Its use for the modulation of muscle target complexes and genes related to muscle health

Abstract

The present invention provides a complex comprising a molecular payload that modulates the expression or activity of genes involved in muscle growth and maintenance (e.g., MSTN, INHBA, and / or ACVR1B), and a muscle targeting agent covalently linked to such molecular payload. [Solution] A complex is provided comprising a muscle targeting agent covalently linked to a molecular payload that modulates the expression or activity of myostatin (MSTN), inhibin beta A (INHBA), and / or activin receptor type 1B (ACVR1B), wherein the muscle targeting agent specifically binds to an internalized cell surface receptor on muscle cells.

Description

[Technical Field]

[0001] Related applications This application claims benefits under 35 U.S. SC §119(e) as of the filing date of U.S. Provisional Application No. 62 / 959,398, entitled “Muscle Target Complex and its Use for Modulation of Myostatin,” U.S. Provisional Application No. 62 / 959,590, entitled “Muscle Target Complex and its Use for Modulation of INHBA,” and U.S. Provisional Application No. 62 / 959,469, entitled “Muscle Target Complex and its Use for Modulation of ACVR1B,” each of which is incorporated herein by reference in its entirety.

[0002] References to sequence listings submitted as text files via EFS-WEB This application contains a sequence listing, which was submitted in ASCII format via EFS-Web and is incorporated herein by reference in its entirety. The ASCII copy, created on 8 January 2021, is named D082470012WO00-SEQ-ZJG and is 333 kilobytes in size. [Background technology]

[0003] Field of the present invention This application relates to a molecular payload (e.g., an oligonucleotide) that modulates the expression or activity of genes (e.g., MSTN, INHBA, or ACVR1B) related to muscle health (e.g., muscle growth and maintenance), and a target complex for delivering such molecular payload (e.g., an oligonucleotide) to cells (e.g., cardiomyocytes), and its use, particularly in relation to the treatment of diseases.

[0004] background The expression and / or activity of several genes, including myostatin (MSTN), inhibin beta A (INHBA), and activin receptor type 1B (ACVR1B), are related to various aspects of muscle health. Aberrant expression of one or more of these genes, or the expression of their variants, can be involved in various muscle disorders, including cardiac and skeletal muscle disorders such as cardiac fibrosis, myocardial atrophy, and skeletal muscle atrophy, among others.

Summary of the Invention

[0005] Summary According to some aspects, the present disclosure provides a complex that targets muscle cells (such as cardiac and / or skeletal muscle cells) for the purpose of delivering a molecular payload (such as an oligonucleotide) that modulates the expression or activity of genes (such as MSTN, INHBA, or ACDR1B) related to muscle health (such as muscle growth and maintenance). In some embodiments, the complexes provided herein are designed to target cardiac muscle cells. In some embodiments, the complexes provided herein are designed to target skeletal muscle cells. In some embodiments, the complexes provided herein are particularly useful for delivering a molecular payload that modulates the expression or activity of genes involved in muscle health such as muscle growth and maintenance. Such genes include, but are not limited to, MSTN, INHBA, and ACVR1B. In some aspects, the present disclosure provides a complex that targets muscle cells for the purpose of delivering a molecular payload that modulates the expression of one or more of MSTN, INHBA, and ACVR1B.

[0006] In some embodiments, the complexes provided herein are particularly useful, for example, for delivering molecular payloads that inhibit the expression or activity of MSTN in subjects having or suspected of having heart failure. For example, this disclosure intends to inhibit the expression or activity of MSTN in subjects having or suspected of having myocardial wasting, cardiomyopathy, or cardiac cachexia (muscle wasting in heart failure). In some aspects, this disclosure also intends to inhibit the expression or activity of MSTN in skeletal muscle, which may have a positive effect on cardiac atrophy by reducing the circulating amount of myostatin. In some aspects, this disclosure further intends to inhibit the expression or activity of MSTN in subjects having skeletal muscle atrophy. In some embodiments, the complexes provided herein are particularly useful, for example, for delivering molecular payloads that inhibit the expression or activity of INHBA and / or activin A in subjects having or suspected of having a disease (e.g., muscle atrophy such as myocardial atrophy). In some embodiments, the complexes provided herein are particularly useful, for example, for delivering molecular payloads that inhibit ACVR1B expression or activity in subjects with or suspected of having cardiac fibrosis or cardiac hypertrophy.

[0007] As a result, in some embodiments, the conjugate provided herein includes a muscle targeting agent (such as a muscle targeting antibody) that specifically binds to a receptor on the surface of muscle cells for the purpose of delivering a molecular payload to muscle cells. In some embodiments, the conjugate is taken up by cells via receptor-mediated endocytosis, after which the molecular payload is released and can perform its function intracellularly. For example, a conjugate modified to deliver an oligonucleotide can release the oligonucleotide such that the oligonucleotide can inhibit gene expression in muscle cells (such as of MSTN, INHBA, and / or ACVR1B). In some embodiments, a conjugate modified to deliver an oligonucleotide can deliver an oligonucleotide capable of inhibiting the expression of two or more of MSTN, INHBA, and ACVR1B. In some embodiments, the oligonucleotide is released by endosomal cleavage of a covalent linker that connects the oligonucleotide to the muscle targeting agent of the conjugate.

[0008] Some aspects of the present disclosure provide conjugates comprising a muscle targeting agent covalently linked to a molecular payload that modulates the expression or activity of myostatin (MSTN), inhibin beta A (INHBA), and / or activin receptor type 1B (ACVR1B), wherein the muscle targeting agent specifically binds to an internalizing cell surface receptor on muscle cells.

[0009] In some embodiments, the muscle cells are cardiomyocytes.

[0010] In some embodiments, the muscle targeting agent is an anti-transferrin receptor (TfR) antibody, and optionally herein, the anti-TfR antibody comprises any of the 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 the anti-TfR antibodies listed in Tables 1, 3, and 6.

[0011] In some embodiments, the antibody comprises heavy chain variable regions (VH) CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 15, and light chain variable regions (VL) CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibody comprises VH CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 204, and VL CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody comprises VH CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 7, and VL CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 8. In some aspects, the antibody comprises VH CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 23, and VL CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 24.

[0012] 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, CDR-H2 of SEQ ID NO: 249, or CDR-H2 of SEQ ID NO: 252, 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 includes CDR-H1 of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257, 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.

[0013] In some embodiments, the antibody comprises a human or humanized framework region and has VH CDR-H1, CDR-H2, CDR-H3 as represented by SEQ ID NO: 15, and VL CDR-L1, CDR-L2, CDR-L3 as represented by SEQ ID NO: 16. In some embodiments, the antibody comprises a human or humanized framework region and has VH CDR-H1, CDR-H2, CDR-H3 as represented by SEQ ID NO: 204, and VL CDR-L1, CDR-L2, CDR-L3 as represented by SEQ ID NO: 205. In some embodiments, the antibody comprises a human or humanized framework region and has VH CDR-H1, CDR-H2, CDR-H3 as represented by SEQ ID NO: 7, and VL CDR-L1, CDR-L2, CDR-L3 as represented by SEQ ID NO: 8. In some embodiments, the antibody comprises a human or humanized framework region and has VH CDR-H1, CDR-H2, CDR-H3 as represented by SEQ ID NO: 23, and VL CDR-L1, CDR-L2, CDR-L3 as represented by SEQ ID NO: 24.

[0014] In some embodiments, the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a VL having an amino acid sequence at least 80% identical to SEQ ID NO: 16. In some embodiments, the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID NO: 204 and a VL having an amino acid sequence at least 80% identical to SEQ ID NO: 205, optionally wherein the antibody comprises a VH having an amino acid sequence of SEQ ID NO: 204 and a VL having an amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID NO: 7 and a VL having an amino acid sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the antibody comprises a VH having an amino acid sequence at least 80% identical to SEQ ID NO: 23 and a VL having an amino acid sequence at least 80% identical to SEQ ID NO: 24.

[0015] In some embodiments, the equilibrium dissociation constant (KD) for antibody binding to the transferrin receptor is 10 -11 M to 10 -6 It falls within the range up to M.

[0016] In some embodiments, the antibody is selected from the group consisting of full-length IgG, Fab fragment, F(ab') fragment, F(ab')2 fragment, scFv, and Fv. In some embodiments, the antibody is a Fab' fragment.

[0017] In some embodiments, the molecular payload is an oligonucleotide comprising an antisense strand containing a region complementary to the MSTN target sequence. In some embodiments, the MSTN target sequence is the MSTN mRNA sequence represented by SEQ ID NO: 300 or SEQ ID NO: 301, or one of SEQ ID NOs: 302-349. In some embodiments, the antisense strand is 18-25 nucleotides long, and / or the complementary region is at least 16 nucleosides long.

[0018] In some embodiments, the antisense strand comprises at least 16 consecutive nucleotides of the nucleotide sequence represented by any one of SEQ ID NOs. 350-373.

[0019] In some embodiments, the molecular payload is an oligonucleotide comprising an antisense chain containing a region complementary to the INHBA target sequence. In some embodiments, the INHBA target sequence is an INHBA mRNA sequence represented by SEQ ID NO: 422 or SEQ ID NO: 423, or an INHBA target sequence represented by any one of SEQ ID NOs: 424-471. In some embodiments, the antisense chain is 18-25 nucleotides in length, and / or the complementary region is at least 16 nucleosides in length.

[0020] In some embodiments, the antisense strand comprises at least 16 consecutive nucleotides of the nucleotide sequence represented by any one of SEQ ID NOs: 472-495.

[0021] In some embodiments, the molecular payload is an oligonucleotide comprising an antisense strand containing a region complementary to the ACVR1B target sequence. In some embodiments, the ACVR1B target sequence is an ACVR1B mRNA sequence represented by any one of SEQ ID NOs. 520–523, or an ACVR1B target sequence represented by any one of SEQ ID NOs. 374–421. In some embodiments, the antisense strand is 18–25 nucleotides in length, and / or the complementary region is at least 16 nucleosides in length.

[0022] In some embodiments, the antisense strand comprises at least 16 consecutive nucleotides of the nucleotide sequence represented by any one of SEQ ID NOs: 496-519.

[0023] In some embodiments, the oligonucleotide further comprises a sense strand that hybridizes to an antisense strand to form a double-stranded siRNA.

[0024] In some embodiments, the oligonucleotide comprises one or more modified nucleosides, optionally wherein each nucleoside in the oligonucleotide is a modified nucleoside.

[0025] In some embodiments, one or more modified nucleosides are 2'-modified nucleotides, optionally here, one or more 2'-modified nucleosides are selected from 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 acid (LNA), ethylene-crosslinked nucleic acid (ENA), and (S)-restricted ethyl-crosslinked nucleic acid (cEt), optionally here, the 2'-modified nucleotide is 2'-O-methyl or 2'-fluoro(2'-F).

[0026] In some embodiments, the oligonucleotide comprises one or more phosphorothioate nucleoside linkages, optionally wherein one or more phosphorothioate nucleoside linkages are located on the antisense strand of the RNAi oligonucleotide, and further optionally wherein two nucleoside linkages at the 3' end of the sense strand are phosphorothioate nucleoside linkages.

[0027] In some embodiments, the oligonucleotides are the siRNAs listed in Table 11.

[0028] In some embodiments, the oligonucleotides are siRNAs listed in Table 14.

[0029] In some embodiments, the oligonucleotides are siRNAs listed in Table 17.

[0030] In some embodiments, the muscle targeting agent is covalently linked to the molecular payload via (i) a cleavable linker, optionally wherein the cleavable linker comprises a valine-citrulline dipeptide sequence; or (ii) an incleavable linker, optionally wherein the incleavable linker is an alkane linker.

[0031] Other aspects of this disclosure provide methods for reducing the expression of MSTN, INHBA, and / or ACVR1B in muscle cells. In some embodiments, the methods include contacting muscle cells with an effective amount of the complex described herein to facilitate the internalization of the molecular payload into the muscle cells.

[0032] Other aspects of this disclosure provide a method for treating muscle atrophy, comprising administering an effective amount of the complex described herein to a subject in need. In some embodiments, the subject has elevated expression or activity of MSTN, INHBA, and / or ACVR1B.

[0033] Further provided herein are the siRNAs listed in Tables 11, 14, and 17. [Brief explanation of the drawing]

[0034] Simple description of the drawing [Figure 1] Figure 1 shows a non-limiting schematic diagram illustrating the effect of transfecting cells with siRNA.

[0035] [Figure 2] Figure 2 shows a non-restrictive schematic diagram illustrating the activity of a muscle target complex containing siRNA.

[0036] [Figure 3] Figures 3A-3B show non-restrictive schematic diagrams illustrating the activity of siRNA-containing muscle target complexes in in vivo mouse muscle tissue (cardiac heart, Figure 3B; and gastrocnemius muscle, Figure 3A) compared to control experiments. (N=4 C57BL / 6 WT mice).

[0037] [Figure 4A-B]Figures 4A–4E show non-limiting schematic diagrams illustrating the tissue selectivity of muscle target complexes containing siRNA. The data show gene expression in the brain (Figure 4A), liver (Figure 4B), lung (Figure 4C), kidney (Figure 4D), and spleen (Figure 4E), demonstrating that the muscle target complexes do not promote gene inhibition in non-muscle tissues. [Figure 4C-D] Figures 4A–4E show non-limiting schematic diagrams illustrating the tissue selectivity of muscle target complexes containing siRNA. The data show gene expression in the brain (Figure 4A), liver (Figure 4B), lung (Figure 4C), kidney (Figure 4D), and spleen (Figure 4E), demonstrating that the muscle target complexes do not promote gene inhibition in non-muscle tissues. [Figure 4E] Figures 4A–4E show non-limiting schematic diagrams illustrating the tissue selectivity of muscle target complexes containing siRNA. The data show gene expression in the brain (Figure 4A), liver (Figure 4B), lung (Figure 4C), kidney (Figure 4D), and spleen (Figure 4E), demonstrating that the muscle target complexes do not promote gene inhibition in non-muscle tissues.

[0038] [Figure 5] Figure 5 shows the inhibition of MSTN gene expression by 24 siRNAs tested at doses of 0.5 nM and 10 nM.

[0039] [Figure 6] Figure 6 shows dose-response curves for inhibition of human MSTN by candidate oligonucleotide sequences in the concentration range of 100 nM to 10 fM.

[0040] [Figure 7] Figure 7 shows the inhibition of INHBA gene expression by 24 siRNAs tested at doses of 0.5 nM and 10 nM.

[0041] [Figure 8] Figure 8 shows dose-response curves for inhibition of human INHBA by candidate oligonucleotide sequences in the concentration range of 100 nM to 10 fM.

[0042] [Figure 9] Figure 9 shows the inhibition of ACVR1B gene expression by 24 siRNAs tested at doses of 0.1 and 10 nM.

[0043] [Figure 10] Figure 10 shows dose-response curves for inhibition of human ACVR1B by candidate oligonucleotide sequences in the concentration range of 100 nM to 10 fM.

[0044] [Figure 11] Figure 11 shows dose-response curves for inhibition of mouse ACVR1B by candidate oligonucleotide sequences in the concentration range of 100 nM to 10 fM.

[0045] Detailed description Some aspects of this disclosure provide molecular payloads (e.g., oligonucleotides) that modulate the expression or activity of genes (e.g., MSTN, INHBA, or ACDR1B) associated with muscle health (e.g., muscle growth and maintenance). Other aspects of this disclosure relate to the recognition that while certain molecular payloads (e.g., oligonucleotides, peptides, small molecules) may have beneficial effects in muscle cells (e.g., cardiomyocytes), effectively targeting such cells has proven difficult. Consequently, further provided herein are conjugates comprising muscle targeting agents covalently linked to a molecular payload to overcome such challenges. In some embodiments, the conjugates are particularly useful for delivering molecular payloads that inhibit the expression or activity of target genes in muscle cells, for example, in subjects with or suspected of having rare muscle diseases. In some embodiments, the conjugates provided herein are designed to target cardiomyocytes or cardiomyocyte tissue. In some embodiments, the conjugates provided herein are provided for treating subjects with muscle atrophy (e.g., muscle loss or cachexia). For example, in some embodiments, the complex is provided to target MSTN expression to treat subjects having myocardial wasting, cardiomyopathy, or cardiac cachexia and / or skeletal muscle atrophy. In some embodiments, the complex is provided to target INHBA to treat subjects having muscle atrophy (e.g., myocardial atrophy). In some embodiments, the complex is provided to target ACVR1B to treat subjects having cardiac fibrosis or cardiac hypertrophy.

[0046] Myostatin, also known as growth factor 8 (GDF8), is a secreted growth factor that negatively regulates muscle mass. In humans, myostatin is encoded by the MSTN gene. Loss-of-function mutations in the myostatin gene (MSTN) lead to a hypermuscular phenotype and have been described in cattle, sheep, fish, dogs, and humans. Myostatin is expressed in skeletal muscle, with lower levels reported in adipose and cardiac tissue. Inhibition of myostatin signaling leads to increased muscle size.

[0047] Myostatin can inhibit cardiomyocyte proliferation and differentiation by manipulating cell cycle progression, and has been shown to prevent the transition from the G1 to the S phase of the cell cycle by decreasing cyclin-dependent kinase complex 2 (CDK2) levels and increasing p21 levels. Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into the serum, with effects limited to muscle growth. However, increased cardiac myostatin can increase its serum concentration, potentially leading to skeletal muscle atrophy.

[0048] Pathological conditions that increase cardiac stress and promote heart failure can induce elevated levels of both cardiac myostatin mRNA and protein within the heart. In ischemic or dilated cardiomyopathy, elevated levels of myostatin mRNA have been detected in the left ventricle. Furthermore, elevated myostatin levels during chronic heart failure have been shown to cause cardiac cachexia. Systemic inhibition of cardiac myostatin has been shown to maintain overall muscle mass in experimental models with pre-existing heart failure.

[0049] Inhibin beta A (INHBA) is a protein that can exist as an oligomeric subunit of activin A and inhibin A. In some cases, INHBA can form a disulfide-linked homodimer (i.e., a dimer between two INHBA molecules) to form activin A, which enhances the biosynthesis and secretion of follicle-stimulating hormone (FSH) and is involved in several biological processes, including cell proliferation and differentiation, immune responses and wound repair, and endocrine function. In other cases, INHBA can dimerize with inhibin alpha to form inhibin A, which reduces the biosynthesis and secretion of FSH.

[0050] Activin A interacts with activin type 1 receptors (e.g., ACVR1, ACVR1B, and ACVR1C) and activin type 2 receptors (ACVR2A and ACVR2B). These protein-protein interactions lead to phosphorylation of SMAD2 and SMAD3, which can ultimately alter the gene expression of a wide variety of genes.

[0051] Activin A has been shown to negatively regulate muscle mass (e.g., in relation to myostatin) and is therefore associated with several muscle disorders, including muscle atrophy (e.g., myocardial atrophy), as described, for example, Lee SJ, et al., "Regulation of muscle mass by follistatin and activins", Mol. Endocrinol. 2010 Oct;24(10):1998-2008; and Lach-Trifilieff et al., Mol Cell Biol. 2014 Feb; 34(4): 606-618. In some cases, muscle atrophy can lead to life-threatening complications. Elevated activin A levels are also associated with myocardial complications in patients with type 2 diabetes (as described, for example, in Lin et al., Acta Cardiol Sin. 2016 Jul; 32(4): 420-427; and Kuo et al., Sci Rep 8, 9957 (2018)). These indications demonstrate that compositions and methods for targeting activin A and its subunit INHBA may offer therapeutic benefits. However, effective treatments targeting the function and expression of INHBA (including, for example, dimerization to form activin A) are limited.

[0052] Activin receptor type 1B (ACVR1B), also known as ALK-4, is a transmembrane serine / threonine kinase activin type 1 receptor that interacts with activin receptor type 2 to form the activin receptor complex. The activin receptor complex binds to activin and functions to regulate a diverse array of cellular processes through signaling, including neuronal differentiation and survival, wound healing, extracellular matrix production, immunosuppression, and oncogenesis. Within the receptor complex, ACVR1B is phosphorylated by the activin receptor type 2 protein following activin binding. Phosphorylated ACVR1B can then propagate activin signaling by phosphorylating several SMAD proteins (e.g., SMAD2 and SMAD3). Interactions between ACVR1B and SMAD7 can alternatively function to inhibit activin signaling.

[0053] Activin, functioning through its signaling pathway via ACVR1B, has been established as a major regulator of cardiac fibrosis (e.g., atrial fibrosis). This regulation is thought to be enhanced by the presence of angiotensin-II. Cardiac fibrosis, a condition characterized by excessive production of extracellular matrix in the cardiomyocyte, is generally associated with abnormal cardiac function, atrial fibrillation, and / or structural remodeling related to heart attack. See, for example, Wang, Q. et al. "The crucial role of activin A / ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation." Basic Res Cardiol. 2017 Jul;112(4):47 (its contents are incorporated herein by reference). Furthermore, targeting ACVR1B has been shown to function in counteracting cardiac fibrosis and dysfunction in subjects with cardiac fibrosis. In addition, inhibition of ACVR1B is effective in subjects with cardiac hypertrophy. For example, see Chen YH et al., "Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function." J Mol Cell Cardiol. 2017 Apr;105:1-11.; and Wang, Q. et al., "Activin Receptor-Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy." J Am Heart Assoc. 2018 Aug 21;7(16):e008842 (the contents of each of these are incorporated herein by reference).

[0054] Further aspects of this disclosure, including the definition of terms, are provided below.

[0055] I. Definition ACVR1B: As used herein, the terms "ACVR1B" or "ALK-4" refer to the gene encoding activin A receptor type 1B. ACVR1B is a transmembrane serine / threonine kinase activin type 1 receptor that interacts with activin receptor type 2 to form an activin receptor complex, enabling activin signaling. In some embodiments, ACVR1B may be a gene from humans (gene ID: 91), non-human primates (e.g., gene ID: 696587, gene ID: 101865702), or rodents (e.g., gene ID: 11479, gene ID: 29381). In addition, several exemplary human transcripts (annotated, for example, under GenBank RefSeq accession numbers: NM_004302.5, NM_020327.3, NM_020328.4, XM_017020201.2, XM_011538966.3, and XM_011538967.3) are characterized. The exemplary ACVR1B protein encoded by the human ACVR1B gene is annotated under NCBI reference sequences: NP_004293.1, NP_064732.3, and NP_064733.3 and has the following amino acid sequence: NP_004293.1 (Sequence ID 251) MAESAGASSFFPLVVLLLAGSGGSGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLDGMEHHVRTCIPKVELVPAGKPFYCLSSEDLRRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVE LVGIIAGPVFLLFLIIIIVFLVINYHQRVYHNRQRLDMEDPSCEMCLSKDKTLQDLVYDLSTSGSGLPLFVQRTVARTIVLQEIIGKGRFGEVWRGRWRGGDVAVKIFSSREERSWFREAEIYQ TVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVTIEGMIKLALSAASGLAHLHMEIVGTQGKPGIAHRDLKSKNILVKKNGMCAIADLGLAVRHDAVTDTIDIAPNQRVGTK RYMAPEVLDETINMKHFDSFKCADIYALGLVYWEIARRCNSGGVHEEYQLPYYDLVPSDPSIEEMRKVVCDQKLRPNIPNWWQSYEALRVMGKMMRECWYANGAARLTALRIKKTLSQLSVQEDVKI NP_064732.3 (Sequence ID 274) MVSIFNLDGMEHHVRTCIPKVELVPAGKPFYCLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELVGIIAGPVFLLFLIIIIVFLVINYHQRVYHNRQRLDME DPSCEMCLSKDKTLQDLVYDLSTSGSGLPLFVQRTVARTIVLQEIIGKGRFGEVWRGRWRGGDVAVKIFSSREERSWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQL WLVSDYHEHGSLFDYLNRYTVTIEGMIKLALSAASGLAHLHMEIVGTQGKPGIAHRDLKSKNILVKKNGMCAIADLGLAVRHDAVTDTIDIAPNQRVGTKRYMAPEVLDETIN MKHFDSFKCADIYALGLVYWEIARRCNSGGVHEEYQLPYYDLVPSDPSIEEMRKVVCDQKLRPNIPNWWQSYEALRVMGKMMRECWYANGAARLTALRIKKTLSQLSVQEDVKI NP_064733.3 (Sequence ID 278) MAESAGASSFFPLVVLLLAGSGGSGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLDGMEHHVRTCIPKVELVPAGKPFYCLSSEDLRRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELVGIIAGPVF LLFLIIIIVFLVINYHQRVYHNRQRLDMEDPSCEMCLSKDKTLQDLVYDLSTSGSGSGLPLFVQRTVARTIVLQEIIGKGRFGEVWRGRWRGGDVAVKIFSSREERSWFREAEIYQTVMLRHENILGFIAADNKADC SFLTLPWEVVMVSAAPKLRSLRLQYKGGRGRARFLFPLNNGTWTQLWLVSDYHEHGSLFDYLNRYTVTIEGMIKLALSAASGLAHLHMEIVGTQGKPGIAHRDLKSKNILVKKNGMCAIADLGLAVRHDAVTDTID IAPNQRVGTKRYMAPEVLDETINMKHFDSFKCADIYALGLVYWEIARRCNSGGVHEEYQLPYYDLVPSDPSIEEMRKVVCDQKLRPNIPNWWQSYEALRVMGKMMRECWYANGAARLTALRIKKTLSQLSVQEDVKI

[0056] Administering: As used herein, the term “administering” or “dosing” means providing a complex to a subject in a physiologically and / or pharmacologically useful manner (for example, treating a disease in the subject).

[0057] Approximately: As used herein, the terms “approximately” or “about” refer to a value similar to the given reference value when applied to one or more values ​​of interest. In some embodiments, unless otherwise stated or evident from the context (except where such a figure exceeds 100% of a feasible value), the terms “approximately” or “about” refer to a broad range of values ​​that fall within plus or minus (greater than or less than) 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than these values.

[0058] Antibody: As used herein, the term “antibody” refers to a polypeptide comprising 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, an F(ab')2 fragment, an Fv fragment, or an scFv fragment. In some embodiments, the antibody is a nanobody derived from an antibody of a camelid animal 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 having a human germline sequence. In another embodiment, the antibody comprises a heavy chain constant region selected from the group consisting of constant regions of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE. In some embodiments, the antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, the antibody comprises a constant region, e.g., an Fc region. The immunoglobulin constant region refers to the heavy chain or light chain constant region. The amino acid sequences of the human IgG heavy chain and light chain constant region and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of the antibody described herein may 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 CH3 domain. In some embodiments, the amino acid sequence of the VH domain includes the amino acid sequence of the human gamma (γ) heavy chain constant region, for example, any sequence known in the art.Non-limiting examples of human constant region sequences are described in the art; see, for example, U.S. Patent No. 5,693,780 and Kabat EA et al. (1991) above. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein. In some embodiments, the antibody is modified, for example, via glycosylation, phosphorylation, SUMOylation, and / or 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 phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules comprise mannose units, glucose units, N-acetylglucosamine units, N-acetylgalactosamine units, galactose units, fucose units, or phospholipid units. In some embodiments, the antibody is a construct comprising a polypeptide containing 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 sites. 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, antibodies may also be part of larger immunoadhesion molecules formed by covalent or noncovalent bonds between the antibody or antibody moiety and one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of streptavidin core regions to construct 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 construct divalent and biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol.Immunol. 31:1047-1058).

[0059] CDR: As used herein, the term "CDR" refers to the complementarity-determining region within the antibody variable sequence. There are three CDRs in each of the heavy and light chain variable regions, designated as CDR1, CDR2, and CDR3 for each variable region. As used herein, the term "CDR set" 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 are defined differently depending on the system. The system described by Kabat et al., Sequence of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and (1991)) not only provides a unique residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define three CDRs. These CDRs are sometimes referred to as Kabat CDRs. Subportions of the CDRs may be designated as 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, which have boundaries that overlap with Kabat CDRs. Other boundaries that define CDRs that overlap with Kabat CDRs are described by Padlan (FASEB J.9:133-139 (1995)) and MacCallum (J Mol Biol This is described in 262(5):732-45(1996). Further CDR boundary definitions do not have to strictly adhere to one of the systems above, but may still overlap with Kabat CDRs, and may be shortened or lengthened based on predictions or experimental findings that specific residues, groups of residues, or even the entire CDR do not significantly affect antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, but preferred embodiments use CDRs defined in Kabat or Chothia.

[0060] CDR-grafted antibody: The term "CDR-grafted antibody" refers to an antibody that contains heavy chain and light chain variable region sequences from one species, but in which one or more sequences of the VH and / or VL CDR regions are replaced with CDR sequences from another species. This includes antibodies that have mouse heavy chain and light chain variable regions, but in which one or more of the mouse CDR (e.g., CDR3) are replaced with human CDR sequences.

[0061] Chimeric antibody: The term "chimeric antibody" refers to an antibody that contains heavy chain and light chain variable region sequences from one species and a constant region sequence from another species, such as an antibody that has mouse heavy chain and light chain variable regions linked to a human constant region.

[0062] Complementary: As used herein, the term “complementary” refers to the capacity for accurate pairing between two nucleotides or between two sets of nucleotides. In particular, complementarity is a term that characterizes the degree of hydrogen bond pairing that results in a bond between two nucleotides or between two sets of nucleotides. For example, if a base of an oligonucleotide at a certain position can hydrogen bond with a base of a target nucleic acid (e.g., mRNA) at a corresponding position, then the bases are considered complementary to each other at that position. Base pairing may include both standard Watson-Crick base pairings and non-Watson-Crick base pairings (e.g., Wobble base pairings and Hoogsteen base pairings). For example, in some embodiments, as complementary base pairings, 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 universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize with any of A, C, U, or T and are considered complementary to them. Inosine (I) is also considered a universal base in the art and is considered complementary to any of A, C, U, or T.

[0063] Conservative amino acid substitutions: As used herein, “conservative amino acid substitutions” refer to amino acid substitutions that do not alter the relative charge or size characteristics of the protein to which the amino acid substitution is made. Variants may be prepared according to methods for modifying polypeptide sequences known to those skilled in the art, for example, references summarizing 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, FMAusubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions made to amino acids in 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.

[0064] Covalently linked: As used herein, the term “covalently linked” refers to the characteristic of two or more molecules linked together by 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) acting as an intermolecular linker. However, in some embodiments, two or more molecules may be covalently linked together by a molecule acting as a linker, which binds 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 an incleavable linker.

[0065] Cross-reactivity: As used herein, and in the context of targeting agents (e.g., antibodies), the term “cross-reactivity” refers to the property of an agent to be able to specifically bind to one or more antigens of a similar type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or binding activity. For example, in some embodiments, an antibody that cross-reacts to antigens of a similar type or class between humans and non-human primates (e.g., human transferrin receptors and non-human primate transferrin receptors) is capable of binding to human antigens and non-human primate antigens with similar affinity or binding activity. In some embodiments, an antibody cross-reacts to human antigens and rodent antigens of a similar type or class. In some embodiments, an antibody cross-reacts to rodent antigens of a similar type or class and non-human primate antigens. In some embodiments, an antibody cross-reacts to human antigens, non-human primate antigens, and rodent antigens of a similar type or class.

[0066] Framework: As used herein, the term “framework” or “framework sequence” refers to the sequence remaining in the variable region after subtracting the CDRs. Since the precise definition of a CDR sequence can be determined by various systems, the meaning of a framework sequence depends on correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 on the light chain, and CDR-H1, CDR-H2, and CDR-H3 on the heavy chain) also divide the framework regions on the light and heavy chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. When referred to elsewhere, framework regions that do not specify a particular sub-region as FR1, FR2, FR3, or FR4 represent the combined FRs within the variable region of a naturally occurring single immunoglobulin chain. When used herein, FR represents one of four subregions, and FR(plural) represents two or more of the four subregions containing the framework region. 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.

[0067] Human Antibodies: When used herein, the term “human antibodies” is intended to encompass antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies in this disclosure may include, for example, amino acid residues not encoded by human germline immunoglobulin sequences (mutations introduced, e.g., by random mutagenesis or site-directed mutagenesis in vitro, or by somatic mutation in vivo), particularly in CDRs, especially CDR3. However, when used herein, the term “human antibodies” is not intended to encompass antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, are conjugated onto a human framework sequence.

[0068] 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 sequence and / or VL sequence has been modified to be more "human-like," i.e., more similar to the human germline variable sequence. One type of humanized antibody is a CDR-conjugated antibody in which a human CDR sequence is introduced onto a non-human VH and VL sequence and replaced with the corresponding non-human CDR sequence. In one embodiment, a humanized anti-transferrin receptor antibody and antigen-binding moiety are provided. Such an antibody may be produced by obtaining a mouse anti-transferrin receptor monoclonal antibody using existing hybridoma technology followed by in vitro genetic engineering (such as disclosed in PCT publication WO 2005 / 123126 A2 by Kasaian et al.).

[0069] INHBA: As used herein, the terms “INHBA” or “inhibin, beta A” refer to the gene encoding inhibin, beta A (INHBA). In some embodiments, the INHBA gene may be the human INHBA gene (gene ID: 3624), the INHBA gene of a non-human primate (e.g., gene ID: 102146142, gene ID: 702734), or the INHBA gene of a rodent (e.g., gene ID: 16323, gene ID: 29200). In addition, the exemplary human transcript (e.g., annotated under GenBank RefSeq accession number: NM_002192.4) is characterized. The exemplary INHBA protein encoded by the human INHBA gene is annotated under NCBI reference sequence: NP_002183.1 and has the following amino acid sequence: MPLLWLRGFLLASCWIIVRSSPTPGSEGHSAAPDCPSCALAALPKDVPNSQPEMVEAVKKHILNMLHLKKRPDVTQPVPKAALLNAIRKLHVGKVGENGYVEIEDDIG RRAEMNELMEQTSEIITFAESGTARKTLHFEISKEGSDLSVVERAEVWLFLKVPKANRTRTKVTIRLFQQQKHPQGSLDTGEEAEEVGLKGERSELLLSEKVVDARKST WHVFPVSSSIQRLLDQGKSSLDVRIACEQCQESGASLVLLGKKKKKEEEGEGKKKGGGEGGAGADEEKEQSHRPFLMLQARQSEDHPHRRRRRGLECDGKVNICCKKQFFVSFKDIGWNDWIIAPSGYHANYCEGECPSHIAGTSGSSLSFHSTVINHYRMRGHSPFANLKSCCVPTKLRPMSMLYYDDGQNIIKKDIQNMIVEECGCS(Sequence ID 286)

[0070] Internalizing cell surface receptors: As used herein, the term “internalizing cell surface receptors” refers, for example, to cell surface receptors that are internalized by a cell in response to an external stimulus (for example, a ligand that binds to the receptor). In some embodiments, internalizing cell surface receptors are internalized by endocytosis. In some embodiments, internalizing cell surface receptors are internalized by clathrin-mediated endocytosis. However, in some embodiments, internalizing cell surface receptors are internalized by clathrin-independent pathways, such as phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake, or clathrin-independent constitutive endocytosis. In some embodiments, internalizing cell surface receptors include an intracellular domain, a transmembrane domain, and / or an extracellular domain, which optionally further include a ligand-binding domain. In some embodiments, cell surface receptors become internalized by the 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.

[0071] Isolated Antibodies: When used herein, “isolated antibodies” are intended to refer to antibodies that are substantially free from other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to the transferrin receptor is substantially free from other 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. Furthermore, isolated antibodies may be substantially free from other cellular material and / or chemicals.

[0072] Kabat Numbering: The terms “Kabat numbering,” “Kabat definition,” and “Kabat labeling” are used interchangeably herein. These terms refer to a system of numbering amino acid residues that are recognized in the art but are more variable (i.e., highly variable) than other amino acid residues in the heavy and light chain variable regions of an antibody or its antigen-binding moiety (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, USD Department of Health and Human Services, NIH Publication No. 91-3242). In the heavy chain variable region, the hypervariable region extends from amino acid positions 31-35 for CDR1, amino acid positions 50-65 for CDR2, and amino acid positions 95-102 for CDR3. In the light chain variable region, the hypervariable region extends to amino acid positions 24-34 for CDR1, amino acid positions 50-56 for CDR2, and amino acid positions 89-97 for CDR3.

[0073] 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 ligated to or otherwise linked to 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 containing a chain having a region complementary to a target gene.

[0074] MSTN: As used herein, the term "MSTN" refers to the gene encoding myostatin, a secreted growth factor that negatively regulates muscle mass. In some embodiments, MSTN may be a human gene (gene ID: 2660), a non-human primate gene (e.g., gene ID: 710114, gene ID: 470605), or a rodent gene (e.g., gene ID: 29152, gene ID: 17700). In addition, an exemplary human transcript (annotated under GenBank RefSeq accession number: NM_005259.3, for example) is characterized. The exemplary myostatin protein encoded by the human MSTN gene is annotated under NCBI reference sequence: NP_005250.1 and has the following amino acid sequence: MQKLQLCVYIYLFMLIVAGPVDLNENSEQKENVEKEGLCNACTWRQNTKSSRIEAIKIQILSKLRLETAPNISKDVIRQLLPKAPPLRELIDQYDVQRDDSSDGSLEDDDYHATTETIITMPTESDFLMQVDGKPKCCFFKFSSKIQYNKVVKAQLWIYLRPVETPTTVFVQILRLIKPMKDGTRYTGIRSLKLDMNPGTGIWQSIDVKTVLQNWLKQPESNLGIEIKALDENGHDLAVTFPGPGEDGLNPFLEVKVTDTPKRSRRDFGLDCDEHSTESRCCRYPLTVDFEAFGWDWIIAPKRYKANYCSGECEFVFLQKYPHTHLVHQANPRGSAGPCCTPTKMSPINMLYFNGKEQIIYGKIPAMVVDRCGCS(Sequence No. 290)

[0075] Muscle atrophy: As used herein, the term “muscle atrophy” refers to a condition characterized by muscle wasting. In some embodiments, muscle atrophy is a highly regulated catabolic process that occurs during periods of disuse and / or in response to systemic inflammation (e.g., cachexia). In some embodiments, muscle atrophy is associated with a decrease in muscle mass, a reduction in muscle size, and / or a reduction in the number of muscle cells in a subject. Conditions including chronic diseases (e.g., congestive heart failure, diabetes, cancer, AIDS, and kidney disease), severe burns, critical care myopathy, denervation of the limbs, stroke, limb fractures, anorexia, spinal cord injury, or other conditions leading to muscle disuse can result in muscle atrophy. In some embodiments, muscle atrophy is caused by cancer cachexia, cardiac cachexia, fasting, diabetes, renal failure, denervation, or glucocorticoid-induced muscle atrophy.

[0076] Muscle Targeting Agent: As used herein, the term “muscle targeting agent” refers to a molecule that specifically binds to an antigen expressed on a muscle cell (e.g., a cardiomyocyte). The antigen in or on the muscle cell may be a membrane protein, e.g., an intrinsic membrane protein or a superficial membrane protein. Typically, a muscle targeting agent specifically binds to an antigen on the muscle cell that facilitates the internalization of the muscle targeting agent (and any associated molecular payload) into the muscle cell. In some embodiments, the muscle targeting agent can specifically bind to an internalizing cell surface receptor on the muscle and be 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.

[0077] Muscle-Targeted Antibodies: As used herein, the term “muscle-targeted antibody” refers to a muscle-targeting agent that is an antibody that specifically binds to an antigen found in or on muscle cells (e.g., cardiomyocytes). In some embodiments, a muscle-targeted antibody specifically binds to an antigen on a muscle cell that facilitates the internalization of the muscle-targeted antibody (and any associated molecular payload) into the muscle cell. In some embodiments, a muscle-targeted antibody specifically binds to an internalizing cell surface receptor present on the muscle cell. In some embodiments, a muscle-targeted antibody is an antibody that specifically binds to a transferrin receptor.

[0078] 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), microRNAs, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNA), etc. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, oligonucleotides may contain one or more modified nucleotides (e.g., 2'-O-methylglycosulfate, purine, or pyrimidine modification). In some embodiments, oligonucleotides may contain one or more modified nucleotide linkages. In some embodiments, oligonucleotides may contain one or more phosphorothioate linkages, which may be in the stereochemical configuration of Rp or Sp.

[0079] Recombinant Antibodies: When used herein, the term “recombinant human antibodies” refers to all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (as described in detail herein), antibodies isolated from recombinant combinatorial human antibody libraries (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), antibodies isolated from human immunoglobulin gene transgenic animals (e.g., mice) (e.g., Taylor, LD, et al.) It is intended to include antibodies prepared, expressed, created, or isolated by any other means involving splicing of human immunoglobulin gene sequences with other DNA sequences, as described by al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370). Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when human Ig sequence transgenic animals are used, in vivo somatic mutagenesis), and therefore, although the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to the VH and VL sequences of the human germline, they may not be naturally present in the germline repertoire of human antibodies in vivo.One aspect of the present disclosure provides fully human antibodies capable of binding to human transferrin receptors, which may be produced using techniques well known in the art, for example, but not limited to, techniques using a human Ig phage library (e.g., disclosed in PCT publication WO 2005 / 007699 A2 by Jermutus et al.).

[0080] Complementary Region: As used herein, the term “complementary region” 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 can anneal to each other under physiological conditions (e.g., in a cell). In some embodiments, the complementary region is fully complementary to the cognate nucleotide sequence of the target nucleic acid. However, in some embodiments, the complementary region is partially complementary to the cognate nucleotide sequence of the target nucleic acid (e.g., at least 80%, 90%, 95%, or 99% complementary). In some embodiments, the complementary region contains one, two, three, or four mismatches compared to the cognate nucleotide sequence of the target nucleic acid.

[0081] Specific binding: As used herein, the term “specific binding” refers to the ability of a molecule to bind to a binding partner to a degree of affinity or binding activity that can be used to distinguish the binding partner from a suitable control in a binding assay or other binding context. With respect to an antibody, the term “specific binding” refers to the ability of an antibody to bind to a particular antigen to a degree of affinity or binding activity (for example, to the extent that it allows preferential targeting to a cell (e.g., muscle cells) through binding to the antigen, as described herein) compared to a suitable reference antigen, or an antigen that can be used to distinguish a particular antigen from other antigens. In some embodiments, when the antibody binds to the target, 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 K less than this D When having, the antibody binds specifically to the target. In some embodiments, the antibody binds specifically to an epitope of the tip domain of the transferrin receptor, for example, the transferrin receptor.

[0082] Subjects: As used herein, the term “subjects” refers to mammals. In some embodiments, subjects are non-human animals of the order Primates, or rodents. In some embodiments, subjects are humans. In some embodiments, subjects are patients, e.g., human patients having or suspected to have a disease. In some embodiments, subjects are patients having type 2 diabetes. In some embodiments, subjects are patients having cancer. In some embodiments, subjects are human patients having or suspected to have heart failure, muscle atrophy (e.g., skeletal and / or myocardial atrophy), muscular dystrophy, cachexia (e.g., cardiac cachexia), muscle hypertrophy, myocardial wasting, and / or cardiomyopathy. In some embodiments, subjects having muscle hypertrophy have at least one mutation in MSTN, as in Schuelke, M. et al., "Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child" N Engl J Med 2004; 350:2682-2688 (incorporated herein by reference). In some embodiments, the subjects are patients with type 2 diabetes who have myocardial complications (e.g., heart failure, myocardial atrophy, cachexia, and / or myocardial hypertrophy). In some embodiments, the subjects are cancer patients with cachexia. In some embodiments, the subjects are human patients who have or are suspected of having cardiac fibrosis or cardiac hypertrophy. In some embodiments, the subjects are human patients who have or are suspected of having angiotensin II-induced cardiac hypertrophy. In some embodiments, the subjects have experienced a myocardial infarction (i.e., a heart attack).

[0083] Transferrin receptor: As used herein, the term “transferrin receptor” (also known as 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, several human transcript variants encoding various isoforms of the receptor have been characterized (e.g., those annotated with GenBank RefSeq accessions: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0084] 2'-Modified Nucleoside: As used herein, the terms “2'-Modified Nucleoside” and “2'-Modified Ribonucleoside” are interchangeable and refer to nucleosides having a sugar moiety modified at the 2' position. In some embodiments, a 2'-modified nucleoside is a 2'-4' bicyclic nucleoside, where the 2' and 4' positions of the sugar are cross-linked (e.g., by methylene, ethylene, or (S)-restricted ethyl cross-linking). In some embodiments, a 2'-modified nucleoside is a non-bicyclic 2'-modified nucleoside, where, for example, the 2' position of the sugar moiety is substituted. Non-limiting examples of 2'-modified nucleosides include: 2'-deoxy, 2'-fluoro (2'-F), 2'-O-methyl (2'-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)-restricted ethyl-bridged nucleic acids (cEt). In some embodiments, the 2'-modified nucleosides described herein are high-affinity modified nucleotides, and oligonucleotides containing 2'-modified nucleotides have increased affinity for target sequences compared to unmodified oligonucleotides. An example of the structure of a 2'-modified nucleoside is provided below: [ka]

[0085] II. Complexes Provided herein are targeting agents, for example, complexes comprising an antibody covalently linked to a molecular payload. In some embodiments, the complex comprises a muscle-targeting antibody covalently linked to an oligonucleotide. The complex may include 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 on different antigens.

[0086] The complex may be used to modulate the activity or function of at least one gene, protein, and / or nucleic acid. In some embodiments, the molecular payload present with the complex is responsible for the modulation of the gene, protein, and / or nucleic acid. The molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any other molecular entity capable of modulating the activity or function of a gene, protein, and / or nucleic acid in a cell. In some embodiments, the molecular payload is an oligonucleotide targeting the MSTN gene in muscle cells (e.g., cardiomyocytes). In some embodiments, the molecular payload is an oligonucleotide targeting INHBA or activin A in muscle cells (e.g., cardiomyocytes). In some embodiments, the molecular payload is an oligonucleotide targeting ACVR1B in muscle cells (e.g., cardiomyocytes).

[0087] In some embodiments, the complex comprises an anti-transferrin receptor antibody covalently linked to a muscle targeting agent, for example, a molecular payload (e.g., an antisense oligonucleotide targeting the MSTN gene, an antisense oligonucleotide targeting INHBA, or an antisense oligonucleotide targeting ACVR1B).

[0088] A. Muscle targeting agents Several aspects of this disclosure provide muscle targeting agents, for example, for delivering molecular payloads to muscle cells (e.g., cardiomyocytes). In some embodiments, such muscle targeting agents are capable of binding to muscle cells, for example, via specific binding to antigens on the muscle cells, and delivering the bound molecular payload to the muscle cells. In some embodiments, the muscle targeting agents are designed to target cardiomyocytes or cardiomyocyte tissue. In some embodiments, the molecular payload is bound to the muscle targeting agent (e.g., covalently) and, upon binding of the muscle targeting agent to an antigen on the muscle cell, is internalized into the muscle cell, for example, via endocytosis. It should be understood that various types of muscle targeting agents may be used in accordance with this disclosure. For example, muscle targeting agents may contain, or consist of, nucleic acids (e.g., DNA or RNA), peptides (e.g., antibodies), lipids (e.g., microvesicles), or sugar moieties (e.g., polysaccharides). While exemplary muscle targeting agents are described in more detail herein, it should be understood that the exemplary muscle targeting agents provided herein are not intended to be limiting.

[0089] Several aspects of this 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 cardiomyocytes, skeletal muscle cells, and / or smooth muscle cells. In some embodiments, any of the muscle targeting agents provided herein bind (e.g., specifically bind) to antigens on cardiomyocytes.

[0090] 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 of 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, a molecular payload conjugated to transferrin or an anti-transferrin receptor antibody may be taken up by muscle cells via binding to the transferrin receptor and then endocytosed, for example, via clathrin-mediated endocytosis.

[0091] The use of muscle-targeting agents can also be useful for enriching molecular payloads (e.g., oligonucleotides) in muscle while reducing toxicity associated with the effect in other tissues. In some embodiments, muscle-targeting agents enrich bound molecular payloads in muscle cells compared to other cell types within the subject. In some embodiments, muscle-targeting agents enrich bound molecular payloads in muscle cells (e.g., cardiomyocytes) to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times more than in non-muscle cells (e.g., liver cells, nerve cells, blood cells, or adipocytes). In some embodiments, the toxicity of the molecular payload in a target 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 it is delivered to the target.

[0092] In some embodiments, muscle recognition elements (e.g., muscle cell antigens) may be required to achieve muscle selectivity. For example, the muscle targeter may be a small molecule that is a substrate of a muscle-specific uptake transporter. Another example is that the muscle targeter may be an antibody that enters muscle cells via transporter-mediated endocytosis. Yet another example is that the muscle targeter may be a ligand that binds to cell surface receptors on muscle cells. It should be understood that while transporter-based approaches provide a direct pathway to cell entry, receptor-based targeting may involve stimulated endocytosis to reach the desired site of action.

[0093] i. Muscle targeting antibody In some embodiments, muscle targeting agents are antibodies. Generally, the high specificity of antibodies against their target antigens provides the potential to selectively target muscle cells (e.g., skeletal muscle cells, smooth muscle cells, and / or cardiomyocytes). 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 this 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 these are incorporated herein by reference.

[0094] a. Anti-transferrin receptor antibody Several aspects of this disclosure are based on the recognition that agents that bind to transferrin receptors, such as anti-transferrin receptor antibodies, can target muscle cells. Transferrin receptors are internalized cell surface receptors that transport transferrin across the cell membrane and contribute to the regulation of intracellular iron levels and homeostasis. Several aspects of this disclosure provide transferrin receptor-binding proteins capable of binding to transferrin receptors. Consequently, aspects of this disclosure provide binding proteins (e.g., antibodies) that bind to transferrin receptors. In some embodiments, binding proteins that bind to transferrin receptors are internalized into muscle cells along with any bound molecular payload. As used herein, antibodies that bind to transferrin receptors may also be interchangeably referred to as transferrin receptor antibodies, anti-transferrin receptor antibodies, or anti-TfR antibodies. Antibodies that bind to transferrin receptors, such as specifically binding antibodies, may be internalized into cells upon binding to the transferrin receptor, for example, through receptor-mediated endocytosis.

[0095] It should be understood that anti-transferrin receptor antibodies may be produced, synthesized, and / or (for example, and) derivatized using several known methodologies, e.g., library design using phage display. Exemplary methodologies are characterized in the art and 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, anti-transferrin antibodies have been characterized or disclosed to date.Antibodies that specifically bind to transferrin receptors are known in the art (for example, U.S. Patent No. 4,364,934, filed 12 / 4 / 1979, "Monoclonal antibody to a human early thymocyte antigen and methods for preparing the same"; U.S. Patent No. 8,409,573, filed 6 / 14 / 2006, "Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells"; U.S. Patent No. 9,708,406, filed 5 / 20 / 2014, "Anti-transferrin receptor antibodies and methods of use"; U.S. Patent No. 9,611,323, filed 12 / 19 / 2014, "Low affinity blood brain barrier receptor antibodies and uses therefor"; WO 2015 / 098989, filed 12 / 24 / 2014, "Novel anti-Transferrin receptor antibody that passes through blood-brain barrier"; Schneider C. et al. "Structural features"). of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9."J Biol Chem.1982,257:14,8516-8522.;Lee et al."Targeting Rat Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse"2000,J (See Pharmacol. Exp. Ther., 292:1048-1052).

[0096] Provided herein are novel anti-TfR antibodies for use as muscle targeting agents (e.g., on muscle targeting complexes) in several aspects. In some aspects, the anti-TfR antibodies described herein bind to transferrin receptors with high specificity and affinity. In some aspects, the anti-TfR antibodies described herein bind specifically to any extracellular epitope of the transferrin receptor or to an epitope that will be exposed to the antibody. In some aspects, the anti-TfR antibodies provided herein bind specifically to transferrin receptors from humans, non-human primate animals, mice, rats, etc. In some aspects, the anti-TfR antibodies provided herein bind to human transferrin receptors. In some aspects, the anti-TfR antibodies described herein bind to amino acid segments of human or non-human primate animal transferrin receptors provided in SEQ ID NOs. 242-244. In some aspects, the anti-TfR antibodies described herein bind to amino acid segments corresponding to amino acids 90-96 of the human transferrin receptor as represented by SEQ ID NOs. 242, which are not in the apex domain of the transferrin receptor.

[0097] 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 -13The antibodies specifically bind to TfR1 (e.g., human or non-human primate TfR1) by a binding affinity of M, or a smaller binding affinity (e.g., indicated by Kd). In some embodiments, the anti-TfR antibodies described herein bind to TfR1 by a KD in the sub-nanomole 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 cynoporin TfR1 (e.g., 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 The antibodies do not bind to mouse TfR1 (by M or a smaller Kd). The affinity and binding kinetics of anti-TfR antibodies can be tested using any preferred method, including but not limited to biosensor technologies (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-beta-2-microglobulin binding to TfR1.

[0098] 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: (Sequence ID 242).

[0099] Examples of non-human primate transferrin receptor amino acid sequences corresponding to the NCBI sequence NP_001244232.1 (transferrin receptor protein 1, Macaca mulatta) are as follows: (Sequence ID 243)

[0100] Examples of non-human primate transferrin receptor amino acid sequences corresponding to the NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) are as follows: (Sequence ID 244).

[0101] 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: (Sequence ID 245)

[0102] In some embodiments, the anti-transferrin receptor antibody comprises the following amino acid segments of the receptor: It binds to FVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKE (SEQ ID NO: 247) and does not inhibit the binding interaction between the transferrin receptor and transferrin and / or (for 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: 247.

[0103] Appropriate methodologies may be used, for example, through the use of recombinant DNA protocols to obtain and / or (for example, and) produce antibodies, antibody fragments, or antigen conjugates. 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 of any type or entity, for example, recombinant or naturally occurring type or entity. Hybridomas are screened using standard methods, for example, ELISA screening, to find at least one hybridoma that produces an antibody targeting a specific antigen. Antibodies may also be produced through screening of protein expression libraries expressing the antibody (for example, phage display libraries). Phage display library designs may also be used in several embodiments (see, for example, U.S. Patent No. 5,223,409, 3 / 1 / 1991, "Directed evolution of novel binding proteins"; WO 1992 / 18619, 4 / 10 / 1992, "Heterodimeric receptor libraries using phagemids"; WO 1991 / 17271, 5 / 1 / 1991, "Recombinant library screening methods"; WO 1992 / 20791, 5 / 15 / 1992, "Methods for producing members of specific binding pairs"; and WO 1992 / 15679, 2 / 28 / 1992, "Improved epitope displaying phage"). In some embodiments, antigens of interest may be used to immunize non-human animals, such as rodents or goats.In some embodiments, once antibodies have been obtained from non-human animals, they may be modified using a number of methodologies, including, for example, recombinant DNA techniques. Examples of antibody production and methodological additions are also known in the art (see, for example, Harlow et al., "Antibodies: A Laboratory Manual", Cold Spring Harbor Laboratory, 1988).

[0104] 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, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glyciation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules comprise mannose units, glucose units, N-acetylglucosamine units, N-acetylgalactosamine units, galactose units, fucose units, or phospholipid units. In some embodiments, the sugar molecules are present in quantities of approximately 1–10, 1–5, 5–10, 1–4, 1–3, or 2. In some embodiments, the glycosylated antibody is glycosylated whole or partially. In some embodiments, the antibody is glycosylated by chemical reaction or by enzymatic means. In some embodiments, the antibody is glycosylated in vitro or in cells (which may optionally be deficient in enzymes in the N- or O-glycosylation pathway, e.g., glycosyltransferase). In some embodiments, the antibody is functionalized with sugar or carbohydrate molecules as described in the international patent application publication WO2014065661, published on May 1, 2014, entitled "Modified antibody, antibody-conjugate and process for the preparation thereof".

[0105] In some embodiments, the anti-TfR antibodies of this disclosure comprise the VL domain and / or (for example, and) the VH domain of any one of the anti-TfR antibodies selected from Table 1, 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 an immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art. For example, see Kabat EA et al., (1991) above.

[0106] Examples of heavy and light chain variable domains and CDR sequences for anti-TfR antibodies are provided in Table 1. Table 1. Examples of anti-TfR1 antibodies (CDR follows IMGT® definition) [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0107] In some aspects, the anti-TfR antibodies of this disclosure comprise 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 1. In some aspects, the anti-TfR antibodies of this disclosure comprise CDR-H1, CDR-H2, and CDR-H3 provided for any one of the antibodies selected from Table 1. In some aspects, the anti-TfR antibodies of this disclosure comprise 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 1. In some aspects, the anti-TfR antibodies of this disclosure comprise CDR-L1, CDR-L2, and CDR-L3 provided for any one of the anti-TfR antibodies selected from Table 1.

[0108] In some embodiments, the anti-TfR antibodies of this disclosure include CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided in any one of the anti-TfR antibodies selected from Table 1. In some embodiments, the heavy and light chain CDR3 domains of the antibody may play a particularly important role in the antibody's binding specificity / affinity to the antigen. Consequently, the anti-TfR antibodies of this disclosure may include at least the heavy chain and / or (for example, and) the light chain CDR3 of any one of the anti-TfR antibodies selected from Table 1.

[0109] In some examples, any of the anti-TfR antibodies of this disclosure has 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 (e.g., and) CDR-L3 sequences from one of the anti-TfR antibodies selected from Table 1. In some embodiments, the positions of one or more CDRs along the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) region and / or VL (e.g., CDR-L1, CDR-L2, or CDR-L3) region of the antibodies described herein may vary by one, two, three, four, five, or six amino acid positions, insofar as immunospecific binding to the transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% compared to the binding of the original antibody from which it originates). For example, in some embodiments, the position defining the CDR of any antibody described herein may vary by one, two, three, four, five, or six amino acid positions compared to any one CDR position of any antibody described herein by shifting the N-terminal and / or C-terminal boundaries of the CDR, as long as immunospecific binding to the transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., maintained by 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 originates).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 the antibody described herein may vary by 1, 2, 3, 4, 5 amino acids, or more (e.g., shorter or longer), insofar as immunospecific binding to the 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 originates).

[0110] Consequently, in some embodiments, the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shorter by a difference of 1, 2, 3, 4, or 5 or more amino acids than one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the transferrin receptor (for example, 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 to the original antibody from which it is derived). In some embodiments, the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be longer by a difference of 1, 2, 3, 4, or 5 or more amino acids than one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the transferrin receptor (for example, 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% 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 (for example, and), CDR-H3 described herein may be elongated by a difference of 1, 2, 3, 4, 5 amino acids, or more compared to one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the transferrin receptor (for example, 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% compared to the binding of the original antibody from which it is derived).The carboxyl portions of CDR-H2 and / or CDR-H3 may be elongated by a difference of 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the 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 originates). 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 shortened by a difference of 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the transferrin receptor (for example, 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% compared to the binding of the original antibody from which it is derived). In some embodiments, the carboxyl portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and), CDR-H3 described herein may be shortened by a difference of 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the transferrin receptor (for example, 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% compared to 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., human transferrin receptor) is maintained, for example, using binding assays and conditions described in the art.

[0111] In some examples, any of the anti-TfR antibodies of this disclosure has 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 1. For example, an antibody may contain one or more CDR sequences from any of the anti-TfR antibodies selected from Table 1 that contain up to 5, 4, 3, 2, or 1 amino acid residue variations compared to the corresponding CDR region in any of the CDRs provided herein (e.g., CDRs from any of the anti-TfR antibodies selected from Table 1), insofar as immunospecific binding to the 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%, or at least 95% compared to the binding of the original antibody from which it originates). 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 CDR at positions where the residue is unlikely to be involved in interaction with the transferrin receptor protein (e.g., human transferrin receptor protein), as determined, for example, based on the crystal structure. Several aspects of this disclosure provide anti-TfR antibodies comprising one or more 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 encompasses one or more CDR-H sequences provided herein (e.g., CDR-H1, CDR-H2, and CDR-H3) (e.g., any of the CDR-H sequences provided in any one of the anti-TfR antibodies selected from Table 1). In some embodiments, any of the VL domains provided herein encompass one or more CDR-L sequences provided herein (e.g., CDR-L1, CDR-L2, and CDR-L3) (e.g., any of the CDR-L sequences provided in any one of the anti-TfR antibodies selected from Table 1).

[0112] In some embodiments, the anti-TfR antibodies of this disclosure encompass any antibody that also includes the heavy chain variable domain and / or (for example, and) the light chain variable domain of any one of the anti-TfR antibodies selected from Table 1, as well as their variants. In some embodiments, the anti-TfR antibodies of this disclosure also encompass any antibody that also includes the heavy chain variable and light chain variable pair of any one of the anti-TfR antibodies selected from Table 1.

[0113] Aspects of this disclosure provide anti-TfR antibodies having a heavy chain variable (VH) domain amino acid sequence and / or (for example, and) a light chain variable (VL) domain amino acid sequence homologous to any of the anti-TfR antibodies described herein. In some embodiments, an anti-TfR antibody contains 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 the heavy chain variable sequence and / or (for example, and) any light chain variable sequence of any anti-TfR antibody, such as any one of the anti-TfR antibodies selected from Table 1. In some embodiments, the homologous heavy chain variable and / or light chain variable amino acid sequences are within the range of any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within a range of heavy chain variable sequences and / or (e.g., and) light chain variable sequences that exclude any of the CDR sequences provided herein. In some embodiments, any of the anti-TfR antibodies provided herein includes a heavy chain variable sequence and a light chain variable sequence that are at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequence of any of the anti-TfR antibodies selected from Table 1.

[0114] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 8.

[0115] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6.

[0116] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having the amino acid sequence of SEQ ID NO: 1; CDR-H2 having the amino acid sequence of SEQ ID NO: 2 with an amino acid substitution at position 5 (for example, asparagine at position 5 is substituted with one of the following, for example, 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 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 this disclosure include: 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-L2 as represented by SEQ ID NO: 2 is N5T or N5S.

[0117] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having the amino acid sequence of SEQ ID NO: 1; CDR-H2 having the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 80; and 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: 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.

[0118] In some aspects, the anti-TfR antibodies of the present disclosure include CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 248, or SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 3. When "together" is used anywhere in the present disclosure, it means that the total number of amino acid variations in all three heavy chain CDRs is within the defined range. Alternatively or in addition (e.g., in addition), the anti-TfR receptor antibodies of the present disclosure include CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to 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.

[0119] In some embodiments, the anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which together 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: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 248, or SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0120] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 1; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 248, or SEQ ID NO: 80; and / or (e.g., and) CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variation) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 4; CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variation) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variation) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0121] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH having the amino acid sequence of SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL having the amino acid sequence of SEQ ID NO: 8.

[0122] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 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 variation) when compared to a VL as represented by SEQ ID NO: 8.

[0123] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) the same amino acid sequence as VH as represented by SEQ ID NO: 7. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) the same amino acid sequence as VL as represented by SEQ ID NO: 8.

[0124] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH as represented by SEQ ID NO: 7 and has an amino acid substitution at position 55 (for example, asparagine at position 55 is substituted with one of the following, for example, 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 in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL as represented by SEQ ID NO: 8. In some embodiments, the amino acid substitution at position 55 of VH as represented by SEQ ID NO: 7 is N55T or N55S. When VH as represented by 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.

[0125] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid substitution at position 64 compared to SEQ ID NO: 7. In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having Met at the position corresponding to position 64 in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 80% (for example, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to the VL as represented by SEQ ID NO: 8.

[0126] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 16.

[0127] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14.

[0128] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0129] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0130] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 9; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 10; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 12; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0131] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 16.

[0132] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 15. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 16.

[0133] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 15. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 16.

[0134] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 24.

[0135] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22.

[0136] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having the amino acid sequence of SEQ ID NO: 17 with an amino acid substitution at position 8 (for example, the cysteine ​​at position 8 is substituted with one of the following: 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)); 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 in addition (for example, in addition), the anti-TfR antibodies of this disclosure include: 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.

[0137] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having the amino acid sequence of SEQ ID NO: 254 or SEQ ID NO: 256; 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 in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: 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 aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 254, or SEQ ID NO: 256, 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0139] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 254, or SEQ ID NO: 256, 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 in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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.

[0140] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 254, or SEQ ID NO: 256; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and / or (e.g., and) CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 20; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0141] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH having the amino acid sequence of SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL having the amino acid sequence of SEQ ID NO: 24.

[0142] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented in SEQ ID NO: 24.

[0143] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 23. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 24.

[0144] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH as represented by SEQ ID NO: 23, having an amino acid substitution at position 33 (for example, the cysteine ​​at position 33 is substituted with any one of the following: 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 in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL as represented by SEQ ID NO: 24. In some embodiments, the amino acid substitution at position 33 of VH as represented by SEQ ID NO: 23 is C33D or C33Y. When VH is annotated by the Kabat numbering system as represented by SEQ ID NO: 23, amino acid 33 of SEQ ID NO: 23 is assigned the number 33.

[0145] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 31. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 32.

[0146] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 25, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 26, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 27, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 28, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 30.

[0147] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0148] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0149] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 25; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 26; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 28; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0150] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH having the amino acid sequence of SEQ ID NO: 31. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL having the amino acid sequence of SEQ ID NO: 32.

[0151] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 31. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented in SEQ ID NO: 32.

[0152] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 31. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 32.

[0153] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 39. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 40.

[0154] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 33, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 34, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 35, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 36, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 37, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 38.

[0155] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0156] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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.

[0157] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 33; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 34; and / or (e.g., and) CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 36; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 37; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0158] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which comprises the amino acid sequence of SEQ ID NO: 39. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which comprises the amino acid sequence of SEQ ID NO: 40.

[0159] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 39. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 40.

[0160] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 39. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 40.

[0161] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 47. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 48.

[0162] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 41, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 42, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 43, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 44, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 46.

[0163] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0164] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0165] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 41; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 42; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 44; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0166] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 47. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 48.

[0167] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 47. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 48.

[0168] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 47. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 48.

[0169] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 54. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 55.

[0170] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 49, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 50, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 51, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 52, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 53.

[0171] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0172] In some embodiments, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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.

[0173] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 49; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 50; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 52; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0174] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH having the amino acid sequence of SEQ ID NO: 54. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL having the amino acid sequence of SEQ ID NO: 55.

[0175] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 54. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to a VL as represented by SEQ ID NO: 55.

[0176] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 54. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 55.

[0177] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 62. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 63.

[0178] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 56, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 57, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 58, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 59, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 61.

[0179] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0180] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0181] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 56; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 57; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 58. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 59; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0182] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which comprises the amino acid sequence of SEQ ID NO: 62. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which comprises the amino acid sequence of SEQ ID NO: 63.

[0183] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 62. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 63.

[0184] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 62. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 63.

[0185] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 70. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 71.

[0186] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 64, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 65, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 66, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 67, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 68, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 69.

[0187] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0188] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0189] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 64; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 65; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 67; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 68; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0190] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH containing the amino acid sequence of SEQ ID NO: 70. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL containing the amino acid sequence of SEQ ID NO: 71.

[0191] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 70. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 71.

[0192] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 70. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 71.

[0193] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 77. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 78.

[0194] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 73, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 76.

[0195] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0196] In some embodiments, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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.

[0197] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 73; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0198] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH having the amino acid sequence of SEQ ID NO: 77. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL having the amino acid sequence of SEQ ID NO: 78.

[0199] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 77. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 78.

[0200] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 77. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 78.

[0201] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 85. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 86.

[0202] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 80, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 81, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 84.

[0203] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0204] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0205] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 80; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0206] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which comprises the amino acid sequence of SEQ ID NO: 85. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which comprises the amino acid sequence of SEQ ID NO: 86.

[0207] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 85. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 86.

[0208] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 85. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 86.

[0209] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 89. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 90.

[0210] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 87, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 88.

[0211] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0212] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 87, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 88.

[0213] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 87; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0214] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 89. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 90.

[0215] In some embodiments, the anti-TfR antibody of the present disclosure contains VH with only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 89. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 90.

[0216] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 89. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 90.

[0217] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 97. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 98.

[0218] In some embodiments, the anti-TfR antibody of the present disclosure includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 91, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 92, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 93, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 94, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 95, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 96.

[0219] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0220] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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.

[0221] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 91; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 92; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: 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: 94; 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: 95; and / or (for example, and) 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: 96.

[0222] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which comprises the amino acid sequence of SEQ ID NO: 97. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which comprises the amino acid sequence of SEQ ID NO: 98.

[0223] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 97. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 98.

[0224] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 97. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 98.

[0225] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 104. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 105.

[0226] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0227] In some embodiments, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0228] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 99; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 100; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 102; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0229] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 104. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 105.

[0230] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 104. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 105.

[0231] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 104. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 105.

[0232] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 112. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 113.

[0233] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 106, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 107, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 108, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 109, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 110, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 111.

[0234] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0235] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical 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 in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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: 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.

[0236] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 106; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 107; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 109; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 110; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0237] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 112. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 113.

[0238] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 112. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 113.

[0239] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 112. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 113.

[0240] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 117. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 118.

[0241] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 114, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 115, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 116.

[0242] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0243] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0244] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 114; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0245] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 117. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 118.

[0246] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 117. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 118.

[0247] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 117. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 118.

[0248] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 124. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 125.

[0249] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a CDR-H1 having the amino acid sequence of SEQ ID NO: 119 (according to the IMGT definition system), a CDR-H2 having the amino acid sequence of SEQ ID NO: 120 (according to the IMGT definition system), a CDR-H3 having the amino acid sequence of SEQ ID NO: 121 (according to the IMGT definition system), a CDR-L1 having the amino acid sequence of SEQ ID NO: 122 (according to the IMGT definition system), a CDR-L2 having the amino acid sequence of SEQ ID NO: 45 (according to the IMGT definition system), and a CDR-L3 having the amino acid sequence of SEQ ID NO: 123 (according to the IMGT definition system).

[0250] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain a total of only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 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., additionally), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain a total of only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 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.

[0251] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are at least 75% (by way of example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical, together, 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 in addition (by way of example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are at least 75% (by way of example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical, together, 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.

[0252] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 119; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 120; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 122; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0253] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 124. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 125.

[0254] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 124. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 125.

[0255] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 124. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 125.

[0256] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 132. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 133.

[0257] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 126, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 127, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 128, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 129, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 130, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 131.

[0258] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0259] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical 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 in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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: 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.

[0260] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 126; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 127; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 128. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 129; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 130; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0261] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 132. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 133.

[0262] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 132. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 133.

[0263] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 132. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 133.

[0264] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 136. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 137.

[0265] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 134, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 135.

[0266] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0267] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 135.

[0268] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 2; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0269] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 136. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 137.

[0270] In some embodiments, the anti-TfR antibodies of the present disclosure include a VH that contains only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VH represented by SEQ ID NO: 136. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure include a VL that contains only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL represented by SEQ ID NO: 137.

[0271] In some embodiments, the anti-TfR antibodies of the present disclosure include a VH that includes an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH represented by SEQ ID NO: 136. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure include a VL that includes an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL represented by SEQ ID NO: 137.

[0272] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1, CDR-H2, and CDR-H3 of the heavy chain variable domain having the amino acid sequence of SEQ ID NO: 143. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure include CDR-L1, CDR-L2, and CDR-L3 of the light chain variable domain having the amino acid sequence of SEQ ID NO: 144.

[0273] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 138, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 139, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 140, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 141, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 142.

[0274] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0275] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0276] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 138; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 139; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: 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: 141; 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: 29; and / or (for example, and) 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: 142.

[0277] In some embodiments, the anti-TfR antibody of the present disclosure comprises VH, which contains the amino acid sequence of SEQ ID NO: 143. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises VL, which contains the amino acid sequence of SEQ ID NO: 144.

[0278] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 143. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VL as represented by SEQ ID NO: 144.

[0279] In some embodiments, the anti-TfR antibody of the present disclosure comprises a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by SEQ ID NO: 143. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 144.

[0280] The CDR of an antibody may have different amino acid sequences when different definition systems are used (e.g., IMGT definition, Kabat definition, or Chothia definition). The 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 2. The CDRs listed in Table 1 are defined according to the IMGT definition. CDR sequences of example anti-TfR antibodies following various definition systems are provided in Table 3. Those skilled in the art can derive the CDR sequences of the anti-TfR antibodies provided in Table 1 using various numbering systems. Table 2. CDR definition [Table 2] Table 3. CDR sequences of examples of anti-TfR1 antibodies according to various definition systems. [Table 3-1] [Table 3-2]

[0281] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 249, or SEQ ID NO: 252, CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6.

[0282] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (for example, only 5, 4, 3, 2, or 1 amino acid variation) 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: 249, or SEQ ID NO: 252, and CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (for example, only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0283] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical 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: 249, or SEQ ID NO: 252, and CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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.

[0284] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 145; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 249, or SEQ ID NO: 252; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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 this disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 148; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 149; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0285] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 250, or SEQ ID NO: 253, CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154.

[0286] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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: 250, or SEQ ID NO: 253, and CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0287] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical 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: 250, or SEQ ID NO: 253, and 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 comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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: 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.

[0288] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 150; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 250, or SEQ ID NO: 253; and / or (e.g., and) CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 153; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0289] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14.

[0290] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0291] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0292] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 155; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 156; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 158; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 159; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0293] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164.

[0294] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0295] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0296] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 160; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 161; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 163; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0297] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257; CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166; CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167; CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168; CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169; and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22.

[0298] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257, CDR-H2 having the amino acid sequence of SEQ ID NO: 166, and CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 168, CDR-L2 having the amino acid sequence of SEQ ID NO: 169, and CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0299] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257, CDR-H2 having the amino acid sequence of SEQ ID NO: 166, and CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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: 168, CDR-L2 having the amino acid sequence of SEQ ID NO: 169, and CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0300] In some embodiments, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 166; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 168; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 169; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0301] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174.

[0302] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) 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.

[0303] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together 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: 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 in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together 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: 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.

[0304] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 170; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 171; and / or CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to 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: CDR-L1 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 173; CDR-L2 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) CDR-L3 having only 3 amino acid variations (for example, only 3, 2, or 1 amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0305] In some embodiments, the anti-TfR antibodies of the Disclosure are humanized antibodies (for example, humanized variants containing one or more CDRs from Table 1 or Table 3). In some embodiments, the anti-TfR antibodies of the Disclosure include the same CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as shown in Table 1 or Table 3, and include a humanized heavy chain variable region and / or (for example, and) a humanized light chain variable region.

[0306] A humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's complementarity-determining region (CDR) are replaced with residues from the CDR of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and volume. In some embodiments, Fv framework region (ER) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, the humanized antibody may also include residues that are not found on the recipient antibody or on the transferred CDR or framework sequence, but are included to further improve and optimize antibody performance. Generally, a humanized antibody will contain substantially all of at least one, typically two, variable domains, where all or substantially all of the CDR region corresponds to that of a non-human immunoglobulin, and all or substantially all of the FR region corresponds to that of the human immunoglobulin consensus sequence. Optimally, the humanized antibody will also contain at least some portion (Fc) of the immunoglobulin constant region or domain, typically that of the human immunoglobulin. Antibodies may have modified Fc regions as described in WO99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six) that are modified from the original antibody. These are also referred to as one or more CDRs derived from one or more CDRs from the original antibody. Affinity maturation may also be involved in humanized antibodies.

[0307] Humanized antibodies and methods for producing them are known, for example, 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. Patents 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 As described in 36:43-60 (2005); Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br.J. Cancer, 83:252-260 (2000). All of these contents 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). All of these contents are incorporated herein by reference. In some embodiments, humanization is achieved by grafting CDRs (as shown, for example, in Table 1 or Table 3) onto the IGKV1-NL1*01 and IGHV1-3*01 human variable domains.

[0308] In some embodiments, the humanized VH framework or VL framework is a consensus human framework. In some embodiments, the consensus humanized framework may represent the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.

[0309] In some embodiments, the consensus human VH framework region suitable for use in heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) is as follows:

[0310] a) VH FR1:EVQLVESGGGLVQPGGSLRLSCAAS(Sequence ID 267);

[0311] b) VH FR2:WVRQAPGKGLEWV(Sequence ID 268);

[0312] c)VH FR3:RFTISRDNSKNTLYLQMNSLRAEDTAVYYC(sequence number 269); and

[0313] d) VH FR4:WGQGTLVTVSS (Sequence ID 270) It includes.

[0314] In some embodiments, the consensus human VH framework region suitable for use in heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) is as follows:

[0315] a) VH FR1:QVQLVQSGAEVKKPGASVKVSCKAS(Sequence ID 271);

[0316] b) VH FR2:WVRQAPGQGLEWM(Sequence ID 272);

[0317] c)VH FR3:RVTITADTSTSTAYMELSSLRSEDTAVYYC(Sequence ID 273); and

[0318] d) VH FR4:WGQGTLVTVSS (Sequence ID 270) It includes.

[0319] In some embodiments, the consensus human VH framework region suitable for use in heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) is as follows:

[0320] a) VH FR1:QVQLQESGPGLVKPSQTLSLTCTVS(Sequence ID 275);

[0321] b) VH FR2:WIRQPPGKGLEWI(Sequence ID 276);

[0322] c)VH FR3:RVTISVDTSKNQFSLKLSSVTAADTAVYYC(Sequence ID 277); and

[0323] d) VH FR4:WGQGTLVTVSS (Sequence ID 270) It includes.

[0324] In some embodiments, the consensus human VL framework region suitable for use in light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) is as follows:

[0325] a) VL FR1:DIQMTQSPSSLSASVGDRVTITC(Sequence ID 279);

[0326] b) VL FR2:WYQQKPGKAPKLLIY(Sequence ID 280);

[0327] c) VL FR3:GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(Sequence ID 281); and

[0328] d) VL FR4:FGQGTKVEIK (Sequence ID 282) It includes.

[0329] In some embodiments, the consensus human VL framework region suitable for use in light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) is as follows:

[0330] a) VL FR1:DIVMTQSPLSLPVTPGEPASISC(Sequence ID 283);

[0331] b) VL FR2:WYLQKPGQSPQLLIY(Sequence ID 284);

[0332] c)VL FR3:GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC(Sequence ID 285); and

[0333] d) VL FR4:FGQGTKVEIK (Sequence ID 282) It includes.

[0334] In some embodiments, the consensus human VL framework region suitable for use in light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) is as follows:

[0335] a) VL FR1:DIVMTQSPDSLAVSLGERATINC(Sequence ID 287);

[0336] b) VL FR2:WYQQKPGQPPKLLIY(Sequence ID 288);

[0337] c)VL FR3:GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC(Sequence ID 289); and

[0338] d) VL FR4:FGQGTKVEIK (Sequence ID 282) It includes.

[0339] In some embodiments, the consensus human VL framework region suitable for use in light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup IV consensus) is as follows:

[0340] a) VL FR1:DIVMTQSPDSLAVSLGERATINC(Sequence ID 287);

[0341] b) VL FR2:WYQQKPGQPPKLLIY(Sequence ID 288);

[0342] c)VL FR3:GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC(Sequence ID 289); and

[0343] d) VL FR4:FGQGTKVEIK (Sequence ID 282) It includes.

[0344] In some embodiments, the humanized anti-TfR antibodies of this disclosure comprise humanized VH framework regions, which together contain as few as 25 amino acid variations (for example, as few as 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) 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 this disclosure include humanized VL framework regions, which together contain as few as 25 amino acid variations (for example, as few as 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to any one of the consensus human VL framework region subgroups described herein.

[0345] In some embodiments, the humanized anti-TfR antibodies of this disclosure include humanized VH framework regions, which together are 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 in addition (e.g., in addition), the humanized anti-TfR antibodies of this disclosure include humanized VL framework regions, which are 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.

[0346] In some embodiments, the anti-TfR antibody of the present disclosure is a humanized variant comprising one or more amino acid variations (e.g., of the VH framework region) compared to any one of the VHs listed in or provided by Table 1, Table 3, or Table 4 and / or (e.g., and) one or more amino acid variations (e.g., of the VL framework region) compared to any one of the VLs listed in or provided by Table 1, Table 3, or Table 4.

[0347] In some embodiments, the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VH containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to any VH of any of the anti-TfR antibodies listed in Table 1. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VL containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to any VL of any of the anti-TfR antibodies listed in Table 1.

[0348] In some embodiments, the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by any one of SEQ ID NOs: 8, 16, and 24.

[0349] In some embodiments, the anti-TfR antibody of the present disclosure is a humanized antibody and includes a VH having only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure is a humanized antibody and includes a VL containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to a VL as represented by any one of SEQ ID NOs.

[0350] In some embodiments, the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VH having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as represented by any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the Disclosure is a humanized antibody comprising a VL having an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by any one of SEQ ID NOs: 8, 16, and 24.

[0351] In some embodiments, the anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VH having one or more (e.g., 10 to 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, compared to VH as represented by any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VL having one or more (for example, 10 to 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 represented by any one of SEQ ID NOs: 8, 16, and 24.

[0352] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 248, or SEQ ID NO: 80, and CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by 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 CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6, and having only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 8.

[0353] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 248, or SEQ ID NO: 80, and 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 to VH as represented by SEQ ID NO: 7 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 4 (according to the IMGT definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 5 (according to the IMGT definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 6 (according to the IMGT definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 8 in the framework region.

[0354] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 249, or SEQ ID NO: 252, and CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by 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 CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6, and containing only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 8.

[0355] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 249, or SEQ ID NO: 252, and 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 to VH as represented by SEQ ID NO: 7 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 148 (according to the Kabat definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 149 (according to the Kabat definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 6 (according to the Kabat definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 8 in the framework region.

[0356] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 250, or SEQ ID NO: 253, and CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL and includes CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 8.

[0357] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 250, or SEQ ID NO: 253, and 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 to VH as represented by SEQ ID NO: 7 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 153 (according to the Chothia definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 5 (according to the Chothia definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 154 (according to the Chothia definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 8 in the framework region.

[0358] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by 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 CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14, and containing only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 16.

[0359] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 15 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 12 (according to the IMGT definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 13 (according to the IMGT definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 14 (according to the IMGT definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 16 in the framework region.

[0360] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL and includes CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 16.

[0361] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 15 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 158 (according to the Kabat definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 159 (according to the Kabat definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 14 (according to the Kabat definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 16 in the framework region.

[0362] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL and includes CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 16.

[0363] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 15 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 163 (according to the Chothia definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 13 (according to the Chothia definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 164 (according to the Chothia definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 16 in the framework region.

[0364] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH and includes CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 254, or SEQ ID NO: 256, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL and includes CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 24.

[0365] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 254, or SEQ ID NO: 256, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 23 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 20 (according to the IMGT definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 21 (according to the IMGT definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 22 (according to the IMGT definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 24 in the framework region.

[0366] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH and includes CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL and includes CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 24.

[0367] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 255, or SEQ ID NO: 257, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 23 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 168 (according to the Kabat definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 169 (according to the Kabat definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 22 (according to the Kabat definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 24 in the framework region.

[0368] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH, and includes CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, and contains only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to VH as represented by 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 CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174, and containing only 25 amino acid variations in the framework region (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the VL as represented by SEQ ID NO: 24.

[0369] In some embodiments, the anti-TfR antibody of the present disclosure comprises humanized VH including CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, which are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to VH as represented by SEQ ID NO: 23 in the framework region. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL having the amino acid sequence of SEQ ID NO: 173 (according to the Chothia definition system), CDR-L2 having the amino acid sequence of SEQ ID NO: 21 (according to the Chothia definition system), and CDR-L3 having the amino acid sequence of SEQ ID NO: 174 (according to the Chothia definition system), which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as represented by SEQ ID NO: 24 in the framework region.

[0370] In some embodiments, the anti-TfR antibodies of this disclosure are chimeric antibodies, which may encompass heavy chain constant regions 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, both the light and heavy chain variable regions mimic the variable region of an antibody derived from one mammalian species (e.g., non-human mammals, e.g., mouse, rabbit, and rat), while the constant portion is homologous to the sequence of an antibody derived from another mammal, e.g., human. In some embodiments, amino acid modifications may be made to the variable region and / or (e.g., and) the constant region.

[0371] In some embodiments, the anti-TfR antibodies described herein are chimeric antibodies, which may encompass the heavy chain constant region and light chain constant region 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, both the light and heavy chain variable regions mimic the variable region of an antibody derived from one mammalian species (e.g., non-human mammals, such as mice, rabbits, and rats), while the constant portion is homologous to the sequence of an antibody derived from another mammal, such as humans. In some embodiments, amino acid modifications may be made to the variable region and / or (e.g., and) the constant region.

[0372] In some embodiments, the heavy chain of any of the anti-TfR antibodies described herein may include a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region may be of any preferred origin, e.g., human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from human IgG (gamma heavy chain), e.g., IgG1, IgG2, or IgG4. An example of the human IgG1 constant region is given below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 175)

[0373] 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 an LALA mutation on the CH2 domain of human IgG1 (a mutant derived from mAb b12 mutated to replace the lower hinge residues Leu234 Leu235 with Ala234 and Ala235) is known to reduce Fcg receptor binding (Bruhns, P., et al. (2009) and Xu, D. et al. (2000)). Mutant human IgG1 constant regions are provided below (mutations are in bold and underlined):

[0374] [ka] (Sequence ID 176)

[0375] In some embodiments, any 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, and this sequence is provided below: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 177)

[0376] The 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.

[0377] In some embodiments, the anti-TfR antibodies described herein include one of the VHs listed in Table 1 or any of their variants, and a heavy chain comprising 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 include one of the VHs listed in Table 1 or any of their variants, and a heavy chain comprising a heavy chain constant region containing only 25 amino acid variations compared to SEQ ID NO: 175 or SEQ ID NO: 176 (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation). In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising one of the VH variants listed in Table 1 and a heavy chain constant region as represented by SEQ ID NO: 175. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising one of the VH variants listed in Table 1 and a heavy chain constant region as represented by SEQ ID NO: 176.

[0378] In some embodiments, the anti-TfR antibodies described herein include a light chain comprising one of the VLs listed in Table 1 or any of their variants, and a light chain comprising 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 include a light chain comprising one of the VLs listed in Table 1 or any of their variants, and a light chain comprising a light chain constant region containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to SEQ ID NO: 177. In some embodiments, the anti-TfR antibodies described herein include a light chain comprising one of the VLs listed in Table 1 or any of their variants, and a light chain comprising a light chain constant region as represented by SEQ ID NO: 177.

[0379] Examples of IgG heavy and light chain amino acid sequences of the described anti-TfR antibodies are provided in Table 4 below. Table 4. Heavy and light chain sequences of example anti-TfR IgGs [Table 4-1] [Table 4-2]

[0380] In some embodiments, the anti-TfR antibodies of the present disclosure include a heavy chain containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of this disclosure include a light chain containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain represented by SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein include a heavy chain containing an amino acid sequence that is at least 75% (for example, 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: 258, SEQ ID NO: 259, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (for example, in addition), the anti-TfR antibodies described herein include a light chain containing 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 include a heavy chain containing the amino acid sequence of SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (for example, in addition), the anti-TfR antibodies described herein include a light chain containing the amino acid sequence of SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183.

[0381] In some embodiments, the anti-TfR antibody of the Disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 178, SEQ ID NO: 258, or SEQ ID NO: 259. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the Disclosure comprises a light chain containing only 25 amino acid variations (e.g., 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 11, 9, 8, 7, 6, only 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 179. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing 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: 258, or SEQ ID NO: 259. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 178, SEQ ID NO: 258, or SEQ ID NO: 259. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 179.

[0382] In some embodiments, the anti-TfR antibody of the present disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 180. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a light chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 181. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 180. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 180. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 181.

[0383] In some embodiments, the anti-TfR antibody of the present disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 182, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a light chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 183. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 182, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 182, SEQ ID NO: 260, or SEQ ID NO: 261. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 183.

[0384] 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 by standard methods (e.g., recombinantly, or by digesting the heavy chain constant region of full-length IgG using an enzyme such as papain). For example, the F(ab')2 fragment may be produced by pepsin or papain digestion of the antibody molecule, and the Fab fragment may be produced by reducing the disulfide crosslinks of the F(ab')2 fragment. In some embodiments, the heavy chain constant region on the F(ab') fragment of the anti-TfR1 antibody described herein is as follows: Contains the amino acid sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (Sequence ID 184).

[0385] In some embodiments, the anti-TfR antibodies described herein include one of the VH variants listed in Table 1 and a heavy chain comprising 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 include one of the VH variants listed in Table 1 and a heavy chain comprising a heavy chain constant region containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to SEQ ID NO: 184. In some embodiments, the anti-TfR antibodies described herein include one of the VH variants listed in Table 1 and a heavy chain comprising a heavy chain constant region as represented by SEQ ID NO: 184.

[0386] Examples of F(ab') amino acid sequences of anti-TfR antibodies described herein are provided in Table 5. Table 5. Heavy and light chain sequences of examples of anti-TfR F(ab'). [Table 5-1] [Table 5-2]

[0387] In some embodiments, the anti-TfR antibodies of the present disclosure include a heavy chain containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of this disclosure include a light chain containing only 25 amino acid variations (for example, only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain represented by SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein include a heavy chain containing an amino acid sequence that is at least 75% (for example, 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: 262, SEQ ID NO: 263, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (for example, in addition), the anti-TfR antibodies described herein include a light chain containing 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 include a heavy chain containing the amino acid sequence of SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (for example, in addition), the anti-TfR antibodies described herein include a light chain containing the amino acid sequence of SEQ ID NO: 179, SEQ ID NO: 181, or SEQ ID NO: 183.

[0388] In some embodiments, the anti-TfR antibody of the present disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 185, SEQ ID NO: 262, or SEQ ID NO: 263. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a light chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 179. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing 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: 262, or SEQ ID NO: 263. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 185, SEQ ID NO: 262, or SEQ ID NO: 263. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 179.

[0389] In some embodiments, the anti-TfR antibody of the present disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 186. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a light chain containing only 25 amino acid variations (e.g., 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 11, 9, 8, 7, 6, only 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 181. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 186. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 186. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 181.

[0390] In some embodiments, the anti-TfR antibody of the present disclosure comprises a heavy chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the heavy chain as represented by SEQ ID NO: 187, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (e.g., in addition), the anti-TfR antibody of the present disclosure comprises a light chain containing only 25 amino acid variations (e.g., only 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) compared to the light chain as represented by SEQ ID NO: 183. In some embodiments, the anti-TfR antibody described herein comprises a heavy chain containing an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 187, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing an amino acid sequence that is 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 antibody described herein comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 187, SEQ ID NO: 264, or SEQ ID NO: 265. Alternatively or in addition (e.g., in addition), the anti-TfR antibody described herein comprises a light chain containing the amino acid sequence of SEQ ID NO: 183.

[0391] The anti-TfR receptor antibodies described herein may be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, their antigen-binding fragments (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 scFv. In some embodiments, the anti-TfR antibodies described herein are scFv-Fab (e.g., scFv fused to a portion of the constant region). In some embodiments, the anti-TfR receptor antibodies described herein are scFv fused to a constant region (e.g., the human IgG1 constant region, or a portion thereof, e.g., the Fc portion, as represented by SEQ ID NO: 175 or SEQ ID NO: 176) at either the N-terminus or the C-terminus.

[0392] In some embodiments, any one of the anti-TfR1 antibodies described herein may comprise a signal peptide (e.g., an N-terminal signal peptide) on the heavy chain and / or (e.g., and) light chain sequences. In some embodiments, the anti-TfR1 antibodies described herein comprise either one of the VH and VL sequences, either one of the IgG heavy chain and light chain sequences, or either one of the F(ab') heavy chain and light chain sequences described herein, and further comprise a signal peptide (e.g., an N-terminal signal peptide). In some embodiments, the signal peptide comprises the amino acid sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 214).

[0393] This disclosure provides another novel anti-TfR antibody that may be used as a muscle targeting agent (e.g., in muscle targeting complexes) in several respects. The CDR sequence and variable domain sequence of the antibody are provided in Table 6. Table 6. CDR sequences and variable domain sequences of anti-TfR antibodies according to various definition systems. [Table 6]

[0394] In some embodiments, the anti-TfR antibodies of this disclosure include one or more CDR-H (e.g., CDR-H1, CDR-H2, and CDR-H3) amino acid sequences from the anti-TfR antibodies provided in Table 6. In some embodiments, the anti-TfR antibodies of this disclosure include CDR-H1, CDR-H2, and CDR-H3 provided for each numbered system provided in Table 6. In some embodiments, the anti-TfR antibodies of this disclosure include one or more CDR-L (e.g., CDR-L1, CDR-L2, and CDR-L3) amino acid sequences from the anti-TfR antibodies provided in Table 6. In some embodiments, the anti-TfR antibodies of this disclosure include CDR-L1, CDR-L2, and CDR-L3 provided for each numbered system provided in Table 6.

[0395] In some embodiments, the anti-TfR antibodies of this disclosure include CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided for each numbering system provided in Table 6. In some embodiments, the CDR3 domains of the heavy and light chains of the antibody may play a particularly important role in the antibody's binding specificity / affinity to the antigen. Consequently, the anti-TfR antibodies of this disclosure may include at least the CDR3 of the heavy chain and / or (for example, and) the light chain of the anti-TfR antibodies provided in Table 6.

[0396] In some examples, any of the anti-TfR antibodies of this 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 (e.g., and) CDR-L3 sequences provided in Table 6. In some embodiments, the positions 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 the antibodies described herein may vary by only one, two, three, four, five, or six amino acid positions, insofar as immunospecific binding to the transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained; for example, 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 originates). For example, in some embodiments, the position defining the CDR of any antibody described herein may be varied by shifting the N-terminal and / or (for example, and) C-terminal boundary of the CDR by 1, 2, 3, 4, 5, or 6 amino acids compared to any one CDR position of any antibody described herein, as long as immunospecific binding to the transferrin receptor (e.g., human transferrin receptor) is maintained (for example, substantially maintained; for example, 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 originates). 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 any antibody described herein may be varied as long as immunospecific binding to the transferrin receptor (e.g., human transferrin receptor) is maintained (for example, substantially maintained).For example, it can vary by only 1, 2, 3, 4, 5 amino acids, or more (for example, shorter or longer), as long as it is 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 originates.

[0397] Consequently, in some embodiments, the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be 1, 2, 3, 4, 5 amino acids, or more shorter than one or more of the CDRs described herein (for example, provided in Table 6), as long as immunospecific binding to the transferrin receptor (for example, 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% compared to the binding of the original antibody from which it originates). In some embodiments, the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be 1, 2, 3, 4, 5 amino acids, or more longer than one or more of the CDRs described herein (for example, CDRs from anti-TfR antibodies provided in Table 6), insofar as immunospecific binding to the transferrin receptor (for example, human transferrin receptor) is maintained (for example, substantially maintained; for example, 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 portions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be extended by only 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from anti-TfR antibodies provided in Table 6), as long as immunospecific binding to the transferrin receptor (for example, human transferrin receptor) is maintained (for example, substantially maintained; for example, 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 carboxyl moieties of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be stretched by only 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from anti-TfR antibodies provided in Table 6), as long as immunospecific binding to the transferrin receptor (for example, human transferrin receptor) is maintained (for example, substantially maintained; for example, 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 portions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shortened by only 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from anti-TfR antibodies provided in Table 6), as long as immunospecific binding to the transferrin receptor (for example, human transferrin receptor) is maintained (for example, substantially maintained; for example, 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 carboxyl portions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shortened by only 1, 2, 3, 4, 5 amino acids, or more, compared to one or more of the CDRs described herein (for example, CDRs from anti-TfR antibodies provided in Table 6), as long as immunospecific binding to the transferrin receptor (for example, human transferrin receptor) is maintained (for example, substantially maintained; for example, 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).For example, any of the binding assays and conditions described in the art may be used to determine whether immunospecific binding to a transferrin receptor (e.g., human transferrin receptor) is maintained.

[0398] In some examples, any of the anti-TfR antibodies of this disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences substantially similar to those of the anti-TfR antibodies provided in Table 6. For example, an antibody may include one or more CDR sequences from an anti-TfR antibody that contain up to 5, 4, 3, 2, or 1 amino acid residue variation compared to any one of the corresponding CDR regions of the CDRs provided in Table 6 and available herein (e.g., CDRs from anti-TfR antibodies available in Table 6), provided that immunospecific binding to the 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 available herein may be conservative variations. Conservative variations can be introduced into the CDR at positions where residues are unlikely to be involved in interaction with transferrin receptor proteins (e.g., human transferrin receptor protein), as can be determined, for example, based on the crystal structure.

[0399] Several aspects of this disclosure provide anti-TfR antibodies comprising one or more heavy-chain variable (VH) and / or (for example, and) light-chain variable (VL) domains provided herein. In some embodiments, the anti-TfR antibodies of this disclosure comprise any antibody comprising the heavy-chain variable domain and / or (for example, and) light-chain variable domains of the anti-TfR1 antibodies provided in Table 6.

[0400] Aspects of this disclosure provide anti-TfR antibodies having heavy-chain variable (VH) and / or (e.g., and) light-chain variable (VL) domain amino acid sequences homologous to any of those 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 sequences and / or light-chain variable sequences provided in Table 6. In some embodiments, the homologous heavy-chain variable and / or (e.g., and) light-chain variable amino acid sequences are not varied in any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within the heavy-chain variable and / or (e.g., and) light-chain variable sequences that exclude any of the CDR sequences provided herein. In some embodiments, any of the anti-TfR antibodies provided herein include a heavy chain variable sequence and a light chain variable sequence that include a framework sequence which is at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequence of the anti-TfR antibodies provided in Table 6.

[0401] In some embodiments, the anti-TfR antibody of the present disclosure comprises heavy chain variable domains CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 204. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises light chain variable domains CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequence of SEQ ID NO: 205.

[0402] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 188, CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 189, CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 190, CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 191, CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 192, and CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 193.

[0403] In some aspects, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 188, CDR-H2 having the amino acid sequence of SEQ ID NO: 189, and CDR-H3 having the amino acid sequence of SEQ ID NO: 190. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 191, CDR-L2 having the amino acid sequence of SEQ ID NO: 192, and CDR-L3 having the amino acid sequence of SEQ ID NO: 193.

[0404] In some embodiments, the anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together are at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 188, CDR-H2 having the amino acid sequence of SEQ ID NO: 189, and CDR-H3 having the amino acid sequence of SEQ ID NO: 190. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together are 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: 191, CDR-L2 having the amino acid sequence of SEQ ID NO: 192, and CDR-L3 having the amino acid sequence of SEQ ID NO: 193.

[0405] In some aspects, the anti-TfR antibodies of the present disclosure include: CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 188; CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H2 having the amino acid sequence of SEQ ID NO: 189; and / or (e.g., and) CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variation) compared to CDR-H3 having the amino acid sequence of SEQ ID NO: 190. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: 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: 191; 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: 192; and / or (for example, and) 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: 193.

[0406] In some embodiments, the anti-TfR antibodies of the present disclosure include CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 194, CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 195, CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 196, CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 197, CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 198, and CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 193.

[0407] In some aspects, the anti-TfR antibodies of the Disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 194, CDR-H2 having the amino acid sequence of SEQ ID NO: 195, and CDR-H3 having the amino acid sequence of SEQ ID NO: 196. "Together" means that the total number of amino acid variations in all three heavy chain CDRs is within the defined range. Alternatively or in addition (e.g., in addition), the anti-TfR antibodies of the Disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which together contain only 5 amino acid variations (e.g., only 5, 4, 3, 2, or 1 amino acid variation) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 197, CDR-L2 having the amino acid sequence of SEQ ID NO: 1...

Claims

1. A complex comprising a muscle targeting agent covalently linked to a molecular payload that modulates the expression or activity of myostatin (MSTN), inhibin beta A (INHBA), and / or activin receptor type 1B (ACVR1B), wherein the muscle targeting agent specifically binds to an internalized cell surface receptor on a muscle cell.

2. The complex according to claim 1, wherein the muscle cells are cardiomyocytes.

3. The muscle targeting agent is an anti-transferrin receptor (TfR) antibody, optionally comprising, wherein the anti-TfR antibody comprises heavy chain complementarity determination region 1 (CDR-H1), heavy chain complementarity determination region 2 (CDR-H2), heavy chain complementarity determination region 3 (CDR-H3), light chain complementarity determination region 1 (CDR-L1), light chain complementarity determination region 2 (CDR-L2), and light chain complementarity determination region 3 (CDR-L3) of any of the anti-TfR antibodies listed in Table 1, according to claim 1 or 2.

4. (i) The antibody comprises heavy chain variable regions (VH) CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 15, and light chain variable regions (VL) CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 16; (ii) The antibody comprises CDR-H1, CDR-H2, and CDR-H3 of VH containing the amino acid sequence of SEQ ID NO: 204, and CDR-L1, CDR-L2, and CDR-L3 of VL containing the amino acid sequence of SEQ ID NO: 205; (iii) The antibody comprises CDR-H1, CDR-H2, and CDR-H3 of VH containing the amino acid sequence of SEQ ID NO: 7, and CDR-L1, CDR-L2, and CDR-L3 of VL containing the amino acid sequence of SEQ ID NO: 8; or (iv) The antibody comprises CDR-H1, CDR-H2, and CDR-H3 of VH containing the amino acid sequence of SEQ ID NO: 23, and CDR-L1, CDR-L2, and CDR-L3 of VL containing the amino acid sequence of SEQ ID NO: 24, The composite according to claim 3.

5. Antibodies, (i) 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; (ii) 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; (iii) CDR-H1 of SEQ ID NO: 145, CDR-H2 of SEQ ID NO: 146, CDR-H2 of SEQ ID NO: 249, or CDR-H2 of SEQ ID NO: 252, 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; or (iv) CDR-H1 of SEQ ID NO: 165, 255, or 257, 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 The composite according to claim 3 or claim 4, comprising:

6. Antibodies, (i) CDR-H1, CDR-H2, CDR-H3 of VH represented by Sequence ID No. 15, and CDR-L1, CDR-L2, CDR-L3 of VL represented by Sequence ID No. 16; (ii) CDR-H1, CDR-H2, CDR-H3 of VH represented by Sequence ID No. 204, and CDR-L1, CDR-L2, CDR-L3 of VL represented by Sequence ID No. 205; (iii) CDR-H1, CDR-H2, CDR-H3 of VH represented by Sequence ID No. 7, and CDR-L1, CDR-L2, CDR-L3 of VL represented by Sequence ID No. 8; or (iv) CDR-H1, CDR-H2, CDR-H3 of VH represented by Sequence ID No. 23, and CDR-L1, CDR-L2, CDR-L3 of VL represented by Sequence ID No. 24 The composite according to any one of claims 3 to 5, comprising a human or humanized framework region having the

7. Antibodies, (i) an antibody comprising VH having an amino acid sequence at least 80% identical to SEQ ID NO: 15, and VL having an amino acid sequence at least 80% identical to SEQ ID NO: 16; (ii) An antibody comprising VH having an amino acid sequence at least 80% identical to SEQ ID NO: 204, and VL having an amino acid sequence at least 80% identical to SEQ ID NO: 205, optionally wherein the antibody comprises VH having the amino acid sequence of SEQ ID NO: 204 and VL having the amino acid sequence of SEQ ID NO: 205; (iii) an antibody comprising VH having an amino acid sequence at least 80% identical to SEQ ID NO: 7, and VL having an amino acid sequence at least 80% identical to SEQ ID NO: 8; and (iv) An antibody comprising VH having an amino acid sequence at least 80% identical to SEQ ID NO: 23, and VL having an amino acid sequence at least 805% identical to SEQ ID NO:

24. A composite according to any one of claims 3 to 6, selected from the above.

8. Equilibrium dissociation constant (K) for antibody binding to transferrin receptors Ｄ ) but 10 －１１ M-10 －６ A composite according to any one of claims 3 to 7, which is in the range of M.

9. The complex according to any one of claims 3 to 8, wherein the antibody is selected from the group consisting of full-length IgG, Fab fragment, F(ab') fragment, F(ab')2 fragment, scFv, and Fv, and optionally the antibody is a Fab' fragment.

10. The complex according to any one of claims 1 to 9, wherein the molecular payload is an oligonucleotide comprising an antisense strand containing a region complementary to an MSTN target sequence, optionally wherein the MSTN target sequence is an MSTN mRNA sequence represented by SEQ ID NO: 300 or SEQ ID NO: 301, or an MSTN target sequence represented by any one of SEQ ID NOs: 302 to 349, and further optionally wherein the antisense strand is 18 to 25 nucleotides in length, and / or the complementary region is at least 16 nucleosides in length.

11. The complex according to claim 10, wherein the antisense strand comprises at least 16 consecutive nucleotides of a nucleotide sequence represented by any one of SEQ ID NOs: 350 to 373, and optionally wherein the antisense strand comprises any one of SEQ ID NOs: 350 to 373.

12. The complex according to any one of claims 1 to 9, wherein the molecular payload is an oligonucleotide comprising an antisense strand containing a region complementary to an INHBA target sequence, optionally wherein the INHBA target sequence is an INHBA mRNA sequence represented by SEQ ID NO: 422 or SEQ ID NO: 423, or an INHBA target sequence represented by any one of SEQ ID NOs: 424 to 471, and further optionally wherein the antisense strand is 18 to 25 nucleotides in length, and / or the complementary region is a nucleoside of at least 16 in length.

13. The complex according to claim 12, wherein the antisense strand comprises at least 16 consecutive nucleotides of a nucleotide sequence represented by any one of SEQ ID NOs: 472 to 495, and optionally wherein the antisense strand comprises any one of SEQ ID NOs: 472 to 495.

14. The complex according to any one of claims 1 to 9, wherein the molecular payload is an oligonucleotide comprising an antisense strand containing a region complementary to the ACVR1B target sequence, optionally wherein the ACVR1B target sequence is the ACVR1B mRNA sequence represented by any one of SEQ ID NOs. 520 to 523, or the ACVR1B target sequence represented by any one of SEQ ID NOs. 374 to 421, and further optionally wherein the antisense strand is 18 to 25 nucleotides in length, and / or the complementary region is a nucleoside of at least 16 in length.

15. The complex according to claim 14, wherein the antisense strand comprises at least 16 consecutive nucleotides of a nucleotide sequence represented by any one of SEQ ID NOs: 496 to 519, and optionally wherein the antisense strand comprises any one of SEQ ID NOs: 496 to 519.

16. The complex according to any one of claims 10 to 15, further comprising a sense strand in which the oligonucleotide hybridizes to an antisense strand to form a double-stranded siRNA.

17. The complex according to any one of claims 10 to 16, wherein the oligonucleotide comprises one or more modified nucleosides, wherein optionally each nucleoside in the oligonucleotide is a modified nucleoside.

18. The complex according to claim 17, wherein one or more modified nucleosides are 2'-modified nucleotides, optionally, wherein one or more 2'-modified nucleosides are selected from 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'-O-N-methylacetamide(2'-O-NMA), locked nucleic acid (LNA), ethylene-bridged nucleic acid (ENA), and (S)-restricted ethyl-bridged nucleic acid (cEt), optionally, wherein the 2'-modified nucleotide is 2'-O-methyl or 2'-fluoro(2'-F).

19. The complex according to any one of claims 10 to 18, wherein the oligonucleotide comprises one or more phosphorothioate nucleoside linkages, optionally wherein one or more phosphorothioate nucleoside linkages are located on the antisense strand of the RNAi oligonucleotide, and further optionally wherein two nucleoside linkages at the 3' end of the sense strand are phosphorothioate nucleoside linkages.

20. The complex according to any one of claims 10, 11, and 16-19, wherein the oligonucleotide is one of the siRNAs listed in Table 11.

21. The complex according to any one of claims 12, 13, and 16-19, wherein the oligonucleotide is one of the siRNAs listed in Table 14.

22. The complex according to any one of claims 14 to 19, wherein the oligonucleotide is one of the siRNAs listed in Table 17.

23. Muscle targeting agents, (i) a cleavable linker, optionally wherein the cleavable linker comprises a valine-citrulline dipeptide sequence; or (ii) An inseparable linker, optionally here an inseparable linker is an Alkane linker. The complex according to any one of claims 1 to 22, wherein the complex is covalently linked to the molecular payload via a .

24. A method for reducing the expression of MSTN, INHBA, and / or ACVR1B in muscle cells, comprising contacting the muscle cells with an effective amount of the complex described in any one of claims 1 to 23 in order to promote the internalization of a molecular payload into the muscle cells.

25. A method for treating muscle atrophy, comprising administering an effective amount of the complex according to any one of claims 1 to 23 to a subject in need thereof, wherein the subject has elevated expression or activity of MSTN, INHBA, and / or ACVR1B.

26. siRNAs listed in Table 11, Table 14, or Table 17.

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