by western blots following two monthly IV infusions of stably expressed Complexes 1 or 9.Neurofilament light chain assessment[000461] Serum NF-L was assessed following two doses of stably expressed Complex 1 or Complex 9 administered two weeks apart, as described in Example 3. Two doses of stably expressed Complexes 1 or Complex 9 administered two weeks apart reduced serum NF-L in hTfRl / 6Neohomozygous mice (FIG. 24). Four doses of stably expressed Complex 1 administered every two weeks reduced serum NF-L in hTfRl / 6Neohomozygous mice (EIG. 46). Lour doses of stably expressed Complex 9 administered every two weeks also reduced serum NE-L in hTfRl / 6Neohomozygous mice (EIG. 53). Two monthly doses of stably expressed Complexes 1 or Complex 9 also reduced serum NF-L in hTfRl / 6Neohomozygous mice (FIG. 35). These data demonstrate that stably expressed Complex 1 or Complex 9 are effective in reducing serum NF-L, a marker of axonal injury, in hTfRl / 6Neohomozygous mice.Assessing neuroinflammation[000462] Paraffin embedded tissues were deparaffinized in Xylenes followed by dehydration in ethanol and rehydration in water. High temperature antigen retrieval followed by blocking in 5%BSA / 0.04% Triton X-100 in PBS for 30 minutes was performed prior to antibody incubations. Primary antibodies (e.g., GFAP or IBA1) were diluted in 5%BSA / 0.04% Triton X-100 / PBS and incubated at 4°C overnight. Following a series of washes in PBS, the slides were incubated in secondary for 1 hour at room temperature. Slides were subsequently washed, mounted in DAPI Fluoromount G, and stored at 4°C prior to imaging on a Zeiss Axioscan 7 and analysis with Zeiss Zen microscopy software. Four doses of stably expressed Complex 1 administered every two weeks, reduced GFAP (astrocytes) and IB Al (microglia) staining, two markers of neuroinflammation in the cerebral cortex of homozygous hTfRl / 6Neomice (FIG. 47).[000463] These data demonstrate the potential of the fusion constructs described herein as an innovative therapy for Pompe that addresses both the muscle and CNS manifestations of the disease.Example 5 - Sustained Activities of stably expressed Complex 9 in a mouse model [000464] Heterozygous and homozygous mice were generated by breeding transgenic mice expressing Human transferrin receptor 1 (hTfRl) with the 6Neomouse (B6;129- GaatmlRabnf JAX:004154) model of Pompe disease to generate the hTfRl / 6Neomouse. Homozygous hTfRl / 6Neomice received IV infusions of vehicle or Complex 9. hTfRl / 6Neomice were treated with stably expressed Complex 9 at enzyme equivalent doses of 20 mg / kg on study day 0.[000465] Following scheduled euthanasia on days 14, 28, 42, and 56 blood was collected and processed to serum, and tissues from the heart, diaphragm, tibialis anterior, quadriceps, and brain were collected in 2 mL tubes.Assessing Glycogen LevelsThe heart, diaphragm, tibialis anterior, quadriceps, cerebral cortex, and cerebellum were weighed and transferred to water. Tissues were subsequently homogenized in water on a PreCellys bead mill homogenizer (Bertin Instruments). Homogenates were boiled and subsequently centrifuged to remove insoluble material. Supernatants were incubated with reaction mixture according to the manufacturer’s instructions (Abeam). Subsequently, absorbance at 450 nm was quantified on a SpectraMax M5 plate reader (Molecular devices). Total glycogen levels demonstrate the sustained and durable glycogen clearance with Complex 9 in the muscles and central nervous system following a single administration in hTfRl / 6NeoPompe disease mice (FIGs. 48A-48F).Neurofilament light chain assessment[000466] Serum samples were collected for neurofilament light chain assessment. Briefly, maximum attainable blood volume was collected via cardiac puncture. After collection, the blood was clotted, and the clot was removed by centrifuging. Immediately after centrifugation, the liquid component was transferred to two clean tubes with equal volumes in each tube using a pipette. Serum Nf-L was analyzed using the Quanterix Nf-L light™ assay kit according to the manufacturer’s instructions. Sustained and durable reduction of serum NF-L is observed with a single administration of Complex 9 in hTfRl / 6NeoPompe disease mice (FIG. 49).Assessing GAA enzyme activity[000467] The heart, diaphragm, tibialis anterior, quadriceps, cerebral cortex, and cerebellum were and transferred to water. Tissues were subsequently homogenized in water on a PreCellys bead mill homogenizer (Bertin Instruments). Tissue supernatants were combined with 2mM 4-MU-Glu in 0.025M acetate buffer, pH=4.0 and were incubated at 37°C for 90 minutes protected from light with shaking (180 rpm). Subsequently, 0.5M bicarbonate buffer, pH=l 1 was added to all wells to terminate the reaction. The output was immediately measured at 360 / 465 nm on a Spectramax M5 plate reader. A single dose of Complex 9 resulted in increased GAA enzyme activity relative to vehicle treated hTfRl / 6Neohomozygous mice in the heart, diaphragm, cerebral cortex, and cerebellum for at least 42 days (i.e., six weeks)following a single administration in hTfRl / 6NeoPompe disease mice (FIGs. 50A-50F). GAA enzyme activity in heart, diaphragm, tibialis anterior, quadriceps, cerebral cortex, and cerebellum was comparable to vehicle treated hTfRl / 6Neohomozygous mice at day 56.ADDITIONAL EMBODIMENTS1. A complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked at the C-terminus to a lysosomal enzyme, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDRH3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2.2. The complex of embodiment 1, wherein the lysosomal enzyme is an acid alphaglucosidase (GAA).3. The complex of embodiment 2, wherein the GAA comprises the amino acid sequence of any one of SEQ ID NOs: 161-170.4. The complex of any one of embodiments 1-3, wherein the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme.5. The complex of any one of embodiments 1-4, wherein the complex comprises a single lysosomal enzyme.6. A complex comprising first polypeptide and a second polypeptide, wherein first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibodycovalently linked to an acid alpha-glucosidase (GAA) comprising the amino acid sequence of any one of SEQ ID NOs: 161-170, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain c...

Claims

CLAIMSWhat is claimed is:

1. A complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked at the C-terminus to a lysosomal enzyme, and the second polypeptide comprises a light chain of the anti-TfRl antibody, wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDRH3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2.

2. The complex of claim 1, wherein the lysosomal enzyme is an acid alpha-glucosidase (GAA).

3. The complex of claim 2, wherein the GAA comprises the amino acid sequence of any one of SEQ ID NOs: 161-170.

4. The complex of any one of claims 1-3, wherein the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the lysosomal enzyme.

5. The complex of any one of claims 1-4, wherein the complex comprises a single lysosomal enzyme.

6. A complex comprising first polypeptide and a second polypeptide, wherein first polypeptide comprises a heavy chain of an anti-transferrin receptor 1 (TfRl) antibody covalently linked to an acid alpha-glucosidase (GAA) comprising the amino acid sequence of any one of SEQ ID NOs: 161-170, and the second polypeptide comprises a light chain of the anti-TfRl antibody,wherein the heavy chain of the anti-TfRl antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), a heavy chain complementarity determining region 3 (CDRH3), wherein the light chain of the anti-TfRl antibody comprises a light chain variable region (VL) comprising light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), a light chain complementarity determining region 3 (CDR-L3), and wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 are selected from any one of the anti-TfRl antibodies listed in Table 2.

7. The complex of claim 6, wherein the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the GAA.

8. The complex of claim 7, wherein the heavy chain of the anti-TfRl antibody is covalently linked at the C-terminus to the N-terminus of the GAA.

9. The complex of any one of claims 6-8, wherein the complex comprises a single GAA.

10. The complex of any one of claims 1-8, wherein the VH and the VL are selected from any of the anti-TfRl antibodies listed in Table 3.

11. The complex of any one of claims 1-10, wherein the anti-TfRl antibody is a Fab, optionally wherein the heavy chain of the anti-TfRl antibody and the light chain of the anti- TfRl antibody are selected from any one of the anti-TfRl Fabs listed in Table 5.

12. The complex of any one of embodiments 1-10, wherein:(i) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 27, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 28, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 29, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the CDR-L2 comprising the amino acid sequence of SEQ ID NO: 31, and a CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32;(ii) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 33, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 34, the CDR-H3 comprises the amino acidsequence of SEQ ID NO: 35, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 36, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 32; or(iii) the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 38, the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 39, the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 40, the CDR-L1 comprises the amino acid sequence of SEQ ID NO: 41, the CDR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and the CDR-L3 comprises the amino acid sequence of SEQ ID NO: 42.

13. The complex of embodiment 12, wherein the VH comprises the amino acid sequence of SEQ ID NO: 76 and the VL comprises the amino acid sequence of SEQ ID NO: 75.

14. The complex of embodiment 12 or embodiment 13, wherein the anti-TfRl antibody is a Fab, wherein the heavy chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 101 and the light chain of the anti-TfRl antibody comprises the amino acid sequence of SEQ ID NO: 90.

15. The complex of claim any one of claims 1-14, wherein the GAA is covalently linked to the anti-TfRl antibody via a linker, optionally wherein the linker is a peptide linker.

16. The complex of claim 15, wherein the linker comprises the amino acid sequence of (GGGGS)n (SEQ ID NO: 106), (EAAAK)n (SEQ ID NO: 130), or PAPAP (SEQ ID NO: 131), wherein n is an integer of 1-10, optionally wherein n=3.

17. The complex of any one of claims 1-16, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 179, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90.

18. The complex of any one of claims 1-16, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 171, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90.

19. The complex of any one of claims 1-18, wherein the first polypeptide comprises an N- terminal pyroglutamate.

20. A composition comprising complexes of any one of claims 1-19.

21. A nucleic acid or a set of nucleic acids encoding the complex of any one of claims 1-20.

22. A vector or a set of vectors comprising the nucleic acid or the set of nucleic acids of claim 21.

23. A cell comprising the nucleic acid or the set of nucleic acids of claim 18, or the vector or the set of vectors of claim 22.

24. A method of producing the complex of any one of claims 1-19, comprising culturing the cell of claim 20 under conditions suitable for the expression of the complex, optionally further comprising isolating the complex.

25. A method of delivering a lysosomal enzyme to a cell, comprising contacting the complex of any one of claims 1-19 or the composition of claim 20 with the cell.

26. The method of claim 25, wherein the cell is a muscle cell, a cell of the nervous system, or a cell of the blood brain barrier, optionally wherein the nervous system is central nervous system (CNS) or peripheral nervous system (PNS).

27. The method of claim 25 or claim 26, wherein the cell is in vitro.

28. The method of claim 25 or claim 26, wherein the cell is in a subject, optionally wherein the subject is human.

29. A method of delivering a lysosomal enzyme to a subject, comprising administering the complex of any one of claims 1-19 or the composition of claim 20 to the subject, optionally, wherein the subject has a lysosomal storage disease, further optionally wherein the subject is human.

30. The method of claim 29, wherein the lysosomal enzyme is delivered to the muscle and / or the central nervous system of the subject.

31. A method of treating a lysosomal storage disease in a subject, comprising administering the complex of any one of claims 1-19 or the composition of claim 20 to the subject, optionally wherein the subject is human.

32. The method of any one of claims 25-30, wherein the lysosomal enzyme is GAA.

33. The method of claim 31 or 32, wherein the lysosomal storage disease is Pompe disease.

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