Anti-transferrin receptor (TFR) antibodies and uses thereof

Abstract

Aspects of the present disclosure relate to antibodies that bind to a transferrin receptor (e.g., transferrin receptor 1), and conjugates that include the antibodies covalently linked to a molecular payload. Methods of making and using the antibodies are also provided.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. § 119(e) of the filing dates of U.S. Provisional Application No. 63 / 055,405, filed July 23, 2020, and entitled "ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF," and U.S. Provisional Application No. 62 / 968,252, filed January 31, 2020, and entitled "ANTI-TRANSFERRIN RECEPTOR (TFR) ANTIBODY AND USES THEREOF," the contents of each of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present application relates to novel anti-transferrin receptor (TfR) antibodies and uses of the antibodies.

[0003] Reference to a sequence listing submitted as a text file via EFS-WEB This application contains a Sequence Listing, which has been submitted via EFS-Web in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on January 8, 2021, is entitled D082470023WO00-SEQ-ZJG and is 180 kilobytes in size. [Background technology]

[0004] background The transferrin receptor (TfR) is a dimeric transmembrane glycoprotein receptor involved in iron transport. Two transferrin receptors, transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2), have been characterized in humans. TfR has been shown to be overexpressed in cancer cells with higher metastatic potential. TfR1 has been shown to be expressed on endothelial cells of the blood-brain barrier, where it can be used to enable the delivery of macromolecules into the brain. Summary of the Invention

[0005] overview The present disclosure is based, at least in part, on the development of new antibodies that bind to the transferrin receptor (anti-TfR antibodies). In some embodiments, the anti-TfR antibodies described herein selectively bind to human or non-human primate (NHP) transferrin receptors with high specificity and affinity (e.g., in the subnanomolar to nanomolar range). In some embodiments, the anti-TfR antibodies described herein are useful for targeting tissues and / or (e.g., and) cells that express TfR. In some embodiments, the anti-TfR antibodies provided herein are used for the detection of TfR in cells or tissues. In some embodiments, the anti-TfR antibodies provided herein are used in diagnostic, therapeutic, or research applications. In some embodiments, the anti-TfR antibodies described herein are used to deliver molecular payloads to target cells or tissues (e.g., cells or tissues that express TfR).

[0006] Thus, in some aspects, conjugates are provided that include an anti-TfR antibody conjugated (e.g., covalently conjugated) to a molecular payload (e.g., a diagnostic or therapeutic agent). In some embodiments, the anti-TfR antibody is used to deliver the conjugated molecular payload to cells or tissues (e.g., muscle or brain) that express TfR1 to diagnose and / or (e.g., and) treat a disease (e.g., a muscular or neurological disease). In some aspects, the present disclosure provides data demonstrating that the anti-TfR antibodies described herein have superior activity in delivering molecular payloads into target cells (e.g., muscle cells) compared to other known anti-TfR antibodies.

[0007] Some aspects of the disclosure provide antibodies that bind to the human transferrin receptor (TfR), wherein the antibody comprises the following: CDR-H1, CDR-H2, and CDR-H3 of any one of the antibodies listed in Table 1; and / or wherein the antibody comprises CDR-L1, CDR-L2, and CDR-L3 of any one of the antibodies listed in Table 1 or Table 3.

[0008] Some aspects of the disclosure provide antibodies (e.g., isolated antibodies) that bind to human transferrin receptor (TfR), wherein the antibody comprises: (i) heavy chain complementarity-determining region 1 (CDR-H1), heavy chain complementarity-determining region 2 (CDR-H2), and heavy chain complementarity-determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:7; and / or (e.g., and), (ii) 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 a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:8.

[0009] In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 1, CDR-H2 as set forth in SEQ ID NO: 2, CDR-H3 as set forth in SEQ ID NO: 3; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO: 4, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 145, CDR-H2 as set forth in SEQ ID NO: 146, CDR-H3 as set forth in SEQ ID NO: 147; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO: 148, CDR-L2 as set forth in SEQ ID NO: 149, and CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 150, CDR-H2 as set forth in SEQ ID NO: 151, CDR-H3 as set forth in SEQ ID NO: 152; and / or (by way of example, and), CDR-L1 as set forth in SEQ ID NO: 153, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 154.

[0010] In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 1, CDR-H2 as set forth in SEQ ID NO: 233 or SEQ ID NO: 80, CDR-H3 as set forth in SEQ ID NO: 3; and / or CDR-L1 as set forth in SEQ ID NO: 4, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 145, CDR-H2 as set forth in SEQ ID NO: 234 or SEQ ID NO: 236, CDR-H3 as set forth in SEQ ID NO: 147; and / or CDR-L1 as set forth in SEQ ID NO: 148, CDR-L2 as set forth in SEQ ID NO: 149, and CDR-L3 as set forth in SEQ ID NO: 6. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 150, CDR-H2 as set forth in SEQ ID NO: 277 or SEQ ID NO: 278, CDR-H3 as set forth in SEQ ID NO: 152; and / or CDR-L1 as set forth in SEQ ID NO: 153, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 154.

[0011] In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO:7, and / or (by way of example only) a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO:8.

[0012] Another aspect of the disclosure provides antibodies (e.g., isolated antibodies) that bind to human transferrin receptor (TfR), wherein the antibody comprises: (i) heavy chain complementarity-determining region 1 (CDR-H1), heavy chain complementarity-determining region 2 (CDR-H2), and heavy chain complementarity-determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 15; and / or (e.g., and), (ii) 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 a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 16.

[0013] In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO:9, CDR-H2 as set forth in SEQ ID NO:10, CDR-H3 as set forth in SEQ ID NO:11; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO:12, CDR-L2 as set forth in SEQ ID NO:13, and CDR-L3 as set forth in SEQ ID NO:14. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO:155, CDR-H2 as set forth in SEQ ID NO:156, CDR-H3 as set forth in SEQ ID NO:157; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO:158, CDR-L2 as set forth in SEQ ID NO:159, and CDR-L3 as set forth in SEQ ID NO:14. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 160, CDR-H2 as set forth in SEQ ID NO: 161, CDR-H3 as set forth in SEQ ID NO: 162; and / or (by way of example, and) CDR-L1 as set forth in SEQ ID NO: 163, CDR-L2 as set forth in SEQ ID NO: 13, and CDR-L3 as set forth in SEQ ID NO: 164.

[0014] In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 237 or SEQ ID NO: 239, CDR-H2 as set forth in SEQ ID NO: 18, CDR-H3 as set forth in SEQ ID NO: 19; and / or CDR-L1 as set forth in SEQ ID NO: 20, CDR-L2 as set forth in SEQ ID NO: 21, and CDR-L3 as set forth in SEQ ID NO: 22. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 238 or SEQ ID NO: 240, CDR-H2 as set forth in SEQ ID NO: 166, CDR-H3 as set forth in SEQ ID NO: 167; and / or CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 22.

[0015] In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO:15, and / or (by way of example only) a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO:16.

[0016] Another aspect of the disclosure provides antibodies (e.g., isolated antibodies) that bind to human transferrin receptor (TfR). In some embodiments, the antibodies comprise: (i) heavy chain complementarity-determining region 1 (CDR-H1), heavy chain complementarity-determining region 2 (CDR-H2), and heavy chain complementarity-determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 23; and / or (e.g., and), (ii) 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 a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

[0017] In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 17, CDR-H2 as set forth in SEQ ID NO: 18, CDR-H3 as set forth in SEQ ID NO: 19; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO: 20, CDR-L2 as set forth in SEQ ID NO: 21, and CDR-L3 as set forth in SEQ ID NO: 22. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, CDR-H3 as set forth in SEQ ID NO: 167; and / or (by way of example and) CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 22. In some embodiments, the antibody comprises CDR-H1 as set forth in SEQ ID NO: 170, CDR-H2 as set forth in SEQ ID NO: 171, CDR-H3 as set forth in SEQ ID NO: 172; and / or (by way of example, and) CDR-L1 as set forth in SEQ ID NO: 173, CDR-L2 as set forth in SEQ ID NO: 21, and CDR-L3 as set forth in SEQ ID NO: 174.

[0018] In some embodiments, the antibody comprises a VH comprising an amino acid sequence at least 85% identical to SEQ ID NO:23, and / or (by way of example only) a VL comprising an amino acid sequence at least 85% identical to SEQ ID NO:24.

[0019] In some embodiments, the antibody comprises human or humanized framework regions and has VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 15, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 16. In some embodiments, the antibody comprises human or humanized framework regions and has VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 7, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises human or humanized framework regions and has VH CDR-H1, CDR-H2, CDR-H3 as set forth in SEQ ID NO: 23, and VL CDR-L1, CDR-L2, CDR-L3 as set forth in SEQ ID NO: 24.

[0020] In some embodiments, the antibody is a humanized antibody. In some embodiments, the humanized antibody comprises a humanized VH and / or (for example, and) a humanized VL. In some embodiments, the antibody is selected from the group consisting of a full-length IgG, a Fab fragment, a F(ab') fragment, a F(ab')2 fragment, an scFv, and an Fv.

[0021] In some embodiments, the antibody is a full-length IgG. In some embodiments, the antibody comprises a heavy chain constant region of isotype IgG1, IgG2, IgG3, or IgG4. In some embodiments, the antibody comprises a heavy chain constant region of isotype IgG1 represented by SEQ ID NO: 175 or SEQ ID NO: 176. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 178, and / or (for example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 179. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 180, and / or (for example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 181. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 182, and / or (for example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 183.

[0022] In some embodiments, the antibody is a F(ab') fragment. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 185 and / or (by way of example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 179. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 186 and / or (by way of example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 181. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 187 and / or (by way of example, and) a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 183.

[0023] Also provided herein are antibodies (e.g., isolated antibodies) that bind to human transferrin receptor (TfR). In some embodiments, the antibodies comprise the following: CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than 10 amino acid variations, preferably no more than 8 amino acid variations, and more preferably no more than 5 amino acid variations, when compared to the CDR-H1, CDR-H2, and CDR-H3 of any one of the antibodies listed in Table 1; and / or (e.g., and), wherein the antibodies comprise CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than 10 amino acid variations, preferably no more than 8 amino acid variations, when compared to the CDR-L1, CDR-L2, and CDR-L3 of any one of the antibodies listed in Table 1. In some embodiments, the antibody comprises the following: CDR-H1, CDR-H2, and CDR-H3 of any one of the antibodies listed in Table 1; and / or (by way of example, and), wherein the antibody comprises CDR-L1, CDR-L2, and CDR-L3 of any one of the antibodies listed in Table 1.

[0024] In some embodiments, an antibody (e.g., an isolated antibody) that binds to human transferrin receptor (TfR) has the following CDR-H1 represented as GYSITSGYX1 (SEQ ID NO: 286) (wherein X1 can be Y or G); CDR-H2 represented as IX2FDGX3X4 (SEQ ID NO: 287) (wherein X2 can be T or N, X3 can be A or N, and X4 can be N, T, or S); X5RX6X7YDYDX8X9DX 10 (SEQ ID NO: 288) (wherein X5 is T or A, X6 is S, F, or I, X7 is S, N, or Y, X8 is P, Y, or V, X9 is I, F, or L, and X 10 is Y or F); and / or (for example, and), QDIX 11 NX 12 (SEQ ID NO: 289) (where X 11is S or T, and X 12 CDR-L1 represented as YTS (SEQ ID NO: 13); and CDR-L2 represented as QQGX (SEQ ID NO: 14). 13 X 14 X 15 PX 16 T (SEQ ID NO: 290) (where X 13 is H or N, and X 14 is T or A, and X 15 is L or Y, and X 16 is Y, W, or F).

[0025] In some embodiments, any one of the anti-TfR antibodies described herein binds to transferrin receptor 1 (TfR1) at a concentration of 10 -8 K less than M D Combine with.

[0026] Nucleic acids encoding any of the antibodies described herein, vectors containing such nucleic acids, and cells containing such vectors are also provided.

[0027] Another aspect of the present disclosure provides a method for producing an anti-TfR1 antibody. In some embodiments, the method comprises culturing a cell containing a nucleic acid encoding any one of the antibodies described herein under conditions suitable for expression of the antibody.

[0028] Another aspect of the present disclosure provides a conjugate comprising any one of the antibodies described herein covalently linked to a molecular payload. In some embodiments, the molecular payload is a diagnostic or therapeutic agent. In some embodiments, the molecular payload is an oligonucleotide, a polypeptide, or a small molecule. In some embodiments, the antibody and the molecular payload are linked via a linker. In some embodiments, the linker is a reversible linker. In some embodiments, the linker is a val-Cit linker.

[0029] Also provided is a composition comprising any one of the antibodies described herein, any one of the nucleic acids described herein, any one of the vectors described herein, or any one of the complexes described herein. In some embodiments, the composition comprises a pharmaceutically acceptable carrier.

[0030] Also provided herein are methods for detecting transferrin receptor in a biological sample. In some embodiments, the method comprises contacting any one of the antibodies described herein with the biological sample and measuring binding of the antibody to the biological sample. In some embodiments, the antibody is covalently linked to a diagnostic agent. In some embodiments, the biological sample is obtained from a human subject suspected of having or at risk for a disease associated with the transferrin receptor. In some embodiments, the contacting step is carried out by administering an effective amount of an anti-TfR antibody to the subject.

[0031] Also provided are methods for delivering a molecular payload to a cell. In some embodiments, the method comprises contacting a cell with any one of the conjugates described herein. In some embodiments, the cell is a muscle cell. In some embodiments, the cell is in vitro. In some embodiments, the cell is in a subject. In some embodiments, the subject is a human.

[0032] In some aspects, a method for delivering a molecular payload to the brain or muscle of a subject is provided. In some embodiments, the method comprises administering an effective amount of any one of the conjugates described herein to the subject. In some embodiments, the administration is intravenous.

[0033] In some aspects, methods for treating a disease are provided. In some embodiments, the method comprises administering to a subject an effective amount of any one of the conjugates described herein (e.g., wherein the molecular payload is a therapeutic agent). In some embodiments, the disease is a neurological disease, and the molecular payload is a drug for treating the neurological disease. In some embodiments, the disease is a muscular disease, e.g., the molecular payload is a drug for treating the muscular disease. In some embodiments, the muscular disease is a rare muscular disease or muscular atrophy. [Brief explanation of the drawings]

[0034] Brief description of the drawings [Figure 1] FIG. 1 depicts the screening process for anti-TfR antibodies.

[0035] [Figure 2A] Figures 2A and 2B are graphs showing the expression of TfR1 in tissues: Figure 2A: Mouse TfR1; Figure 2B: Cynomolgus monkey (Cyno) TfR1. [Figure 2B] Figures 2A and 2B are graphs showing the expression of TfR1 in tissues: Figure 2A: Mouse TfR1; Figure 2B: Cynomolgus TfR1.

[0036] [Figure 3] Figure 3 is a graph showing the DMPK knockdown (KD) efficiency of conjugates containing selected anti-TfR1 antibodies covalently conjugated to a control antisense oligonucleotide targeting DMPK in non-human primate (NHP) cells or cells from human DM1 patients (DM1).

[0037] [Figure 4] FIG. 4 shows the serum stability over time of linkers used to connect anti-TfR antibodies and molecular payloads (e.g., oligonucleotides) in various species after intravenous administration. DETAILED DESCRIPTION OF THE INVENTION

[0038] Detailed Description The present disclosure is based, at least in part, on the development of anti-TfR antibodies, e.g., the antibodies and variants thereof listed in Table 1, that have demonstrated high binding affinity and specificity for human TfR. Also provided are uses of the anti-TfR antibodies and variants thereof in research, diagnostic / detection, and therapeutic applications. In some embodiments, the anti-TfR antibodies described herein are used to deliver molecular payloads (e.g., oligonucleotides, peptides, small molecules) to target cells or tissues that express TfR. In some embodiments, the molecular payload to be delivered is conjugated to the anti-TfR antibody and delivered to target cells or tissues that express TfR via receptor internalization. Exemplary tissues that express TfR and can be targeted using the anti-TfR antibodies described herein include, but are not limited to, the brain, muscle, adrenal gland, appendix, bone marrow, colon, duodenum, endometrium, esophagus, fat, gallbladder, heart, kidney, liver, lung, lymph node, ovary, pancreas, placenta, prostate, salivary gland, skin, small intestine, spleen, stomach, testis, thyroid, and bladder. In some embodiments, such approaches have beneficial effects on muscle cells and across the blood-brain barrier, which has proven difficult. In some aspects, the present disclosure provides data demonstrating that the anti-TfR antibodies described herein have superior activity in delivering molecular payloads into target cells (e.g., muscle cells) compared to other known anti-TfR antibodies.

[0039] Thus, the present disclosure also provides conjugates comprising any one of the anti-TfR1 antibodies covalently linked to a molecular payload. In some embodiments, the conjugates are particularly useful for delivering molecular payloads that inhibit the expression or activity of target genes in muscle cells, e.g., in subjects having or suspected of having a rare muscle disease or muscle atrophy (e.g., as listed in Table 7). In some embodiments, the conjugates are particularly useful for delivering drugs to the brain to treat neurological diseases (e.g., as listed in Table 8).

[0040] Further aspects of the disclosure, including descriptions of defined terms, are provided below.

[0041] I. Definition Administering: As used herein, the terms "administering" or "administration" mean providing a conjugate to a subject in a physiologically and / or (for example, and) pharmacologically useful manner (for example, treating a disease in a subject).

[0042] about: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to the stated reference value. In some embodiments, the term "approximately" or "about" refers to a broad range of values ​​that fall within plus or minus (greater or less than) 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the stated reference value, unless otherwise stated or clear from the context (except when such number exceeds 100% of a feasible value).

[0043] antibody: As used herein, the term "antibody" refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., a paratope, that specifically binds to an antigen. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, F(ab') fragment, F(ab')2 fragment, Fv fragment, or scFv fragment. In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody comprises a framework with human germline sequences. In another embodiment, the antibody comprises a heavy chain constant region selected from the group consisting of the constant regions of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or (for example, and), a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant region, for example, an Fc region. An immunoglobulin constant region refers to a heavy or light chain constant region. Human IgG heavy and light chain constant region amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein can be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In specific embodiments, the antibody described herein comprises a human gamma 1 CH1 domain, CH2 domain, and / or (for example, and), CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (γ) heavy chain constant region, such as any sequence known in the art.Non-limiting examples of human constant region sequences are described in the art; see, e.g., U.S. Patent No. 5,693,780 and Kabat EA et al. (1991), supra. In some embodiments, the VH domain comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein. In some embodiments, the antibody is modified, e.g., via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules comprise a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, the antibody is a construct comprising a polypeptide comprising one or more antigen-binding fragments of the present disclosure linked to a linker polypeptide or an immunoglobulin constant region. The linker polypeptide comprises two or more amino acid residues linked by a peptide bond and is used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123).Furthermore, an antibody may be part of a larger immunoadhesion molecule formed by covalent or noncovalent association of one or more other proteins or peptides with the antibody or antibody portion. Examples of such immunoadhesion molecules include the use of streptavidin core regions to generate tetrameric scFv molecules (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101), and the use of cysteine ​​residues, marker peptides, and C-terminal polyhistidine tags to generate bivalent and biotinylated scFv molecules (Kipriyanov, SM, et al. (1994) Mol. Immunol. 31:1047-1058).

[0044] CDR: As used herein, the term "CDR" refers to the complementarity-determining regions within an antibody variable sequence. A typical antibody molecule contains a heavy chain variable region (VH) and a light chain variable region (VL), which are primarily responsible for antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as "complementarity-determining regions" ("CDRs"), interspersed with more conserved regions known as "framework regions" ("FRs"). Each VH and VL typically consists of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methodologies known in the art, such as the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or (by way of example) the contact definition, all of which are well known in the art.For example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242; IMGT (registered trademark), the international ImMunoGeneTics information system (registered trademark) http: / / www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids. Res.,27:209-212(1999);Ruiz,M.et al.,Nucleic Acids Res.,28:219-221(2000);Lefranc,M.-P.,Nucleic Acids Res.,29:207-209(2001);Lefranc,M.-P.,Nucleic Acids Res.,31:307-310(2003);Lefranc,M.-P.et al.,In Silico Biol.,5,0006(2004)[Epub],5:45-60(2005);Lefranc,M.-P.et al.,Nucleic Acids Res.,33:D593-597(2005);Lefranc,M.-P.et al.,Nucleic Acids Res.,37:D1006-1012(2009);Lefranc,M.-P.et al.,Nucleic Acids Res.,43:D413-422 (2015);Chothia et al.,(1989)Nature 342:877;Chothia,C.et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al. al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, CDR may refer to a CDR defined by any method known in the art.Two antibodies with the same CDR mean that the two antibodies have the same amino acid sequence for that CDR as determined by the same method, for example, the IMGT definition.

[0045] There are three CDRs in each of the heavy and light chain variable regions, designated CDR1, CDR2, and CDR3 for each variable region. The term "CDR set" as used herein refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs have been defined differently according to various systems. The system described by Kabat (Kabat et al., Sequence of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any antibody variable region, but also provides precise residue boundaries defining the three CDRs. These CDRs are sometimes referred to as Kabat CDRs. Sub-portions of the CDRs are sometimes designated L1, L2, and L3, or H1, H2, and H3, where "L" and "H" designate the light chain and heavy chain regions, respectively. These regions are sometimes referred to as Chothia CDRs, whose boundaries overlap with the Kabat CDRs. Other boundaries defining CDRs that overlap with the Kabat CDRs are described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly adhere to one of the above systems, but may still overlap with the Kabat CDRs, and may be shortened or extended in light of predictions or experimental findings that particular residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding. While the methods used herein may utilize CDRs defined according to any of these systems, preferred embodiments use CDRs defined by Kabat or Chothia.

[0046] CDR-grafted antibodies: The term "CDR-grafted antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of its VH and / or VL have been replaced with CDR sequences from another species, such as an antibody having murine heavy and light chain variable regions but in which one or more of the murine CDRs (e.g., CDR3) have been replaced with human CDR sequences.

[0047] Chimeric antibodies: The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species and constant region sequences from another species, such as an antibody having murine heavy and light chain variable regions linked to human constant regions.

[0048] Complementary: As used herein, the term "complementary" refers to the ability for precise pairing between two nucleotides or two pairs of nucleotides.In particular, complementary is a term that characterizes the degree of hydrogen bond pairing that results in binding between two nucleotides or two pairs of nucleotides.For example, if the base of an oligonucleotide at a certain position can hydrogen bond with the base of target nucleic acid (for example, mRNA) at the corresponding position, then the bases are considered to be complementary to each other at that position.Base pairing may include both standard Watson-Crick base pairing and non-Watson-Crick base pairing (for example, Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, an adenosine-type base (A) is complementary to a thymidine-type base (T) or a uracil-type base (U), a cytosine-type base (C) is complementary to a guanosine-type base (G), and a universal base such as 3-nitropyrrole or 5-nitroindole can hybridize with and be considered complementary to any A, C, U, or T. Inosine (I) is also considered a universal base in the art and is considered complementary to any A, C, U, or T.

[0049] Conservative amino acid substitutions: As used herein, "conservative amino acid substitution" refers to an amino acid substitution that does not change the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for modifying polypeptide sequences known to those skilled in the art, and can be found, for example, in references that summarize such methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, FMA Usubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include those made to amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0050] Covalently linked: As used herein, the term "covalently linked" refers to the characteristic of two or more molecules being linked together via at least one covalent bond. In some embodiments, two molecules may be covalently linked together by a single bond (e.g., a disulfide bond or disulfide bridge) that acts as an intermolecular linker. However, in some embodiments, two or more molecules may be covalently linked together via a molecule that acts as a linker that connects two or more molecules together through multiple covalent bonds. In some embodiments, the linker may be a cleavable linker. However, in some embodiments, the linker may be a non-cleavable linker.

[0051] Cross-reacting: As used herein, and in the context of targeting agents (e.g., antibodies), the term "cross-reacting" refers to the property of an agent that can specifically bind to more than one antigen of the same type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or avidity. For example, in some embodiments, an antibody that cross-reacts to a similar type or class of human and non-human primate antigens (e.g., human transferrin receptor and non-human primate transferrin receptor) is capable of binding to a human antigen and a non-human primate antigen with similar affinity or avidity. In some embodiments, an antibody cross-reacts to a similar type or class of human antigen and rodent antigen. In some embodiments, an antibody cross-reacts to a similar type or class of rodent antigen and non-human primate antigen. In some embodiments, an antibody cross-reacts to a similar type or class of human antigen, non-human primate antigen, and rodent antigen.

[0052] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of the variable region minus the CDRs. Because the precise definition of a CDR sequence can be determined by various systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) also divide the framework regions on the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 is located between FR2 and FR3, and CDR3 is located between FR3 and FR4. When framework regions that do not specify a specific subregion as FR1, FR2, FR3, or FR4 are referred to by others, they represent the combined FRs in the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR refers to one of the four subregions, and FR(s) refers to two or more of the four subregions containing framework regions. Human heavy and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0053] Human antibodies: The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include, for example, in the CDRs, particularly CDR3, amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0054] Humanized antibodies: The term "humanized antibody" refers to an antibody that contains heavy and light chain variable region sequences from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or (e.g., and) VL sequences have been altered to be more "human-like," i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody in which human CDR sequences are introduced onto non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-TfR antibodies and antigen-binding portions are provided. Such antibodies may be produced by obtaining a murine anti-transferrin receptor monoclonal antibody using conventional hybridoma technology, followed by humanization using in vitro genetic engineering (such as that disclosed in PCT Publication No. WO 2005 / 123126 A2 to Kasaian et al.).

[0055] Isolated antibodies: An "isolated antibody," as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to the transferrin receptor is substantially free of antibodies that specifically bind to antigens other than the transferrin receptor). However, an isolated antibody that specifically binds to the transferrin receptor complex may have cross-reactivity to other antigens, such as transferrin receptor molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and / or (by way of example and) chemicals.

[0056] Molecular payload: As used herein, the term "molecular payload" refers to a molecule or species that functions to modulate a biological outcome. In some embodiments, the molecular payload is linked to or otherwise associated with an anti-TfR antibody. In some embodiments, the molecular payload is a small molecule, protein, peptide, nucleic acid, or oligonucleotide. In some embodiments, the molecular payload functions to modulate the transcription of a DNA sequence, to modulate the expression of a protein, or to modulate the activity of a protein. In some embodiments, the molecular payload is an oligonucleotide comprising a strand having a region complementary to a target gene.

[0057] Oligonucleotides: As used herein, the term "oligonucleotide" refers to an oligomeric nucleic acid compound up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNA, shRNA), microRNA, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNA), and the like. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, oligonucleotides may contain one or more modified nucleotides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, oligonucleotides may contain one or more modified internucleotide linkages. In some embodiments, oligonucleotides may contain one or more phosphorothioate linkages, which may be in an Rp or Sp stereochemical configuration.

[0058] Recombinant antibodies: The term "recombinant human antibody," as used herein, refers to any human antibody that is prepared, expressed, created, or isolated by recombinant means, e.g., an antibody expressed using a recombinant expression vector transfected into a host cell (as described in more detail in this disclosure), an antibody isolated from a recombinant combinatorial human antibody library (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), or an antibody isolated from a human immunoglobulin gene transgenic animal (e.g., a mouse) (see, e.g., Taylor, LD, et al. (See, e.g., Kellermann SA, and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370), or any other means involving splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when human Ig sequence transgenic animals are used, in vivo somatic mutagenesis), such that the amino acid sequences of the VH and VL regions of the recombinant antibodies, while derived from and related to human germline VH and VL sequences, are sequences that may not naturally occur within the germline repertoire of human antibodies in vivo.One aspect of the present disclosure provides fully human antibodies capable of binding to the human transferrin receptor that can be produced using techniques well known in the art, including, but not limited to, techniques using human Ig phage libraries (e.g., those disclosed in PCT Publication No. WO 2005 / 007699 A2 to Jermutus et al.).

[0059] Regions of complementarity: As used herein, the term "region of complementarity" refers to a nucleotide sequence (e.g., a nucleotide sequence of an oligonucleotide) that is sufficiently complementary to a cognate nucleotide sequence (e.g., a nucleotide sequence of a target nucleic acid) such that the two nucleotide sequences are capable of annealing to each other under physiological conditions (e.g., in a cell). In some embodiments, the region of complementarity is fully complementary to the cognate nucleotide sequence of the target nucleic acid. However, in some embodiments, the region of complementarity is only partially complementary (e.g., at least 80%, 90%, 95%, or 99% complementary) to the cognate nucleotide sequence of the target nucleic acid. In some embodiments, the region of complementarity contains one, two, three, or four mismatches compared to the cognate nucleotide sequence of the target nucleic acid.

[0060] Specific binding to: As used herein, the term "specifically binds" refers to the ability of a molecule to bind to a binding partner in a binding assay or other binding context, with a degree of affinity or avidity that can be used to distinguish the binding partner from an appropriate control. With respect to an antibody, the term "specifically binds" refers to the ability of an antibody to bind to a specific antigen, relative to an appropriate reference antigen, or an antigen that can be used to distinguish the specific antigen from other antigens, with a degree of affinity or avidity (e.g., that allows preferential targeting to certain cells (e.g., muscle cells) through binding to the antigen, as described herein). In some embodiments, the antibody binds to the target with at least about 10-4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M or less K D In some embodiments, the antibody specifically binds to the transferrin receptor.

[0061] subject: As used herein, the term "subject" refers to a mammal. In some embodiments, the subject is a non-human primate animal or a rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, e.g., a human patient, having or suspected of having a disease. In some embodiments, the subject is a human patient having or suspected of having a disease resulting from a disease-associated repeat expansion (e.g., in a DMPK allele).

[0062] Transferrin receptor: As used herein, the term "transferrin receptor" (also known as TFRC, CD71, p90, TfR, or TFR1) refers to an internalized cell surface receptor that binds to transferrin to facilitate iron uptake by endocytosis. In some embodiments, the transferrin receptor may originate from humans (NCBI Gene ID 7037), non-human primates (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodents (e.g., NCBI Gene ID 22042). In addition, multiple human transcript variants encoding different isoforms of the receptor have been characterized (e.g., those annotated with GenBank RefSeq accession numbers: NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0063] An example of a human transferrin receptor amino acid sequence, corresponding to the NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens), is as follows: (SEQ ID NO: 228).

[0064] An example of a primate non-human transferrin receptor amino acid sequence, corresponding to the NCBI sequence NP_001244232.1 (Transferrin receptor protein 1, Macaca mulatta), is as follows: (SEQ ID NO: 229)

[0065] An example of a primate non-human transferrin receptor amino acid sequence corresponding to the NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) is as follows: (SEQ ID NO: 230).

[0066] 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 no. 231)

[0067] 2'modificationヌクレオシド: As used herein, the terms "2'-modified nucleoside" and "2'-modified ribonucleoside" are used interchangeably and refer to a nucleoside having a sugar moiety modified at the 2'-position. In some embodiments, the 2'-modified nucleoside is a 2'-4' bicyclic nucleoside, in which the 2' and 4' positions of the sugar are bridged (e.g., by a methylene, ethylene, or (S)-constrained ethyl bridge). In some embodiments, the 2'-modified nucleoside is a non-bicyclic 2'-modified nucleoside, e.g., in which the 2' position of the sugar moiety is substituted. Non-limiting examples of 2'-modified nucleosides include the following: 2'-deoxy, 2'-fluoro (2'-F), 2'-O-methyl (2'-O-Me), 2'-O-methoxyethyl (2'-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), 2'-ON-methylacetamide (2'-O-NMA), locked nucleic acids (LNA, methylene-bridged nucleic acids), ethylene-bridged nucleic acids (ENA), and (S)-constrained ethyl-bridged nucleic acids (cEt). In some embodiments, the 2'-modified nucleosides described herein are high-affinity modified nucleotides, and oligonucleotides comprising the 2'-modified nucleotides have increased affinity for target sequences compared to unmodified oligonucleotides. Examples of structures of 2'-modified nucleosides are provided below: [ka]

[0068] II. Anti-TfR antibody In some embodiments, an agent that binds to the transferrin receptor, e.g., an anti-TfR antibody, can target muscle cells and / or (e.g., and) mediate transport of the agent across the blood-brain barrier. The transferrin receptor is an internalizing cell surface receptor that transports transferrin across the cell membrane and participates in the regulation and homeostasis of intracellular iron levels. Some aspects of the present disclosure provide transferrin receptor-binding proteins capable of binding to the transferrin receptor. An antibody that binds to the transferrin receptor, e.g., an antibody that specifically binds thereto, may be internalized into the cell upon binding to the transferrin receptor, e.g., through receptor-mediated endocytosis.

[0069] Provided herein are, in some aspects, antibodies that bind to the transferrin receptor with high specificity and affinity. In some embodiments, the anti-TfR antibodies described herein specifically bind to any extracellular epitope of the transferrin receptor or epitope that becomes exposed to the antibody. In some embodiments, the anti-TfR antibodies provided herein specifically bind to transferrin receptor from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-TfR antibodies provided herein bind to the human transferrin receptor. In some embodiments, the anti-TfR antibodies described herein bind to an amino acid segment of the human or non-human primate transferrin receptor as provided in SEQ ID NOs: 228-231. In some embodiments, the anti-TfR antibodies described herein bind to an amino acid segment corresponding to amino acids 90-96 of the human transferrin receptor as set forth in SEQ ID NO: 228 (which is not in the apical domain of the transferrin receptor).

[0070] 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 -13 In some embodiments, the anti-TfR antibodies described herein bind to TfR1 (e.g., human or non-human primate TfR1) with a binding affinity (e.g., indicated by Kd) of 1 M or less. In some embodiments, the anti-TfR antibodies described herein bind to TfR1 with a Kd in the sub-nanomolar range. In some embodiments, the anti-TfR antibodies described herein selectively bind to transferrin receptor 1 (TfR1) but not to transferrin receptor 2 (TfR2). In some embodiments, the anti-TfR antibodies described herein bind to human TfR1 and cynomolgus TfR1 (e.g., 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M or smaller Kd) do not bind to mouse TfR1. The affinity and binding kinetics of anti-TfR antibodies can be tested using any suitable method, including, but not limited to, biosensor technology (e.g., OCTET or BIACORE). In some embodiments, the binding of any one of the anti-TfR antibodies described herein does not compete with or inhibit transferrin binding to TfR1. In some embodiments, the binding of any one of the anti-TfR antibodies described herein does not compete with or inhibit HFE-beta2-microglobulin binding to TfR1.

[0071] Heavy and light chain variable domain and CDR sequences of non-limiting example anti-TfR antibodies are provided in Table 1. Table 1. Examples of anti-TfR1 antibodies (CDRs according to IMGT® definitions) [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0072] In some embodiments, an anti-TfR antibody of the present disclosure comprises one or more of the CDR-H (e.g., CDR-H1, CDR-H2, and CDR-H3) amino acid sequences from any one of the anti-TfR antibodies selected from Table 1. In some embodiments, an anti-TfR antibody of the present disclosure comprises the CDR-H1, CDR-H2, and CDR-H3 provided for any one of the antibodies selected from Table 1. In some embodiments, an anti-TfR antibody of the present disclosure comprises one or more of the CDR-L (e.g., CDR-L1, CDR-L2, and CDR-L3) amino acid sequences from any one of the anti-TfR antibodies selected from Table 1. In some embodiments, an anti-TfR antibody of the present disclosure comprises the CDR-L1, CDR-L2, and CDR-L3 provided for any one of the anti-TfR antibodies selected from Table 1.

[0073] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfR antibodies selected from Table 1. In some embodiments, antibody heavy and light chain CDR3 domains may play a particularly important role in the binding specificity / affinity of an antibody to an antigen. Consequently, an anti-TfR antibody of the present disclosure may include at least the heavy and / or (by way of example) light chain CDR3 of any one of the anti-TfR antibodies selected from Table 1.

[0074] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences that are substantially similar to any of the CDR-H1 sequence, CDR-H2 sequence, CDR-H3 sequence, CDR-L1 sequence, CDR-L2 sequence, and / or (e.g., and) CDR-L3 sequence from one of the anti-TfR antibodies selected from Table 1. In some embodiments, the position of one or more CDRs along the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) and / or VL (e.g., CDR-L1, CDR-L2, or CDR-L3) regions of an antibody described herein may vary by one, two, three, four, five, or six amino acid positions, so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the positions defining the CDRs of any of the antibodies described herein may vary by one, two, three, four, five, or six amino acid positions compared to the CDR positions of any one of the antibodies described herein by shifting the N-terminal and / or (for example, and) C-terminal boundaries of the CDR, so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% maintained relative to the binding of the original antibody from which it is derived).In another embodiment, the length of one or more CDRs along the VH (e.g., CDR-H1, CDR-H2, or CDR-H3) region and / or (e.g., and) the VL (e.g., CDR-L1, CDR-L2, or CDR-L3) region of an antibody described herein can be varied by 1, 2, 3, 4, 5, or more amino acids (e.g., shorter or longer), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).

[0075] Consequently, in some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shorter by 1, 2, 3, 4, 5, or more amino acids than one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be shorter by 1, 2, 3, 4, 5, or more amino acids than one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein may be extended by a difference of 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).The carboxy portion of CDR-H2 and / or CDR-H3 can be extended by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (e.g., a human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the amino portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and / or (for example, and) CDR-H3 described herein can be shortened by 1, 2, 3, 4, 5, or more amino acids compared to one or more of the CDRs described herein (for example, a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to a transferrin receptor (for example, a human transferrin receptor) is maintained (for example, substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).Either method can be used to determine whether immunospecific binding to the transferrin receptor (e.g., the human transferrin receptor) is maintained, using, for example, binding assays and conditions described in the art.

[0076] In some examples, any of the anti-TfR antibodies of the present disclosure have one or more CDR (e.g., CDR-H or CDR-L) sequences substantially similar to any one of the anti-TfR antibodies selected from Table 1. For example, an antibody may include one or more CDR sequence(s) from any of the anti-TfR antibodies selected from Table 1 containing up to 5, 4, 3, 2, or 1 amino acid residue variations compared to the corresponding CDR region in any one of the CDRs provided herein (e.g., a CDR from any of the anti-TfR antibodies selected from Table 1), so long as immunospecific binding to transferrin receptor (e.g., human transferrin receptor) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% maintained relative to the binding of the original antibody from which it was derived). In some embodiments, any amino acid variations in any of the CDRs provided herein may be conservative variations. Conservative variations can be introduced into CDRs at positions where the residues are unlikely to be involved in interactions with a transferrin receptor protein (e.g., human transferrin receptor protein), e.g., as determined based on a crystal structure. Some aspects of the present disclosure provide anti-TfR antibodies comprising one or more of the heavy chain variable (VH) domains and / or (e.g., and) light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein include one or more of the CDR-H sequences (e.g., CDR-H1, CDR-H2, and CDR-H3) provided herein (e.g., any of the CDR-H sequences provided in any one of the anti-TfR antibodies selected from Table 1). In some embodiments, any of the VL domains provided herein include one or more of the CDR-L sequences (e.g., CDR-L1, CDR-L2, and CDR-L3) provided herein (e.g., any of the CDR-L sequences provided in any one of the anti-TfR antibodies selected from Table 1).

[0077] In some embodiments, the anti-TfR antibodies of the present disclosure include any antibodies that include the heavy chain variable domain and / or (by way of example and not limitation) the light chain variable domain of any one of the anti-TfR antibodies selected from Table 1, as well as variants thereof. In some embodiments, the anti-TfR antibodies of the present disclosure include any antibodies that also include the heavy chain variable and light chain variable pair of any one of the anti-TfR antibodies selected from Table 1.

[0078] Aspects of the present disclosure provide anti-TfR antibodies having a heavy chain variable (VH) domain amino acid sequence and / or (by way of example, and) a light chain variable (VL) domain amino acid sequence homologous to any of the anti-TfR antibodies described herein. In some embodiments, the anti-TfR antibody comprises a heavy chain variable sequence or a light chain variable sequence that is at least 75% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the heavy chain variable sequence and / or (by way of example, and) any light chain variable sequence of any anti-TfR antibody, such as any one of the anti-TfR antibodies selected from Table 1. In some embodiments, the homologous heavy chain variable and / or light chain variable amino acid sequence does not vary within any of the CDR sequences provided herein. For example, in some embodiments, a degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within the heavy chain variable sequence and / or (by way of example and) light chain variable sequence excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-TfR antibodies provided herein comprise heavy and light chain variable sequences that comprise framework sequences that are at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequences of any of the anti-TfR antibodies selected from Table 1.

[0079] In some embodiments, the anti-TfR antibodies of the present disclosure have relatively high affinity, e.g., 10 -6 Under M, 10 -7 Under M, 10 -8 Under M, 10 -9 Under M, 10 -10 Under M, 10-11 K less than or equal to M D For example, an anti-TfR antibody of the present disclosure may bind to a transferrin receptor protein (e.g., human transferrin receptor) with an affinity between 5 pM and 500 nM, e.g., between 50 pM and 100 nM, e.g., between 500 pM and 50 nM. The present disclosure also encompasses antibodies that compete with any of the antibodies described herein for binding to a transferrin receptor protein (e.g., human transferrin receptor) and have an affinity of 50 nM or less (e.g., 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of anti-TfR antibodies can be tested using any suitable method, including, but not limited to, biosensor technology (e.g., OCTET or BIACORE).

[0080] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VL domain and / or (by way of example and not limitation) a VH domain of any one of the anti-TfR antibodies selected from Table 1, and comprises 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 of immunoglobulin molecule (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b). Non-limiting examples of human constant regions are described in the art; see, e.g., Kabat EA et al., (1991) supra.

[0081] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 8.

[0082] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6.

[0083] In some embodiments, an anti-TfR antibody of the present disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 1; a CDR-H2 having the amino acid sequence of SEQ ID NO: 2 with an amino acid substitution at position 5 (e.g., wherein the asparagine at position 5 is substituted with, e.g., any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Cys (C), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)); and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally (by way of example, additionally), an anti-TfR antibody of the present disclosure comprises the following: CDR-L1 having the amino acid sequence of SEQ ID NO: 4; CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and CDR-L3 having the amino acid sequence of SEQ ID NO: 6. In some embodiments, the amino acid substitution at position 5 of CDR-H2 as represented by SEQ ID NO: 2 is N5T or N5S.

[0084] In some embodiments, an anti-TfR antibody of the disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 1; a CDR-H2 having the amino acid sequence of SEQ ID NO: 233 or SEQ ID NO: 80; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or in addition (by way of example, in addition), an anti-TfR antibody of the disclosure comprises the following: a CDR-L1 having the amino acid sequence of SEQ ID NO: 4; a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0085] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) when compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 233, or SEQ ID NO: 80, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. "Combined," as used anywhere in this disclosure, means that the total number of amino acid variations in all three heavy chain CDRs is within a defined range. Alternatively or additionally (e.g., in addition), an anti-TfR receptor antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) when compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0086] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, CDR-H2, and CDR-H3 that, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 233, or SEQ ID NO: 80, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0087] In some embodiments, the anti-TfR antibodies of the present disclosure include: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO:1; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:233, or SEQ ID NO:80; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO:3. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 4; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0088] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 8.

[0089] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) when compared to a VH as set forth in SEQ ID NO:7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) when compared to the VL as set forth in SEQ ID NO:8.

[0090] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 7. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 8.

[0091] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH as set forth in SEQ ID NO:7, with an amino acid substitution at position 55 (e.g., the asparagine at position 55 is replaced with, for example, any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Cys (C), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)). Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL as set forth in SEQ ID NO:8. In some embodiments, the amino acid substitution at position 55 of a VH as set forth in SEQ ID NO:7 is N55T or N55S. When the VH as represented in SEQ ID NO:7 is annotated using the Kabat numbering system, amino acid position 55 of SEQ ID NO:7 is assigned the number 54. When N54T or N54S is referred to herein, it refers to a mutation using the Kabat numbering system.

[0092] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid substitution at position 64 relative to SEQ ID NO: 7. In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising a Met at a position corresponding to position 64 of SEQ ID NO: 7. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (for example, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a VL as set forth in SEQ ID NO:8.

[0093] In some embodiments, the anti-TfR antibody of the disclosure has a CDR-H1 represented as GYSITSGYX1 (SEQ ID NO: 286) (wherein X1 can be Y or G); a CDR-H2 represented as IX2FDGX3X4 (SEQ ID NO: 287) (wherein X2 can be T or N, X3 can be A or N, and X4 can be N, T, or S); and X5RX6X7YDYDX8X9DX 10(SEQ ID NO: 288) (wherein X5 is T or A, X6 is S, F, or I, X7 is S, N, or Y, X8 is P, Y, or V, X9 is I, F, or L, and X 10 is Y or F). Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a CDR-H3 represented as QDIX 11 NX 12 (SEQ ID NO: 289) (where X 11 is S or T, and X 12 CDR-L1 represented as YTS (SEQ ID NO: 13), and CDR-L2 represented as QQGX (wherein QQGX is F, C, S, or Y). 13 X 14 X 15 PX 16 T (SEQ ID NO: 290) (where X 13 is H or N, and X 14 is T or A, and X 15 is L or Y, and X 16 is Y, W, or F).

[0094] In some embodiments, an anti-TfR antibody of the disclosure comprises CDR-H1, CDR-H2, and CDR-H3 as listed in Table 11. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the disclosure comprises CDR-L1, CDR-L2, and CDR-L3 as listed in Table 11.

[0095] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 15. Alternatively or in addition (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 16.

[0096] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14.

[0097] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 9, CDR-H2 having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 12, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0098] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 9, CDR-H2 having the amino acid sequence of SEQ ID NO: 10, and CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 12, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0099] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 9; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 10; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 11. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 12; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0100] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 15. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 16.

[0101] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO: 15. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VL as set forth in SEQ ID NO: 16.

[0102] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 15. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 16.

[0103] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 24.

[0104] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22.

[0105] In some embodiments, an anti-TfR antibody of the present disclosure comprises the following: a CDR-H1 having the amino acid sequence of SEQ ID NO: 17 with an amino acid substitution at position 8 (e.g., wherein the cysteine ​​at position 8 is replaced with, e.g., any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Asn (N), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)); a CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (by way of example, additionally), an anti-TfR antibody of the present disclosure comprises the following: CDR-L1 having the amino acid sequence of SEQ ID NO: 20; CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and CDR-L3 having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the amino acid substitution at position 8 of CDR-H1 as represented by SEQ ID NO: 17 is C8D or C8Y.

[0106] In some embodiments, an anti-TfR antibody of the disclosure comprises the following: CDR-H1 having the amino acid sequence of SEQ ID NO: 237 or SEQ ID NO: 239; 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), an anti-TfR antibody of the disclosure comprises the following: CDR-L1 having the amino acid sequence of SEQ ID NO: 20; CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0107] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 237, or SEQ ID NO: 239, CDR-H2 having the amino acid sequence of SEQ ID NO: 18, and CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 20, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0108] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 237, or SEQ ID NO: 239, a CDR-H2 having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO:20, CDR-L2 having the amino acid sequence of SEQ ID NO:21, and CDR-L3 having the amino acid sequence of SEQ ID NO:22.

[0109] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 237, or SEQ ID NO: 239; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 18; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 19 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 20; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0110] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 23. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 24.

[0111] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:24.

[0112] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 24.

[0113] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH as set forth in SEQ ID NO: 23 with an amino acid substitution at position 33 (e.g., the cysteine ​​at position 33 is replaced with, for example, any one of Arg (R), Lys (K), Asp (D), Glu (E), Gln (Q), His (H), Ser (S), Thr (T), Tyr (Y), Asn (N), Trp (W), Met (M), Ala (A), Ile (I), Leu (L), Phe (F), Val (V), Pro (P), Gly (G)). Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL as set forth in SEQ ID NO: 24. In some embodiments, the amino acid substitution at position 33 of a VH as set forth in SEQ ID NO: 23 is C33D or C33Y. When VH as represented in SEQ ID NO:23 is annotated according to the Kabat numbering system, amino acid 33 of SEQ ID NO:23 is assigned the number 33.

[0114] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 31. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 32.

[0115] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 25, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 26, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 27, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 28, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 30.

[0116] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 25, CDR-H2 having the amino acid sequence of SEQ ID NO: 26, and CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 28, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0117] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 25, CDR-H2 having the amino acid sequence of SEQ ID NO: 26, and CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 28, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0118] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 25; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 26; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 27. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 28; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 30.

[0119] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 31. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 32.

[0120] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO: 31. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 32.

[0121] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 31. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 32.

[0122] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 39. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 40.

[0123] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 33, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 34, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 35, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 36, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 37, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 38.

[0124] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 33, CDR-H2 having the amino acid sequence of SEQ ID NO: 34, and CDR-H3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 36, CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0125] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 33, CDR-H2 having the amino acid sequence of SEQ ID NO: 34, and CDR-H3 having the amino acid sequence of SEQ ID NO: 35. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 36, CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0126] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 33; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 34; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 35 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 36; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 37; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 38.

[0127] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 39. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 40.

[0128] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:39. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:40.

[0129] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 39. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 40.

[0130] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 48.

[0131] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 41, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 42, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 43, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 44, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 46.

[0132] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 41, CDR-H2 having the amino acid sequence of SEQ ID NO: 42, and CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 44, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0133] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 41, CDR-H2 having the amino acid sequence of SEQ ID NO: 42, and CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 44, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0134] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 41; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 42; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 43. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 44; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 46.

[0135] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 47. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 48.

[0136] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:47. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:48.

[0137] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH as set forth in SEQ ID NO: 47. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as set forth in SEQ ID NO: 48.

[0138] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 54. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 55.

[0139] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 49, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 50, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 51, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 52, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 53.

[0140] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 49, CDR-H2 having the amino acid sequence of SEQ ID NO: 50, and CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 52, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0141] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 49, CDR-H2 having the amino acid sequence of SEQ ID NO: 50, and CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 52, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0142] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 49; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 50; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 51. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 52; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 53.

[0143] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 54. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 55.

[0144] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:54. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:55.

[0145] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 54. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 55.

[0146] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 62. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 63.

[0147] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 56, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 57, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 58, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 59, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 60, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 61.

[0148] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 56, CDR-H2 having the amino acid sequence of SEQ ID NO: 57, and CDR-H3 having the amino acid sequence of SEQ ID NO: 58. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 59, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0149] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 56, CDR-H2 having the amino acid sequence of SEQ ID NO: 57, and CDR-H3 having the amino acid sequence of SEQ ID NO: 58. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 59, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0150] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H1 having the amino acid sequence of SEQ ID NO: 56; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H2 having the amino acid sequence of SEQ ID NO: 57; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to the CDR-H3 having the amino acid sequence of SEQ ID NO: 58 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 59; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 61.

[0151] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 62. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 63.

[0152] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:62. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 63.

[0153] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 62. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 63.

[0154] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 70. Alternatively or in addition (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 71.

[0155] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 64, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 65, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 66, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 67, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 68, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 69.

[0156] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 64, CDR-H2 having the amino acid sequence of SEQ ID NO: 65, and CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 67, CDR-L2 having the amino acid sequence of SEQ ID NO: 68, and CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0157] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 64, CDR-H2 having the amino acid sequence of SEQ ID NO: 65, and CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 67, CDR-L2 having the amino acid sequence of SEQ ID NO: 68, and CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0158] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 64; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 65; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 66. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 67; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L2 having the amino acid sequence of SEQ ID NO: 68; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to CDR-L3 having the amino acid sequence of SEQ ID NO: 69.

[0159] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 70. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 71.

[0160] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO: 70. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 71.

[0161] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 70. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 71.

[0162] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 78.

[0163] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 73, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 76.

[0164] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 73, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0165] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 73, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which, collectively, are at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0166] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 72; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 73; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 76.

[0167] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 78.

[0168] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO: 77. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:78.

[0169] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 77. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 78.

[0170] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 85. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 86.

[0171] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 80, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 81, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 84.

[0172] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0173] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 80, and CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0174] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 80; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 81. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 82; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 84.

[0175] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 85. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 86.

[0176] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:85. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:86.

[0177] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 85. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 86.

[0178] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 89. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 90.

[0179] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 72, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 87, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 74, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 88.

[0180] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 87, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0181] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 72, CDR-H2 having the amino acid sequence of SEQ ID NO: 87, and CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0182] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 72; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 87; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 74. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 88.

[0183] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 89. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 90.

[0184] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in SEQ ID NO:89. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO:90.

[0185] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 89. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 90.

[0186] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 97. Alternatively or additionally (for example, additionally), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 98.

[0187] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 91, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 92, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 93, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 94, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 95, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 96.

[0188] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 91, CDR-H2 having the amino acid sequence of SEQ ID NO: 92, and CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 94, CDR-L2 having the amino acid sequence of SEQ ID NO: 95, and CDR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0189] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 91, CDR-H2 having the amino acid sequence of SEQ ID NO: 92, and CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 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.

[0190] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 91; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 92; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 93. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 94; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 95; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 96.

[0191] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 97. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 98.

[0192] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 97. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 98.

[0193] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 97. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 98.

[0194] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 104. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 105.

[0195] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 99, CDR-H2 having the amino acid sequence of SEQ ID NO: 100, and CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 102, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0196] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 99, CDR-H2 having the amino acid sequence of SEQ ID NO: 100, and CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 102, CDR-L2 having the amino acid sequence of SEQ ID NO: 60, and CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0197] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 99; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 100; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 101. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 102; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 60; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 103.

[0198] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 104. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 105.

[0199] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 104. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 105.

[0200] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 104. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 105.

[0201] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 112. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 113.

[0202] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 106, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 107, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 108, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 109, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 110, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 111.

[0203] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 106, CDR-H2 having the amino acid sequence of SEQ ID NO: 107, and CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 109, CDR-L2 having the amino acid sequence of SEQ ID NO: 110, and CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0204] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 106, a CDR-H2 having the amino acid sequence of SEQ ID NO: 107, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 109, a CDR-L2 having the amino acid sequence of SEQ ID NO: 110, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0205] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 106; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 107; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 108. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 109; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 110; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 111.

[0206] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 112. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 113.

[0207] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 112. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 113.

[0208] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 112. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 113.

[0209] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 117. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 118.

[0210] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 114, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 115, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 82, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 83, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 116.

[0211] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 114, and CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0212] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 114, and CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 82, CDR-L2 having the amino acid sequence of SEQ ID NO: 83, and CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0213] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 114; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 115. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 82; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 83; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 116.

[0214] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 117. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 118.

[0215] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 117. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 118.

[0216] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 117. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 118.

[0217] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 124. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 125.

[0218] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 119, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 120, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 121, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 122, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 123.

[0219] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 119, CDR-H2 having the amino acid sequence of SEQ ID NO: 120, and CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 122, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0220] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 119, CDR-H2 having the amino acid sequence of SEQ ID NO: 120, and CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 122, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0221] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 119; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 120; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 121. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 122; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 123.

[0222] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 124. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 125.

[0223] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 124. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 125.

[0224] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 124. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 125.

[0225] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 132. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 133.

[0226] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 126, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 127, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 128, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 129, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 130, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 131.

[0227] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 126, CDR-H2 having the amino acid sequence of SEQ ID NO: 127, and CDR-H3 having the amino acid sequence of SEQ ID NO: 128. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 129, CDR-L2 having the amino acid sequence of SEQ ID NO: 130, and CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0228] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 126, a CDR-H2 having the amino acid sequence of SEQ ID NO: 127, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 128. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 129, a CDR-L2 having the amino acid sequence of SEQ ID NO: 130, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0229] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 126; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 127; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 128 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 129; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 130; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 131.

[0230] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 132. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 133.

[0231] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 132. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 133.

[0232] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 132. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 133.

[0233] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 136. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 137.

[0234] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 79, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 134, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 75, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 45, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 135.

[0235] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0236] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 79, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, and CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 75, CDR-L2 having the amino acid sequence of SEQ ID NO: 45, and CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0237] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 79; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 2; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 134. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 75; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 45; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 135.

[0238] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 136. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 137.

[0239] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 136. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 137.

[0240] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 136. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 137.

[0241] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 143. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain having the amino acid sequence of SEQ ID NO: 144.

[0242] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 138, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 139, a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 140, a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 141, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 29, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 142.

[0243] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 138, CDR-H2 having the amino acid sequence of SEQ ID NO: 139, and CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 141, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0244] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 138, CDR-H2 having the amino acid sequence of SEQ ID NO: 139, and CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 141, CDR-L2 having the amino acid sequence of SEQ ID NO: 29, and CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0245] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 138; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 139; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 140. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 141; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 29; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 142.

[0246] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 143. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 144.

[0247] In some embodiments, an anti-TfR antibody of the disclosure comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH as set forth in SEQ ID NO: 143. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL as set forth in SEQ ID NO: 144.

[0248] In some embodiments, an anti-TfR antibody of the present disclosure comprises a VH comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in SEQ ID NO: 143. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises a VL comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in SEQ ID NO: 144.

[0249] The CDRs of an antibody may have different amino acid sequences when different definition systems are used (e.g., the IMGT definition, the Kabat definition, or the Chothia definition). A definition system annotates each amino acid in a given antibody sequence (e.g., a VH or VL sequence) with a number, and the numbers corresponding to the heavy and light chain CDRs are provided in Table 2. The CDRs listed in Table 1 are defined according to the IMGT definition. CDR sequences of example anti-TfR antibodies according to various definition systems are provided in Table 4. One skilled in the art can derive CDR sequences for the anti-TfR antibodies provided in Table 2 using various numbering systems. Table 2. CDR definition [Table 2] 1 IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999) 2 Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 3 Chothia et al., J. Mol. Biol. 196:901-917 (1987)) Table 3. CDR sequences of example anti-TfR1 antibodies according to various definition systems [Table 3-1] [Table 3-2]

[0250] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6.

[0251] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 145, CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236, and CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 148, CDR-L2 having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0252] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 147. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 148, CDR-L2 having the amino acid sequence of SEQ ID NO: 149, and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0253] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 145; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 147 (e.g., and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 148; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 149; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0254] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154.

[0255] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 150, CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278, and CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 153, CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0256] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0257] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 150; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 152. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 153; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 5; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 154.

[0258] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14.

[0259] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 155, CDR-H2 having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 158, CDR-L2 having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0260] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 155, CDR-H2 having the amino acid sequence of SEQ ID NO: 156, and CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 158, CDR-L2 having the amino acid sequence of SEQ ID NO: 159, and CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0261] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 155; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 156; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 157. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 158; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 159; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 14.

[0262] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164.

[0263] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 160, CDR-H2 having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 163, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0264] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 160, CDR-H2 having the amino acid sequence of SEQ ID NO: 161, and CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 163, CDR-L2 having the amino acid sequence of SEQ ID NO: 13, and CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0265] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 160; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 161; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 162. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 163; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 13; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 164.

[0266] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22.

[0267] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240, 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 additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 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.

[0268] In some embodiments, an anti-TfR antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240, a CDR-H2 having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 167. Alternatively or additionally (for example, in addition), an anti-TfR antibody of the present disclosure comprises a CDR-L1, CDR-L2, and CDR-L3 that are collectively at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a CDR-L1 having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0269] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 166; and / or a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 167 (for example, and). Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 168; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 169; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 22.

[0270] In some embodiments, an anti-TfR antibody of the disclosure comprises a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174.

[0271] In some embodiments, an anti-TfR antibody of the present disclosure comprises CDR-H1, CDR-H2, and CDR-H3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-H1 having the amino acid sequence of SEQ ID NO: 170, CDR-H2 having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure comprises CDR-L1, CDR-L2, and CDR-L3, which collectively contain no more than five amino acid variations (e.g., no more than five, four, three, two, or one amino acid variations) compared to CDR-L1 having the amino acid sequence of SEQ ID NO: 173, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0272] In some embodiments, anti-TfR antibodies of the present disclosure comprise CDR-H1, CDR-H2, and CDR-H3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-H1 having the amino acid sequence of SEQ ID NO: 170, CDR-H2 having the amino acid sequence of SEQ ID NO: 171, and CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or additionally (e.g., in addition), anti-TfR antibodies of the present disclosure comprise CDR-L1, CDR-L2, and CDR-L3, which are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to CDR-L1 having the amino acid sequence of SEQ ID NO: 173, CDR-L2 having the amino acid sequence of SEQ ID NO: 21, and CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0273] In some embodiments, an anti-TfR antibody of the present disclosure comprises: a CDR-H1 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H1 having the amino acid sequence of SEQ ID NO: 170; a CDR-H2 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H2 having the amino acid sequence of SEQ ID NO: 171; and / or (for example, and) a CDR-H3 having only three amino acid variations (e.g., only three, two, or one amino acid variations) compared to a CDR-H3 having the amino acid sequence of SEQ ID NO: 172. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure include: a CDR-L1 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L1 having the amino acid sequence of SEQ ID NO: 173; a CDR-L2 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L2 having the amino acid sequence of SEQ ID NO: 21; and / or (for example, and) a CDR-L3 having only three amino acid variations (for example, only three, two, or one amino acid variations) compared to a CDR-L3 having the amino acid sequence of SEQ ID NO: 174.

[0274] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody (e.g., a humanized variant containing one or more CDRs of Table 1 or Table 3). In some embodiments, an anti-TfR antibody of the disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that are the same as those shown in Table 1 or Table 3, and comprises a humanized heavy chain variable region and / or (by way of example) a humanized light chain variable region.

[0275] Humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (ER) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are found neither on the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. Generally, humanized antibodies will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are of human immunoglobulin consensus sequences. Optimally, humanized antibodies will also comprise at least some portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have an altered Fc region as described in WO99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) that are altered relative to the original antibody. These are also referred to as one or more CDRs derived from one or more CDRs from the original antibody. Humanized antibodies may also involve affinity maturation.

[0276] Humanized antibodies and methods for making them are known, see, e.g., Almagro et al., Front. Biosci. 13:1619-1633 (2008); Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005); Padlan et al., Mol. Immunol. 28:489-498 (1991); Dall'Acqua et al., Methods 36:43-60 (2005); Osbourn et al., Methods 36:61-68 (2005); and Klimka et al., Br. J. Cancer, 83:252-260 (2000), the contents of all of which are incorporated herein by reference. Human framework regions that can be used for humanization are described, for example, in Sims et al. J. Immunol. 151:2296 (1993); Carter et al. Proc. Natl. Acad. Sci. USA 89:4285 (1992); Presta et al. J. Immunol. 151:2623 (1993); Almagro et al., Front. Biosci. 13:1619-1633 (2008)); Baca et al., J. Biol. Chem. 272:10678-10684 (1997); and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996), the contents of all of which are incorporated herein by reference. In some embodiments, humanization is achieved by grafting CDRs (eg, as shown in Table 1 or Table 3) onto IGKV1-NL1*01 and IGHV1-3*01 human variable domains.

[0277] In some embodiments, the humanized VH or VL framework is a consensus human framework, which may represent the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.

[0278] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) are as follows:

[0279] a) VH FR1: EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 241);

[0280] b) VH FR2: WVRQAPGKGLEWV (SEQ ID NO: 242);

[0281] c) VH FR3: RFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 243); and

[0282] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 244) Includes.

[0283] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) are as follows:

[0284] a) VH FR1: QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 245);

[0285] b) VH FR2: WVRQAPGQGLEWM (SEQ ID NO: 246);

[0286] c) VH FR3:RVTITADTSTSTAYMELSSLRSEDTAVYYC (SEQ ID NO: 247); and

[0287] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 244) Includes.

[0288] In some embodiments, consensus human VH framework regions suitable for use in the heavy chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) are as follows:

[0289] a) VH FR1: QVQLQESGPGLVKPSQTLSLTCTVS (SEQ ID NO: 249);

[0290] b) VH FR2: WIRQPPGKGLEWI (SEQ ID NO: 250);

[0291] c) VH FR3: RVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO: 251); and

[0292] d) VH FR4: WGQGTLVTVSS (SEQ ID NO: 244) Includes.

[0293] In some embodiments, the consensus human VL framework region suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup I consensus) is as follows:

[0294] a) VL FR1:DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 253);

[0295] b) VL FR2: WYQQKPGKAPKLLIY (SEQ ID NO: 254);

[0296] c) VL FR3: GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 256); and

[0297] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 248) Includes.

[0298] In some embodiments, the consensus human VL framework region suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup II consensus) is as follows:

[0299] a) VL FR1: DIVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 257);

[0300] b) VL FR2: WYLQKPGQSPQLLIY (SEQ ID NO: 258);

[0301] c) VL FR3: GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC (SEQ ID NO: 259); and

[0302] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 248) Includes.

[0303] In some embodiments, the consensus human VL framework region suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup III consensus) is as follows:

[0304] a) VL FR1: DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 252);

[0305] b) VL FR2: WYQQKPGQPPKLLIY (SEQ ID NO: 255);

[0306] c) VL FR3: GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC (SEQ ID NO: 263); and

[0307] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 248) Includes.

[0308] In some embodiments, the consensus human VL framework region suitable for use in the light chain CDRs of the humanized anti-TfR antibodies described herein (subgroup IV consensus) is as follows:

[0309] a) VL FR1: DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 252);

[0310] b) VL FR2: WYQQKPGQPPKLLIY (SEQ ID NO: 255);

[0311] c) VL FR3: GVPDRFSGSGSGTDFTLTISSLQAEDFAVYYC (SEQ ID NO: 260); and

[0312] d) VL FR4: FGQGTKVEIK (SEQ ID NO: 248) Includes.

[0313] In some embodiments, the humanized anti-TfR antibodies of the present disclosure comprise humanized VH framework regions that contain a combined total of no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to any one of the consensus human VH framework region subgroups described herein. Alternatively or in addition (for example, in addition), the humanized anti-TfR antibodies of the present disclosure comprise humanized VL framework regions that contain a combined total of no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to any one of the consensus human VL framework region subgroups described herein.

[0314] In some embodiments, the humanized anti-TfR antibodies of the present disclosure comprise humanized VH framework regions that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of the consensus human VH framework region subgroups described herein. Alternatively or additionally (e.g., in addition), the humanized anti-TfR antibodies of the present disclosure comprise humanized VL framework regions that are collectively at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of the consensus human VL framework region subgroups described herein.

[0315] In some embodiments, the anti-TfR antibodies of the present disclosure are humanized variants and include one or more amino acid variations (e.g., in the VH framework regions) compared to any one of the VHs listed in Table 1 or Table 3 and / or (e.g., and) one or more amino acid variations (e.g., in the VL framework regions) compared to any one of the VLs listed in Table 1 or Table 3.

[0316] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VH of any of the anti-TfR antibodies listed in Table 2. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VL that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the VL of any one of the anti-TfR antibodies listed in Table 1.

[0317] In some embodiments, an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0318] In some embodiments, the anti-TfR antibodies of the present disclosure are humanized antibodies and comprise a VH that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure are humanized antibodies and comprise a VL that contains no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0319] In some embodiments, an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VH comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the present disclosure is a humanized antibody and comprises a VL comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0320] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody and comprises a VH having one or more (e.g., 10-25) amino acid variations at positions 1, 2, 5, 9, 11, 12, 13, 17, 20, 23, 33, 38, 40, 41, 42, 43, 44, 45, 48, 49, 55, 67, 68, 70, 71, 72, 76, 77, 80, 81, 82, 84, 87, 88, 91, 95, 112, or 115 relative to a VH as set forth in any one of SEQ ID NOs: 7, 15, and 23. Alternatively or additionally (for example, in addition), the anti-TfR antibodies of the present disclosure are humanized antibodies and include a VL having one or more (for example, 10-20) amino acid variations at positions 4, 7, 8, 9, 11, 15, 17, 18, 19, 22, 39, 41, 42, 43, 50, 62, 64, 72, 75, 77, 79, 80, 81, 82, 83, 85, 87, 89, 100, 104, or 109 compared to a VL as set forth in any one of SEQ ID NOs: 8, 16, and 24.

[0321] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 233, or SEQ ID NO: 80, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0322] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 1, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 233, or SEQ ID NO: 80, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 3, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 4, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 6, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VL as set forth in SEQ ID NO: 8.

[0323] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0324] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 145, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 146, SEQ ID NO: 234, or SEQ ID NO: 236, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 147, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 148, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 149, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 6, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 8.

[0325] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 8.

[0326] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 150, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 151, SEQ ID NO: 277, or SEQ ID NO: 278, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 152, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 7. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 153, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 154, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 8.

[0327] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0328] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 9, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 10, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 11, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 12, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 14, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VL as set forth in SEQ ID NO: 16.

[0329] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0330] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 155, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 156, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 157, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 158, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 159, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 14, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 16.

[0331] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 16.

[0332] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 160, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 161, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 162, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 15. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 163, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 13, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 164, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 16.

[0333] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 237, or SEQ ID NO: 239, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0334] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 237, or SEQ ID NO: 239, a CDR-H2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 19, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 20, a CDR-L2 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the IMGT definition system) having the amino acid sequence of SEQ ID NO: 22, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0335] In some embodiments, the anti-TfR antibodies of the present disclosure comprise a humanized VH, comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0336] In some embodiments, an anti-TfR antibody of the present disclosure comprises a humanized VH comprising a CDR-H1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 165, SEQ ID NO: 238, or SEQ ID NO: 240, a CDR-H2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 166, and a CDR-H3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 167, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 168, a CDR-L2 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 169, and a CDR-L3 (according to the Kabat definition system) having the amino acid sequence of SEQ ID NO: 22, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0337] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH, comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, and containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibodies of the present disclosure comprise a humanized VL, comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174, and containing no more than 25 amino acid variations (for example, no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) in the framework regions compared to the VL as set forth in SEQ ID NO: 24.

[0338] In some embodiments, an anti-TfR antibody of the disclosure comprises a humanized VH comprising a CDR-H1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 170, a CDR-H2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 171, and a CDR-H3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 172, which is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to a VH as set forth in SEQ ID NO: 23. Alternatively or in addition (for example, in addition), the anti-TfR antibody of the present disclosure comprises a humanized VL comprising a CDR-L1 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 173, a CDR-L2 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 (according to the Chothia definition system) having the amino acid sequence of SEQ ID NO: 174, which is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical in the framework regions to the VL as set forth in SEQ ID NO: 24.

[0339] In some embodiments, the anti-TfR antibodies of the present disclosure are chimeric antibodies, which may include heavy and light chain constant regions from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of antibodies from one mammalian species (e.g., non-human mammals, such as mice, rabbits, and rats), while the constant portions are homologous to the sequences of antibodies from another mammal, such as humans. In some embodiments, amino acid modifications can be made to the variable region and / or (for example, and) the constant region.

[0340] In some embodiments, the anti-TfR antibodies described herein are chimeric antibodies, which may include heavy and light chain constant regions from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically, in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of an antibody from one mammalian species (e.g., a non-human mammal, such as a mouse, rabbit, or rat), and the constant portions are homologous to the sequences of an antibody from another mammal, such as a human. In some embodiments, amino acid modifications can be made to the variable region and / or (for example, and) the constant region.

[0341] In some embodiments, the heavy chain of any of the anti-TfR antibodies described herein can comprise a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, such as human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (gamma heavy chain), such as IgG1, IgG2, or IgG4. An example of a human IgG1 constant region is provided below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 175)

[0342] In some embodiments, the heavy chain of any of the anti-TfR antibodies described herein comprises a mutant human IgG1 constant region. For example, the introduction of the LALA mutation on the CH2 domain of human IgG1 (a mutant derived from mAb b12 in which the lower hinge residues Leu234 and Leu235 are mutated to replace Ala234 and Ala235) is known to reduce Fcg receptor binding (Bruhns, P., et al. (2009) and Xu, D. et al. (2000)). The mutant human IgG1 constant region is provided below (mutations are bold and underlined):

[0343] [ka] (SEQ ID NO: 176)

[0344] In some embodiments, the light chain of any of the anti-TfR antibodies described herein may further comprise a light chain constant region (CL), which may be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 177)

[0345] 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.

[0346] In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising a VH listed in Table 1 or any one of its variants, and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 175 or SEQ ID NO: 176. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising a VH listed in Table 1 or any one of its variants, and a heavy chain constant region that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to SEQ ID NO: 175 or SEQ ID NO: 176. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 1 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 175. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 1 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 176.

[0347] In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 1 or any variant thereof, and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 177. In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 1 or any variant thereof, and a light chain constant region that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to SEQ ID NO: 177. In some embodiments, the anti-TfR antibodies described herein comprise a light chain comprising any one of a VL listed in Table 1 or any variant thereof, and a light chain constant region as set forth in SEQ ID NO: 177.

[0348] 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] [Table 4-3] *VH / VL sequences are underlined

[0349] In some embodiments, an anti-TfR antibody of the present disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as set forth in any one of SEQ ID NOs: 178, 180, 182, and 269-272. Alternatively or additionally (e.g., additionally), anti-TfR antibodies of the present disclosure comprise a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in any one of SEQ ID NOs: 179, 181, and 183. In some embodiments, anti-TfR antibodies described herein comprise a heavy chain that comprises an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 178, 180, 182, and 269-272. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 179, 181, and 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 178, 180, 182, and 269-272. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 179, 181, and 183.

[0350] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as set forth in SEQ ID NO: 178, SEQ ID NO: 269, or SEQ ID NO: 270. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 178, SEQ ID NO: 269, or SEQ ID NO: 270. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 178, SEQ ID NO: 269, or SEQ ID NO: 270. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179.

[0351] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the heavy chain as set forth in SEQ ID NO: 180. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the light chain as set forth in SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 180. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 180. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 181.

[0352] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as represented by SEQ ID NO: 182, SEQ ID NO: 271, or SEQ ID NO: 272. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as represented by SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 182, SEQ ID NO: 271, or SEQ ID NO: 272. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 182, SEQ ID NO: 271, or SEQ ID NO: 272. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 183.

[0353] In some embodiments, the anti-TfR antibody is a FAB fragment, F(ab') fragment, or F(ab')2 fragment of an intact antibody (full-length antibody). Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared via conventional methods (e.g., recombinantly or by digesting the heavy chain constant region of a full-length IgG using an enzyme such as papain). For example, F(ab')2 fragments can be generated by pepsin or papain digestion of an antibody molecule, and Fab fragments can be produced by reducing the disulfide bridges of an F(ab')2 fragment. In some embodiments, the heavy chain constant region on the F(ab')2 fragment of an anti-TfR1 antibody described herein is as follows: It contains the amino acid sequence of ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 184).

[0354] In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 1 or any variant thereof, and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 184. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 1 or any variant thereof, and a heavy chain constant region that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to SEQ ID NO: 184. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising any one of a VH listed in Table 1 or any variant thereof, and a heavy chain constant region as set forth in SEQ ID NO: 184.

[0355] Exemplary F(ab') amino acid sequences of the anti-TfR antibodies described herein are provided in Table 5. Table 5. Heavy and light chain sequences of example anti-TfR F(ab')s [Table 5-1] [Table 5-2] *VH / VL sequences are underlined

[0356] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as set forth in any one of SEQ ID NOs: 185, 186, 187, and 273-276. Alternatively or additionally (e.g., additionally), anti-TfR antibodies of the present disclosure comprise a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in any one of SEQ ID NOs: 179, 181, and 183. In some embodiments, anti-TfR antibodies described herein comprise a heavy chain that comprises an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 185, 186, 187, and 273-276. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence that is at least 75% (for example, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 179, 181, and 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 185, 186, 187, and 273-276. Alternatively or additionally (for example, in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 179, 181, and 183.

[0357] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as set forth in SEQ ID NO: 185, SEQ ID NO: 273, or SEQ ID NO: 274. Alternatively or additionally (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 185, SEQ ID NO: 273, or SEQ ID NO: 274. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 179. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 185, SEQ ID NO: 273, or SEQ ID NO: 274. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 179.

[0358] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to the heavy chain as set forth in SEQ ID NO: 186. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 11, 9, 8, 7, 6, or no more than 5, 4, 3, 2, or 1 amino acid variations) compared to the light chain as set forth in SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 186. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 181. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 186. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 181.

[0359] In some embodiments, an anti-TfR antibody of the disclosure comprises a heavy chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a heavy chain as set forth in SEQ ID NO: 187, SEQ ID NO: 275, or SEQ ID NO: 276. Alternatively or in addition (e.g., in addition), an anti-TfR antibody of the disclosure comprises a light chain that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variations) compared to a light chain as set forth in SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 187, SEQ ID NO: 275, or SEQ ID NO: 276. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising an amino acid sequence at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to SEQ ID NO: 183. In some embodiments, the anti-TfR antibodies described herein comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 187, SEQ ID NO: 275, or SEQ ID NO: 276. Alternatively or additionally (e.g., in addition), the anti-TfR antibodies described herein comprise a light chain comprising the amino acid sequence of SEQ ID NO: 183.

[0360] The anti-TfR receptor antibodies described herein can be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (e.g., Fab, F(ab'), F(ab')2, Fv), single-chain antibodies, bispecific antibodies, or nanobodies. In some embodiments, the anti-TfR antibodies described herein are scFvs. In some embodiments, the anti-TfR antibodies described herein are scFv-Fabs (e.g., scFvs fused to a portion of a constant region). In some embodiments, the anti-TfR receptor antibodies described herein are scFvs fused at either the N- or C-terminus to a constant region (e.g., a human IgG1 constant region, or a portion thereof, e.g., an Fc portion, as set forth in SEQ ID NO: 175 or SEQ ID NO: 176).

[0361] In some embodiments, conservative mutations may be introduced into an antibody sequence (e.g., a CDR or framework sequence) at a position where the residue is unlikely to be involved in interactions with the target antigen (e.g., transferrin receptor) as determined, e.g., based on a crystal structure. In some embodiments, one or more mutations (e.g., amino acid substitutions) are introduced into the Fc region (e.g., in the CH2 domain (residues 231-340 of human IgG1), and / or (e.g., in the CH3 domain (residues 341-447 of human IgG1), and / or (e.g., in the hinge region), numbered according to the Kabat numbering system (e.g., EU index of Kabat)) of an anti-TfR antibody described herein to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or (e.g., and) antigen-dependent cellular cytotoxicity.

[0362] In some embodiments, one or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) such that the number of cysteine ​​residues in the hinge region can be varied (e.g., increased or decreased), e.g., as described in U.S. Patent No. 5,677,425. The number of cysteine ​​residues in the hinge region of the CH1 domain can be altered, e.g., to facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody, or to facilitate linker conjugation.

[0363] In some embodiments, one or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a muscle-targeting antibody described herein (e.g., in the CH2 domain (residues 231-340 of human IgG1), and / or (e.g., and) in the CH3 domain (residues 341-447 of human IgG1), and / or (e.g., and) in the hinge region, numbered according to the Kabat numbering system (e.g., EU index of Kabat)) to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that increase or decrease the affinity of the antibody for an Fc receptor, and techniques for introducing such mutations into an Fc receptor or fragment thereof, are known to those of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody to the Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109:6181-6186, U.S. Patent No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0364] In some embodiments, one or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into an IgG constant region or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., increase or decrease) the half-life of the antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745, for mutations that may alter (e.g., increase or decrease) the half-life of an antibody in vivo.

[0365] In some embodiments, one or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant region or FcRn-binding fragment thereof (preferably, the Fc or hinge-Fc domain fragment) to decrease the half-life of the anti-TfR antibody in vivo. In some embodiments, one or more amino acid mutations (i.e., substitutions, insertions, or deletions) are introduced into the IgG constant region or FcRn-binding fragment thereof (preferably, the Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibody may have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or (for example, and) in the third constant (CH3) domain (residues 341-447 of human IgG1) numbered according to the EU index of Kabat (Kabat EA et al. (1991) supra). In some embodiments, the IgG1 constant region of the antibodies described herein comprises a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamic acid (E) substitution at position 256, numbered according to the EU index as in Kabat. See U.S. Patent No. 7,658,921, which is incorporated herein by reference. Mutant IgGs of this type, termed "YTE mutants," have been shown to exhibit a four-fold increased half-life compared to the wild-type version of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281:23514-24). In some embodiments, the antibody comprises an IgG constant region comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat.

[0366] In some embodiments, one or more amino acid substitutions are introduced into the IgG constant region Fc region to alter the effector function(s) of the anti-TfR antibody. The effector ligand with altered affinity can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In some embodiments, deletion or inactivation of the constant region domain (through point mutation or other means) can reduce binding of circulating antibodies to Fc receptors, thereby increasing tumor localization. See, e.g., U.S. Patent Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate constant regions, thereby increasing tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites in the Fc region, which may reduce binding to Fc receptors (see, e.g., Shields RL et al., (2001) J Biol Chem 276:6591-604).

[0367] In some embodiments, one or more amino acid residues in the constant region of an anti-TfR antibody described herein can be replaced with a different amino acid residue so that the antibody can have altered Clq binding and / or (for example, and) reduced or eliminated complement-dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 (Idusogie et al.). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the antibody's ability to fix complement. This approach is further described in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the antibody's ability to mediate antibody-dependent cellular cytotoxicity (ADCC) to cells and / or (for example, and) increase the antibody's affinity for Fcγ receptors. This approach is further described in International Publication No. WO 00 / 42072.

[0368] In some embodiments, the heavy and / or (by way of example) light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or composite human antibodies, or antigen-binding fragments, as described elsewhere herein. As will be understood by one of skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibody derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will retain the ability to specifically bind to the transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody may have at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to the transferrin receptor compared to the original antibody from which it was derived.

[0369] In some embodiments, the antibodies provided herein contain mutations that confer desired properties to the antibody. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur in native IgG4 mAbs, the antibodies provided herein may contain the stabilizing "Adair" mutation (Angal S., et al., "A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody", Mol Immunol 30, 105-108; 1993), in which serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline, resulting in an IgG1-like hinge sequence. Consequently, any of the antibodies may include the stabilizing "Adair" mutation.

[0370] In some embodiments, the antibody is modified (e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation). In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules include a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules present. In some embodiments, the glycosylated antibody is fully or partially glycosylated. In some embodiments, the antibody is glycosylated by chemical reaction or by enzymatic means. In some embodiments, the antibody is glycosylated in vitro or inside a cell (optionally deficient in an enzyme (e.g., glycosyltransferase) in the N- or O-glycosylation pathway). In some embodiments, the antibody is functionalized with a sugar or carbohydrate molecule as described in International Patent Application Publication WO2014065661, published May 1, 2014, entitled "Modified antibody, antibody-conjugate and process for the preparation thereof."

[0371] In some embodiments, any one of the anti-TfR1 antibodies described herein can include a signal peptide (e.g., an N-terminal signal peptide) on the heavy and / or (e.g., and) light chain sequence. In some embodiments, the anti-TfR1 antibodies described herein include any one of the VH and VL sequences, any one of the IgG heavy and light chain sequences, or any one of the F(ab') heavy and light chain sequences described herein, and further include a signal peptide (e.g., an N-terminal signal peptide). In some embodiments, the signal peptide includes the amino acid sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 232).

[0372] In some embodiments, an anti-TfR antibody of the disclosure is a humanized antibody and comprises human framework regions with the CDRs of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12). In some embodiments, an anti-TfR antibody of the disclosure is an IgG1 kappa that comprises human framework regions with the CDRs of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12). In some embodiments, an anti-TfR antibody of the disclosure is an IgG1 kappa Fab' fragment that comprises human framework regions with the CDRs of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12).

[0373] In some embodiments, the antibodies provided herein may have one or more post-translational modifications. In some embodiments, N-terminal cyclization, also referred to as pyroglutamic acid formation (pyroGlu), may occur in antibodies at N-terminal glutamic acid (Glu) and / or glutamine (Gln) residues during production. In some embodiments, pyroglutamic acid formation occurs in heavy chain sequences. In some embodiments, pyroglutamic acid formation occurs in light chain sequences.

[0374] III. Preparation of anti-TfR antibodies Antibodies capable of binding to TfR as described herein can be made by any method known in the art, see, e.g., Harlow and Lane, (1998) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.

[0375] In some embodiments, antibodies specific to a target antigen (e.g., TfR) can be produced by conventional hybridoma technology. A full-length target antigen or a fragment thereof, optionally coupled to a carrier protein such as KLH, can be used to immunize a host animal to generate antibodies that bind to the antigen. The route and schedule for immunizing a host animal generally follow established and conventional techniques for antibody stimulation and production, as further described herein. Production techniques for producing murine, humanized, and human antibodies are known in the art and are described herein. It is contemplated that any mammalian subject, including humans or antibody-producing cells derived from humans, can be engineered to serve as a base for the production of mammals, including human hybridoma cell lines. Typically, a host animal is inoculated intraperitoneally, intramuscularly, orally, subcutaneously, intraplantarly, and / or (for example, and) intradermally with an amount of immunogen (including those described herein).

[0376] If desired, the antibody (monoclonal or polyclonal) of interest (e.g., produced by a hybridoma) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained in the vector in a host cell, which may then be expanded and frozen for future use. Alternatively, the polynucleotide sequence may be used for genetic engineering to "humanize" the antibody or improve its affinity (affinity maturation) or other characteristics. For example, the constant region may be modified to more resemble a human constant region so as to avoid an immune response when the antibody is used in human clinical trials and treatments. It may also be desirable to genetically engineer an antibody sequence to obtain greater affinity for the target antigen and greater efficacy. It will be apparent to those skilled in the art that one or more polynucleotide changes can be made to an antibody and still maintain its binding specificity for the target antigen.

[0377] In other embodiments, fully human antibodies can be obtained by using commercially available mice that have been modified to express specific human immunoglobulin proteins. Transgenic animals designed to generate a more desirable (e.g., fully human) or more robust immune response may also be used to generate humanized or human antibodies. Examples of such technology are the Xenomouse® from Amgen, Inc. (Fremont, CA), and the HuMAb-Mouse® and TC Mouse® from Medarex, Inc. (Princeton, NJ), or the H2L2 mouse from Harbour Antibodies BV (Holland). In another alternative, antibodies may be produced recombinantly by phage display or yeast technology. See, e.g., U.S. Patent Nos. 5,565,332; 5,580,717; 5,733,743; and 6,265,150; and Winter et al., (1994) Annu. Rev. Immunol. 12:433-455. Alternatively, phage display technology (McCafferty et al., (1990) Nature 348:552-553) can be used to produce human antibodies and antibody fragments in vitro from immunoglobulin variable (V) domain gene repertoires from unimmunized donors.

[0378] Antigen-binding fragments of intact antibodies (full-length antibodies) can be prepared via conventional methods. For example, F(ab')2 fragments can be produced by pepsin digestion of antibody molecules, and Fab fragments can be generated by reducing the disulfide bridges of F(ab')2 fragments. Genetically modified antibodies, such as humanized antibodies, chimeric antibodies, single-chain antibodies, and bispecific antibodies, can be produced, for example, via conventional recombinant techniques. In one example, DNA encoding a monoclonal antibody specific for a target antigen can be readily isolated and sequenced using conventional procedures (for example, by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the monoclonal antibody). Hybridoma cells serve as a preferred source of such DNA. Once isolated, the DNA is placed into one or more expression vectors, which are then transfected into host cells such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells, human HEK293 cells, or myeloma cells (which do not otherwise produce immunoglobulin proteins), resulting in the synthesis of monoclonal antibodies in the recombinant host cells. See, e.g., PCT Publication No. WO 87 / 04462. The DNA can then be modified, for example, by substituting sequences encoding human heavy and light chain constant regions for the homologous murine sequences (Morrison et al., (1984) Proc. Nat. Acad. Sci. 81:6851), or by covalently linking all or part of a sequence encoding a non-immunoglobulin polypeptide to the immunoglobulin-encoding sequence. In this manner, genetically engineered antibodies, such as "chimeric" or "hybrid" antibodies, with the binding specificity of a target antigen can be prepared.

[0379] Single-chain antibodies can be prepared via recombinant techniques by linking a nucleotide sequence encoding a heavy chain variable region and a nucleotide sequence encoding a light chain variable region, preferably incorporating a flexible linker between the two variable regions.

[0380] Alternatively, techniques described for the production of single-chain antibodies (U.S. Pat. Nos. 4,946,778 and 4,704,692) can be adapted to generate phage or yeast scFv libraries, and TfR-specific scFv clones can be identified from the libraries following routine procedures. Positive clones can be subjected to further screening to identify those with high TfR-binding affinity.

[0381] The antibodies obtained according to the methods known in the art and the methods described herein can be characterized using methods well known in the art. For example, one method is to identify the epitope to which an antigen binds, or "epitope mapping." Many methods for mapping and characterizing the location of an epitope on a protein are known in the art, including, for example, solving the crystal structure of an antibody-antigen complex, competitive assays, gene fragment expression assays, and synthetic peptide-based assays, as described in Chapter 11 of Harlow and Lane, "Using Antibodies," a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999. In one example, epitope mapping can be achieved using H / D-Ex (hydrogen-deuterium exchange) coupled with proteolysis and mass spectrometry. In another example, epitope mapping can be used to determine the sequence to which an antibody binds. Epitopes can be linear epitopes, i.e., those contained in a single stretch of amino acids, or conformational epitopes formed by 3-dimensional interactions of amino acids that are not necessarily contained in a single stretch (linear sequence of primary structure). Peptides of varying lengths (e.g., at least 4-6 amino acids long) can be isolated or synthesized (e.g., recombinantly) and used in antibody binding assays. In another example, the epitope to which an antibody binds can be determined in a systematic screen by using overlapping peptides derived from the target antigen sequence and determining binding by the antibody. According to gene fragment expression assays, the open reading frame encoding the target antigen is fragmented, either randomly or by specific gene construction, and the reactivity of the expressed fragments of the antigen with the antibody being tested is determined. Gene fragments can be produced, for example, by PCR, and then transcribed and translated into protein in vitro in the presence of radioactive amino acids.The binding of the antibody to the radiolabeled antigen fragment is then determined by immunoprecipitation and gel electrophoresis. An epitope can also be identified by using a large library of random peptide sequences (phage libraries) displayed on the surface of phage particles. Alternatively, a defined library of overlapping peptide fragments can be tested for binding to the test antibody in a simple binding assay. In additional examples, mutagenesis of the antigen-binding domain, domain swapping experiments, and alanine scanning mutagenesis can also be performed to identify residues required, sufficient, and / or (for example, and necessary) for epitope binding. Alternatively, a competition assay can be performed using other antibodies known to bind to the same antigen to determine whether the antibody binds to the same epitope as the other antibodies. Competition assays are well known to those skilled in the art.

[0382] In some examples, anti-TfR antibodies are prepared by recombinant techniques as exemplified below. Nucleic acids encoding the heavy and light chains of an anti-TfR antibody as described herein can be cloned into an expression vector, with each nucleotide sequence operably linked to a suitable promoter. In one example, the nucleotide sequences encoding the heavy and light chains are each operably linked to a separate promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains can be operably linked to a single promoter so that both the heavy and light chains are expressed from the same promoter. If necessary, an internal ribosome entry site (IRES) can be inserted between the sequence encoding the heavy chain and the sequence encoding the light chain.

[0383] In some instances, the nucleotide sequences encoding the two chains of an antibody are cloned into two vectors, which can be introduced into the same cell or different cells. When the two chains are expressed in different cells, each can be isolated from the host cell expressing that chain, and the isolated heavy and light chains can be mixed and incubated under suitable conditions to allow antibody formation.

[0384] Generally, a nucleic acid sequence encoding one or all chains of an antibody can be cloned into a suitable expression vector, operably linked to a suitable promoter, using methods known in the art. For example, the nucleotide sequence and the vector can be contacted with a restriction enzyme under suitable conditions to create complementary ends on each molecule, which can then pair and be ligated together with a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the ends of the gene. These synthetic linkers contain nucleic acid sequences that correspond to specific restriction sites in the vector. The choice of expression vector / promoter will depend on the type of host cell to be used in producing the antibody.

[0385] A wide variety of promoters can be used to express the antibodies described herein, including, but not limited to, the cytomegalovirus (CMV) immediate early promoter, the Rous sarcoma virus LTR, the HIV-LTR, the LTR of viruses such as HTLV-1 LTR, the Simian Virus 40 (SV40) early promoter, the E. coli lac UV promoter, and the herpes simplex tk virus promoter.

[0386] Regulatable promoters can also be used, including those that use the lac repressor from E. coli as a transcriptional modulator to regulate transcription from mammalian cell promoters carrying the lac operator [Brown, M. et al., Cell, 49:603-612 (1987)] and those that use the tetracycline repressor (tetR) [Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-555115 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P., et al., Proc. Natl. Acad. Sci. USA 92:6522-6526 (1995)]. Other systems include FK506 dimers, VP16 or p65 using astradiol, RU486, diphenol murislerone, or rapamycin. Inducible systems are available from Invitrogen, Clontech, and Ariad, among others.

[0387] Regulatable promoters containing a repressor along with an operon can be used. In one embodiment, the lac repressor from E. coli can function as a transcriptional modulator to regulate transcription from a mammalian cell promoter carrying a lac operator [M. Brown et al., Cell, 49:603-612 (1987)]; Gossen and Bujard (1992); [M. Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992)]. The tetracycline repressor (tetR) is combined with a transcriptional activator (VP16) to create a tetR-mammalian cell transcriptional activator fusion protein, tTa (tetR-VP16), which is combined with a tetO-carrying minimal promoter derived from the human cytomegalovirus (hCMV) promoter to create a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline-inducible switch is used. When the tetracycline operator is properly positioned downstream of the TATA element of the CMVIE promoter, the tetracycline repressor (tetR) alone can regulate gene expression in mammalian cells by functioning as a potent trans-modulator, rather than a tetR-mammalian cell transcription factor fusion derivative (Yao et al., Human Gene Therapy). One particular advantage of this tetracycline-inducible switch is that it does not require the use of tetracycline repressor-mammalian cell transactivator or repressor fusion proteins, which may be toxic to cells in some cases, to achieve its regulatable effect (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)).

[0388] In addition, the vector may contain, for example, some or all of the following: a selectable marker gene, such as the neomycin gene, for the selection of stable or transient transfectants in mammalian cells; an enhancer / promoter sequence from the immediate early gene of human CMV for high-level transcription; a transcription termination and RNA processing signal from SV40 for mRNA stability; an SV40 polyoma replication origin and ColE1 for correct episomal replication; internal ribosome binding sites (IRESes), a versatile multiple cloning site; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Methods for producing suitable vectors and vectors containing transgenes are well known and available in the art. Examples of polyadenylation signals useful for practicing the methods described herein include, but are not limited to, the human collagen I polyadenylation signal, the human collagen II polyadenylation signal, and the SV40 polyadenylation signal.

[0389] One or more vectors (e.g., expression vectors) containing nucleic acids encoding any of the antibodies may be introduced into host cells suitable for producing the antibodies. The host cells may be cultured under conditions suitable for expression of the antibody or any of its polypeptide chains. Such antibodies or their polypeptide chains may be recovered by the cultured cells (e.g., from the cells or culture supernatant) via conventional methods (e.g., affinity purification). If necessary, the antibody polypeptide chains may be cultured under suitable conditions for a suitable period of time to allow production of the antibody.

[0390] In some embodiments, methods for preparing antibodies described herein involve a recombinant expression vector encoding both the heavy and light chains of an anti-TfR antibody, as also described herein. The recombinant expression vector can be introduced into suitable host cells (e.g., dhfr-CHO cells) by conventional methods, e.g., calcium phosphate-mediated transfection. Positively transformed host cells can be selected and cultured under conditions suitable to allow expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or from the culture medium. If necessary, the two chains recovered from the host cells can be incubated under conditions suitable to allow antibody formation. In some embodiments, the host cells used to express the anti-TfR antibodies described herein are CHO-S cells (e.g., ThermoFisher Catalog # R80007).

[0391] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of an anti-TfR antibody and the other encoding the light chain of an anti-TfR antibody, and both recombinant expression vectors can be introduced into suitable host cells (e.g., dhfr-CHO cells) by conventional methods, e.g., calcium phosphate-mediated transfection.

[0392] Alternatively, each expression vector can be introduced into a suitable host cell. Positive transformants can be selected and cultured under conditions suitable for allowing the expression of the antibody polypeptide chains. When two expression vectors are introduced into the same host cell, the antibody produced therein can be recovered from the host cell or from the culture medium. If necessary, the polypeptide chains can be recovered from the host cell or from the culture medium and then incubated under conditions suitable for allowing antibody formation. When two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cell or from the corresponding culture medium. The two polypeptide chains can then be incubated under conditions suitable for antibody formation.

[0393] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells, and recover the antibody from the culture medium. For example, some antibodies can be isolated by affinity chromatography on a matrix coupled with Protein A or Protein G.

[0394] Nucleic acids encoding the heavy chain, light chain, or both, of anti-TfR antibodies as described herein (e.g., as provided in Table 6), vectors containing them (e.g., expression vectors); and host cells containing the vectors are all within the scope of the present disclosure. Table 6. Nucleic acid sequences encoding the VH / VL of the anti-TfR antibodies listed in Table 1 [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0395] In some embodiments, the anti-TfR antibody is a humanized antibody comprising a VH containing human framework regions with CDR-H1, CDR-H2, and CDR-H3 of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12), and a VL containing human framework regions with CDR-L1, CDR-L2, and CDR-L3 of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12), wherein the antibody is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture, optionally in CHO-K1 cell (e.g., CHO-K1 cell Cat. No. 85051005 from the European Collection of Animal Cell Culture) suspension culture.

[0396] In some embodiments, the anti-TfR antibody is an IgG1 kappa comprising human framework regions with the CDRs of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12), wherein the antibody is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture, optionally in CHO-K1 cell (e.g., CHO-K1 cell Cat. No. 85051005 from the European Collection of Animal Cell Culture) suspension culture.

[0397] In some embodiments, the anti-TfR antibody is a Fab' fragment of IgG1 kappa comprising human framework regions with the CDRs of a murine antibody listed in Table 1 or Table 3 (e.g., 3A4, 3M12, or 5H12), wherein the antibody is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture, optionally in CHO-K1 cell (e.g., CHO-K1 cell Cat. No. 85051005 from the European Collection of Animal Cell Culture) suspension culture.

[0398] IV. Complex In some embodiments, the anti-TfR antibodies described herein can be used to deliver a molecular payload to a target cell or tissue (e.g., a cell or tissue that expresses TfR). Accordingly, some aspects of the present disclosure provide conjugates comprising any one of the anti-TfR antibodies described herein (e.g., 3-A4, 3-M12, or 5-H12 in IgG or FAB form as provided in Tables 4 and 5, and variants thereof (e.g., humanized variants)) for a molecular payload. The conjugates described herein may be used in a variety of applications, e.g., diagnostic or therapeutic applications.

[0399] In some embodiments, the complex comprises an anti-TfR antibody covalently linked to an oligonucleotide (e.g., an antisense oligonucleotide). In some embodiments, the complexes described herein may be used to modulate the activity or function of at least one gene, protein, and / or (e.g., and) nucleic acid. In some embodiments, the molecular payload present with the complex is responsible for modulating the gene, protein, and / or (e.g., and) nucleic acid. The molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity capable of modulating the activity or function of a gene, protein, and / or (e.g., and) nucleic acid in a cell. In some embodiments, the molecular payload is an oligonucleotide that targets disease-associated repeats in muscle cells.

[0400] A. Molecular Payload Some aspects of the present disclosure provide molecular payloads that can be linked to any one of the anti-TfR antibodies described herein, e.g., for modulating a biological outcome (e.g., transcription of a DNA sequence, expression of a protein, or activity of a protein). In some embodiments, such molecular payloads are capable of targeting muscle cells, e.g., via specific binding to a nucleic acid or protein in muscle cells delivered to the muscle cells by the linked anti-TfR antibody. It should be understood that various types of molecular payloads may be used in accordance with the present disclosure. For example, a molecular payload may comprise or consist of an oligonucleotide (e.g., an antisense oligonucleotide), a peptide (e.g., a peptide that binds to a nucleic acid or protein in a muscle cell associated with a disease), a protein (e.g., a protein that binds to a nucleic acid or protein in a muscle cell associated with a disease), or a small molecule (e.g., a small molecule that modulates the function of a nucleic acid or protein in a muscle cell associated wit...

Claims

1. An antibody that binds to the human transferrin receptor (TfR), (i) heavy chain complementarity determining region 1 (CDR-H1) as set forth in SEQ ID NO: 155, heavy chain complementarity determining region 2 (CDR-H2) as set forth in SEQ ID NO: 156, heavy chain complementarity determining region 3 (CDR-H3) as set forth in SEQ ID NO: 157; and light chain complementarity determining region 1 (CDR-L1) as set forth in SEQ ID NO: 158, light chain complementarity determining region 2 (CDR-L2) as set forth in SEQ ID NO: 159, and light chain complementarity determining region 3 (CDR-L3) as set forth in SEQ ID NO: 14; (ii) CDR-H1 as set forth in SEQ ID NO:9, CDR-H2 as set forth in SEQ ID NO:10, CDR-H3 as set forth in SEQ ID NO:11; and CDR-L1 as set forth in SEQ ID NO:12, CDR-L2 as set forth in SEQ ID NO:13, and CDR-L3 as set forth in SEQ ID NO:14; or (iii) CDR-H1 as set forth in SEQ ID NO: 160, CDR-H2 as set forth in SEQ ID NO: 161, CDR-H3 as set forth in SEQ ID NO: 162; and CDR-L1 as set forth in SEQ ID NO: 163, CDR-L2 as set forth in SEQ ID NO: 13, and CDR-L3 as set forth in SEQ ID NO:

164. The antibody comprising:

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

3. The antibody of claim 1 or 2, wherein the antibody comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15, and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:

16.

4. The antibody of any one of claims 1 to 3, wherein the antibody is selected from the group consisting of a full-length IgG, a Fab fragment, a F(ab') fragment, a F(ab')2 fragment, an scFv, and an Fv.

5. An antibody described in any one of claims 1 to 4, wherein the antibody is a full-length IgG.

6. An antibody described in any one of claims 1 to 5, wherein the antibody comprises a heavy chain constant region of isotype IgG1 represented by sequence number 175 or sequence number 176.

7. The antibody of claim 5 or 6, wherein the antibody comprises a heavy chain comprising an amino acid sequence at least 80% identical to SEQ ID NO: 180, and a light chain comprising an amino acid sequence at least 80% identical to SEQ ID NO:

181.

8. The antibody according to any one of claims 1 to 4, wherein the antibody is a Fab fragment.

9. An antibody described in any one of claims 1 to 8, wherein the antibody comprises a heavy chain comprising an amino acid sequence at least 85% identical to SEQ ID NO: 186, and a light chain comprising an amino acid sequence at least 85% identical to SEQ ID NO:

181.

10. An antibody described in any one of claims 1 to 9, wherein the antibody comprises a heavy chain comprising an N-terminal pyroglutamic acid.

11. A nucleic acid encoding the antibody of any one of claims 1 to 10.

12. A method for producing an anti-TfR1 antibody, comprising culturing a cell containing the nucleic acid of claim 11 under conditions suitable for expression of the antibody.

13. A conjugate comprising the antibody of any one of claims 1 to 10 covalently linked to a molecular payload.

14. The conjugate of claim 13 , wherein the molecular payload is a diagnostic or therapeutic agent.

15. 15. The conjugate of claim 13 or 14, wherein the molecular payload comprises an oligonucleotide, a protein, a peptide, a nucleic acid, a polypeptide, or a small molecule.

16. The anti-transferrin receptor antibody is covalently linked to the molecular payload via a cleavable linker. The composite according to any one of claims 13 to 15.

17. The complex described in claim 16, wherein the cleavable linker comprises a valine-citrulline sequence.

18. The conjugate of any one of claims 13 to 15, wherein the anti-transferrin receptor antibody is covalently linked to the molecular payload via a non-cleavable linker.

19. The complex of claim 18, wherein the non-cleavable linker is an alkane linker.

20. A conjugate according to any one of claims 13 to 19, wherein the molecular payload is covalently linked to the antibody via conjugation to a lysine residue of the antibody.

21. A conjugate according to any one of claims 13 to 19, wherein the molecular payload is covalently linked to the antibody via conjugation to a cysteine ​​residue of the antibody.

22. 11. A method for detecting transferrin receptor in an in vitro biological sample, the method comprising contacting the biological sample with an antibody according to any one of claims 1 to 10, and measuring binding of the antibody to the biological sample.

23. The method of claim 22, wherein the antibody is covalently linked to the diagnostic agent.

24. 22. The conjugate of any one of claims 13 to 21 for use in a method of in vivo diagnosis, the method comprising delivering the conjugate to a target cell or tissue expressing a transferrin receptor, wherein the molecular payload is a diagnostic agent.

25. The complex of claim 24, wherein the target cell is a muscle cell.

26. The complex of claim 24, wherein the target tissue is muscle tissue or brain tissue.

27. The complex of claim 24, wherein the target cell or tissue crosses the blood-brain barrier.

28. 22. The conjugate of any one of claims 13 to 21 for use in a method for treating a disease, the method comprising administering to a subject an effective amount of the conjugate, wherein the molecular payload is a therapeutic agent.

29. 29. The conjugate of claim 28, wherein the disease is a neurological disease and the molecular payload is a drug for treating the neurological disease.

30. The complex described in claim 28, wherein the disease is a muscle disease and the molecular payload is a drug for treating the muscle disease.

31. The complex described in claim 30, wherein the muscle disease is a rare muscle disease or muscle atrophy.

32. The conjugate according to any one of claims 28 to 31, wherein the subject is a human.

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