Muscle-targeting complexes and their uses for treating dystrophinopathies

Abstract

The objective is to provide a conjugate comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle targeting agent specifically binds to an internalized cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in mRNA expressed from a mutant DMD allele.

Description

[Technical Field]

[0001] Related Applications This application is related to U.S. Provisional Application No. 63 / 132,929, filed December 31, 2020, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF," U.S. Provisional Application No. 63 / 069,066, filed August 23, 2020, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," U.S. Provisional Application No. 63 / 055,537, filed July 23, 2020, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," U.S. Provisional Application No. 63 / 055,537, filed February 24, 2020, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," U.S. Provisional Application No. 62 / 980,874, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," filed January 31, 2020; U.S. Provisional Application No. 62 / 968,443, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," filed January 24, 2020; and U.S. Provisional Application No. 62 / 959,796, entitled "MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES," filed January 10, 2020, all of which are hereby incorporated by reference. The benefit of this application under USC § 119(e) is claimed; the contents of each of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION This application relates to targeting complexes for delivering molecular payloads (eg, oligonucleotides) to cells and their uses, particularly for the treatment of disease.

[0003] Reference to a sequence listing submitted as a text file via EFS-WEB This application contains a Sequence Listing, which has been submitted via EFS-Web in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on January 8, 2021, is designated D082470031WO00-SEQ-ZJG and is XX kilobytes in size. [Background technology]

[0004] background Dystrophinopathies are a group of distinct neuromuscular diseases resulting from mutations in the dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy. Dystrophin (DMD) is a large gene containing 79 exons and approximately 26 million total base pairs. Numerous mutations in DMD, including exon frameshifts, deletions, substitutions, and duplications, can reduce the expression of functional dystrophin, leading to dystrophinopathies. One drug targeting exon 51 of human DMD has been preliminarily approved by the U.S. Food and Drug Administration (FDA), but its efficacy is still under evaluation. Summary of the Invention

[0005] overview According to some aspects, the present disclosure provides a complex that targets muscle cells for the purpose of delivering a molecular payload to those cells. In some embodiments, the complexes provided herein are particularly useful for delivering a molecular payload that increases or restores functional DMD expression or activity. In some embodiments, the complex comprises an oligonucleotide-based molecular payload that promotes normal expression of functional DMD via in-frame exon skipping or stop codon suppression. In some embodiments, the complex is configured to deliver a mini-dystrophin gene or synthetic mRNA that increases or restores functional dystrophin activity. Thus, in some embodiments, the complexes provided herein comprise a muscle-targeting agent (e.g., a muscle-targeting antibody) that specifically binds to a receptor on the surface of muscle cells for the purpose of delivering the molecular payload to muscle cells. In some embodiments, the complex may be internalized into cells via receptor-mediated internalization, whereupon the molecular payload may be released inside the cells to perform its function. For example, a complex modified to deliver an oligonucleotide may release the oligonucleotide so that the oligonucleotide can promote functional DMD expression in muscle cells (e.g., via an exon skipping mechanism). In some embodiments, the oligonucleotide is released by endosomal cleavage of a covalent linker connecting the oligonucleotide and the muscle-targeting agent of the conjugate.

[0006] Some aspects of the present disclosure provide conjugates comprising an anti-transferrin receptor antibody covalently linked to a molecular payload configured to induce exon skipping in dystrophin (DMD) mRNA. In some embodiments, the anti-TfR antibody comprises heavy chain complementarity-determining region 1 (CDR-H1), heavy chain complementarity-determining region 2 (CDR-H2), heavy chain complementarity-determining region 3 (CDR-H3), light chain complementarity-determining region 1 (CDR-L1), light chain complementarity-determining region 2 (CDR-L2), and light chain complementarity-determining region 3 (CDR-L3) of any of the anti-TfR antibodies listed in Tables 2, 4, and 7.

[0007] In some embodiments, the antibody comprises heavy chain complementarity determining regions (CDR-H1), CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 15, and CDR-L1, CDR-L2, and CDR-L3 of the light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequence of SEQ ID NO: 204, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequence of SEQ ID NO: 7, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequence of SEQ ID NO: 23, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequence of SEQ ID NO: 24.

[0008] In some embodiments, the antibody comprises CDR-H1 of SEQ ID NO: 155, CDR-H2 of SEQ ID NO: 156, CDR-H3 of SEQ ID NO: 157, CDR-L1 of SEQ ID NO: 158, CDR-L2 of SEQ ID NO: 159, and CDR-L3 of SEQ ID NO: 14. In some embodiments, the antibody comprises CDR-H1 of SEQ ID NO: 194, CDR-H2 of SEQ ID NO: 195, CDR-H3 of SEQ ID NO: 196, CDR-L1 of SEQ ID NO: 197, CDR-L2 of SEQ ID NO: 198, and CDR-L3 of SEQ ID NO: 193. In some embodiments, the antibody comprises CDR-H1 of SEQ ID NO: 145, CDR-H2 of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, CDR-H3 of SEQ ID NO: 147, CDR-L1 of SEQ ID NO: 148, CDR-L2 of SEQ ID NO: 149, and CDR-L3 of SEQ ID NO: 6. In some embodiments, the antibody comprises CDR-H1 of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, CDR-H2 of SEQ ID NO: 166, CDR-H3 of SEQ ID NO: 167, CDR-L1 of SEQ ID NO: 168, CDR-L2 of SEQ ID NO: 169, and CDR-L3 of SEQ ID NO: 22.

[0009] In some embodiments, the antibody comprises human or humanized framework regions and has VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 15, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 16. In some embodiments, the antibody comprises human or humanized framework regions and has VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 204, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 205. In some embodiments, the antibody comprises human or humanized framework regions and VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 7, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises human or humanized framework regions and has CDR-H1, CDR-H2, CDR-H3 of the VH as set forth in SEQ ID NO: 23, and CDR-L1, CDR-L2, CDR-L3 of the VL as set forth in SEQ ID NO: 24.

[0010] In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 16. In some embodiments, the antibody comprises an antibody comprising a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 204 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 205. In some embodiments, the antibody comprises a VH comprising an amino acid sequence of SEQ ID NO: 204 and a VL comprising the amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 7 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 23 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO: 24.

[0011] In some embodiments, the equilibrium dissociation constant (KD) for binding of the antibody to the transferrin receptor is 10 -11 M to 10 -6 It ranges up to M.

[0012] In some embodiments, the antibody is selected from the group consisting of a full-length IgG, a Fab fragment, a F(ab') fragment, a F(ab')2 fragment, an scFv, and an Fv. In some embodiments, the antibody is a Fab' fragment.

[0013] In some embodiments, the molecular payload is an oligonucleotide.

[0014] In some embodiments, the oligonucleotide comprises a region of complementarity of at least 15 nucleotides to DMD mRNA.

[0015] In some embodiments, the oligonucleotide comprises at least 15 contiguous nucleotides of any one of SEQ ID NOs: 257-508. In some embodiments, the oligonucleotide comprises the nucleotide sequence of any one of SEQ ID NOs: 257-508.

[0016] In some embodiments, the oligonucleotide comprises one or more modified nucleosides. In some embodiments, one or more modified nucleosides is a phosphorodiamidate morpholino.

[0017] In some embodiments, the oligonucleotide is a phosphorodiamidate morpholino oligomer.

[0018] In some embodiments, the molecular payload induces skipping of exon 8, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55.

[0019] In some embodiments, the antibody is covalently linked to the molecular payload via a cleavable linker. In some embodiments, the cleavable linker comprises a valine-citrulline dipeptide sequence; or

[0020] In some embodiments, the antibody is covalently linked to the molecular payload via a non-cleavable linker. In some embodiments, the non-cleavable linker is an alkane linker.

[0021] In some embodiments, the molecular payload is linked to the antibody via conjugation to a lysine or cysteine ​​residue of the antibody.

[0022] In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein.

[0023] Another aspect of the present disclosure provides a method for inducing exon skipping in DMD mRNA in a muscle cell, the method comprising contacting the muscle cell with a complex described herein in an amount effective to promote internalization of the molecular payload into the cell.

[0024] In some embodiments, the cells comprise a DMD mRNA transcript that comprises one or more frameshift mutations.

[0025] Another aspect of the present disclosure provides a method for promoting the expression or activity of a DMD protein in a cell. In some embodiments, the method comprises contacting a cell with a complex described herein in an amount effective to promote internalization of the molecular payload into the cell.

[0026] Further provided herein is a method for treating a subject with DMD. In some embodiments, the method comprises administering an effective amount of a complex described herein to a subject, for example, the subject comprises a mutated DMD mRNA allele associated with dystrophinopathy. In some embodiments, the subject is a human. In some embodiments, the administration is via intravenous infusion. [Brief explanation of the drawings]

[0027] Brief description of the drawings [Figure 1] FIG. 1 depicts a non-limiting schematic diagram showing the effect of transfecting cells with siRNA.

[0028] [Figure 2] FIG. 2 depicts a non-limiting schematic showing the activity of muscle-targeting complexes containing siRNA.

[0029] [Figure 3A-B] 3A-3B depict non-limiting schematic diagrams showing the activity of siRNA-containing muscle-targeting complexes in mouse muscle tissue (gastrocnemius and heart) in vivo compared to control experiments (N=4 C57BL / 6 WT mice).

[0030] [Figure 4A-B] 4A-4E depict non-limiting schematic diagrams showing the tissue selectivity of muscle-targeting complexes containing siRNA. [Figure 4C-D] 4A-4E depict non-limiting schematic diagrams showing the tissue selectivity of muscle-targeting complexes containing siRNA. [Figure 4E] 4A-4E depict non-limiting schematic diagrams showing the tissue selectivity of muscle-targeting complexes containing siRNA.

[0031] [Figure 5]FIG. 5 depicts a non-limiting schematic diagram showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping phosphorodiamidate morpholino oligomer (PMO) to dose-dependently enhance exon skipping in muscle tissue of an mdx mouse model.

[0032] [Figure 6A] 6A-6B depict non-limiting schematic diagrams showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping PMO to dose-dependently increase dystrophin in skeletal muscle of an mdx mouse model. [Figure 6B] 6A-6B depict non-limiting schematic diagrams showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping PMO to dose-dependently increase dystrophin in skeletal muscle of an mdx mouse model.

[0033] [Figure 7A] 7A-7C depict non-limiting schematic diagrams showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping PMO to improve functional performance (FIGS. 7A-7B) and reduce creatine kinase levels (FIG. 7C) in an mdx mouse model. [Figure 7B] 7A-7C depict non-limiting schematic diagrams showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping PMO to improve functional performance (FIGS. 7A-7B) and reduce creatine kinase levels (FIG. 7C) in an mdx mouse model. [Figure 7C] 7A-7C depict non-limiting schematic diagrams showing the ability of an anti-transferrin receptor muscle-targeting complex containing an exon 23 skipping PMO to improve functional performance (FIGS. 7A-7B) and reduce creatine kinase levels (FIG. 7C) in an mdx mouse model.

[0034] [Figure 8]Figure 8 is a graph showing the DMPK knockdown efficiency of conjugates containing selected anti-TfR1 antibodies covalently conjugated to antisense oligonucleotides targeting DMPK in non-human primate (NHP) cells or cells from human DM1 patients (DM1).

[0035] [Figure 9A-B] 9A-9B show the binding of various anti-TfR1 antibody formats to human (FIG. 9A) or cynomolgus (FIG. 9B) transferrin receptor 1.

[0036] [Figure 10] Figure 10 shows an assessment of the degree of detectable binding for various anti-TfR1 antibody formats to human transferrin receptor 2. An anti-TfR2 monoclonal antibody (OTI1B1) was used as a control. None of the antibodies tested bind to TfR2.

[0037] [Figure 11] FIG. 11 is a graph showing the DMPK knockdown efficiency of conjugates containing an anti-TfR1 antibody described herein covalently conjugated to an antisense oligonucleotide targeting DMPK in non-human primate (NHP) cells or cells from a human DM1 patient (DM1).

[0038] [Figure 12A-B] Figures 12A-12B show the binding of oligonucleotide-conjugated or unconjugated anti-TfR to human TfR1 (hTfR1) and cynomolgus monkey TfR1 (cTfR1) as measured by ELISA. The anti-TfR is one of those listed in Table 7. Figure 12A shows the binding of anti-TfR alone (EC50 26.6 nM) or in conjugate with DMPK-targeted oligo (EC50 8.2 nM) to hTfR1. Figure 12B shows the binding of anti-TfR alone (EC50 33.6 nM) or in conjugate with DMPK-targeted oligo (EC50 5.3 nM) to cTfR1.

[0039] [Figure 13] Figure 13 shows the quantified cellular uptake of anti-TfR Fab conjugates into rhabdomyosarcoma (RD) cells. The molecular payload of the tested conjugates was a DMPK-targeting oligonucleotide, and conjugate uptake was facilitated by the indicated anti-TfR Fab. Conjugates with a negative control Fab (anti-mouse TfR) or a positive control Fab (anti-human TfR1) were also included in the assay. Cells were incubated with the indicated conjugates at a concentration of 100 nM for 4 hours. Cell uptake was measured by mean Cypher5e fluorescence. The anti-TfR was one of those listed in Table 7.

[0040] [Figure 14] Figure 14 shows DMPK expression in RD cells treated with various concentrations of conjugates containing an anti-TfR antibody (anti-TfR in Table 7) conjugated to a DMPK-targeting oligonucleotide (control DMPK-ASO). The duration of treatment was 3 days. A control DMPK-ASO delivered using a transfection agent was used as a control.

[0041] [Figure 15] FIG. 15 shows the serum stability over time of linkers used to connect anti-TfR antibodies and molecular payloads (e.g., oligonucleotides) in various species after intravenous administration.

[0042] [Figure 16] Figure 16 shows exon 51 skipping in human DMD myotubes facilitated by DMD exon 51 skipping oligonucleotides (PMOs). Cells were treated with naked PMOs or PMOs conjugated to anti-TfR1 Fab (Ab-PMO).

[0043] [Figure 17]Figure 17 shows a dose-dependent increase in dystrophin expression in the quadriceps muscle of mdx mice after treatment with anti-mouse TfR1 (RI7 217) conjugated to an oligonucleotide (PMO) targeted to exon 23, as measured by Western blotting of dystrophin with alpha-actin as a loading control. Standards were generated using pooled wild-type protein and pooled mdx protein. Percentages indicate the amount of WT protein spiked into the sample.

[0044] [Figure 18] FIG. 18 shows quantification of dystrophin protein levels in the quadriceps muscle of mdx mice after treatment with various doses of anti-mouse TfR (RI7 217) conjugated to an oligonucleotide (PMO) targeting exon 23.

[0045] [Figure 19] Figure 19 shows immunofluorescence staining images of quadriceps muscles from wild-type (WT) mice treated with saline, or mdx mice treated with saline, naked oligonucleotide, or oligonucleotide conjugated to anti-mouse TfR1 (RI7 217).

[0046] [Figure 20] FIG. 20 shows data illustrating that a conjugate containing an anti-TfR Fab′ (HC of SEQ ID NO: 559 and LC of SEQ ID NO: 212) conjugated to a DMD exon skipping oligonucleotide resulted in enhanced exon skipping in DMD patient myotubes compared to the naked DMD exon skipping oligo.

[0047] [Figure 21A]21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21B-C] 21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21D-E] 21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21F-G] 21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21H-I]21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21J-K] 21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 21L] 21A-21L depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey muscle tissue in vivo relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237.

[0048] [Figure 22A] 22A-22B depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey smooth muscle tissue in vivo, relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 22B] 22A-22B depict non-limiting schematic diagrams showing the ability of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) to reduce gene expression levels in cynomolgus monkey smooth muscle tissue in vivo, relative to vehicle experiments and compared to a naked ASO (control DMPK-ASO). (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237.

[0049] [Figure 23A] Figures 23A-23D depict non-limiting schematic diagrams showing the tissue selectivity of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody). The muscle-targeting complex does not reduce gene expression levels in cynomolgus monkey liver, kidney, brain, or spleen tissues in vivo relative to vehicle experiments. (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 23B-C] Figures 23A-23D depict non-limiting schematic diagrams showing the tissue selectivity of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody). The muscle-targeting complex does not reduce gene expression levels in cynomolgus monkey liver, kidney, brain, or spleen tissues in vivo relative to vehicle experiments. (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. [Figure 23D]Figures 23A-23D depict non-limiting schematic diagrams showing the tissue selectivity of a muscle-targeting complex (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody). The muscle-targeting complex does not reduce gene expression levels in cynomolgus monkey liver, kidney, brain, or spleen tissues in vivo relative to vehicle experiments. (N=3 male cynomolgus monkeys) The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237.

[0050] [Figure 24] Figure 24 shows normalized mRNA tissue expression levels across several tissue types in cynomolgus monkeys. (N=3 male cynomolgus monkeys)

[0051] [Figure 25] Figure 25 shows that a single dose of a muscle-targeting conjugate (DTX-C-012) comprising an anti-transferrin receptor antibody (15G11 antibody) is safe and tolerated in cynomolgus monkeys (N=3 male cynomolgus monkeys). The 15G11 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:237. DETAILED DESCRIPTION OF THE INVENTION

[0052] Detailed Description Aspects of the present disclosure relate to the recognition that while certain molecular payloads (e.g., oligonucleotides, peptides, small molecules) can have beneficial effects on muscle cells, effectively targeting such cells can be challenging. As described herein, the present disclosure provides a conjugate comprising a muscle targeting agent covalently linked to a molecular payload to overcome such challenges. In some embodiments, the conjugate is particularly useful for delivering a molecular payload that modulates (e.g., promotes) the expression or activity of a target gene in muscle cells, e.g., in a subject having or suspected of having a rare muscle disease. For example, in some embodiments, a conjugate is provided for targeting DMD, e.g., a mutated DMD allele. In some embodiments, the conjugates provided herein may include an oligonucleotide that promotes normal expression and activity of DMD. As another example, the conjugate may include an oligonucleotide that induces exon skipping in DMD mRNA. In some embodiments, a synthetic nucleic acid payload (e.g., a DNA or RNA payload) may be used that expresses one or more proteins that promote normal expression and activity of DMD.

[0053] In some embodiments, the complex may comprise a molecular payload of, for example, synthetic cDNA and / or (for example, and) synthetic mRNA (for example, a dystrophin minigene) that expresses dystrophin or a fragment thereof. In some embodiments, the complex may comprise a molecular payload such as a guide molecule (for example, a guide RNA) that can target a nucleic acid programmable nuclease (for example, Cas9) to a sequence in or near a disease-associated DMD mutation, for example, a mutated DMD exon. In some embodiments, such a nucleic acid programmable nuclease may be used to cleave part or all of a disease-associated DMD mutation, for example, a mutated DMD exon, to promote the expression of functional DMD. In some embodiments, the complex may comprise a molecular payload that upregulates the expression and / or (for example, and) activity of a gene that can replace the function of dystrophin, such as utrophin.

[0054] Further aspects of the disclosure, including a description of defined terms, are provided below.

[0055] I. Definition Administering: As used herein, the terms "administering" or "administration" mean providing a conjugate to a subject in a physiologically and / or pharmacologically useful manner (e.g., treating a disease in a subject).

[0056] about: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to the stated reference value. In some embodiments, the term "approximately" or "about" refers to a broad range of values ​​that fall within plus or minus (greater or less than) 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the stated reference value, unless otherwise stated or clear from the context (except when such number exceeds 100% of a feasible value).

[0057] 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., a paratope, that specifically binds to an antigen. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, F(ab') fragment, F(ab')2 fragment, Fv fragment, or scFv fragment. In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody comprises a framework with human germline sequences. In another embodiment, the antibody comprises a heavy chain constant region selected from the group consisting of the constant regions of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or (for example, and), a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant region, for example, an Fc region. An immunoglobulin constant region refers to a heavy or light chain constant region. Human IgG heavy and light chain constant region 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 (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In specific embodiments, the antibody described herein comprises a human gamma 1 CH1 domain, CH2 domain, and / or (for example, and), CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (γ) heavy chain constant region, such as any sequence known in the art.Non-limiting examples of human constant region sequences are described in the art; see, e.g., U.S. Patent No. 5,693,780 and Kabat EA et al. (1991), supra. In some embodiments, the VH domain comprises an amino acid sequence 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, the antibody is modified, e.g., via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules 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 molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules comprise 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, the antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the present disclosure linked to a linker polypeptide or an immunoglobulin constant region. The linker polypeptide comprises two or more amino acid residues linked by a peptide bond and is used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123).Furthermore, an antibody may be part of a larger immunoadhesion molecule formed by covalent or noncovalent association of one or more other proteins or peptides with the antibody or antibody portion. Examples of such immunoadhesion molecules include the use of streptavidin core regions to generate tetrameric scFv molecules (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101), and the use of cysteine ​​residues, marker peptides, and C-terminal polyhistidine tags to generate bivalent and biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol. Immunol. 31:1047-1058).

[0058] CDR: As used herein, the term "CDR" refers to a complementarity-determining region within an antibody variable sequence. There are three CDRs in each of the heavy and light chain variable regions, designated CDR1, CDR2, and CDR3 for each variable region. The term "CDR set" as used herein refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs have been defined differently according to various systems. The system described by Kabat (Kabat et al., Sequence 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 antibody variable region, but also provides precise residue boundaries defining the three CDRs. These CDRs are sometimes referred to as Kabat CDRs. Sub-portions of the CDRs are sometimes designated L1, L2, and L3, or H1, H2, and H3, where "L" and "H" designate the light chain and heavy chain regions, respectively. These regions are sometimes referred to as Chothia CDRs, whose boundaries overlap with the Kabat CDRs. Other boundaries defining CDRs that overlap with the Kabat CDRs are described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly adhere to one of the above systems, but may still overlap with the Kabat CDRs, and may be shortened or extended in light of predictions or experimental findings that particular residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding. While the methods used herein may utilize CDRs defined according to any of these systems, preferred embodiments use CDRs defined by Kabat or Chothia.

[0059] CDR-grafted antibodies: The term "CDR-grafted antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of its VH and / or VL have been replaced with CDR sequences from another species, such as an antibody having murine heavy and light chain variable regions but in which one or more of the murine CDRs (e.g., CDR3) have been replaced with human CDR sequences.

[0060] Chimeric antibodies: The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species and constant region sequences from another species, such as an antibody having murine heavy and light chain variable regions linked to human constant regions.

[0061] Complementary: As used herein, the term "complementary" refers to the ability for precise pairing between two nucleotides or two pairs of nucleotides.In particular, complementary is a term that characterizes the degree of hydrogen bond pairing that results in binding between two nucleotides or two pairs of nucleotides.For example, if the base of an oligonucleotide at a certain position can hydrogen bond with the base of target nucleic acid (for example, mRNA) at the corresponding position, then the bases are considered to be complementary to each other at that position.Base pairing may include both standard Watson-Crick base pairing and non-Watson-Crick base pairing (for example, Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, an adenosine-type base (A) is complementary to a thymidine-type base (T) or a uracil-type base (U), a cytosine-type base (C) is complementary to a guanosine-type base (G), and a universal base such as 3-nitropyrrole or 5-nitroindole can hybridize with and be considered complementary to any A, C, U, or T. Inosine (I) is also considered a universal base in the art and is considered complementary to any A, C, U, or T.

[0062] Conservative amino acid substitutions: As used herein, "conservative amino acid substitution" refers to an amino acid substitution that does not change 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 modifying polypeptide sequences known to those skilled in the art, and can be found, for example, in references that summarize such methods, such as 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, FMA Usubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include those made to 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.

[0063] Covalently linked: As used herein, the term "covalently linked" refers to the characteristic of two or more molecules being linked together via at least one covalent bond. In some embodiments, two molecules may be covalently linked together by a single bond (e.g., a disulfide bond or disulfide bridge) that acts as an intermolecular linker. However, in some embodiments, two or more molecules may be covalently linked together via a molecule that acts as a linker that connects two or more molecules together through multiple covalent bonds. In some embodiments, the linker may be a cleavable linker. However, in some embodiments, the linker may be a non-cleavable linker.

[0064] Cross-reacting: As used herein, and in the context of targeting agents (e.g., antibodies), the term "cross-reacting" refers to the property of an agent that can specifically bind to more than one antigen of the same type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or avidity. For example, in some embodiments, an antibody that cross-reacts to a similar type or class of human and non-human primate antigens (e.g., human transferrin receptor and non-human primate transferrin receptor) is capable of binding to a human antigen and a non-human primate antigen with similar affinity or avidity. In some embodiments, an antibody cross-reacts to a similar type or class of human antigen and rodent antigen. In some embodiments, an antibody cross-reacts to a similar type or class of rodent antigen and non-human primate antigen. In some embodiments, an antibody cross-reacts to a similar type or class of human antigen, non-human primate antigen, and rodent antigen.

[0065] DMD As used herein, the term "DMD" refers to the gene encoding the dystrophin protein, which is an important component of the internal cytoskeleton and extracellular matrix in muscle cells, specifically the dystrophin-glycoprotein complex that bridges muscle fibers. Deletions, duplications, and point mutations in DMD can cause dystrophinopathies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, or cardiomyopathy. Alternative promoter usage and alternative splicing result in multiple distinct transcript variants and protein isoforms for this gene. In some embodiments, the dystrophin gene may be a human (gene ID: 1756), non-human primate (e.g., gene ID: 465559), or rodent gene (e.g., gene ID: 13405; gene ID: 24907). Furthermore, several human transcript variants (e.g., designated GenBank RefSeq Accession Numbers: NM_000109.3, NM_004006.2, NM_004009.3, NM_004010.3, and NM_004011.3) encoding different protein isoforms have been characterized.

[0066] DMD allele: As used herein, the term "DMD allele" refers to any one of the alternative forms (e.g., wild-type or mutant) of the DMD gene. In some embodiments, a DMD allele may encode dystrophin that retains its normal and typical function. In some embodiments, a DMD allele may contain one or more mutations that result in muscular dystrophy. Common mutations that lead to Duchenne muscular dystrophy include frameshift, deletion, substitution, and duplication mutations in one or more of the 79 exons present in dystrophin alleles, such as exon 8, exon 23, exon 41, exon 44, exon 50, exon 51, exon 52, exon 53, or exon 55. Further examples of DMD mutations are disclosed, e.g., in Flanigan KM, et al., Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec; 30 (12):1657-66, the entire contents of which are incorporated herein by reference.

[0067] Dystrophinopathy: As used herein, the term "dystrophinopathy" refers to a muscle disease resulting from one or more mutated DMD alleles. Dystrophinopathy encompasses a spectrum of conditions (ranging from mild to severe), including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). In some embodiments, at one end of the spectrum, dystrophinopathy is phenotypically associated with asymptomatic increases in plasma concentrations of creatine phosphokinase (CK) and / or muscle spasms with myoglobinuria (for example, and). In some embodiments, at the other end of the spectrum, dystrophinopathy is phenotypically associated with progressive muscle diseases generally classified as Duchenne muscular dystrophy or Becker muscular dystrophy when primarily affecting skeletal muscle, and as DMD-associated dilated cardiomyopathy (DCM) when primarily affecting the heart. Symptoms of Duchenne muscular dystrophy include muscle loss or degeneration, decreased muscle function, pseudohypertrophy of the tongue and calf muscles, high risk of neurological abnormalities, and shortened lifespan. Duchenne muscular dystrophy is associated with Online Mendelian Inheritance in Man (OMIM) Entry # 310200. Becker muscular dystrophy is associated with OMIM Entry # 300376. Dilated cardiomyopathy is associated with OMIM Entry X# 302045.

[0068] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of the variable region minus the CDRs. Because the precise definition of a CDR sequence can be determined by various systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) also divide the framework regions on the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 is located between FR2 and FR3, and CDR3 is located between FR3 and FR4. When framework regions that do not specify a specific subregion as FR1, FR2, FR3, or FR4 are referred to by others, they represent the combined FRs in the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR refers to one of the four subregions, and FR(s) refers to two or more of the four subregions containing framework regions. Human heavy and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0069] Human antibodies: 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 present disclosure may include, for example, in the CDRs, particularly CDR3, 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). 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.

[0070] Humanized antibodies: The term "humanized antibody" refers to an antibody that contains heavy and light chain variable region sequences from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or (e.g., and) VL sequences have 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 onto non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-transferrin receptor antibodies and antigen-binding portions are provided. Such antibodies may be produced by obtaining a murine anti-transferrin receptor monoclonal antibody using conventional hybridoma technology, followed by humanization using in vitro genetic engineering (such as that disclosed in PCT Publication No. WO 2005 / 123126 A2 to Kasaian et al.).

[0071] Internalizing cell surface receptors: As used herein, the term "internalizing cell surface receptor" refers to a cell surface receptor that is internalized by a cell upon an external stimulus (e.g., a ligand binding to the receptor). In some embodiments, the internalizing cell surface receptor is internalized by endocytosis. In some embodiments, the internalizing cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, the internalizing cell surface receptor is internalized by a clathrin-independent pathway, such as phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake, or clathrin-independent constitutive 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 optionally further comprise a ligand-binding domain. In some embodiments, the cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, the ligand may be a muscle-targeting agent or a muscle-targeting antibody. In some embodiments, the internalizing cell surface receptor is a transferrin receptor.

[0072] Isolated antibodies: 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 to the transferrin receptor is substantially free of antibodies that specifically bind to antigens other than the transferrin receptor). However, an isolated antibody that specifically binds to the transferrin receptor complex may 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 (by way of example and) chemicals.

[0073] Kabat numbering: The terms "Kabat numbering," "Kabat definition," and "Kabat labeling" are used interchangeably herein. These terms, recognized in the art, refer to a system for numbering amino acid residues that are more variable (i.e., more hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or its antigen-binding portion (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). In the heavy chain variable region, the hypervariable region spans amino acid positions 31-35 for CDR1, positions 50-65 for CDR2, and positions 95-102 for CDR3. In the light chain variable region, the hypervariable region spans amino acid positions 24-34 for CDR1, amino acid positions 50-56 for CDR2, and amino acid positions 89-97 for CDR3.

[0074] 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, the molecular payload is linked to or otherwise associated with a muscle-targeting agent. In some embodiments, the molecular payload is a small molecule, protein, peptide, nucleic acid, or oligonucleotide. In some embodiments, the molecular payload functions to modulate the transcription of a DNA sequence, to modulate the expression of a protein, or to modulate the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide comprising a strand having a region complementary to a target gene.

[0075] Muscle-targeting agents: As used herein, the term "muscle targeting agent" refers to a molecule that specifically binds to an antigen expressed on a muscle cell. The antigen in or on a muscle cell may be a membrane protein, e.g., an integral membrane protein or a peripheral membrane protein. Typically, a muscle targeting agent specifically binds to an antigen on a muscle cell, facilitating internalization of the muscle targeting agent (and any associated molecular payload) into the muscle cell. In some embodiments, the muscle targeting agent specifically binds to an internalizing cell surface receptor on muscle and is capable of being internalized into the muscle cell through receptor-mediated internalization. In some embodiments, the muscle targeting agent is a small molecule, protein, peptide, nucleic acid (e.g., an aptamer), or antibody. In some embodiments, the muscle targeting agent is linked to a molecular payload.

[0076] Muscle targeting antibodies: As used herein, the term "muscle-targeting antibody" refers to a muscle-targeting agent that is an antibody that specifically binds to an antigen found in or on muscle cells. In some embodiments, the muscle-targeting antibody specifically binds to an antigen on muscle cells that facilitates internalization of the muscle-targeting antibody (and any attached molecular payload) into the muscle cells. In some embodiments, the muscle-targeting antibody specifically binds to an internalizing cell surface receptor present on muscle cells. In some embodiments, the muscle-targeting antibody is an antibody that specifically binds to the transferrin receptor.

[0077] Oligonucleotides: As used herein, the term "oligonucleotide" refers to an oligomeric nucleic acid compound up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNA, shRNA), microRNA, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNA), and the like. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, oligonucleotides may contain one or more modified nucleotides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, oligonucleotides may contain one or more modified internucleotide linkages. In some embodiments, oligonucleotides may contain one or more phosphorothioate linkages, which may be in an Rp or Sp stereochemical configuration.

[0078] Recombinant antibodies: The term "recombinant human antibody," as used herein, refers to any human antibody that is prepared, expressed, created, or isolated by recombinant means, e.g., an antibody expressed using a recombinant expression vector transfected into a host cell (as described in more detail in this disclosure), an antibody isolated from a recombinant combinatorial human antibody library (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), or an antibody isolated from a human immunoglobulin gene transgenic animal (e.g., a mouse) (see, e.g., Taylor, LD, et al. (See, e.g., Kellermann SA, and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370), or any other means involving splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when human Ig sequence transgenic animals are used, in vivo somatic mutagenesis), such that the amino acid sequences of the VH and VL regions of the recombinant antibodies, while derived from and related to human germline VH and VL sequences, are sequences that may not naturally occur within the germline repertoire of human antibodies in vivo.One aspect of the present disclosure provides fully human antibodies capable of binding to the human transferrin receptor that can be produced using techniques well known in the art, including, but not limited to, techniques using human Ig phage libraries (e.g., those disclosed in PCT Publication No. WO 2005 / 007699 A2 to Jermutus et al.).

[0079] Regions of complementarity: As used herein, the term "region of complementarity" refers to a nucleotide sequence (e.g., a nucleotide sequence of an oligonucleotide) that is sufficiently complementary to a cognate nucleotide sequence (e.g., a nucleotide sequence of a target nucleic acid) such that the two nucleotide sequences are capable of annealing to each other under physiological conditions (e.g., in a cell). In some embodiments, the region of complementarity is fully complementary to the cognate nucleotide sequence of the target nucleic acid. However, in some embodiments, the region of complementarity is only partially complementary (e.g., at least 80%, 90%, 95%, or 99% complementary) to the cognate nucleotide sequence of the target nucleic acid. In some embodiments, the region of complementarity contains one, two, three, or four mismatches compared to the cognate nucleotide sequence of the target nucleic acid.

[0080] Specific binding to: As used herein, the term "specifically binds" refers to the ability of a molecule to bind to a binding partner in a binding assay or other binding context, with a degree of affinity or avidity that can be used to distinguish the binding partner from an appropriate control. With respect to an antibody, the term "specifically binds" refers to the ability of an antibody to bind to a specific antigen, relative to an appropriate reference antigen, or an antigen that can be used to distinguish the specific antigen from other antigens, with a degree of affinity or avidity (e.g., that allows preferential targeting to certain cells (e.g., muscle cells) through binding to the antigen, as described herein). In some embodiments, the antibody binds to the target with at least about 10-4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M or less K D In some embodiments, the antibody specifically binds to a transferrin receptor, e.g., an epitope in the apical domain of the transferrin receptor.

[0081] subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate animal or a rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient with or suspected of having a disease, e.g., a human patient. In some embodiments, the subject is a human patient with or suspected of having a disease resulting from a mutated DMD gene sequence, e.g., a mutation in an exon of the DMD gene sequence. In some embodiments, the subject has a dystrophinopathy, e.g., Duchenne muscular dystrophy.

[0082] Transferrin receptor: As used herein, the term "transferrin receptor" (also known as TFRC, CD71, p90, TFR, or TFR1) refers to an internalized cell surface receptor that binds to transferrin to facilitate iron uptake by endocytosis. In some embodiments, the transferrin receptor may originate from humans (NCBI Gene ID 7037), non-human primates (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodents (e.g., NCBI Gene ID 22042). In addition, multiple human transcript variants encoding different isoforms of the receptor have been characterized (e.g., those annotated with GenBank RefSeq accession numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0083] 2'-modified nucleoside: As used herein, the terms "2'-modified nucleoside" and "2'-modified ribonucleoside" are used interchangeably and refer to a nucleoside having a sugar moiety modified at the 2'-position. In some embodiments, the 2'-modified nucleoside is a 2'-4' bicyclic nucleoside, in which the 2' and 4' positions of the sugar are bridged (e.g., by a methylene, ethylene, or (S)-constrained ethyl bridge). In some embodiments, the 2'-modified nucleoside is a non-bicyclic 2'-modified nucleoside, e.g., in which the 2' position of the sugar moiety is substituted. Non-limiting examples of 2'-modified nucleosides include the following: 2'-deoxy, 2'-fluoro (2'-F), 2'-O-methyl (2'-O-Me), 2'-O-methoxyethyl (2'-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), 2'-ON-methylacetamide (2'-O-NMA), locked nucleic acids (LNA, methylene-bridged nucleic acids), ethylene-bridged nucleic acids (ENA), and (S)-constrained ethyl-bridged nucleic acids (cEt). In some embodiments, the 2'-modified nucleosides described herein are high-affinity modified nucleotides, and oligonucleotides comprising the 2'-modified nucleotides have increased affinity for target sequences compared to unmodified oligonucleotides. Examples of structures of 2'-modified nucleosides are provided below: [ka]

[0084] II. Complex Provided herein are conjugates comprising a targeting agent, for example, an antibody covalently linked to a molecular payload. In some embodiments, the conjugate comprises a muscle-targeting antibody covalently linked to an oligonucleotide. The conjugate may comprise an antibody that specifically binds to a single antigen site, or an antibody that binds to at least two antigen sites, which may be present on the same antigen or different antigens.

[0085] The complex may be used to modulate the activity or function of at least one gene, protein, and / or (for example, and) nucleic acid. In some embodiments, the molecular payload present with the complex is responsible for modulating the gene, protein, and / or (for example, and) nucleic acid. The molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity capable of modulating the activity or function of a gene, protein, and / or (for example, and) nucleic acid in a cell. In some embodiments, the molecular payload is an oligonucleotide that targets a disease-associated repeat in muscle cells.

[0086] In some embodiments, the conjugate comprises a muscle targeting agent (e.g., an anti-transferrin receptor antibody) covalently linked to a molecular payload (e.g., a mixmer antisense oligonucleotide targeting a mutated DMD allele) to facilitate exon skipping.

[0087] A. Muscle-targeting agents Some aspects of the present disclosure provide muscle-targeting agents, e.g., muscle-targeting agents for delivering molecular payloads to muscle cells. In some embodiments, such muscle-targeting agents are capable of binding to muscle cells and delivering the associated molecular payload to muscle cells, e.g., via specific binding to an antigen on the muscle cells. In some embodiments, the molecular payload is attached (e.g., covalently attached) to the muscle-targeting agent, and is internalized into the muscle cells upon binding to the antigen on the muscle cells, e.g., via endocytosis. It should be understood that various types of muscle-targeting agents may be used in accordance with the present disclosure. For example, the muscle-targeting agent may comprise or consist of a nucleic acid (e.g., DNA or RNA), a peptide (e.g., an antibody), a lipid (e.g., a microvesicle), or a sugar moiety (e.g., a polysaccharide). Exemplary muscle-targeting agents are described in further detail herein; however, it should be understood that the exemplary muscle-targeting agents provided herein are not intended to be limiting.

[0088] Some aspects of the present disclosure provide muscle targeting agents that specifically bind to antigens on muscles, such as skeletal muscle, smooth muscle, or cardiac muscle. In some embodiments, any of the muscle targeting agents provided herein bind (e.g., specifically bind) to antigens on skeletal muscle cells, smooth muscle cells, and / or (e.g., and) cardiac muscle cells.

[0089] Interaction with muscle-specific cell surface recognition elements (e.g., cell membrane proteins) can achieve both tissue localization and selective uptake into muscle cells. In some embodiments, molecules that are substrates for muscle uptake transporters are useful for delivering molecular payloads into muscle tissue. Binding to muscle surface recognition elements, followed by endocytosis, can allow even macromolecules, such as antibodies, to enter muscle cells. As another example, molecular payloads conjugated to transferrin or anti-transferrin receptor antibodies can be taken up by muscle cells via binding to the transferrin receptor and then endocytosed, e.g., via clathrin-mediated endocytosis.

[0090] The use of muscle-targeting agents can be useful for concentrating molecular payloads (e.g., oligonucleotides) in muscle while reducing toxicity associated with effects in other tissues. In some embodiments, muscle-targeting agents concentrate the bound molecular payload in muscle cells compared to other cell types within a subject. In some embodiments, muscle-targeting agents concentrate the bound molecular payload in muscle cells (e.g., skeletal muscle cells, smooth muscle cells, or cardiomyocytes) at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold greater than the amount in non-muscle cells (e.g., liver cells, nerve cells, blood cells, or adipocytes). In some embodiments, the toxicity in a subject of the molecular payload when conjugated to a muscle-targeting agent is reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 95% when delivered to a subject.

[0091] In some embodiments, a muscle recognition element (e.g., a muscle cell antigen) may be required to achieve muscle selectivity. As one example, the muscle targeting agent may be a small molecule that is a substrate for a muscle-specific uptake transporter. As another example, the muscle targeting agent may be an antibody that enters muscle cells via transporter-mediated endocytosis. As another example, the muscle targeting agent may be a ligand that binds to a cell surface receptor on muscle cells. It should be understood that transporter-based approaches provide a direct pathway for cell entry, whereas receptor-based targeting may involve stimulated endocytosis to reach the desired site of action.

[0092] i. Muscle targeting antibody In some embodiments, the muscle targeting agent is an antibody. Generally, the high specificity of antibodies for their target antigens offers the potential to selectively target muscle cells (e.g., skeletal muscle cells, smooth muscle cells, and / or (e.g., and) cardiac muscle cells). This specificity may also limit off-target toxicity. Examples of antibodies capable of targeting surface antigens of muscle cells have been reported and are within the scope of the present disclosure. For example, antibodies that target the surface of muscle cells are described in Arahata K., et al., "Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide," Nature 1988;333:861-3; Song KS, et al., "Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins," J Biol Chem 1996;271:15160-5; and Weisbart RH et al., "Cell type-specific targeted intracellular delivery into muscle of a monoclonal antibody that binds myosin IIb," Mol Immunol. 2003 Mar,39(13):78309; the entire contents of each of which are incorporated herein by reference.

[0093] a. Anti-transferrin receptor antibody Some aspects of the present disclosure are based on the recognition that agents that bind to the transferrin receptor, e.g., anti-transferrin receptor antibodies, can target muscle cells. The transferrin receptor is an internalized cell surface receptor that transports transferrin across the cell membrane and participates in the regulation and homeostasis of intracellular iron levels. Some aspects of the present disclosure provide transferrin receptor binding proteins capable of binding to the transferrin receptor. Consequently, aspects of the present disclosure provide binding proteins (e.g., antibodies) that bind to the transferrin receptor. In some embodiments, the binding proteins that bind to the transferrin receptor are internalized into muscle cells along with any attached molecular payload. As used herein, antibodies that bind to the transferrin receptor may be referred to interchangeably as transferrin receptor antibodies, anti-transferrin receptor antibodies, or anti-TfR antibodies. Antibodies that bind, e.g., specifically bind, to the transferrin receptor may be internalized into cells upon binding to the transferrin receptor, e.g., through receptor-mediated endocytosis.

[0094] It should be understood that anti-transferrin receptor antibodies may be produced, synthesized, and / or (for example, and) derivatized using several known methodologies, for example, 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 MH and Stanley, JR "Antibody Phage Display: Technique and Applications," J Invest Dermatol. 2014, 134:2; Engleman, Edgar (Ed.) "Human Hybridomas and Monoclonal Antibodies," 1985, Springer). In other embodiments, the anti-transferrin antibody has been previously characterized or disclosed.Antibodies that specifically bind to the transferrin receptor are known in the art (see, e.g., U.S. Pat. No. 4,364,934, filed December 4, 1979, "Monoclonal antibody to a human early thymocyte antigen and methods for preparing the same"; U.S. Pat. No. 8,409,573, filed June 14, 2006, "Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells"; U.S. Pat. No. 9,708,406, filed May 20, 2014, "Anti-transferrin receptor antibodies and methods of use"; U.S. Pat. No. 9,611,323, filed December 19, 2014, "Low affinity blood-brain barrier receptor antibodies and uses therefor"; WO 2015 / 098989, filed December 24, 2014, "Novel anti-Transferrin receptor antibody that passes through the 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 Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse”2000,J (See Pharmacol. Exp. Ther., 292:1048-1052).

[0095] Provided herein are, in some aspects, novel anti-TfR antibodies for use as muscle-targeting agents (e.g., in muscle-targeting complexes). In some embodiments, the anti-TfR antibodies described herein bind to the transferrin receptor with high specificity and affinity. In some embodiments, the anti-TfR antibodies described herein specifically bind to any extracellular epitope of the transferrin receptor or an epitope that becomes exposed to the antibody. In some embodiments, the anti-TfR antibodies provided herein specifically bind to the transferrin receptor from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-TfR antibodies provided herein bind to the human transferrin receptor. In some embodiments, the anti-TfR antibodies described herein bind to the amino acid segment of the human or non-human primate transferrin receptor provided in SEQ ID NOs: 242-245. In some embodiments, the anti-TfR antibodies described herein bind to the amino acid segment corresponding to amino acids 90-96 of the human transferrin receptor as set forth in SEQ ID NO: 242, which is not in the apical domain of the transferrin receptor.

[0096] In some embodiments, the anti-TFR antibody is at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13In some embodiments, the anti-TfR antibodies described herein bind to TfR1 (e.g., human or non-human primate TfR1) with a binding affinity (e.g., indicated by Kd) of 1 M or less. In some embodiments, the anti-TfR antibodies described herein bind to TfR1 with a Kd in the sub-nanomolar range. In some embodiments, the anti-TfR antibodies described herein selectively bind to transferrin receptor 1 (TfR1) but not to transferrin receptor 2 (TfR2). In some embodiments, the anti-TfR antibodies described herein bind to human TfR1 and cynomolgus TfR1 (e.g., 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 The anti-TfR antibodies do not bind to mouse TfR1 (by virtue of a smaller Kd, M, or smaller). The affinity and binding kinetics of the anti-TfR antibodies can be tested using any suitable method, including, but not limited to, biosensor technology (e.g., OCTET or BIACORE). In some embodiments, the binding of any one of the anti-TfR antibodies described herein does not compete with or inhibit transferrin binding to TfR1. In some embodiments, the binding of any one of the anti-TfR antibodies described herein does not compete with or inhibit HFE-beta2-microglobulin binding to TfR1.

[0097] An example of a human transferrin receptor amino acid sequence, corresponding to the NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens), is as follows: (SEQ ID NO: 242).

[0098] An example of a primate non-human transferrin receptor amino acid sequence corresponding to the NCBI sequence NP_001244232.1 (transferrin receptor protein 1, Macaca mulatta) is as follows: (SEQ ID NO: 243)

[0099] An example of a primate non-human transferrin receptor amino acid sequence corresponding to the NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) is as follows: (SEQ ID NO: 244).

[0100] An example of a mouse transferrin receptor amino acid sequence, corresponding to the NCBI sequence NP_001344227.1 (transferrin receptor protein 1, mus musculus), is as follows: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNHVEMKLAADEEENADNNMKASVRKPKRFNGRLCFAAIALVIFFLIGFMSGYLGYCKRVEQKEECVKLAETEETDKSETMETEDVPTSSRLYWADLKTLLSEKLNSIEFADTIKQLSQNTYTPREAGSQKDESLAYYIENQFHEFKFSKVWRDEHYV KIQVKSSIGQNMVTIVQSNGNLDPVESPEGYVAFSKPTEVSGKLVHANFGTKKDFEELSYSVNGSLVIVRAGEITFAEKVANAQSFNAIGVLIYMDKNKFPVVEADLALFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGKMEGSCPARWNIDSSCKLELSQNQNVKLIVKN VLKERRILNIFGVIKGYEEPDRYVVVGAQRDALGAGVAAKSSVGTGLLLKLAQVFSDMISKDGFRPSRSIIFASWTAGDFGAVGATEWLEGYLSSLHLKAFTYINLDKVVLGTSNFKVSASPLLYTLMGKIMQDVKHPVDGKSLYRDSNWISKVEKLSFDNAAYPFLAYSGIPAVSFCFCEDADYPYLGTR LDTYEALTQKVPQLNQMVRTAAEVAGQLIIKLTHDVELNLDYEMYNSKLLSFMKDLNQFKTDIRDMGLSLQWLYSARGDYFRATSRLTTDFHNAEKTNRFVMREINDRIMKVEYHFLSPYVSPRESPFRHIFWGSGSHTLSALVENLKLRQKNITAFNETLFRNQLALATWTIQGVANALSGDIWNIDNEF (SEQ ID NO: 245)

[0101] In some embodiments, the anti-transferrin receptor antibody is an amino acid segment of the receptor as follows: FVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKE (SEQ ID NO: 246) and do not inhibit the binding interaction between transferrin receptor and transferrin and / or (by way of example and) human hemochromatosis protein (also known as HFE). In some embodiments, the anti-transferrin receptor antibodies described herein do not bind to the epitope of SEQ ID NO: 246.

[0102] Suitable methodologies may be used to obtain and / or (for example, and) produce antibodies, antibody fragments, or antigen-binding agents, for example, through the use of recombinant DNA protocols. In some embodiments, antibodies may also be produced through the generation of hybridomas (see, for example, 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 an immunogen in any form or entity, for example, in a recombinant or naturally occurring form or entity. Hybridomas are screened using standard methods, for example, ELISA screening, to find at least one hybridoma producing an antibody that targets a specific antigen. Antibodies may also be produced through screening of protein expression libraries (for example, phage display libraries) that express antibodies. Phage display library design may also be used in some embodiments (see, e.g., U.S. Pat. No. 5,223,409, filed March 1, 1991, "Directed evolution of novel binding proteins"; WO 1992 / 18619, filed April 10, 1992, "Heterodimeric receptor libraries using phagemids"; WO 1991 / 17271, filed May 1, 1991, "Recombinant library screening methods"; WO 1992 / 20791, filed May 15, 1992, "Methods for producing members of specific binding pairs"; and WO 1992 / 15679, filed February 28, 1992, "Improved epitope displaying phage"). In some embodiments, the antigen of interest may be used to immunize a non-human animal, e.g., a rodent or goat.In some embodiments, once the antibody is obtained from the non-human animal, it may then optionally be modified using a number of methodologies, for example, using recombinant DNA techniques. Additional examples of antibody production and methodologies are also known in the art (see, for example, Harlow et al. "Antibodies: A Laboratory Manual," Cold Spring Harbor Laboratory, 1988).

[0103] In some embodiments, the antibody is modified (e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation). In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules 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 molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules include 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 present. In some embodiments, the glycosylated antibody is fully or partially glycosylated. In some embodiments, the antibody is glycosylated by chemical reaction or by enzymatic means. In some embodiments, the antibody is glycosylated in vitro or inside a cell (optionally deficient in an enzyme (e.g., glycosyltransferase) in the N- or O-glycosylation pathway). In some embodiments, the antibody is functionalized with a sugar or carbohydrate molecule as described in International Patent Application Publication WO2014065661, published May 1, 2014, entitled "Modified antibody, antibody-conjugate and process for the preparation thereof."

[0104] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a VL domain and / or (for example, and) a VH domain of any one of the anti-TfR antibodies selected from Table 2, and comprise a constant region comprising the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (for example, IgG2a and IgG2b) of immunoglobulin molecules. Non-limiting examples of human constant regions have been described in the art. See, e.g., Kabat EA et al., (1991) supra.

[0105] Heavy and light chain variable domain and CDR sequences of non-limiting example anti-TfR antibodies are provided in Table 2. Table 2. Examples of anti-TfR1 antibodies (CDRs according to IMGT® definitions) [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0106] In some embodiments, an anti-TfR antibody of the present disclosure comprises 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-TfR antibodies selected from Table 2. In some embodiments, an anti-TfR antibody of the present disclosure comprises the CDR-H1, CDR-H2, and CDR-H3 provided for any one of the antibodies selected from Table 2. In some embodiments, an anti-TfR antibody of the present disclosure comprises one or more of the CDR-L (e.g., CDR-L1, CDR-L2, and CDR-L3) amino acid sequences from any one of the anti-TfR antibodies selected from Table 2. In some embodiments, an anti-TfR antibody of the present disclosure comprises the CDR-L1, CDR-L2, and CDR-L3 provided for any one of the anti-TfR antibodies selected from Table 2.

[0107] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfR antibodies selected from Table 2. In some embodiments, antibody heavy and light chain CDR3 domains may play a particularly important role in the binding specificity / affinity of an antibody to an antigen. Consequently, an anti-TfR antibody of the present disclosure may include at least the heavy and / or (by way of example) light chain CDR3 of any one of the anti-TfR antibodies selected from Table 2.

[0108] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences that are substantially similar to any of the CDR-H1 sequence, CDR-H2 sequence, CDR-H3 sequence, CDR-L1 sequence, CDR-L2 sequence, and / or (e.g., and) CDR-L3 sequence from one of the anti-TfR antibodies selected from Table 2. In some embodiments, the position of one or more CDRs along the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) and / or VL (e.g., CDR-L1, CDR-L2, or CDR-L3) regions of an antibody described herein may vary by one, two, three, four, five, or six amino acid positions, so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the positions defining the CDRs of any of the antibodies described herein may vary by one, two, three, four, five, or six amino acid positions compared to the CDR positions of any one of the antibodies described herein by shifting the N-terminal and / or (for example, and) C-terminal boundaries of the CDR, so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% maintained relative to the binding of the original antibody from which it is derived).In another embodiment, the length of one or more CDRs along the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) region and / or (e.g., and) the VL (e.g., CDR-L1, CDR-L2, or CDR-L3) region of an antibody described herein can be varied by 1, 2, 3, 4, 5, or more amino acids (e.g., shorter or longer), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).

[0109] Consequently, in some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shorter by 1, 2, 3, 4, 5, or more amino acids than one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shorter by 1, 2, 3, 4, 5, or more amino acids than one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be extended by a difference of 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).The carboxy portion of CDR-H2 and / or CDR-H3 can be extended by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example, and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).Either method can be used to determine whether immunospecific binding to the transferrin receptor (e.g., the human transferrin receptor) is maintained, using, for example, binding assays and conditions described in the art.

[0110] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences substantially similar to any one of the anti-TfR antibodies selected from Table 2. For example, an antibody may include one or more CDR sequence(s) from any of the anti-TfR antibodies selected from Table 2 containing up to 5, 4, 3, 2, or 1 amino acid residue variations compared to the corresponding CDR region in any one of the CDRs provided herein (e.g., a CDR from any of the anti-TfR antibodies selected from Table 2), so long as immunospecific binding to transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% maintained relative to the binding of the original antibody from which it was derived). In some embodiments, any amino acid variations in any of the CDRs provided herein may be conservative variations. Conservative variations can be introduced into CDRs at positions where the residues are unlikely to be involved in interactions with a transferrin receptor protein (e.g., human transferrin receptor protein), e.g., as determined based on a crystal structure. Some aspects of the present disclosure provide anti-TfR antibodies comprising one or more of the heavy chain variable (VH) domains and / or (e.g., and) light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein include one or more of the CDR-H sequences (e.g., CDR-H1, CDR-H2, and CDR-H3) provided herein (e.g., any of the CDR-H sequences provided in any one of the anti-TfR antibodies selected from Table 2). In some embodiments, any of the VL domains provided herein include one or more of the CDR-L sequences (e.g., CDR-L1, CDR-L2, and CDR-L3) provided herein (e.g., any of the CDR-L sequences provided in any one of the anti-TfR antibodies selected from Table 2).

[0111] In some embodiments, the anti-TfR antibodies of the present disclosure include any antibodies that also include the heavy chain variable domain and / or (by way of example and not limitation) the light chain variable domain of any one of the anti-TfR antibodies selected from Table 2, as well as variants thereof. In some embodiments, the anti-TfR antibodies of the present disclosure include any antibodies that also include the heavy chain variable and light chain variable pair of any one of the anti-TfR antibodies selected from Table 2.

[0112] Aspects of the present disclosure provide anti-TfR antibodies having a heavy chain variable (VH) domain amino acid sequence and / or (by way of example, and) a light chain variable (VL) domain amino acid sequence homologous to any of the anti-TfR antibodies described herein. In some embodiments, the anti-TfR 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 (by way of example, and) any light chain variable sequence of any anti-TfR antibody, such as any one of the anti-TfR antibodies selected from Table 2. In some embodiments, the homologous heavy chain variable and / or light chain variable amino acid sequence does not vary within any of the CDR sequences provided herein. For example, in some embodiments, a degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within the heavy chain variable sequence and / or (by way of example and) light chain variable sequence excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-TfR antibodies provided herein comprise heavy and light chain variable sequences that comprise framework sequences that are at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequences of any of the anti-TfR antibodies selected from Table 2.

[0113] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 8.

[0114] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6.

[0115] In some embodiments, an anti-TfR antibody of the present disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 1; a CDR-H2 having the amino acid sequence of SEQ ID NO: 2 with an amino acid substitution at position 5 (e.g., wherein the asparagine at position 5 is substituted with, e.g., any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Cys (C), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)); and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally (by way of example, additionally), an anti-TfR antibody of the present disclosure comprises the following: CDR-L1 having the amino acid sequence of SEQ ID NO: 4; CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and CDR-L3 having the amino acid sequence of SEQ ID NO: 6. In some embodiments, the amino acid substitution at position 5 of CDR-H2 as represented by SEQ ID NO: 2 is N5T or N5S.

[0116] In some embodiments, an anti-TfR antibody of the disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 1; a CDR-H2 having the amino acid sequence of SEQ ID NO: 513 or SEQ ID NO: 80; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or in addition (by way of example, in addition), an anti-TfR antibody of the disclosure comprises the following: a CDR-L1 having the amino acid sequence of SEQ ID NO: 4; a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0117] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) when compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 513, or SEQ ID NO: 80, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. "Combined," as used anywhere in this disclosure, means that the total number of amino acid variations in all three heavy chain CDRs is within a defined range. Alternatively or additionally (e.g., in addition), an anti-TfR receptor antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) when compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0118] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 that, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 513, or SEQ ID NO: 80, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0119] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO:1; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:513, or SEQ ID NO:80; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO:3. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0120] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 8.

[0121] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) when compared to a VH as set forth in SEQ ID NO:7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) when compared to the VL as set forth in SEQ ID NO:8.

[0122] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 7. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 8.

[0123] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH as set forth in SEQ ID NO:7, with an amino acid substitution at position 55 (e.g., the asparagine at position 55 is replaced with, for example, any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Cys (C), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)). Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL as set forth in SEQ ID NO:8. In some embodiments, the amino acid substitution at position 55 of a VH as set forth in SEQ ID NO:7 is N55T or N55S. When the VH as represented in SEQ ID NO:7 is annotated using the Kabat numbering system, amino acid position 55 of SEQ ID NO:7 is assigned the number 54. When N54T or N54S is referred to herein, it refers to a mutation using the Kabat numbering system.

[0124] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid substitution at position 64 relative to SEQ ID NO: 7. In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising a Met at a position corresponding to position 64 of SEQ ID NO: 7. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (for example, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a VL as set forth in SEQ ID NO:8.

[0125] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 15. Alternatively or in addition (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 16.

[0126] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14.

[0127] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 9, CDR-H2 having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 12, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0128] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 9, CDR-H2 having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 12, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0129] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 9; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 10; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 12; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0130] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 16.

[0131] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO: 15. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to a VL as set forth in SEQ ID NO: 16.

[0132] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 15. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 16.

[0133] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 24.

[0134] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22.

[0135] In some embodiments, an anti-TfR antibody of the present disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 17 with an amino acid substitution at position 8 (e.g., wherein the cysteine ​​at position 8 is replaced with, e.g., any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Asn (N), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)); a CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (by way of example, additionally), an anti-TfR antibody of the present disclosure comprises the following: CDR-L1 having the amino acid sequence of SEQ ID NO: 20; CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and CDR-L3 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the amino acid substitution at position 8 of CDR-H1 as represented by SEQ ID NO: 17 is C8D or C8Y.

[0136] In some embodiments, an anti-TfR antibody of the disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 517 or SEQ ID NO: 519; a CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (for example, in addition), an anti-TfR antibody of the disclosure comprises the following: a CDR-L1 having the amino acid sequence of SEQ ID NO: 20; a CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0137] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 517, or SEQ ID NO: 519, CDR-H2 having the amino acid sequence of SEQ ID NO: 18, and CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 20, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0138] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 517, or SEQ ID NO: 519, a CDR-H2 having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO:20, CDR-L2 having the amino acid sequence of SEQ ID NO:21, and CDR-L3 having the amino acid sequence of SEQ ID NO:22.

[0139] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 517, or SEQ ID NO: 519; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 19 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 20; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0140] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 24.

[0141] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:24.

[0142] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 24.

[0143] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH as set forth in SEQ ID NO: 23 with an amino acid substitution at position 33 (e.g., the cysteine ​​at position 33 is replaced with, for example, any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Asn (N), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)). Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL as set forth in SEQ ID NO: 24. In some embodiments, the amino acid substitution at position 33 of a VH as set forth in SEQ ID NO: 23 is C33D or C33Y. When VH as represented in SEQ ID NO:23 is annotated according to the Kabat numbering system, amino acid 33 of SEQ ID NO:23 is assigned the number 33.

[0144] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 31. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 32.

[0145] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 25, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 26, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 27, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 28, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 30.

[0146] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 25, CDR-H2 having the amino acid sequence of SEQ ID NO: 26, and CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 28, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0147] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 25, CDR-H2 having the amino acid sequence of SEQ ID NO: 26, and CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 28, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0148] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 25; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 26; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 28; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0149] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 31. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 32.

[0150] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO: 31. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO: 32.

[0151] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 31. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 32.

[0152] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 39. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 40.

[0153] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 33, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 34, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 35, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 36, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 37, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 38.

[0154] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 33, CDR-H2 having the amino acid sequence of SEQ ID NO: 34, and CDR-H3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 36, CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0155] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 33, CDR-H2 having the amino acid sequence of SEQ ID NO: 34, and CDR-H3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 36, CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0156] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 33; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 34; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 35 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 36; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 37; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0157] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 39. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 40.

[0158] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:39. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:40.

[0159] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 39. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 40.

[0160] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 48.

[0161] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 41, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 42, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 43, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 44, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 46.

[0162] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 41, CDR-H2 having the amino acid sequence of SEQ ID NO: 42, and CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 44, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0163] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 41, CDR-H2 having the amino acid sequence of SEQ ID NO: 42, and CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 44, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0164] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 41; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 42; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 44; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0165] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 48.

[0166] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:47. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:48.

[0167] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as set forth in SEQ ID NO: 47. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as set forth in SEQ ID NO: 48.

[0168] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 54. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 55.

[0169] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 49, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 50, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 51, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 52, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 53.

[0170] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 49, CDR-H2 having the amino acid sequence of SEQ ID NO: 50, and CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 52, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0171] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 49, CDR-H2 having the amino acid sequence of SEQ ID NO: 50, and CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 52, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0172] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 49; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 50; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 52; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0173] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 54. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 55.

[0174] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:54. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:55.

[0175] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 54. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 55.

[0176] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 62. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 63.

[0177] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 56, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 57, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 58, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 59, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 60, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 61.

[0178] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 56, CDR-H2 having the amino acid sequence of SEQ ID NO: 57, and CDR-H3 having the amino acid sequence of SEQ ID NO: 58. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 59, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0179] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 56, CDR-H2 having the amino acid sequence of SEQ ID NO: 57, and CDR-H3 having the amino acid sequence of SEQ ID NO: 58. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 59, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0180] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 56; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 57; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 58 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 59; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0181] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 62. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 63.

[0182] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:62. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO: 63.

[0183] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 62. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 63.

[0184] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 70. Alternatively or in addition (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 71.

[0185] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 64, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 65, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 66, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 67, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 68, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 69.

[0186] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 64, CDR-H2 having the amino acid sequence of SEQ ID NO: 65, and CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 67, CDR-L2 having the amino acid sequence of SEQ ID NO: 68, and CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0187] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 64, CDR-H2 having the amino acid sequence of SEQ ID NO: 65, and CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 67, CDR-L2 having the amino acid sequence of SEQ ID NO: 68, and CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0188] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 64; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 65; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 67; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 68; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0189] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 70. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 71.

[0190] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO: 70. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO: 71.

[0191] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 70. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 71.

[0192] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 78.

[0193] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 73, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 76.

[0194] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 73, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0195] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 73, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0196] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 72; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 73; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0197] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 78.

[0198] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO: 77. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:78.

[0199] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 77. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 78.

[0200] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 85. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 86.

[0201] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 80, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 81, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 84.

[0202] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0203] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0204] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 80; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 82; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0205] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 85. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 86.

[0206] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:85. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:86.

[0207] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 85. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 86.

[0208] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 89. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 90.

[0209] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 87, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 88.

[0210] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 87, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0211] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 87, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0212] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 72; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 87; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0213] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 89. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 90.

[0214] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to a VH as set forth in SEQ ID NO:89. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to the VL as set forth in SEQ ID NO:90.

[0215] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 89. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 90.

[0216] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 97. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 98.

[0217] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 91, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 92, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 93, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 94, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 95, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 96.

[0218] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 91, CDR-H2 having the amino acid sequence of SEQ ID NO: 92, and CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 94, CDR-L2 having the amino acid sequence of SEQ ID NO: 95, and CDR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0219] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 91, CDR-H2 having the amino acid sequence of SEQ ID NO: 92, and CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 94, CDR-L2 having the amino acid sequence of SEQ ID NO: 95, and CDR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0220] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 91; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 92; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 94; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 95; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0221] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 97. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 98.

[0222] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 97. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 98.

[0223] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 97. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 98.

[0224] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 104. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 105.

[0225] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 99, CDR-H2 having the amino acid sequence of SEQ ID NO: 100, and CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 102, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0226] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 99, CDR-H2 having the amino acid sequence of SEQ ID NO: 100, and CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 102, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0227] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 99; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 100; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 102; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0228] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 104. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 105.

[0229] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 104. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 105.

[0230] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 104. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 105.

[0231] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 112. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 113.

[0232] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 106, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 107, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 108, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 109, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 110, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 111.

[0233] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 106, CDR-H2 having the amino acid sequence of SEQ ID NO: 107, and CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 109, CDR-L2 having the amino acid sequence of SEQ ID NO: 110, and CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0234] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 106, a CDR-H2 having the amino acid sequence of SEQ ID NO: 107, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 109, a CDR-L2 having the amino acid sequence of SEQ ID NO: 110, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0235] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 106; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 107; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 109; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 110; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0236] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 112. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 113.

[0237] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 112. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 113.

[0238] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 112. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 113.

[0239] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 117. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 118.

[0240] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 114, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 115, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 116.

[0241] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 114, and CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0242] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 114, and CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0243] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 114; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 82; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0244] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 117. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 118.

[0245] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 117. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 118.

[0246] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 117. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 118.

[0247] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 124. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 125.

[0248] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 119, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 120, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 121, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 122, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 123.

[0249] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 119, CDR-H2 having the amino acid sequence of SEQ ID NO: 120, and CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 122, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0250] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 119, CDR-H2 having the amino acid sequence of SEQ ID NO: 120, and CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 122, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0251] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 119; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 120; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 122; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0252] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 124. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 125.

[0253] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 124. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 125.

[0254] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 124. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 125.

[0255] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 132. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 133.

[0256] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 126, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 127, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 128, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 129, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 130, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 131.

[0257] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 126, CDR-H2 having the amino acid sequence of SEQ ID NO: 127, and CDR-H3 having the amino acid sequence of SEQ ID NO: 128. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 129, CDR-L2 having the amino acid sequence of SEQ ID NO: 130, and CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0258] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 126, a CDR-H2 having the amino acid sequence of SEQ ID NO: 127, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 128. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 129, a CDR-L2 having the amino acid sequence of SEQ ID NO: 130, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0259] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 126; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 127; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 128 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 129; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 130; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0260] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 132. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 133.

[0261] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 132. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 133.

[0262] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 132. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 133.

[0263] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 136. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 137.

[0264] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 134, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 135.

[0265] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0266] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0267] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 2; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0268] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 136. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 137.

[0269] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 136. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 137.

[0270] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 136. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 137.

[0271] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 143. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 144.

[0272] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 138, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 139, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 140, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 141, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 142.

[0273] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 138, CDR-H2 having the amino acid sequence of SEQ ID NO: 139, and CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 141, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0274] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 138, CDR-H2 having the amino acid sequence of SEQ ID NO: 139, and CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 141, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0275] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 138; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 139; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 141; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0276] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 143. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 144.

[0277] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH 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 variations) compared to the VH as set forth in SEQ ID NO: 143. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL 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 variations) compared to the VL as set forth in SEQ ID NO: 144.

[0278] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 143. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 144.

[0279] The CDRs of an antibody may have different amino acid sequences when different definition systems are used (e.g., the IMGT definition, the Kabat definition, or the Chothia definition). A definition system annotates each amino acid in a given antibody sequence (e.g., a VH or VL sequence) with a number, and the numbers corresponding to the heavy and light chain CDRs are provided in Table 3. The CDRs listed in Table 2 are defined according to the IMGT definition. CDR sequences of example anti-TfR antibodies according to various definition systems are provided in Table 4. One skilled in the art can derive CDR sequences for the anti-TfR antibodies provided in Table 2 using various numbering systems. Table 3. CDR definition [Table 3] 1 IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999) 2 Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 3 Chothia et al., J. Mol. Biol. 196:901-917 (1987)) Table 4. CDR sequences of example anti-TfR1 antibodies according to various definition systems [Table 4-1] [Table 4-2]

[0280] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6.

[0281] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 145, CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, and CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 148, CDR-L2 having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0282] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 148, CDR-L2 having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0283] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 145; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 147 (e.g., and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 148; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 149; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0284] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154.

[0285] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 150, CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522, and CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 153, CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0286] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0287] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 150; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 153; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0288] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14.

[0289] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 155, CDR-H2 having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 158, CDR-L2 having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0290] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 155, CDR-H2 having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 158, CDR-L2 having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0291] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 155; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 156; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 158; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 159; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0292] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164.

[0293] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 160, CDR-H2 having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 163, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0294] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 160, CDR-H2 having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 163, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0295] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 160; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 161; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 163; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0296] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22.

[0297] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, a CDR-H2 having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0298] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, a CDR-H2 having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0299] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 166; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 167 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 168; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 169; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0300] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174.

[0301] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 170, CDR-H2 having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 173, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0302] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 170, CDR-H2 having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 173, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0303] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 170; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 171; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 173; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0304] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody (e.g., a humanized variant containing one or more CDRs of Table 2 or Table 4). In some embodiments, an anti-TfR antibody of the disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that are the same as those shown in Table 2 or Table 4, and comprises a humanized heavy chain variable region and / or (by way of example) a humanized light chain variable region.

[0305] Humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (ER) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are found neither on the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. Generally, humanized antibodies will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are of human immunoglobulin consensus sequences. Optimally, humanized antibodies will also comprise at least some portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have an altered Fc region as described in WO99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) that are altered relative to the original antibody. These are also referred to as one or more CDRs derived from one or more CDRs from the original antibody. Humanized antibodies may also involve affinity maturation.

[0306] Humanized antibodies and methods for making them are known, see, e.g., Almagro et al., Front. Biosci. 13:1619-1633 (2008); Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005); Padlan et al., Mol. Immunol. 28:489-498 (1991); Dall'Acqua et al., Methods 36:43-60 (2005); Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br. J. Cancer, 83:252-260 (2000), the contents of all of which are incorporated herein by reference. Human framework regions that can be used for humanization are described, for example, in Sims et al. J. Immunol. 151:2296 (1993); Carter et al. Proc. Natl. Acad. Sci. USA 89:4285 (1992); Presta et al. J. Immunol. 151:2623 (1993); Almagro et al., Front. Biosci. 13:1619-1633 (2008)); Baca et al., J. Biol. Chem. 272:10678-10684 (1997); and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996), the contents of all of which are incorporated herein by reference. In some embodiments, humanization is achieved by grafting CDRs (eg, as shown in Table 2 or Table 4) onto IGKV1-NL1*01 and IGHV1-3*01 human variable domains.

[0307] In some embodiments, the humanized VH or VL framework is a consensus human framework, which may represent the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.

[0308] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) are as follows:

[0309] a) VH FR1: EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 523);

[0310] b) VH FR2: WVRQAPGKGLEWV (SEQ ID NO: 524);

[0311] c) VH FR3: RFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 525); and

[0312] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 526) Includes.

[0313] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) are as follows:

[0314] a) VH FR1: QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 527);

[0315] b) VH FR2: WVRQAPGQGLEWM (SEQ ID NO: 528);

[0316] c) VH FR3:RVTITADTSTSTAYMELSSLRSEDTAVYYC (SEQ ID NO: 529); and

[0317] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 526) Includes.

[0318] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) are as follows:

[0319] a) VH FR1: QVQLQESGPGLVKPSQTLSLTCTVS (SEQ ID NO: 531);

[0320] b) VH FR2: WIRQPPGKGLEWI (SEQ ID NO: 532);

[0321] c) VH FR3: RVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO: 533); and

[0322] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 526) Includes.

[0323] In some embodiments, consensus human VL framework regions suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) are as follows:

[0324] a) VL FR1:DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 535);

[0325] b) VL FR2: WYQQKPGKAPKLLIY (SEQ ID NO: 536);

[0326] c) VL FR3: GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 537); and

[0327] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 538) Includes.

[0328] In some embodiments, consensus human VL framework regions suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) are as follows:

[0329] a) VL FR1: DIVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 539);

[0330] b) VL FR2: WYLQKPGQSPQLLIY (SEQ ID NO: 540);

[0331] c) VL FR3: GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC (SEQ ID NO: 541); and

[0332] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 538) Includes.

[0333] In some embodiments, consensus human VL framework regions suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) are as follows:

[0334] a) VL FR1: DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 530);

[0335] b) VL FR2: WYQQKPGQPPKLLIY (SEQ ID NO: 534);

[0336] c) VL FR3: GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC (SEQ ID NO: 542); and

[0337] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 538) Includes.

[0338] In some embodiments, the consensus human VL framework region suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup IV consensus) is as follows:

[0339] a) VL FR1: DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 530);

[0340] b) VL FR2: WYQQKPGQPPKLLIY (SEQ ID NO: 534);

[0341] c) VL FR3: GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC (SEQ ID NO: 542); and

[0342] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 538) Includes.

[0343] In some embodiments, the humanized anti-TfR antibodies of the present disclosure comprise humanized VH framework regions that contain a combined total of 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 variations) compared to any one of the consensus human VH framework region subgroups described herein. Alternatively or in addition (for example, in addition), the humanized anti-TfR antibodies of the present disclosure comprise humanized VL framework regions that contain a combined total of no more than 25 amino acid variations (for example, 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 variations) compared to any one of the consensus human VL framework region subgroups described herein.

[0344] In some embodiments, the humanized anti-TfR antibodies of the present disclosure comprise humanized VH framework regions that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of the consensus human VH framework region subgroups described herein. Alternatively or additionally (e.g., in addition), the humanized anti-TfR antibodies of the present disclosure comprise humanized VL framework regions that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of the consensus human VL framework region subgroups described herein.

[0345] In some embodiments, the anti-TfR antibodies of the present disclosure are humanized variants and include one or more amino acid variations (e.g., in the VH framework regions) compared to any one of the VHs listed in Table 2 or Table 4 and / or (e.g., and) one or more amino acid variations (e.g., in the VL framework regions) compared to any one of the VLs listed in Table 2 or Table 4.

[0346] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VH 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 variations) compared to the VH of any of the anti-TfR antibodies listed in Table 2. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VL 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 variations) compared to the VL of any one of the anti-TfR antibodies listed in Table 2.

[0347] In some embodiments, an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0348] In some embodiments, the anti-TfR antibodies of the present disclosure are humanized antibodies and comprise a VH 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 variations) compared to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure are humanized antibodies and comprise a VL that contains no more than 25 amino acid variations (for example, 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 variations) compared to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0349] In some embodiments, an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0350] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VH having one or more (e.g., 10-25) amino acid variations at positions 1, 2, 5, 9, 11, 12, 13, 17, 20, 23, 33, 38, 40, 41, 42, 43, 44, 45, 48, 49, 55, 67, 68, 70, 71, 72, 76, 77, 80, 81, 82, 84, 87, 88, 91, 95, 112, or 115 relative to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure are humanized antibodies and include a VL having one or more (for example, 10-20) amino acid variations at positions 4, 7, 8, 9, 11, 15, 17, 18, 19, 22, 39, 41, 42, 43, 50, 62, 64, 72, 75, 77, 79, 80, 81, 82, 83, 85, 87, 89, 100, 104, or 109 compared to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0351] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 513, or SEQ ID NO: 80, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0352] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 513, or SEQ ID NO: 80, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VL as set forth in SEQ ID NO: 8.

[0353] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0354] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 514, or SEQ ID NO: 516, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 8.

[0355] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0356] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 521, or SEQ ID NO: 522, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 8.

[0357] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, and 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 variations) in the framework regions compared to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0358] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VL as set forth in SEQ ID NO: 16.

[0359] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0360] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 16.

[0361] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0362] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 16.

[0363] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 517, or SEQ ID NO: 519, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0364] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 517, or SEQ ID NO: 519, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0365] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0366] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 518, or SEQ ID NO: 520, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0367] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, and 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 variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174, and containing no more than 25 amino acid variations (for example, 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 variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0368] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0369] In some embodiments, the anti-TfR antibodies of the present disclosure are chimeric antibodies, which may include heavy and light chain constant regions from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of antibodies from one mammalian species (e.g., non-human mammals, such as mice, rabbits, and rats), while the constant portions are homologous to the sequences of antibodies from another mammal, such as humans. In some embodiments, amino acid modifications can be made to the variable region and / or (for example, and) the constant region.

[0370] In some embodiments, the anti-TfR antibodies described herein are chimeric antibodies, which may include heavy and light chain constant regions from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of an antibody from one mammalian species (e.g., a non-human mammal, such as a mouse, rabbit, or rat), and the constant portions are homologous to the sequences of an antibody from another mammal, such as a human. In some embodiments, amino acid modifications can be made to the variable region and / or (for example, and) the constant region.

[0371] In some embodiments, the heavy chain of any of the anti-TfR antibodies described herein can comprise a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, such as human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (gamma heavy chain), such as IgG1, IgG2, or IgG4. An example of a human IgG1 constant region is provided below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 175)

[0372] In some embodiments, the heavy chain of any of the anti-TfR antibodies described herein comprises a mutant human IgG1 constant region. For example, the introduction of the LALA mutation on the CH2 domain of human IgG1 (a mutant derived from mAb b12 in which the lower hinge residues Leu234 and Leu235 are mutated to replace Ala234 and Ala235) is known to reduce Fcg receptor binding (Bruhns, P., et al. (2009) and Xu, D. et al. (2000)). The mutant human IgG1 constant region is provided below (mutations are bold and underlined):

[0373] [ka] (SEQ ID NO: 176)

[0374] In some embodiments, the light chain of any of the anti-TfR antibodies described herein may further comprise a light chain constant region (CL), which may 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: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 177)

[0375] Heavy and light chain constant regions of other antibodies are well known in the art and are provided, for example, in the IMGT database (www.imgt.org) or at www.vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0376] In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising a VH listed in Table 2 or any one of its variants, 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: 175 or SEQ ID NO: 176. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising a VH listed in Table 2 or any one of its variants, 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 variations) compared to SEQ ID NO: 175 or SEQ ID NO: 176. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 2 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 175. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 2 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 176.

[0377] In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 2 or any variant 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: 177. In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 2 or any variant thereof, and a light 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 variations) compared to SEQ ID NO: 177. In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 2 or any variant thereof, and a light chain constant region as set forth in SEQ ID NO: 177.

[0378] Examples of IgG heavy and light chain amino acid sequences of the described anti-TfR antibodies are provided in Table 5 below. Table 5. Heavy and light chain sequences of example anti-TfR IgGs [Table 5-1] [Table 5-2] [Table 5-3] *VH / VL sequences are underlined

[0379] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to a heavy chain as set forth in SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 551, SEQ ID NO: 552, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or additionally (e.g., additionally), an anti-TfR antibody of the disclosure comprises a light chain 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 variations) compared to a light chain as set forth in SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, an anti-TfR antibody described herein comprises a heavy chain that comprises an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 551, SEQ ID NO: 552, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence that is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 551, SEQ ID NO: 552, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183.

[0380] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to a heavy chain as set forth in SEQ ID NO: 178, SEQ ID NO: 551, or SEQ ID NO: 552. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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, 10, 11, 9, 8, 7, 6, or no more than 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 178, SEQ ID NO: 551, or SEQ ID NO: 552. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 178, SEQ ID NO: 551, or SEQ ID NO: 552. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179.

[0381] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to the heavy chain as set forth in SEQ ID NO: 180. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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 variations) compared to the light chain as set forth in SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 180. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 180. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 181.

[0382] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to a heavy chain as set forth in SEQ ID NO: 182, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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 variations) compared to a light chain as set forth in SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 182, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 182, SEQ ID NO: 553, or SEQ ID NO: 554. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 183.

[0383] In some embodiments, the anti-TfR antibody is a FAB fragment, F(ab') fragment, or F(ab')2 fragment of an intact antibody (full-length antibody). Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared via conventional 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 generated by pepsin or papain digestion of an antibody molecule, and Fab fragments can be produced by reducing the disulfide bridges of an F(ab')2 fragment. In some embodiments, the heavy chain constant region on the F(ab')2 fragment of an anti-TfR1 antibody described herein is as follows: It contains the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 184).

[0384] In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 2 or any variant 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: 184. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 2 or any variant 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 variations) compared to SEQ ID NO: 184. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 2 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 184.

[0385] Exemplary F(ab') amino acid sequences of the anti-TfR antibodies described herein are provided in Table 6. Table 6. Heavy chains and nucleotides of exemplary anti-TfR F(ab')s Light chain sequence [Table 6-1] [Table 6-2] [Table 6-3] *VH / VL sequences are underlined

[0386] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to the heavy chain as set forth in SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:555, SEQ ID NO:556, SEQ ID NO:557, or SEQ ID NO:558. Alternatively or additionally (e.g., additionally), an anti-TfR antibody of the present disclosure comprises a light chain 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 variations) compared to the light chain as set forth in SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, an anti-TfR antibody described herein comprises a heavy chain that comprises an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 555, SEQ ID NO: 556, SEQ ID NO: 557, or SEQ ID NO: 558. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence that is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 555, SEQ ID NO: 556, SEQ ID NO: 557, or SEQ ID NO: 558. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183.

[0387] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to a heavy chain as set forth in SEQ ID NO: 185, SEQ ID NO: 555, or SEQ ID NO: 556. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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 variations) compared to a light chain as set forth in SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 185, SEQ ID NO: 555, or SEQ ID NO: 556. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 185, SEQ ID NO: 555, or SEQ ID NO: 556. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179.

[0388] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to the heavy chain as set forth in SEQ ID NO: 186. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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, 10, 11, 9, 8, 7, 6, or no more than 5, 4, 3, 2, or 1 amino acid variations) compared to the light chain as set forth in SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 186. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 186. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 181.

[0389] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain 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 variations) compared to a heavy chain as set forth in SEQ ID NO: 187, SEQ ID NO: 557, or SEQ ID NO: 558. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain 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 variations) compared to a light chain as set forth in SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 187, SEQ ID NO: 557, or SEQ ID NO: 558. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 187, SEQ ID NO: 557, or SEQ ID NO: 558. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 183.

[0390] The anti-TfR receptor antibodies described herein can be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (e.g., Fab, F(ab'), F(ab')2, Fv), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-TfR antibodies described herein are scFvs. In some embodiments, the anti-TfR antibodies described herein are scFv-Fabs (e.g., scFvs fused to a portion of a constant region). In some embodiments, the anti-TfR receptor antibodies described herein are scFvs fused at either the N- or C-terminus to a constant region (e.g., a human IgG1 constant region, or a portion thereof, e.g., an Fc portion, as set forth in SEQ ID NO: 175 or SEQ ID NO: 176).

[0391] In some embodiments, any one of the anti-TfR1 antibodies described herein can include a signal peptide (e.g., an N-terminal signal peptide) on the heavy and / or (e.g., and) light chain sequence. In some embodiments, the anti-TfR1 antibodies described herein include any one of the VH and VL sequences, any one of the IgG heavy and light chain sequences, or any one of the F(ab') heavy and light chain sequences described herein, and further include a signal peptide (e.g., an N-terminal signal peptide). In some embodiments, the signal peptide includes the amino acid sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 214).

[0392] The present disclosure provides, in some aspects, additional novel anti-TfR antibodies that can be used as muscle-targeting agents (e.g., in muscle-targeting complexes). The antibody CDR and variable domain sequences are provided in Table 7. Table 7. CDR and variable domain sequences of anti-TfR antibodies according to various definition systems [Table 7]

[0393] In some embodiments, an anti-TfR antibody of the present disclosure comprises one or more CDR-H (e.g., CDR-H1, CDR-H2, and CDR-H3) amino acid sequences from any one of the anti-TfR antibodies selected from Table 7. In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 as provided for each numbering system provided in Table 7. In some embodiments, an anti-TfR antibody of the present disclosure comprises one or more CDR-L (e.g., CDR-L1, CDR-L2, and CDR-L3) amino acid sequences from any one of the anti-TfR antibodies selected from Table 7. In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 as provided for each numbering system provided in Table 7.

[0394] In some embodiments, an anti-TfR antibody of the present disclosure comprises the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided for each numbering system provided in Table 7. In some embodiments, the heavy and light chain CDR3 domains of an antibody may play a particularly important role in the binding specificity / affinity of the antibody for a given antigen. Thus, an anti-TfR antibody of the present disclosure may include at least the heavy and / or (by way of example) light chain CDR3 of any one of the anti-TfR antibodies provided in Table 7.

[0395] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences substantially similar to any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or (by way of example) CDR-L3 sequences provided in Table 7. In some embodiments, the position of one or more CDRs on the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) and / or (e.g., and) VL (e.g., CDR-L1, CDR-L2, or CDR-L3) regions of an antibody described herein may be varied by 1, 2, 3, 4, 5, or 6 amino acid positions, so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the positions defining the CDRs of any of the antibodies described herein can be varied by shifting the N-terminal and / or (e.g., and) C-terminal boundaries of the CDR by 1, 2, 3, 4, 5, or 6 amino acids compared to the CDR positions of any one of the antibodies described herein, so long as immunospecific binding to a transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In another embodiment, the length of one or more CDRs on the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) and / or (e.g., and) VL (e.g., CDR-L1, CDR-L2, or CDR-L3) regions of an antibody described herein is such that immunospecific binding to a transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%) of the binding of the original antibody from which it is derived.For example, it may vary by 1, 2, 3, 4, 5 amino acids or more (e.g., shorter or longer) as long as it has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived.

[0396] Consequently, in some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein can be 1, 2, 3, 4, 5, or more amino acids shorter than one or more of the CDRs described herein (by way of example, provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%) compared to the binding of the original antibody from which it is derived. In some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein can be 1, 2, 3, 4, 5, or more amino acids longer than one or more of the CDRs described herein (e.g., CDRs from anti-TfR antibodies provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein may be extended by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (by way of example, the CDRs from the anti-TfR antibodies provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., the human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%) compared to the binding of the original antibody from which it is derived.In some embodiments, the carboxy portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein may be extended by 1, 2, 3, 4, 5, or more amino acids relative to one or more of the CDRs described herein (e.g., CDRs from anti-TfR antibodies provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs from anti-TfR antibodies provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (by way of example and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs from anti-TfR antibodies provided in Table 7), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% compared to the binding of the original antibody from which it is derived).Any method can be used to determine whether immunospecific binding to the transferrin receptor (e.g., the human transferrin receptor) is maintained, for example, using binding assays and conditions described in the art.

[0397] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences substantially similar to any one of the anti-TfR antibodies provided in Table 7. For example, an antibody may include one or more CDR sequence(s) from an anti-TfR antibody provided in Table 7 that contains up to 5, 4, 3, 2, or 1 amino acid residue variations compared to the corresponding CDR region of any one of the CDRs provided herein (e.g., a CDR from an anti-TfR antibody provided in Table 7), so long as immunospecific binding to transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% compared to the binding of the original antibody from which it is derived). In some embodiments, any of the amino acid variations in any of the CDRs provided herein may be conservative variations. Conservative variations can be introduced into the CDRs at positions where the residues are unlikely to be involved in interactions with the transferrin receptor protein (e.g., human transferrin receptor protein), e.g., as determined based on a crystal structure.

[0398] Some aspects of the disclosure provide anti-TfR antibodies comprising one or more of the heavy chain variable (VH) and / or (by way of example and) light chain variable (VL) domains provided herein. In some embodiments, the anti-TfR antibodies of the disclosure include any antibodies comprising the heavy chain variable domain and / or (by way of example and) the light chain variable domain of the anti-TfR1 antibodies provided in Table 7.

[0399] Aspects of the present disclosure provide anti-TfR antibodies having heavy chain variable (VH) and / or (for example, and) light chain variable (VL) domain amino acid sequences homologous to any of those described herein. In some embodiments, the anti-TfR antibodies comprise a heavy chain variable sequence or a light chain variable sequence that is at least 75% (for example, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a heavy chain variable sequence and / or any light chain variable sequence ...

Claims

1. A complex in which an anti-transferrin receptor (TfR) antibody is covalently linked to at least one oligonucleotide, The anti-transferrin receptor antibody is a Fab comprising a heavy chain variable region (VH) and a light chain variable region (VL). (i) The VH includes the heavy chain complementarity determination region 1 (CDR-H1) of SEQ ID NO: 155, the heavy chain complementarity determination region 2 (CDRH2) of SEQ ID NO: 156, and the heavy chain complementarity determination region 3 (CDRH3) of SEQ ID NO: 157, and the VL includes the light chain complementarity determination region 1 (CDRL1) of SEQ ID NO: 158, the light chain complementarity determination region 2 (CDRL2) of SEQ ID NO: 159, and the light chain complementarity determination region 3 (CDRL3) of SEQ ID NO: 14; (ii) The VH includes CDRH1 of SEQ ID NO: 9, CDRH2 of SEQ ID NO: 10, and CDRH3 of SEQ ID NO: 11, and the VL includes CDRL1 of SEQ ID NO: 12, CDRL2 of SEQ ID NO: 13, and CDRL3 of SEQ ID NO: 14; or (iii) The VH includes CDRH1 of sequence number 160, CDRH2 of sequence number 161, and CDRH3 of sequence number 162, and the VL includes CDRL1 of sequence number 163, CDRL2 of sequence number 13, and CDRL3 of sequence number 164, The complex wherein the oligonucleotide is 20 to 30 nucleotides long and comprises at least 20 consecutive nucleotides of sequence number 449 or 584, where one or more uracil bases may be thymine bases, and one or more thymine bases may be uracil bases.

2. The complex according to claim 1, wherein the antibody comprises a human or humanized framework region.

3. The complex according to claim 1 or 2, wherein VH contains an amino acid sequence that is at least 85% identical to SEQ ID NO: 15, and VL contains an amino acid sequence that is at least 85% identical to SEQ ID NO:

16.

4. The complex according to any one of claims 1 to 3, wherein the anti-transferrin receptor antibody comprises a heavy chain containing an N-terminal pyroglutamate.

5. The complex according to any one of claims 1 to 4, wherein the oligonucleotide comprises the nucleotide sequence of sequence number 449 or 584, where one or more uracil bases may be thymine bases, and one or more thymine bases may be uracil bases.

6. The complex according to any one of claims 1 to 5, wherein the oligonucleotide comprises the nucleotide sequence of SEQ ID NO:

584.

7. The complex according to any one of claims 1 to 6, wherein the oligonucleotide is 30 nucleotides in length.

8. The complex according to any one of claims 1 to 7, wherein the oligonucleotide comprises one or more phosphorodiamidate morpholino.

9. The complex according to any one of claims 1 to 8, wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer.

10. The complex according to any one of claims 1 to 9, wherein an anti-transferrin receptor antibody is covalently linked to the oligonucleotide via a cleavable linker.

11. The complex according to claim 10, wherein the cleavable linker comprises a valine-citrulline sequence.

12. The anti-transferrin receptor antibody and oligonucleotide have the following structure: 【Chemistry 1】 is covalently linked via, where n is an integer from 0 to 10, m is an integer from 0 to 10, L1 is a substituted or unsubstituted aliphatic, heteroaliphatic, carbocyclylene, heterocyclylene, arylene, heteroarylene, -O-, -N(R Ａ ), -S-, -C(=O)-, -C(=O)O-, -C(=O)NR Ａ -, -NRAC(=O)-, -NR Ａ C(=O)R Ａ -, -C(=O)R Ａ -, -NR Ａ C(=O)O-, -NR Ａ C(=O)N(R Ａ ), -OC(=O)-, -OC(=O)O-, -OC(=O)N(R Ａ ), -S(O) ２ NR Ａ -, -NR Ａ S(O) ２ -, or a combination thereof, and each RA is hydrogen or a substituted or unsubstituted alkyl. The complex according to any one of claims 1 to 11.

13. The composite according to claim 12, wherein X is NH.

14. The complex has the following structure: 【Chemistry 2】 The set comprises, where n is an integer from 0 to 10, m is an integer from 0 to 10, and L1 is a substituted or unsubstituted aliphatic, a substituted or unsubstituted heteroaliphatic, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, -O-, -N(R Ａ )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR Ａ -, -NR Ａ C(=O)-, -NR Ａ C(=O)R Ａ -, -C(=O)R Ａ -, -NR Ａ C(=O)O-, -NR Ａ C(=O)N(R) Ａ )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R Ａ )-,-S(O) ２ NR Ａ -, -NR Ａ S(O) ２ -, or a combination thereof, each R Ａ The composite according to any one of claims 1 to 13, wherein is hydrogen or a substituted or unsubstituted alkyl group.

15. The composite according to any one of claims 12 to 14, wherein n is 3 and m is 4.

16. L1 has the following structure: 【Transformation 3】 Here, the piperazine moiety binds to the oligonucleotide, L2 is 【Chemistry 4】 The composite according to any one of claims 12 to 15.

17. The complex according to any one of claims 1 to 16, wherein the molecular payload is covalently linked via a lysine residue of the anti-transferrin receptor antibody.

18. The complex according to any one of claims 1 to 17, wherein the oligonucleotide promotes the expression or activity of a functional dystrophin protein.

19. The complex according to any one of claims 1 to 18, wherein an anti-transferrin receptor antibody is covalently linked to one to three oligonucleotides.

20. A composition comprising a plurality of the complexes described in any one of claims 1 to 19.

21. The composition according to claim 20, wherein the anti-transferrin receptor antibodies contained in a plurality of complexes are covalently linked to an average of 1 to 3 oligonucleotides.

22. A complex according to any one of claims 1 to 19, or a composition according to claim 20 or 21, for use in a method of treating a disease or condition that can be improved or prevented by inducing exon skipping of dystrophin RNA in muscle cells, wherein the method comprises bringing the muscle cells into contact with the complex or the composition.

23. A complex according to any one of claims 1 to 19, or a composition according to claim 20 or 21, for use in a method of treating a disease or condition that can be improved or prevented by promoting the expression or activity of dystrophin protein in cells, wherein the method comprises bringing the cells into contact with the complex or the composition.

24. A complex according to any one of claims 1 to 19, or a composition according to claim 20 or 21, for use in a method of treating a subject having Duchenne muscular dystrophy (DMD), The method comprises administering the complex or the composition to the subject.

25. The complex or composition according to claim 24, wherein the subject comprises a mutated dystrophin allele associated with dystrophin disorders.

26. The complex or composition according to claim 24 or 25, wherein the subject is human.

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