TRANSFERRIN RECEPTOR-BINDING ANTIBODIES AND MEDICATIONS CONTAINING THESE ANTIBODIES

Abstract

The invention relates to proteins comprising transferrin receptor-binding antibodies (TfR), conjugates comprising such TfR-binding antibodies, e.g., TfR-binding antibody dsRNA conjugates, pharmaceuticals comprising such TfR-binding antibodies or conjugates. Such TfR-binding antibodies or conjugates are useful for the treatment of diseases of the central nervous system (CNS) (e.g., neurodegenerative diseases). The invention also relates to the nucleic acid molecule encoding this antibody, the vector comprising this nucleic acid molecule, and mammalian cells comprising this nucleic acid molecule. The invention also relates to a method for generating conjugates containing this antibody.

Description

TRANSFERRIN RECEPTOR BINDING PROTEINS AND USES THEREOFFIELD OF THE INVENTION

[0001] The present disclosure is related to, at least in part, antibodies or antigen-binding fragments thereof that bind transferrin receptor, have low risk of immunogenicity (e.g, in a subject), and may be used for delivery of a molecular payload (such as a therapeutic) to various tissues, such as, brain, cancerous cells, and dorsal root ganglions (e.g., DRG neurons).SEQUENCE LISTING

[0002] The present application is being fded along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “30761_WO.xml” created 18-Sep-2024 and is 104 kilobytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.BACKGROUND

[0003] Transferrin receptor (TfR) (also known as CD71) is a dimeric type II transmembrane glycoprotein made of two 90-kDa monomers on the surface of cells. It is a vital protein involved in iron homeostasis and the regulation of cell growth (Daniels et al., “The Transferrin Receptor Part I: Biology and Targeting with Cytotoxic Antibodies for the Treatment of Cancer,” Clin. Immunol. 121(2): 144-58 (2006)). Two types of transferrin receptors have been characterized in humans, transferrin receptor 1 (TfRl) and transferrin receptor 2 (TfR2). It has been shown that TfR is overexpressed in cancer cells with higher metastatic potential. Since transferrin receptors are strongly expressed by most malignant cells, are present on cell surfaces, and have the properties of being bound and detected easily and mediated by endocytosis, they have long been considered an effective target for targeted cancer therapies (Daniels et al., “The Transferrin Receptor and the Targeted Delivery of Therapeutic Agents against Cancer,” Biochim. Biophys. Acta. 1820(3):291 -317 (2012)). TfR has also been shown to express on the endothelial cells of the blood brain barrier (BBB) and, therefore, can be used to deliver large molecules intothe brain (Johnsen et al., “Targeting the Transferrin Receptor for Brain Drug Delivery,” Prog. Neurobiol. 181 : 101665 (2019)). Dorsal root ganglia (DRG) have cell surface transferrin receptors and play an important role in modulation of peripheral and central sensory processing that includes inflammation, somatic pain, and the development of aberrant, neuropathic pain (NP) (Elliot S. Krames, “The Role of the Dorsal Root Ganglion in the Development of Neuropathic Pain,” Pain Med., Volume 15, Issue 10, Pages 1669-1685 (2014)). DRG is an important clinical target for pain control. The DRG is also a known clinical target for delivery of anti-inflammatory steroids and for surgery (ganglionectomy). The current delivery methods, such as viral vectors, have several disadvantages, including potential injury to DRG neurons due to toxicity (Fader et al., “Circulating Neurofilament Light Chain as a Promising Biomarker of AAV-induced Dorsal Root Ganglia Toxicity in Nonclinical Toxicology Species,” Mol. Ther. Methods Clin. Dev. 25:264-277 (2022); Bolt, Michael W., et al. “Development Challenges Associated with rAAV-based Gene Therapies,” J. Toxicol. Sci. 46.2: 57-68 (2021)). Moreover, delivery using viral vectors creates a permanent change in the genome and such changes might not be desirable for delivery of some therapeutics. Accordingly, there is a need for a delivery vehicle that can deliver a payload to cells having TfR, such as, DRG neurons that is safe, effective, and does not cause permanent changes to the genome.

[0004] Additionally, even though antibodies may be used in the treatment of diseases or for selective delivery of therapeutics, their use often causes a problem of immunogenicity when administered to a subject. The immunogenic effect of antibodies is often hard to predict and control. Immunogenicity can cause an anti-drug antibody (ADA) response (Vaisman-Mentesh et al., “Molecular Landscape of Anti-drug Antibodies Reveals the Mechanism of the Immune Response following Treatment with TNFa Antagonists,” Front. Immunol., p.2921 (2019); Mosch et al., “Immunogenicity of Monoclonal Antibodies and the Potential Use of HLA Haplotypes to Predict Vulnerable Patients,” Front. Immunol. 13 :885672 (2022)). Such AD As may intervene with efficacy of an antibody or neutralize the antibody completely. AD As can alter the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the antibody. ADAs can also lead to adverse immune reactions (Hansel, et al., “The Safety and Side Effects of Monoclonal Antibodies,” Nature Rev. Drug Discov. 9, 325-338 (2010); De Groot, et al., “Immunogenicity of Protein Therapeutics,” Trends Immunol. 28.11 : 482-490 (2007)). The adverse effects of immunogenicity elicited by antibodies range from absence of effect of the mAh to severe and life-threatening responses (Kuus- Reichel et al., “Will Immunogenicity Limit the Use, Efficacy, and Future Development ofTherapeutic Monoclonal Antibodies?” Clin. Diagn. Lab. Immunol. 1 (4):365- 72 (1994); Koren et al., “Immune Responses to Therapeutic Proteins in Humans-Clinical Significance, Assessment and Prediction,” Curr. Pharm. Biotechnol. 3(4):349-60 (2002); Schellekens et al., “Immunogenicity of Recombinant Human Proteins: Causes and Consequences,” J. Neurol. 251 Suppl 2 (2004)). Some adverse events include infusion reaction, anaphylaxis, immune complex- mediated diseases, and loss of efficacy.

[0005] Accordingly, there remains a need for TfR binding antibodies that may be used to deliver therapeutics with minimal immunogenicity risk to different tissues in a subject’s body and to targets such as cancer cells, across the BBB into the brain, and / or to the DRGs.SUMMARY OF INVENTION

[0006] The present disclosure is based, at least in part, on the development of transferrin receptor binding proteins (also referred to herein as anti-TfR antibodies or antigen-binding fragments thereof) that bind transferrin receptor, have low immunogenicity risk, and may be used for delivery of a molecular payload (such as a therapeutic or a drug) to different tissues in a subject’s body, such as, muscle, pancreas, brain, cancerous cells, or dorsal root ganglions (DRG) neurons.

[0007] In some embodiments, transferrin receptor binding proteins (TBPs) described herein bind to human transferrin receptor with high specificity, affinity, and with reduced immunogenicity risk. In some embodiments, the TBPs provide for a range of affinities to TfR.

[0008] In some embodiments, the TBPs described herein may be used for targeting tissues and / or cells that express TfR. In some embodiments, the TBPs provided herein may be used for detection of TfR in a cell or a tissue. In some embodiments, the TBPs provided herein may be used in diagnostic, therapeutic, or research applications. In some embodiments, the TBPs described herein may be used to deliver a molecular payload to a target cell or tissue (e.g., a cell or tissue that expresses TfR).

[0009] In some aspects the present invention is related to complexes (or conjugates) including at least one TBP of the present invention conjugated (e.g., covalently) to at least one molecular payload (e.g., a diagnostic agent or a therapeutic agent). In some embodiments, the TBPs of the present invention may be used to deliver the conjugate (which includes the TBP anda molecular payload) to a cell or a tissue that expresses TfRl (e.g., muscle, pancreas, DRG neurons, or the brain) for diagnosing disease; treating or reducing pain; and / or treating a disease (e.g., a muscle disease or a neurological disease).

[0010] In some aspects, the present disclosure provides data demonstrating that certain TBPs described herein have superior benefit in that they have reduced immunogenicity risk as compared to other anti-TfR antibodies. In some aspects, the present disclosure provides TBPs that have superior benefit in that they can deliver a molecular payload to dorsal root ganglion (DRG) neurons. In some aspects, the present disclosure provides TBPs that have superior benefit in that they can deliver a molecular payload to dorsal root ganglion (DRG) neurons with reduced immunogenicity risk as compared to other anti-TfR antibodies.

[0011] One aspect of the present invention is related to an antibody or antigen-binding fragment thereof (TBP) that binds human transferrin receptor (TfR) including a heavy chain variable region (HCVR) comprising heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), and a light chain variable region (LCVR) comprising light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3), and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are selected from the group consisting of a) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 13; b) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 16; c) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 17; andd) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 18.

[0012] In some aspects, the present invention is related to a nucleic acid encoding the antibody or the antigen-binding fragments of the present disclosure. In some aspects, the present invention is related to vectors that may be used to express the antibodies or the antigen-binding fragments thereof in a cell. In some aspects, the present invention is related to cells (e.g., mammalian cells) that may be used to express the antibodies or the antigen-binding fragments thereof.

[0013] In some aspects, the present invention is related to a composition comprising the antibody or antigen-binding fragment thereof of the present disclosure and a carrier, diluent, or excipient. In some aspects, the present invention is related to a pharmaceutical composition comprising conjugates and a pharmaceutically acceptable carrier, diluent, or excipient wherein the conjugate includes the antibody or antigen-binding fragment thereof of the present disclosure and a payload or a therapeutic agent. In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure is covalently linked to a payload or a therapeutic agent, optionally via a linker.

[0014] In some aspects, the present invention is related to a method of treating a CNS disease in a patient in need thereof, the method comprising administering to the patient an effective amount of i) a conjugate comprising the antibody or antigen-binding fragment thereof of the present disclosure and a payload or a therapeutic agent, or ii) a pharmaceutical composition of the present disclosure.

[0015] In some aspects, the present invention is related to a method of treating or reducing pain in a patient in need thereof, the method comprising administering to the patient an effective amount of i) a conjugate comprising the antibody or antigen-binding fragment thereof of the present disclosure and a payload or a therapeutic agent, or ii) the pharmaceutical composition of the present disclosure. In some embodiments, the present disclosure is related to a method of making a conjugate, the method comprising conjugating the antibody or antigen-binding fragment thereof of the present disclosure to a therapeutic agent or a payload.

[0016] In some aspects, the present invention is related to a method of delivering a therapeutic agent to a dorsal root ganglion (DRG) of a patient in need thereof, the methodcomprising administering an effective amount of the conjugate to the patient wherein the conjugate comprises the antibody or antigen-binding fragment thereof of the present disclosure and a therapeutic agent or a payload.

[0017] In some aspects, the present invention is related to the use of the antibody or antigen-binding fragment thereof of the present disclosure in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain. In some aspects, the present invention is related to the use of the pharmaceutical composition of the present disclosure in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain. In some aspects, the present invention is related to an antibody or antigen-binding fragment thereof for use in treatment of a CNS disease in a patient in need thereof. In some aspects, the present invention is related to an antibody or antigen-binding fragment thereof for use in treatment or reduction of pain in a patient in need thereof. In some aspects, the present invention is related to a pharmaceutical composition for use in the treatment of a CNS disease. In some aspects, the present invention is related to a pharmaceutical composition for use in the treatment of pain. In some aspects, the present invention is related to a pharmaceutical composition for use in the reduction of pain.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 shows human TfR binding by ELISA (enzyme-linked immunosorbent assay) demonstrating relative binding affinity.Figure 2 shows cynomolgus monkey TfR binding by ELISA demonstrating relative binding affinity.Figure 3 shows in vivo testing of the B09 antibody conjugated to a rodent tool SCN10A siRNA. In vivo dosing of the B09 siRNA conjugate resulted in a significant decrease in SCN10A transcript in humanized transferrin receptor mice (65.7% of control, p<0.0001, one-way ANOVA).Figures 4A-B show internalization of exemplified antibodies in humanized transferrin mouse DRGs with 4X objective. Figure 4A shows an increase in total (black bars) and internalized (grey bars) DL650 fluorescent signal as measured by dots / cell. Figure 4B shows an increase in total (black bars) and internalized (grey bars) DL650 fluorescent signal as measured by fluorescent intensity / cell. All data were multiplied by le-5 as a correction factor for ease of graphing.Figures 5A-B show internalization of exemplified antibodies in humanized transferrin mouse DRGs with 20X objective. Figure 5 A shows an increase in total (black bars) and internalized (grey bars) DL650 fluorescent signal as measured by dots / cell. Figure 5B shows an increase in total (black bars) and internalized (grey bars) DL650 fluorescent signal as measured by fluorescent intensity / cell. All data were multiplied by le-5 as a correction factor for ease of graphing.DETAILED DESCRIPTION

[0018] The present disclosure provides antibodies or antigen-binding fragments thereof that are capable of binding TfR receptor. In some embodiments, the antibodies, or antigen-binding fragments thereof have low immunogenicity risk. In some embodiments, the antibodies, or antigen-binding fragments thereof are capable of delivering a molecular payload to DRG neurons, the brain, or to cancerous cells. The present disclosure is also related to conjugates comprising such antibodies or antigen-binding fragments thereof, e.g., TfR binding antibody-dsRNA conjugates. The present disclosure also includes pharmaceutical compositions comprising antibodies or antigen-binding fragments thereof or conjugates. The present disclosure also includes i) methods of treating CNS diseases or ii) treating or reducing pain using such antibodies or anti gen -binding fragments thereof or conjugates thereof.TfR Binding Proteins

[0019] One aspect of the present invention is related to human transferrin receptor (TfR) binding proteins which include the antibodies or antigen-binding fragments thereof disclosed herein. One aspect of the present invention is related to an antibody or antigen-binding fragment thereof that binds human transferrin receptor (TfR) including a heavy chain variable region (VH or HCVR) comprising heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), and a light chain variable region (VL or LCVR) comprising light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3). In some embodiments, the TfR binding protein comprises a heavy chain variable region (VH or HCVR) and a light chain variable region (VL or LCVR), and the VH comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises lightchain complementarity determining regions LCDR1, LCDR2, and LCDR3. In one embodiment, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are selected from the groupa) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 13; b) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 16; c) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 17; and d) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 18.In some embodiments, the TfR binding protein comprises a VH (also described as HCVR herein) comprising HCDR1, HCDR2, and HCDR3 selected from Table 1.Table 1: Examples of Transferrin Receptor Binding Protein (TBP) Heavy Chain Complementarity-determining Regions (HCDRs)

[0020] In some embodiments, the TfR binding protein comprises a VL (also described as LCVR herein) comprising LCDR1, LCDR2, and LCDR3 selected from Table 2.Table 2: Examples of Transferrin Receptor Binding Protein (TBP) Light Chain Complementarity-determining Regions (LCDRs)

[0021] In some embodiments, the present invention is related to an antibody or antigenbinding fragment thereof including a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3 wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 13.

[0022] In some embodiments, the present invention is related to an antibody or antigenbinding fragment thereof including a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3 wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 16.

[0023] In some embodiments, the present invention is related to an antibody or antigenbinding fragment thereof including a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3 wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 17.

[0024] In some embodiments, the present invention is related to an antibody or antigenbinding fragment thereof including a VH comprising HCDR1, HCDR2, and HCDR3, and a VL comprising LCDR1, LCDR2, and LCDR3 wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 18.

[0025] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the LCVR and HCVR are polypeptides selected from the group consisting of: a) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 22; b) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 25; c) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 26; and d) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 27.

[0026] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include a heavy chain variable region (HCVR) of SEQ ID NO: 19 and a light chain variable region (LCVR) of SEQ ID NO: 22. In some embodiments, the antibody or antigenbinding fragment thereof of the present invention include a heavy chain variable region (HCVR)of SEQ ID NO: 19 and a light chain variable region (LCVR) of SEQ ID NO: 25. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include a heavy chain variable region (HCVR) of SEQ ID NO: 19 and a light chain variable region (LCVR) of SEQ ID NO: 26. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include a heavy chain variable region (HCVR) of SEQ ID NO: 19 and a light chain variable region (LCVR) of SEQ ID NO: 27.

[0027] In some embodiments, the TfR binding protein comprises a VH comprising HCDR1, HCDR2, and HCDR3 selected from Table 1, and / or a VL comprising LCDR1, LCDR2, and LCDR3 selected from Table 2. In some embodiments, the Tf binding protein comprises a VH (HCVR) and / or a VL (LCVR) selected from Table 3.Table 3: Transferrin Receptor Binding Protein (TBP) Heavy Chain Variable Region (HCVR) and Light Chain Variable Region (LCVR)

[0028] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include a heavy chain (HC) and a light chain (LC), wherein the HC and LC polypeptides are selected from the group consisting of: a) HC of SEQ ID NO: 28 and LC of SEQ ID NO: 37; b) HC of SEQ ID NO: 29 and LC of SEQ ID NO: 37; c) HC of SEQ ID NO: 33 and LC of SEQ ID NO: 39; and d) HC of SEQ ID NO: 36 and LC of SEQ ID NO: 39.

[0029] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include one heavy chain (HC) and one light chain (LC), and wherein the HCcomprises SEQ ID NO: 28 and the LC comprises SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 29 and the LC comprises SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 33 and the LC comprises SEQ ID NO: 39. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 36 and the LC comprises SEQ ID NO: 39.

[0030] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two heavy chains (HC) and two light chains (LC), wherein the HC and LC polypeptides are selected from the group consisting of: a) HC of SEQ ID NO: 28 and LC of SEQ ID NO: 37; b) HC of SEQ ID NO: 29 and LC of SEQ ID NO: 37; c) HC of SEQ ID NO: 33 and LC of SEQ ID NO: 39; and d) HC of SEQ ID NO: 36 and LC of SEQ ID NO: 39.

[0031] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two heavy chains (HC) and two light chains (LC), and wherein the HC comprises SEQ ID NO: 28 and the LC comprises SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two heavy chains (HC) and two light chains (LC), and wherein the HC comprises SEQ ID NO: 29 and the LC comprises SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two heavy chains (HC) and two light chains (LC), and wherein the HC comprises SEQ ID NO: 33 and the LC comprises SEQ ID NO: 39. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two heavy chains (HC) and two light chains (LC), and wherein the HC comprises SEQ ID NO: 36 and the LC comprises SEQ ID NO: 39.

[0032] In some embodiments, the antibody or the antigen-binding fragment thereof is conjugated to one payload (e.g., a drug, a therapeutic agent, or siRNA) and has a drug to antibody ratio (DAR) of 1. In some embodiments, the antibody or the antigen-binding fragment thereof is conjugated to two payloads (e.g., a drug, a therapeutic agent, or siRNA) and has a drug to antibodyratio (DAR) of 2. In some embodiments, two variants of heavy chain (HCA and HCB) are such that one variant includes an engineered cysteine (eCys) for site-specific conjugation to, e.g., a payload. Such conjugation to one variant of the heavy or the light chain, e.g., may be done to yield a highly homogenous DARI conjugate or product. In some embodiments, HCA has the eCys site for site-specific conjugation. In some embodiments, HCB has the eCys site for site-specific conjugation.

[0033] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention is a heteromab and includes two variants of heavy chain (HCA and HCB) and a light chain (LC), wherein the HC and LC polypeptides are selected from the group consisting of: a) HCA of SEQ ID NO:30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 37; b) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 42; c) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 43; and d) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 44.

[0034] Such heteromab antibodies are described, e.g., in Example 1 of US Patent Application Publication No. 2021 / 0054103, which is hereby incorporated by reference in its entirety. Heterodimeric antibodies such as heteromab, orthomab, or duobody have been described in WO2014150973, WO2016118742, WO2018118616, WO2011131746, which are hereby incorporated by reference in their entireties. In some embodiments, the antibody or antigenbinding fragment thereof of the present invention include two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two variants of heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two variants of heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention include two variants of heavy chain (HCA and HCB)and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 44.

[0035] In some embodiments, the TfR binding protein comprises a heavy chain and / or a light chain selected from Table 4. In some embodiments, the TfR binding protein (“TBP”) is TBP1, TBP2, TBP3, TBP4, TBP5, TBP6, TBP7, TBP8, TBP9, TBP10, or TBP11, e.g., as shown in Table 4. Table 4 further provides examples of the type of conjugation that may be used for making conjugates with the antibody or antigen-binding fragment thereof. The term “nCys” in Table 4 refers to a conjugation method where one or more native cysteine residues are used for conjugation of the antibody or antigen-binding fragment thereof to a molecular payload (e.g., siRNA). The term “eCys” in Table 4 refers to a method where one or more engineered cysteine residues are used for conjugation of the antibody or antigen-binding fragment thereof to a molecular payload (e.g., siRNA). The approach of including engineered cysteines as a means for conjugation has been described in WO2018232088, which is hereby incorporated by reference in its entirety.Table 4: Transferrin Receptor Binding Protein Heavy Chain (HC) and Light Chain (LC):

[0036] In Table 4 and this disclosure, the term “EN” refers to effector null mutations. In some embodiment, the term “EN” refers to mutations L234A / L235E / G237A / A330S / P331 S in the Fc region of the antibody or derivatives thereof.

[0037] In Table 4 and this disclosure, the term “AAS” refers to L234A / L235A / D265S mutations. This is an example of effector null mutations in the Fc region. For more information see, e.g., Pejchal et al., “Profiling the Biophysical Developability Properties of Common IgGl Fc Effector Silencing Variants,” Antibodies, 12, 54 (2023), which is hereby incorporated by reference in its entirety.

[0038] In Table 4 and this disclosure, the term “9F10” refers to antibody or derivatives thereof (e.g., TBP7) whose epitope spans the apical and protease like domains of the TfR.

[0039] In Table 4 and this disclosure, the term “211” refers to an antibody or derivatives thereof that bind to only the apical domain of the TfR. In Table 4 and this disclosure, the term “Com29 WT” refers to an antibody or derivatives thereof (e.g., TBP6) that was engineered forhigh affinity and approximately equivalent human / cyno affinity. In Table 4 and this disclosure, the term “TBP4” refers to a monovalent Fab fragment of TBP6 with eCys site engineered in.

[0040] In Table 4 and this disclosure, “Com29 B09” (e.g., TBP1) refers to antibody or derivative thereof engineered from TBP6 for reduced affinity and reduced immunogenicity risk. In Table 4 and this disclosure, “TBP2” has, among other things, symmetric eCys site introduced, and “TBP3” is in heteromab format that has, among other things, an asymmetric / single eCys site. “TBP5” is a monovalent Fab fragment of TBP3 that has, among other things, an eCys site engineered in. “TBP8” is “TBP5” with an albumin targeting VHH appended for extended halflife.

[0041] In Table 4 and this disclosure, “TBP9,” “TBP10,” and “TBPH” are heteromab antibodies derived from TBP3 and having W96T, W96P, and W96L mutations in CDR3 of the light chain, respectively. These mutations are outside the MHC-associated peptide proteomics (MAPPs) presented peptides so they are less likely to increase immunogenicity risk but can increase affinity or broaden the affinity range available for a given antibody.

[0042] In some embodiments, the TfR. binding proteins of the present disclosure include a VH and a VL, and wherein the VH and VL comprise are selected from the group consisting of: a) VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 95% sequence identity to SEQ ID NO: 22; b) VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 95% sequence identity to SEQ ID NO: 25; c) VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 95% sequence identity to SEQ ID NO: 26; d) VH comprises a sequence having at least 95% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 95% sequence identity to SEQ ID NO: 27.

[0043] In some embodiments, the TfR. binding proteins of the present disclosure include a VH and a VL, and wherein the VH and VL comprise are selected from the group consisting of: a) VH comprises a sequence having at least 90% sequence identity to SEQ ID NO:19 and VL comprises a sequence having at least 90% sequence identity to SEQ ID NO: 22;b) VH comprises a sequence having at least 90% sequence identity to SEQ ID NO:19 and VL comprises a sequence having at least 90% sequence identity to SEQ ID NO: 25; c) VH comprises a sequence having at least 90% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 90% sequence identity to SEQ ID NO: 26; d) VH comprises a sequence having at least 90% sequence identity to SEQ ID NO: 19 and VL comprises a sequence having at least 90% sequence identity to SEQ ID NO: 27.

[0044] In some embodiments, the TfR binding protein described herein is a human IgGl antibody with effector null mutations that comprises a HC and a LC, wherein the HC comprises the sequence of SEQ ID NO: 28 and the LC comprises the sequence of SEQ ID NO: 37. In some embodiments, the TBP is TBP1 of Table 4.

[0045] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl antibody with effector null mutations and a cysteine at position 124 of the HC and the TBP comprises a HC and a LC, wherein the HC comprises the sequence of SEQ ID NO: 29 and the LC comprises the sequence of SEQ ID NO: 37. In some embodiments, the TBP is TBP2 of Table 4.

[0046] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl antibody heteromab with AAS effector null mutations and the TBP comprises two variants of HC (HCA and HCB) and a LC, wherein the HCA comprises the sequence of SEQ ID NO: 30 which includes 124S, HCB comprises the sequence of SEQ ID NO: 31 which includes 124C, and the LC comprises the sequence of SEQ ID NO: 37. In some embodiments, the TBP is TBP3 of Table 4.

[0047] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl Fab with a cysteine at position 124 of the HC and the Fab comprises a HC and a LC, wherein the HC comprises the sequence of SEQ ID NO: 33 and the LC comprises the sequence of SEQ ID NO: 39. In some embodiments, the TBP is TBP5 of Table 4.

[0048] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl Fab with a cysteine at position 124 of the HC and the Fab comprises a HC and a LC, wherein the HC comprises the sequence of SEQ ID NO: 36 and the LC comprises the sequence of SEQ ID NO: 39. In some embodiments, the TBP is TBP8 of Table 4. In some embodiments, the TBP8 Fab is attached to a VHH which acts as a half-life extender and, optionally, binds to human serumalbumin (HSA). In some embodiments, the TBP is a Fab and is attached to a VHH which acts as a half-life extender and, optionally, binds to HSA.

[0049] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl antibody heteromab with W96T mutation, AAS effector null mutations, and the TBP comprises two variants of HC (HCA and HCB) and a LC, wherein the HCA comprises the sequence of SEQ ID NO: 30 which includes 124S, HCB comprises the sequence of SEQ ID NO: 31 which includes 124C, and the LC comprises the sequence of SEQ ID NO: 42. In some embodiments, the TBP is TBP9 of Table 4.

[0050] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl antibody heteromab with W96P mutation, AAS effector null mutations, and the TBP comprises two variants of HC (HCA and HCB) and a LC, wherein the HCA comprises the sequence of SEQ ID NO: 30 which includes 124S, HCB comprises the sequence of SEQ ID NO: 31 which includes 124C, and the LC comprises the sequence of SEQ ID NO: 43. In some embodiments, the TBP is TBP10 of Table 4.

[0051] In some embodiments, the TfR binding protein (TBP) described herein is a human IgGl antibody heteromab with W96L mutation, AAS effector null mutations, and the TBP comprises two variants of HC (HCA and HCB) and a LC, wherein the HCA comprises the sequence of SEQ ID NO: 30 which includes 124S, HCB comprises the sequence of SEQ ID NO: 31 which includes 124C, and the LC comprises the sequence of SEQ ID NO: 43. In some embodiments, the TBP is TBP11 of Table 4.

[0052] In some embodiments, provided herein are proteins comprising human transferrin receptor (TfR) binding protein, wherein the TfR binding protein binds an epitope comprising one or more residues in LFGNMEGDCPSDWKTDSTCR (SEQ ID NO: 45) of TfR.

[0053] In some embodiments, the present invention is related to nucleic acids that encode the antibodies or antigen-binding fragments thereof. In some embodiments, the nucleic acidsshown in Table 5 are included in the present disclosure and may be used to express the heavy chain or light chain of the TBPs of the present invention.Table 5: Nucleic Acid Sequences for Transferrin Receptor Binding Protein (TBP) Heavy Chain (HC) and Light Chain (LC)

[0054] The TfR binding proteins described herein can be recombinantly produced in a host cell, for example, using an expression vector. For example, an expression vector may include a sequence that encodes one or more signal peptides that facilitate secretion of the polypeptide(s) from a host cell. Expression vectors containing a polynucleotide of interest (e.g., a polynucleotide encoding a heavy chain or light chain of the TfR binding proteins) may be transferred into a host cell by well-known methods. Additionally, expression vectors may contain one or more selection markers, e.g., tetracycline, neomycin, and dihydrofolate reductase, to aide in detection of host cells transformed with the desired polynucleotide sequences.

[0055] A host cell (e.g., a mammalian cell) includes cells stably or transiently transfected, transformed, transduced, or infected with one or more expression vectors expressing all or a portion of the TfR binding proteins described herein. According to some embodiments, a host cell may be stably or transiently transfected, transformed, transduced, or infected with an expression vector expressing HC polypeptides and an expression vector expressing LC polypeptides of the TfR binding proteins described herein. In some embodiments, a host cell may be stably or transiently transfected, transformed, transduced, or infected with an expression vector expressing HC and LC polypeptides of the TfR binding proteins described herein. The TfR binding proteinsmay be produced in mammalian cells such as CHO, NSO, HEK293 or COS cells according to techniques well known in the art.

[0056] In some embodiments, the cell growth medium, into which the TfR binding proteins has been secreted, may be purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the cell growth medium may be applied to and eluted from a Protein A or G column using conventional methods; mixedmode methods of ion-exchange and hydrophobic interaction chromatography may also be used. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. Various methods of protein purification may be employed, and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994).Conjugates Comprising TfR Binding Protein

[0057] In another aspect, provided herein are conjugates comprising TfR. binding proteins (TBP) described herein (antibody or anti gen -binding fragment thereof), a therapeutic agent and an optional linker connecting the TfR. binding protein to the therapeutic agent. In some embodiments, the therapeutic agent is selected from a double stranded RNA (e.g., siRNA, saRNA), oligonucleotide (e.g., antisense oligonucleotide), peptide, small molecule, nanoparticle, lipid nanoparticle, exosome, antibody, or antigen binding fragment thereof, or a combination thereof. In some embodiments, the therapeutic agent is a double stranded RNA (dsRNA). In some embodiments, the dsRNA comprises a sense strand and an antisense stand, wherein the antisense strand is complementary to a target mRNA selected from SNCA, MAPT, APP, ATXN2, ATXN3, SARM1, APOE, BACE1, FMRI, LRRK2, HTT, SOD1, SCN10A, SCN9A, or CACNA1B mRNA.

[0058] In some embodiments, a linker is present in the conjugate and connects the TBP to a payload. See, e.g., US Patent Application Publication No. 2020 / 0325237, which is hereby incorporated by reference in its entirety. In some embodiments, a linker described herein is a cleavable linker or a non-cleavable linker. In some instances, the linker is a cleavable linker. In other instances, the linker is a non-cleavable linker. In some cases, the linker is a non-polymeric linker. A non-polymeric linker refers to a linker that does not contain a repeating unit of monomersgenerated by a polymerization process. In some embodiments, the linker is the same as described in US Patent Application Publication No. 2020 / 0325237. In some embodiments, the linker is SMCC linker (succinimidyl-4-(N-maleimidomethyl)cyclohexane-l-carboxylate (SMCC; Thermo Scientific™)). SMCC is a hetero-bifunctional crosslinker that contain N-hydroxysuccinimide (NHS) ester and maleimide groups that allow covalent conjugation of amine- and sulfhydryl- containing molecules (see, e.g., Hatakeyama et al., “Targeted Drug Delivery to Tumor Vasculature by a Carbohydrate Mimetic Peptide,” Proc. Natl. Acad. Sci. USA. 108(49): 19587-92 (2011), which is hereby incorporated by reference in its entirety). In some embodiments, the linker is absent. In some embodiments, the TBP is linked to the 3’ end of the sense strand of the dsRNA. In some embodiments, the TBP is linked to the 5’ end of the sense strand of the dsRNA. In some embodiments, the TBP is linked to an internal position of the sense strand of the dsRNA. In some embodiments, the TBP is linked to the 3’ end of the antisense strand of the dsRNA. In some embodiments, the TBP is linked to an internal position of the antisense strand of the dsRNA.

[0059] In some embodiments, the sense strand and the antisense strand of the dsRNA are each 15-30 nucleotides in length, e.g., 20-25 nucleotides in length. In some embodiments, the dsRNA has a sense strand of 21 nucleotides and an antisense strand of 23 nucleotides. In some embodiments, the dsRNA has a sense strand of 19 nucleotides and an antisense strand of 21 nucleotides. In some embodiments, the dsRNA has a sense strand of 19 nucleotides and an antisense strand of 19 nucleotides, optionally, including a 2-nucleotide overhang. In some embodiments, the sense strand and antisense strand of the dsRNA may have overhangs at either the 5’ end or the 3’ end (i.e., 5’ overhang or 3’ overhang). For example, the sense strand and the antisense strand may have 5’ or 3’ overhangs of 1 to 5 nucleotides or 1 to 3 nucleotides. In some embodiments, the antisense strand comprises a 3’ overhang of two nucleotides.Exemplary Conjugate Methods Using Cysteine Residues

[0060] In some embodiments, the TfR binding proteins described herein comprise one or more native cysteine residues, which can be used for conjugation (also, described herein as nCys). For example, in some embodiments, the TfR binding protein described herein comprises a nativecysteine in the light chain and / or a native cysteine in the heavy chain, which can be used for conjugation.

[0061] In some embodiments, the TfR binding proteins described herein comprise one or more engineered cysteine residues for conjugation. The approach of including engineered cysteines as a means for conjugation has been described in WO2018232088, which is hereby incorporated by reference in its entirety. In some embodiments, the TfR binding proteins described herein comprise a heavy chain comprising one or more engineered cysteines at the following residues: 124, 157, 162, 262, 373, 375, 397, 415 (all residues according to the EU Index numbering). In some embodiments, the TfR binding proteins described herein comprise a light chain (e.g., a kappa light chain) comprising one or more engineered cysteines at the following residues: 156, 171, 191, 193, 202, 208 (all residues according to the EU Index numbering). In some embodiments, the TfR binding proteins described herein comprise a heavy chain constant region comprising cysteine at residue 124 (according to the EU Index numbering). In some embodiments, the TfR binding proteins described herein comprise a light chain constant region comprising cysteine at residue 156 (according to the EU Index numbering). In some embodiments, the TfR binding proteins described herein comprise an immunoglobulin Fc region comprising cysteine at residue 378 (according to the EU Index numbering).

[0062] The conjugates described herein can be made by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the preparations and examples below. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare conjugates. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

[0063] In some embodiments, the TfR binding proteins with native or engineered cysteines described herein can be first treated with a reducing agent, e.g., dithiothreitol (DTT), and then re-oxidized with an oxidizing agent, e.g., dehydroascorbic acid (DHAA). The resultingoxidized TfR binding proteins are then incubated with a linker functionalized therapeutic agent, e.g., linker-dsRNA, to produce the conjugates.

[0064] In some embodiments, the antibody or the antigen-binding fragment thereof includes a cysteine residue that is capable of conjugating to one payload (e.g., a drug, a therapeutic agent, or siRNA) to form a DARI conjugate, wherein the conjugate has a drug to antibody ratio (DAR) of 1. In some embodiments, the antibody or the antigen-binding fragment thereof includes two cysteine residues that are capable of conjugating to two payloads (e.g., a drug, a therapeutic agent, or siRNA) to form a DAR2 conjugate, wherein the conjugate has a DAR of 2. In some embodiments, the antibody or the antigen-binding fragment thereof includes more than two cysteine residues that are capable of conjugating to more than two payloads (e.g., a drug, a therapeutic agent, or siRNA) to form a conjugate, wherein the conjugate has a drug to antibody ratio (DAR) of more than 2.Alternative Antibody Formats

[0065] Embodiments of the present disclosure also include antibody fragments or antigenbinding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as, Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, scFv-Fc, diabody, scFab, scFv-CH3, Fv, scFa, disulfide-linked Fvs (sdFv), and a Fd fragment.

[0066] In some embodiments, the TfR binding protein is scFv. In some embodiments, the TfR binding protein is Fab. In some embodiments, the TfR binding protein is a Fab and a VHH linked to the Fab, wherein the VHH binds human serum albumin (HSA). In some embodiments, the TfR binding protein further comprises a heavy chain constant region comprising cysteine at residue 124 (according to the EU Index numbering). EU numbering system is used in the present disclosure for numbering the residues of antibodies or fragments thereof.Half-life Extenders

[0067] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention further comprises a half-life extender, e.g., an immunoglobulin Fc region or a VHH that binds human serum albumin (see, e.g., WO2022169766, which is hereby incorporated by reference in its entirety). In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises an immunoglobulin Fc region, e.g., a modified humanIgG4 Fc region or a modified human IgGl Fc region. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a modified human IgG4 Fc region comprising proline at residue 228, and alanine at residues 234 and 235 (all residues are numbered according to the EU Index numbering, also called hIgG4PAA Fc region). In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a modified human IgGl Fc region comprising alanine at residues 234, 235, and 329, serine at position 265, aspartic acid at position 436 (all residues are numbered according to the EU Index numbering, all called hlgGl effector null or hlgGlEN Fc region).

[0068] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a VHH that binds HSA. In some embodiments, the VHH also binds mouse, rat, and / or cynomolgus monkey albumin. In some embodiments, such a VHH comprises CDR1 comprising SEQ ID NO: 72, CDR2 comprising SEQ ID NO: 73, and CDR3 comprising SEQ ID NO: 74. In some embodiments, such a VHH comprises SEQ ID NO: 75. In some embodiments, the VHH is linked to the TfR binding domain through a peptide linker, e.g., (GGGGQ)s (SEQ ID NO: 76).Table 6: Exemplary Sequences of VHH that Bind Human Serum Albumin (HSA)Pharmaceutical Compositions

[0069] Another aspect of the present invention is related to pharmaceutical compositions comprising i) any of the antibody or antigen-binding fragments thereof described herein or ii) conjugates described herein and a pharmaceutically acceptable carrier, diluent, or excipient. Such pharmaceutical compositions can comprise one or more pharmaceutically acceptable excipient, diluent, or carrier. Pharmaceutical compositions can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 23rd edition (2020), A. Loyd et al., Academic Press).Method of Treatment and Therapeutic Use

[0070] In another aspect, provided herein are methods of treating a CNS disease, e.g., a neurodegenerative disease, in a patient in need thereof. Such methods comprise administering to the patient an effective amount of a conjugate as described herein or ii) a pharmaceutical composition described herein.

[0071] In a further aspect, provided herein are methods of treating a neurodegenerative synucleinopathy in a patient in need thereof, and the methods comprise administering to the patient an effective amount of i) the conjugate as described herein, or ii) the pharmaceutical composition as described herein. Exemplary neurodegenerative synucleinopathy includes, but are not limited to, Parkinson’s disease; multiple system atrophy; Lewy body dementia or dementia with Lewy bodies; pure autonomic failure; Alzheimer’s disease; Lewy body dysphagia; and incidental Lewy body disease. In some embodiments, the neurodegenerative synucleinopathy is selected from Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, or Lewy body dementia.

[0072] In another aspect, provided herein are methods of treating or reducing pain in a patient in need thereof. Such methods comprise administering to the patient an effective amount of i) a conjugate as described herein or ii) a pharmaceutical composition described herein. In some embodiments, the present disclosure is related to a method of making a conjugate, the method comprising conjugating the antibody or antigen-binding fragment thereof of the present disclosure to a therapeutic agent or a payload.

[0073] In some aspects, the present invention is related to a method of delivering a therapeutic agent to a dorsal root ganglion (DRG) (e.g., neurons) of a patient in need thereof, the method comprising administering an effective amount of the conjugate to the patient wherein theconjugate comprises the antibody or antigen-binding fragment thereof of the present disclosure and a therapeutic agent or a payload.

[0074] In some aspects, the present invention is related to the use of the antibody or antigen-binding fragment thereof of the present disclosure in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain. In some aspects, the present invention is related to the use of the pharmaceutical composition of the present disclosure in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain. In some aspects, the present invention is related to an antibody or antigen-binding fragment thereof for use in treatment of a CNS disease in a patient in need thereof. In some aspects, the present invention is related to an antibody or antigen-binding fragment thereof for use in treatment or reduction of pain in a patient in need thereof. In some aspects, the present invention is related to a pharmaceutical composition for use in the treatment of a CNS disease. In some aspects, the present invention is related to a pharmaceutical composition for use in the treatment of pain. In some aspects, the present invention is related to a pharmaceutical composition for use in the reduction of pain.

[0075] In some embodiments, the present invention is related to the use of the antibody or antigen-binding fragment thereof of the present disclosure in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain. In another aspect, provided herein are uses of TfR binding proteins or conjugates described herein in the manufacture of a medicament for treating a CNS disease, e.g., a neurodegenerative disease. In another aspect, provided herein are uses of TfR binding proteins or conjugates described herein in the manufacture of a medicament for treating or reducing pain.

[0076] In some embodiments, i) the antibody or antigen-binding fragment thereof as described herein, ii) the conjugate as described herein, or iii) the pharmaceutical composition described herein can be administered to the patient intravenously. The dosing regimens of the antibody or fragment thereof, the conjugate, or the pharmaceutical composition as described herein may be adjusted to provide the optimum desired response (e g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

[0077] Dosage values may vary with the type and severity of the condition to be alleviated. It is further understood that for any subject, specific dosage regimens should beadjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.Definitions

[0078] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0079] The term “antibody,” as used herein, refers to a molecule that binds an antigen. Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, heterodimeric antibody, bispecific or multispecific antibody, or conjugated antibody. The antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4). In some embodiments, the antibody of the present invention is an IgGl antibody.

[0080] An immunoglobulin G (IgG) type antibody is comprised of four polypeptide chains: two heavy chains (HC) and two light chains (LC) that are cross-linked via inter-chain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region. The IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).

[0081] The VH (also referred to herein as HCVR) and VL (also referred to herein as LCVR) regions can be further subdivided into regions of hyper-variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specificinteractions with the antigen. Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, MD. (1991), which is hereby incorporated by reference in its entirety), Chothia (Chothia et al., “Canonical Structures for the Hypervariable Regions of Immunoglobulins,” J. Mol. Biol., 196, 901-917 (1987); Al-Lazikani et al., “Standard Conformations for the Canonical Structures of Immunoglobulins,” J. Mol. Biol., 273, 927-948 (1997), which are hereby incorporated by reference in their entirety), North (North et al., “A New Clustering of Antibody CDR Loop Conformations,” J. Mol. Biol., 406, 228-256 (2011)), or IMGT® (the International ImMunoGeneTics database available on at imgt.org; see Lefranc et al., Nucleic Acids Res. 27:209-212 (1999), which are hereby incorporated by reference in their entireties).

[0082] The term “antigen-binding fragments”, as used herein, refers to a portion of an antibody that binds an antigen or an epitope of the antigen. For example. “TfR binding protein” refers to a portion of an antibody or antibody fragment that binds TfR or an epitope of TfR.

[0083] As used herein, “antisense strand” means a single-stranded oligonucleotide that is complementary to a region of a target sequence. Likewise, and as used herein, “sense strand” means a single-stranded oligonucleotide that is complementary to a region of an antisense strand.

[0084] The terms “bind” and “binds” as used herein are intended to mean, unless indicated otherwise, the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in proximity of the two proteins or molecules as determined by common methods known in the art.

[0085] As used herein, “complementary” means a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand, e.g., a hairpin) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. Complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. Likewise, two nucleic acids may have regions ofmultiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

[0086] As used herein, “duplex,” in reference to nucleic acids or oligonucleotides, means a structure formed through complementary base pairing of two antiparallel sequences of nucleotides (i.e., in opposite directions), whether formed by two separate nucleic acid strands or by a single, folded strand (e.g., via a hairpin).

[0087] An “effective amount” refers to an amount necessary (for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of a protein or conjugate may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the protein or conjugate to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the protein or conjugate are outweighed by the therapeutically beneficial effects.

[0088] As referred to herein, the term “epitope” refers to the amino acid residues, of an antigen, that are bound by an antibody. An epitope can be a linear epitope, a conformational epitope, or a hybrid epitope. The term “epitope” may be used in reference to a structural epitope. A structural epitope, according to some embodiments, may be used to describe the region of an antigen which is covered by an antibody or antigen binding protein. In some embodiments, a structural epitope may describe the amino acid residues of the antigen that are within a specified proximity (e.g., within a specified number of angstroms) of an amino acid residue of the antibody or antigen binding protein. The term “epitope” may also be used in reference to a functional epitope. A functional epitope, according to some embodiments, may be used to describe amino acid residues of the antigen that interact with amino acid residues of the antibody or antigen binding protein in a manner contributing to the binding energy between the antigen and the antibody or antigen binding protein.

[0089] An epitope can be determined according to different experimental techniques, also called “epitope mapping techniques.” It is understood that the determination of an epitope may vary based on the different epitope mapping techniques used and may also vary with the different experimental conditions used, e.g., due to the conformational changes or cleavages of the antigen induced by specific experimental conditions. Epitope mapping techniques are known in the art (e.g., Rockberg and Nilvebrant, Epitope Mapping Protocols: Methods in Molecular Biology, Humana Press, 3rd ed. 2018), including but not limited to, X-ray crystallography, nuclear magneticresonance (NMR) spectroscopy, site-directed mutagenesis, species swap mutagenesis, alanine- scanning mutagenesis, hydrogen-deuterium exchange (HDX) and cross-blocking assays.

[0090] The term “Fc region” as used herein refers to a polypeptide comprising the CH2 and CH3 domains of a constant region of an immunoglobulin, e.g., IgGl, IgG2, IgG3, or IgG4. Optionally, the Fc region may include a portion of the hinge region or the entire hinge region of an immunoglobulin, e.g., IgGl, IgG2, IgG3, or IgG4. In some embodiments, the Fc region is a human IgGFc region, e.g., a human IgGl Fc region, human IgG2 Fc region, human IgG3 Fc region or human IgG4 Fc region. In some embodiments, the Fc region is a modified IgG Fc region with reduced or eliminated effector functions compared to the corresponding wild type IgG Fc region. The numbering of the residues in the Fc region is based on the EU index as described in Kabat (Kabat et al, Sequences of Proteins of Immunological Interest, 5th edition, Bethesda, MD: U.S. Dept, of Health and Human Services, Public Health Service, National Institutes of Health, 1991). The boundaries of the Fc region of an immunoglobulin heavy chain might vary, and the human IgG heavy chain Fc region is usually defined as the stretch from the N-terminus of the CH2 domain (e.g., the amino acid residue at position 231 according to the EU index numbering) to the C- terminus of the CH3 domain (or the C-terminus of the immunoglobulin).

[0091] The term “knockdown” or “expression knockdown” refers to reduced mRNA or protein expression of a gene after treatment of a reagent.

[0092] As used herein, the term “neurodegenerative synucleinopathy” refers to a neurodegenerative disorder characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia in the central and / or peripheral nervous systems.

[0093] The term “patient”, as used herein, refers to a human patient. In some embodiments, the TBP may be used for treatment of certain diseases in humans.

[0094] The term “% sequence identity” or “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computersoftware programs, for example, those described in Current Protocols in Molecular Biology (Ausubel et al., eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), and including BLAST, BLAST- 2, ALIGN, Megalign (DNASTAR), Clustal W2.0 or Clustal X2.0 software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the nucleic acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence.

[0095] The term “polypeptide” or “protein”, as used herein, refers to a polymer of amino acid residues. The term applies to polymers comprising naturally occurring amino acids and polymers comprising one or more non-naturally occurring amino acids.

[0096] As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). A strand can have two free ends (e.g., a 5’ end and a 3’ end).

[0097] As used herein, “TfR” refers to a transferrin receptor protein or polypeptide, e.g., a human transferrin receptor protein or polypeptide. The amino acid sequence of the human transferrin receptor protein (hTFR) can be found at NCBI Reference Sequence: NP 001121620. 1, which is hereby incorporated by reference in its entirety.

[0098] As used herein, “treatment” or “treating” refers to all processes wherein there may be a slowing, controlling, delaying, or stopping of the progression of the disorders or disease disclosed herein, or ameliorating disorder or disease symptoms, but does not necessarily indicate a total elimination of all disorder or disease symptoms. Treatment includes administration of a protein or nucleic acid or vector or composition for treatment of a disease or condition in a patient, particularly in a human.

[0099] The following examples are offered to illustrate, but not to limit, the claimed inventions.EXAMPLESExample 1: Generation and Characterization of TfR Binding Proteins.

[0100] Antibodies against human transferrin receptor (TfR) were generated by immunizing AlivaMab® transgenic mice with the extracellular domains (ECD) of human Transferrin Receptor 1 protein with a His tag (hTfR-ECD-6His, SEQ ID NO: 76, see Table 7) and mouse Transferrin Receptor protein with a His tag (mTfR-ECD-6His, SEQ ID NO: 77, see Table 7). Antigen positive B-cells were sorted from pooled spleens. Binding of individual antibodies cloned from those B-cells to his-tagged hTfR-ECD was verified. 9F10 parental clone was derived from this campaign. TBP7 is a derivative of the 9F10 parental clone.

[0101] Additional antibodies against TfR were generated by immunizing AlivaMab® transgenic mice with the apical domain of human Transferrin Receptor 1 protein with a His tag (hTfR-ApD-6His, SEQ ID NO: 78, see Table 7). Antigen positive B-cells were sorted from pooled spleens. Binding of individual antibodies cloned from those B-cells to Histidine (His)- tagged hTfR-ECD was verified. The 211 parental clone is derived from this campaign. TBP1-6 and 8-11 are derivatives of the parental 211 clone.Table 7: Sequences of Immunogens Used to Generate TfR Antibodies.

[0102] Variants of each parental clone were made by systematically introducing mutations into individual CDR of initial hits; each antibody and the resulting variants were subjected to multiple rounds of selection with decreasing concentrations of antigen and / or increasing periods of dissociation to isolate clones with improved affinities. The sequences of individual variants were used to construct a combinatorial library which was subjected to an additional round of selection with increased stringency to identify additive or synergistic mutational pairings between the individual CDR regions. Individual combinatorial clones were then sequenced. Clones with a range of affinities to TfR, with comparable affinity between humanand cynomolgus monkey TfR, and with predicted lower immunogenicity risk were selected for further characterization: TBP1, TBP6, and TBP7. TBP1 was further engineered to introduce a symmetric engineered cysteine at position 124 of the HC (TBP2) or an asymmetric engineered cysteine at position 124C of the HC (TBP3) to enable site specific conjugation with a DAR of 2 or 1, respectively. TBP3 was further engineered to generate monovalent Fab fragment (TBP5) or monovalent Fab fragment with an albumin binding VHH for extended half-life (TBP8). Similarly, TBP4 was generated as the Fab fragment of TBP6 with the 124C engineered cysteine. TBP3 was further engineered at LCDR position 96 to generate TBP9, TBP10, and TBP11 with a range of affinities.Example 2: Expression and Purification.

[0103] It is known that various methods of protein purification may be employed, and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994).

[0104] The exemplified anti -TfR antibodies and antibody fragments of the present disclosure were expressed and purified as follows. Antibodies were expressed in an appropriate host cell, such as HEK293 or CHO, either transiently or stably transfected with an expression system for secreting the antibodies using an optimal predetermined HC:LC vector ratio or a single vector system encoding both HC and LC. The expression plasmid contains cDNA versions of the LC and HC genes for the antibodies and are expressed from a commonly used and suitable construct for this purpose, such as one based on human cytomegalovirus major immediate early promoters.

[0105] Medium, into which an antibody of the present invention has been secreted, was purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the medium was applied to and eluted from a Protein A or G column using conventional methods; mixed-mode methods of ion-exchange and hydrophobic interaction chromatography may also be used. Soluble aggregate and multimers can be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The product was immediatelyfrozen, for example at -70 °C, refrigerated, or lyophilized. Purified antibodies were immediately frozen at -70 °C or stored at 2-8 °C for several months, or lyophilized, or preserved in 4 °C for immediate use.Example 3: Characterization of TfR Binding.

[0106] Initial assessment of TfR binding proteins to human and cyno TfR was determined by ELISA using human and cynomolgus monkey TfR extracellular domains (TfR ECD) (See Table 8).Table 8: Sequences of the Immunogens Used to Measure TfR Binding.

[0107] TfR ECD proteins were coated on high binding ELISA plates (Greiner Bio- One) at Ipg / mL in PBS >12 hours at 2-8 °C. Plates were washed in PBST (PBS + 0.1% v / v Tween-20), then blocked for 1 hour at room temperature with casein in PBS blocking buffer (Thermo Scientific™). TBP were serially diluted in blocking buffer, then added to the ELISA plate and incubated for 1 hour at room temperature with shaking. TBP solution was removed, plate was washed, and then biotinylated goat anti-human kappa antibody (Southern Biotech)(diluted 1,000-fold in blocking buffer) was added to the plate. This was incubated for 1 hour at room temperature with shaking, then solution was removed, and the plate was washed as before. HRP streptavidin (Invitrogen) diluted 5,000-fold in blocking buffer was added to the plate and incubated for 30 minutes at room temperature with shaking. Solution was removed and plate was washed as before, then 3,3',5,5'-tetramethylbenzidine substrate solution (TMB, Thermo Scientific™) was added to the plate. The reaction was allowed to proceed at room temperature until a blue color developed (approximately 30-60 seconds), then was quenched by addition of IN HC1. Absorbance at 450 nm was read using a microplate reader (Molecular Devices).

[0108] Data were fit to a sigmoidal 4-point logistic curve using GraphPad Prism 9.5.0. Representative curves are shown in Figure 1 and Figure 2, and n=3 independent replicate data are shown in Table 9.Table 9: TfR Binding by ELISA, EC50 Values for n=3 Independent Replicates.

[0109] The results demonstrate both human and cynomolgus monkey TfR binding for the exemplified TBPs, the increased apparent binding for bivalent compared to monovalent TBPs with the same variable domains (e g., TBP3 compared to TBP5 or TBP6 compared to TBP4), and comparable bivalent binding of the same variable domains on different constant domain backbones (TBP1, TBP2, and TBP3). The results also demonstrate a range of affinities across the TBPs which could lead to different delivery capabilities.

[0110] Binding was further characterized by surface plasmon resonance (SPR) using the same human and cynomolgus monkey TfR ECDs. All SPR reagents were from Cytiva Life Sciences unless otherwise indicated. To prepare the SPR chip, ECDs were diluted in acetate pH 4.5 and immobilized in flow cells 2 and 3, respectively, of a CM4 series S chip with the aminecoupling kit and a target immobilization level of 100 RU. Flow cell 1 was blank immobilized and subsequently used as the reference flow cell. Kinetic data was collected at 37 °C in IX HBS-EP+ pH 7.4 running buffer (Teknova). TBPs were diluted in running buffer at appropriate initial concentrations (e.g., 4500 nM for TBP5, 1500 nM for TBP7, 56 nM for TBP4, and 500 nM for all others), then 3X serially diluted for a total of 7 concentrations. Samples were injected for 240 seconds followed by an appropriate dissociation time (900 seconds for TBP4 and TBP8, 400 seconds for all others) with a 50 pL / min flowrate throughout. Following each cycle, the chip surface was regenerated with a 30 second injection of 3M MgCh at 100 pL / min and a 30 second injection of running buffer at 100 pL / min.

[0111] Analysis was performed in BiaEvaluation 3.1 using double referenced data (reference flow cell subtracted, buffer blank injection subtracted). Bivalent antibodies were fit to the heterogenous ligand model with the dissociation constant, KD, value of the higher RUmax component reported to approximate the 1 :1 binding affinity. Monovalent Fabs were fit to the 1 : 1 binding model. Results for n=3 independent replicates are shown in Table 10 and demonstrate a wide range of affinities to human TfR and cross-reactivity to cyno TfR.Table 10: TfR Binding by SPR at 37 °C.Epitope Mapping by Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS)

[0112] Hydrogen deuterium exchange coupled with mass spectrometry (HDX-MS) was performed to determine where a variant of TBP1 (which includes the same HCDR and LCDRs except one mutation in HCDR3; also referred to herein as TBP1 variant) binds TfR extracellular domain (TfR-ECD). Peptide identification for TfR-ECD was performed on a Waters Synapt G2Si Mass Spec. (Waters Corporation™) instrument using 5 pg of TfR-ECD protein at zero exchange(1: 10 dilution in 0.1X phosphate buffered saline in H2O) using nepenthesin II (Nep II) for digestion. The mass spectrometer was set in HDMSe (Mobility ESI+ mode) using a mass acquisition range of m / z 255.00-1950.00 with a scan time of 0.4 s. Data was processed using ProteinLynx Global SERVER™ (PLGS) 2.3.02 (Waters Corporation™). For the exchange experiments, the complex of TfR-ECD protein with individual TfR binding protein was prepared at the molar ratio of 1: 1.2 in 10 mM sodium phosphate buffer, pH 7.4 containing 150 mM NaCl (IxPBS buffer). The experiment was initiated by adding 25 pL of D2O buffer containing 0. lx PBS to 2.5 pL of TfR-ECD (0.9 mg / mL) or TfR-ECD + protein complex at 15 °C for various amounts of time (0 s, 10 s, 2 min, 10 min and 60 min) using a custom TEC AN sample preparation system (Espada et al., J Am Soc Mass Spectrom. (12):2580-2583 (2019), which is hereby incorporated by reference in its entirety). The reaction was quenched using equal volume of was 0.32M TCEP, 3 M guanidine HC1, 0.1M phosphate pH 2.5 for two minutes at 4 °C and immediately frozen at -70 °C. The sample injection system was comprised of a UR3 robot, a LEAP PAL3 HDX autosampler, and a high-performance liquid chromatography (HPLC) system interfaced with a Waters Synapt G2Si Mass Spec. (Waters Corporation™), with modification as described (Espada et al., 2019, J Am Soc Mass Spectrom. (12):2580-2583 (2019), which is hereby incorporated by reference in its entirety). The LC mobile phases consisted of water (A) and acetonitrile (B), each containing 0.2% formic acid. Each sample was thawed using 50 pL of 1.5 M guanidine HC1, 0.1M phosphate pH 2.5, for 1 min and injected on to a Nep II column for digestion at 4 °C with mobile phase A at a flow rate of 250 pL / min for 2.5 minutes. The resulting peptides were trapped on a Waters BEH Vanguard Pre-column at 4 °C, and chromatographically separated using a Waters Acquity UPLC BEH C18 analytical column at 4 °C with a flow rate of 200 pL / min and a gradient of 3%- 85% mobile phase B over 7 minutes and directed into mass spectrometer for mass analysis. The Synapt G2Si was calibrated with Glu-fibrinopeptide (Waters Corporation™) prior to use. Mass spectra were acquired over the m / z range of 255 to 1950 in HDMS mode, with the lock mass m / z of 556.2771 (Leucine Enkephalin, Waters Corporation™). The relative deuterium incorporation for each peptide was determined by processing the MS data for deuterated samples along with the undeuterated control using the identified peptide list in DynamX 3.0 (Waters Corporation™). Thefree and bound states of TfR-ECD were compared for deuterium incorporation differences to identify protected regions indicative of the binding epitope.

[0113] For the TBP1 variant decrease in deuterium uptake upon binding to TfR- ECD was observed in residues LFGNMEGDCPSDWKTDSTCR (SEQ ID NO: 45), pointing to the epitope region for the antibody.Example 4: Alternative Scaffolds.

[0114] Alternative scaffolds, antibody fragments, or antibody formats of the exemplified TBPs (e.g., as shown in Example 3) may be deemed preferable in certain circumstances. For example, a smaller Fab fragment may provide dosing advantage by reducing amount of protein needed to achieve a biological effect but may require increased affinity to compensate for the loss of bivalent engagement and / or extended half-life to compensate for the shorter in vivo exposure of a Fab fragment relative to an antibody. Altered affinity may also be used to control delivery to a specific tissue and / or selectivity of one tissue over another (see Table 11). Extended half-life of the Fab can be achieved for example by fusion with an albumin binding VHH domain using methods well-known to a person of ordinary skill in the art (see, e.g., WO2022169766, which is hereby incorporated by reference in its entirety).Table 11: KD Values for Various TBPs.Example 5: MAPPS Assay (MHC-associated Peptide Proteomics).

[0115] To assess immunogenicity risk, aMAPPs assay was performed to determine what peptides from the TBPs are presented by antigen presenting cells. Presentation of nongermline sequence confers higher risk of immunogenicity. Primary human dendritic cells from 10 normal human donors were prepared from buffy coats by isolation of CD-14 positive cells and differentiated into immature dendritic cells by incubation with 20 ng / mL IL-4 and 40 ng / mL GM- CSF in complete RPMI media containing 5% Serum Replacement (Thermo Fisher Scientific,cat#A2596101) for 3 days at 37 °C and 5% CO2 as described in Knierman et al., “The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein,” Cell Reports, 33, 108454 (2020), which is hereby incorporated by reference in its entirety. Test antibody (3 pM) was added to approximately 5xl06cells on day 4 and fresh media containing 5 mg / mL of LPS (to transform the cells into mature dendritic cells) was exchanged after 5-hour incubation. The matured cells were lysed in 1 mL of RIPA buffer with protease inhibitors and DNAse the following day. The lysates were stored at -80 °C until sample analysis.

[0116] An automated liquid handling system is used to isolate the HLA-II molecules from thawed lysate using biotinylated anti-pan HLA class II antibody (clone Tu39). The bound receptor-peptide complex is eluted with 5% acetic acid, 0.1% TFA. The eluted MHC-11 peptides are passed over a prewashed 10k MWCO filter to remove high molecular weight proteins. The isolated MHC-11 peptides are analyzed by nano liquid chromatography / mass spectrometry (LC / MS) using a Thermo easy 1200 nLC-HPLC system with a Thermo LUMOS mass spectrometer. The separation used a 75 pm * 7 cm YMC-ODS C18 column for 65-minute gradient with a 250 nL / min flow rate and 0.1% formic acid in water as A solvent and 80% acetonitrile with 0.1% formic acid as B solvent. Mass spectrometry is run in full scan mode with 240,000 resolution followed by a 3 second data dependent MS / MS cycle comprised of ion trap rapid scans with higher energy collision dissociation (HCD) and electron-transfer and higher-energy collision dissociation (EThcD) fragmentation.

[0117] Peptide identifications are generated by an internal proteomics pipeline (Higgs et al., “Label-free LC-MS method for the identification of biomarkers,” Meth. Mol. Biol., 428, 209-230 (2008), which is hereby incorporated by reference in its entirety) using multiple search algorithms with no enzyme search parameter against a bovine / human database containing the test antibody sequences. A KNIME workflow is used to process the identification files for the samples. Peptides identified from the test articles are aligned against the parent sequence. A summary is created for all donors that annotates the percent of donors that display non-germline residues, the number of different regions that display peptides with non-germline residues and the depth of peptide display at each region with non-germline residues. Increases in the extent of display of non-germline peptides is associated with increased risk for immunogenicity.

[0118] Results in Table 12 show decreased display of non-germline peptides for the variable domains from TBP3 compared to the variable domains from the parental TBP6, andtherefore a decreased risk of immunogenicity for TBP3. The variable domains from the unrelated TBP7 also shows a further decreased display of non-germline peptides and therefore a lower risk of immunogenicity compared to both TBP3 and TBP6 based on MAPPs results only.Table 12: MAPPs ResultsExample 6: T Cell Proliferation with MAPPs Peptides.

[0119] This assay assesses the ability of test candidate or test candidate’s MAPPs peptides to activate CD4+ T cells by inducing cellular proliferation (Walsh, et al., “Post-hoc Assessment of the Immunogenicity of Three Antibodies Reveals Distinct Immune Stimulatory Mechanisms,” MAbs 12, 1764829, (2020), which is hereby incorporated by reference in its entirety).

[0120] CD8+ T cell depleted PBMC’s were prepared and labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). Each sample was tested with media control, keyhole limpet haemocyanin (KLH; positive control), the respective therapeutic control (positive clinical benchmark antibody or peptide immunogenic control), test candidate, or test candidate MAPPs peptides. Cells were cultured and incubated for 7 days. On day 7, samples were analyzed by flow cytometry for a CD4+ T cell proliferative response. A median cellular division index (CDI) was calculated. Donors that produced a CDI > 2.5 were considered as positive responders. A percent donor frequency across all donors was evaluated.

[0121] The results in Table 13 demonstrate that TBP3 despite having a higher number of non-germline peptides and non-germline residues observed in MAPPs in fact carries alower risk of immunogenicity compared to TBP7 as there is a lower percentage of positive responders for the identified MAPPs peptides.Table 13: T cell Proliferation ResultsExample 7: Knockdown of a Targeted mRNA by B09 Antibody-siRNA Conjugate.

[0122] In Vivo Study Design: Transgenic mice expressing a chimeric TfR protein with human TfR extra cellular domain (ECD) and mouse TfR transmembrane and intracellular domains were generated by Taconic (animal line 18913). These mice expressed the chimeric TfR protein under endogenous control and expression of the human ECD was confirmed across various mouse tissues via qPCR and western blot. Four female and four male mice aged 6-7 weeks were dosed intravenously weekly for 4 weeks (day 0, 7, 14, and 21) with either PBS or test article at 10 mg / kg. Test article consisted of a human TfR antibody (B09 antibody, also referred to herein as TBP2, Eli Lilly) conjugated to a commercially available rodent SCN10A siRNA (Dharmacon) to make B09-siRNA conjugate. SMCC functionalized siRNA duplex was conjugated to the 124C engineered cysteine site to yield a DAR2 conjugate. On day 28 mice were euthanized via CO2 followed by a cold PBS perfusion and right and left L1-L5 lumbar dorsal root ganglia (DRG) were collected, trimmed, and snap frozen in liquid nitrogen.

[0123] qPCR Analysis: SCN10A mRNA level in collected DRG neurons were tested by probe Mm00501467_ml and normalized by Hprt, probe Mm03024075_ml (Thermo Fisher Scientific). The percentage knockdown was expressed by 2A(-ddCT). The CT value of SCN10A ranged from 21-23 and HPRT from 23-25. The percent knockdown of combined mice (female and male) in each group were tested by one way ANOVA in comparison to PBS.

[0124] Results and Conclusion: The administration of the B09-siRNA conjugate demonstrated approximately 35% knockdown of the targeted mRNA (SCN10A) following IV dose (N=8 for PBS and N=7 for the B09-siRNA conjugate, p<0.0001, one-way ANOVA) (Figure 3). SCN10A is the gene encoding the sodium channel Navi.8 which is a specific marker of DRGneurons in humans and rodents. The knockdown demonstrated in this example is evidence that the TfR antibody B09 (also referred to as TBP2 herein), when conjugated to a rodent tool siRNA targeting SCN10A, delivers the oligonucleotide successfully to DRG neurons in the humanized TfR mouse and results in functional effects on the targeted transcript.Example 8: Receptor Internalization Assay.

[0125] Tissue Harvest and Plating: Transgenic mice expressing a chimeric TfR protein with human TfR. ECD and mouse TfR transmembrane and intracellular domains were generated by Taconic (animal line 18913). These mice expressed the chimeric TfR protein under endogenous control. Following humane euthanasia, mouse spinal columns were removed and placed into a Hibernate A minus CaCh media solution (Brainbits, LLC) and stored on ice. The spinal columns were carefully divided into two halves and each dorsal root ganglion (DRG) was removed from its socket and placed into a dish containing fresh ice cold Hibernate A solution. Once all the ganglia were collected, they were transferred to a 50 mL conical tube containing 3 mL ice cold bfDMEM (bicarbonate and serum free sterile DMEM, ThermoFisher Scientific) and 2 mL dissociation enzyme cocktail (5 mg / mL dispase and 5 mg / mL collagenase (Worthington Biochemical) dissolved in bfDMEM) and then placed into a 37 °C water bath for 40 minutes. Following the enzymatic dissociation, the suspension was manually triturated, centrifuged, and resuspended in DMEM culture media with IX Pen / Strep (ThermoFisher Scientific). The cell suspension was then carefully layered on to 5 mL of warmed 15% BSA (Sigma Aldrich) in a 15 mL conical tube and then spun for 10 min @ 900 RPM. The BSA, interface layer, and media supernatant were aspirated, and the cell pellet was resuspended in DMEM plating media (consisting of DMEM culture media supplemented with 2% HI FBS (ThermoFisher Scientific), 30 ng / mL rat NGF-Beta (Eli Lilly and Company), 30 ng / mL human GDNF (Alomone Labs), and 10 ng / mL human NT3 (Alomone Labs). Cells were counted and seeded at a density of 2000 cells in 100 pL per well into wells of a 96-well lysine coated microplate (Corning, Inc) previously coated with a 20 ng / mL Laminin solution (Sigma Aldrich). Cultures were then incubated for 48 hours in a 37 °C / 5% CO2 Incubator.

[0126] Antibody Treatments: DRG plating media (as described above) was supplemented with 2 mg / mL goat gamma globulin (Jackson ImmunoResearch Labs) and used for preparing primary and secondary antibody treatments. Each primary antibody being tested(huIgGl-EN isotype, and human TfR antibodies TBP6, and TBP1) was diluted (separately) into plating media at a concentration of 10 pg / mL. Plating media contained 20 pg / mL Fc-specific goat anti-human Fab secondary antibodies (Jackson ImmunoResearch Labs) labeled with DL650 (ThermoFisher Scientific) or BHQ-conjugated DL650 (BHQ3, ThermoFisher Scientific). Primary / secondary antibody solutions were added to each well at 100 pL / well (in triplicate). Addition to the existing 100 pL / well of plated neurons resulted in final primary and secondary antibody concentrations of 5 pg / mL and 10 pg / mL, respectively. The DRG neuronal cultures were exposed to primary and secondary antibodies for 24 hours prior to imaging.

[0127] Imaging Assay: Following 24-hour antibody treatments, the DRG neuronal culture plate was washed 2 times with 150 pL / well Wash Media (EndoGro Basal Medium, Millipore) supplemented with 2% FBS (Hyclone). 100 pL / well NucBlue Live Cell Nuclear Stain (ThermoFisher Scientific) was added to the culture plate and incubated in the dark for 20 minutes. The nuclear stain was then aspirated and replaced with 100 pL / well wash buffer and imaged on the Cytation 5 Imaging Plate Reader (Agilent) at 4X and 20X magnifications. The DL650 fluorescent signal was measured across all wells. The unconjugated DL650 group measured total fluorescent signal, while receptor internalization was assessed with the BHQ-conjugated DL650 group. The presence of BHQ inhibits the DL650 signal when the secondary antibody remains intact. When the primary / secondary antibody complex is internalized and degraded within the neuron, the quencher is cleaved and the DL650 fluorescence is restored. Output measurements (at each magnification) included cell count, DL650 dots per cell, and DL650 sum intensity per cell. Average DL650 dots per cell were calculated by dividing the DL650 dot count by cell count and the DL650 sum intensity per cell was derived by dividing the DL650 sum intensity count by the cell count. Both measurements were multiplied by a scaling factor of le-5 for ease of graphing.

[0128] Results and Conclusions: The isotype antibody had relatively low background under all conditions. Treatment with the human TfR antibodies TBP6 and TBP1 demonstrated relatively high fluorescent signal with both the BHQ-conjugated and unconjugated groups versus isotype control. The increased unconjugated DL650 signal with the test TfR antibodies (both dots / cell and intensity / cell) is indicative of high levels of total antibody binding versus the isotype control. The high BHQ-conjugated DL650 signal is indicative of a significant degree of internalization / degradation over the 24-hour exposure time. Together these data (including Figures 4 and 5) provide good evidence that the TfR antibodies TBP6 and TBP1 bindand internalize within the DRG neurons from humanized TfR mice and are likely good candidates for the intracellular delivery of therapeutic payloads.SEQUENCE LISTINGTBP1-6, TBP8-11; HCDR1 SEQ ID NO: 1 SYSMNTBP7; HCDR1 SEQ ID NO: 2TYWMHTBP1-3, TBP5, TBP8-11; HCDR2 SEQ ID NO: 3SISSSSSYIYYADSVKGTBP4, TBP6; HCDR2 SEQ ID NO: 4SISRSSSYIYYADSVKGTBP7; HCDR2 SEQ ID NO: 5RSNSDGSRTNYADSVKGTBP1-3, TBP5, TBP8-11; HCDR3 SEQ ID NO: 6 RHGYSNSDAFDTTBP4, TBP6; HCDR3 SEQ ID NO: 7IHGYSNSDAFDITBP7; HCDR3-3 SEQ ID NO: 8SNYGFDVTBP1-6, TBP8-11; LCDR1 SEQ ID NO: 9RASQGISHYLVTBP7; LCDR1 SEQ ID NO: 10RSSQSLLDSDLGSTYLDTBP1-6, TBP8-11; LCDR2 SEQ ID NO: 11AASSLQSTBP7; LCDR2 SEQ ID NO: 12TLSYRASTBP1-3, TBP5, TBP8; LCDR3 SEQ ID NO: 13LQHNSYPWTTBP4, TBP6; LCDR3 SEQ ID NO: 14LQHNSYPRTTBP7; LCDR3 SEQ ID NO: 15MQRIEFPLTTBP9; LCDR3 SEQ ID NO: 16 LQHNSYPTTTBP10; LCDR3 SEQ ID NO: 17LQHNSYPPTTBP11; LCDR3 SEQ ID NO: 18LQHNSYPLTTBP1-3, TBP5, TBP8-11; HCVR SEQ ID NO: 19EVQLVESGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YI YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSTBP4, TBP6; HCVR SEQ ID NO: 20EVQLVESGGGLVKPGGSLRLSCVASGFTFSSYSMNWVRQAPGKGLEWVSSISRSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIHGYSNSDAFDIWGQGTLVTV SSTBP7; HCVR SEQ ID NO: 21EVQLVESGGGLVQPGGSLRLSCAASGFTHRTYWMHWVRQAPGKGLVWVSRSNSDGSR TNYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCGRSNYGFDVWGQGTLVTV SSTBP1-3, TBP5, TBP8; LCVR SEQ ID NO: 22DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKTBP4, TBP6; LCVR SEQ ID NO: 23DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPRTFGQGTKVEIKTBP7; LCVR SEQ ID NO: 24DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDLGSTYLDWYLQKPGQSPQLLIYTLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFPLTFGGGTKVEIKTBP9; LCVR SEQ ID NO: 25DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPTTFGQGTKVEIKTBP10; LCVR SEQ ID NO: 26DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGQGTKVEIKTBP11; LCVR SEQ ID NO: 27DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPLTFGQGTKVEIKTBP1; Heavy Chain A SEQ ID NO: 28EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKRVEPKSCDKTHTCPPCP AP EAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTBP2; Heavy Chain A SEQ ID NO: 29EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS S VVT VP S S SLGTQT YICNVNHKP SNTK VDKRVEPKSCDKTHTCPPCP AP EAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTBP3, TBP9, TBP10, TBP11; Heavy Chain A SEQ ID NO: 30EVQLVESGGGLVKPGGSLRLSCVASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS SWT VP S S SLGTQT YICNVNHKP SNTK VDKRVEPKSCDKTHTCPPCP AP EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKP REEQ YNSTYRVVS VLTVLHQDWLNGKEYKCKVSNK ALP APIEKTISKAKGQPRRPRVY TLPPSREEMTKNQVSLVCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS VLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTBP3, TBP9, TBP10, TBP11; Heavy Chain B SEQ ID NO: 31EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS SWT VP S S SLGTQT YICNVNHKP SNTK VDKRVEPKSCDKTHTCPPCP AP EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKP REEQ YNSTYRVVS VLTVLHQDWLNGKEYKCKVSNK ALP APIEKTISKAKGQPREPQVY TLPPSREEMTDNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLMSDGSFFLAS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTBP4; Heavy Chain A SEQ ID NO: 32EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SISRS S S YIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIHGYSNSDAFDIWGQGTLV TVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQS SGL YSLS S VVT VP S S SLGTQTYICNVNHKP SNTK VDKRVTBP5; Heavy Chain A SEQ ID NO: 33EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS SWT VP S S SLGTQTYICNVNHKP SNTK VDKRVTBP6; Heavy Chain A SEQ ID NO: 34EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEW VS SISRS S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIHGYSNSDAFDIWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQS SGL YSLS SVVTVPS S SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP APE AEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTBP7; Heavy Chain A SEQ ID NO: 35EVQLVESGGGLVQPGGSLRLSCAASGFTHRTYWMHWVRQAPGKGLVWVSRSNSDGSR TNYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCGRSNYGFDVWGQGTLVTV S S ASTKGP S VFPL AP S SKST SGGTAALGCL VKD YFPEP VT VS WNSGALT SGVHTFP A VLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAE GAP S VFLFPPKPKDTLMISRTPE VTC V V VD V SHEDPE VKFN W Y VDGVE VHN AKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPP SREEMTKNQ VSLTCLVKGF YP SDI A VEWESNGQPENNYKTTPPVLD SDGSFFL YSKLTV DKSRWQQGNVF SC S VMHEALHNHYTQKSLSLSPGKTBP8; Heavy Chain A SEQ ID NO: 36EVQLVE SGGGLVKPGGSLRL SC VASGFTF S S YSMNWVRQ APGKGLEWVS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDTWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKD YFPEP VTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVGGGGQGGGGQGGGGQ GGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREF VAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCGARPGRPLIT SKVADL YP YWGQGTLVTVS SPPTBP1-3; Light Chain SEQ ID NO: 37DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECTBP4; Light Chain SEQ ID NO: 38DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SK AD YEKHK VYACEVTHQGL S SP VTK SFNRGETBP5, TBP8; Light Chain SEQ ID NO: 39DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGT AS VVCLLNNF YPREAKVQWKVDNALQ SGNSQES VTEQD SKD ST YSL S STL TLSKAD YEKHK VYACEVTHQGLSSPVTKSFNRGETBP6; Light Chain SEQ ID NO: 40DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SK AD YEKHK VYACEVTHQGL S SP VTK SFNRGECTBP7; Light Chain SEQ ID NO: 41DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDLGSTYLDWYLQKPGQSPQLLIYTLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS L S S TLTL SK AD YEKHK VYACEVTHQGL S SP VTK SFNRGECTBP9; Light Chain SEQ ID NO: 42DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPTTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGT AS VVCLLNNF YPREAKVQWKVDNALQ S GNSQES VTEQD SKD STYSL S STLTL SKAD YEKHK VYACEVTHQGL S SP VTKSFNRGECTBP10; Light Chain SEQ ID NO: 43DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGT AS VVCLLNNF YPREAKVQWKVDNALQ S GNSQES VTEQD SKD STYSL S STLTL SKAD YEKHK VYACEVTHQGL S SP VTK SFNRGECTBP11; Light Chain SEQ ID NO: 44DIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKAD YEKHK VYACEVTHQGL S SP VTKSFNRGECAnti-TfR Antibody Epitope; SEQ ID NO: 45LFGNMEGDCPSDWKTDSTCRTBP1; Heavy Chain A; SEQ ID NO: 46GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP2; Heavy Chain A; SEQ ID NO: 47GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTT CTATCCCAGCGACATCGCTGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACT ACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAA ATBP3; Heavy Chain A; SEQ ID NO: 48GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCG CCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTAT TACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAA GGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCG GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCG TGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAA ACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTC CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTG GACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACA GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAAGACCACGGGTGTACACCCTGCCCCCATC CCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGGTCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCGTGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP4; Heavy Chain A; SEQ ID NO: 49GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGGAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTCATGGCTACAGTAACTCCGATGCTTTTGATATCTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTTBP5; Heavy Chain A; SEQ ID NO: 50GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTTBP6; Heavy Chain A; SEQ ID NO: 51GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTAGGAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAATTCATGGCTACAGTAACTCCGATGCTTTTGATATCTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP7; Heavy Chain A; SEQ ID NO: 52GAGGTGCAGCTGGTGGAGTCCGGGGGAGGTTTAGTTCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCACAGGACCTACTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGGTCTCACGTTCAAATAGTGATGGGAGTAGAACAAACTACGCGGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAATACGCTGTATCTGCAAATGAACAGTCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGGCAGGAGCAACTATGGTTTTGATGTCTGGGGCCAAGGGACACTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCATCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP8; Heavy Chain A; SEQ ID NO: 53GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCACTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGGTGGAGGTGGGCAAGGCGGAGGTGGCCAAGGAGGAGGAGGACAGGGAGGTGGTGGTCAAGGCGGGGGAGGTCAGGAGGTCCAACTTTTGGAGTCTGGCGGGGGACTGGTACAACCTGGAGGTTCATTGCGGCTCTCCTGCGCCGCAAGCGGCAGATACATTGACGAGACTGCAGTCGCCTGGTTCCGACAGGCTCCCGGGAAGGGACGGGAGTTCGTCGCTGGTATTGGTGGAGGGGTAGACATAACCTACTACGCAGATTCCGTCAAAGGCCGTTTCACCATTAGTCGGGACAATTCTAAAAACACTTTGTACCTTCAAATGAATAGTTTGCGCCCTGAGGATACTGCCGTCTATTACTGCGGCGCTCGCCCAGGGAGACCCCTGATCACAAGTAAAGTCGCCGACCTGTACCCCTATTGGGGCCAAGGGACCTTGGTTACAGTGAGTAGCCCTCCCTBP9; Heavy Chain A; SEQ ID NO: 54GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAAGACCACGGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGGTCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCGTGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP10; Heavy Chain A; SEQ ID NO: 55GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAAGACCACGGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGGTCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCGTGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP11; Heavy Chain A; SEQ ID NO: 56GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATTAGTTCCAGTAGTAGTTACATATATTATGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGCATGGCTACAGTAACTCCGATGCTTTTGATACTTGGGGCCAAGGGACATTGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAAGACCACGGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAAGTCAGCCTGGTCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATTCCGTGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP3; Heavy Chain B; SEQ ID NO: 57GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCGACAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGATGTCCGACGGCTCCTTCTTCCTCGCCTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP9; Heavy Chain B; SEQ ID NO: 58GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCGACAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGATGTCCGACGGCTCCTTCTTCCTCGCCTCCAAGCTC ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP10; Heavy Chain B; SEQ ID NO: 59GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCGACAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGATGTCCGACGGCTCCTTCTTCCTCGCCTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP11; Heavy Chain B; SEQ ID NO: 60GAAGTGCAGCTGGTCGAGTCAGGAGGCGGCCTCGTGAAACCGGGTGGTAGCCTGAGGCTGTCCTGCGTGGCATCAGGGTTCACCTTCTCGTCCTACTCCATGAACTGGGTCAGACAGGCCCCCGGAAAGGGACTTGAATGGGTGTCCAGCATCAGCAGCTCCTCCTCGTACATCTACTACGCCGATTCCGTGAAGGGCCGGTTCACCATTAGCCGCGACAATGCCAAGAACTCGCTGTATTTGCAAATGAACTCTCTGCGCGCCGAGGACACTGCTGTGTACTACTGTGCGCGGAGACACGGGTACTCCAACTCCGATGCCTTTGACACCTGGGGCCAGGGAACTCTCGTGACCGTGTCGTCCGCCAGCACCAAGGGCCCATGCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCGCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGTCCGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAAGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCGACAACCAAGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGATGTCCGACGGCTCCTTCTTCCTCGCCTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAATBP1; Light Chain; SEQ ID NO: 61GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACA CAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGCTBP2; Light Chain; SEQ ID NO: 62GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP3; Light Chain; SEQ ID NO: 63GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP4; Light Chain; SEQ ID NO: 64GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTBP5; Light Chain; SEQ ID NO: 65GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTBP6; Light Chain; SEQ ID NO: 66GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP7; Light Chain; SEQ ID NO: 67GATATTGTGATGACTCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCTTGGATAGTGATCTAGGAAGCACCTATTTGGACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATACACTTTCCTATCGGGCCTCTGGAGTCCCAGACAGGTTCAGTGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCCGTGTGGAGGCTGAGGATGTTGGAGTTTATTACTGCATGCAACGTATAGAGTTTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP8; Light Chain; SEQ ID NO: 68GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTBP9; Light Chain; SEQ ID NO: 69GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTACCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAAGAACTGTGGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP10; Light Chain; SEQ ID NO: 70GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCCCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAAGAACTGTGGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGCTBP11; Light Chain; SEQ ID NO: 71GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAGCCACTATTTAGTGTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCTGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAAGAACTGTGGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACA CAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGCVHH; CDR1; SEQ ID NO: 72ETAVAVHH; CDR2; SEQ ID NO: 73GIGGGVDITYYADSVKGVHH; CDR3; SEQ ID NO: 74RPGRPLIT SK VADL YP YVHH; Full Length; SEQ ID NO: 75EVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCGARPGRPLITSKVADLYPYWG QGTLVTVSSPPVHH; Exemplary Linker; SEQ ID NO: 76GGGGQGGGGQGGGGQGGGGQGGGQ hTfR-ECD-6His; SEQ ID NO: 77HHHHHHCKGVEPKTECERLAGTESPVREEPGEDFPAARRLYWDDLKRKLSEKLDSTDF TGTIKLLNENSYVPREAGSQKDENLALYVENQFREFKLSKVWRDQHFVKIQVKDSAQN SVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLYTPVNGSIVIV RAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGTGDPYTPGFPSFN HTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLT VSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAWGPGAAKSGVGTALLLKLAQMFS DMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSN FKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERFPELNKVARAAAEVAGQFVIKLTHDVELNLDY ERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARGDFFRATSRLTTDFGNAEKTDRF VMKK LNDR VMR VE YHF L SP YVSPKE SPFRHVFWGSGSHTLP ALLENLK LRKQNNG AFN ETLFRNQLALATWTIQGAANALSGDVWDIDNEF mTfR-ECD-6His; SEQ ID NO: 78HHHHHHCKRVEQKEECVKLAETEETDKSETMETEDVPTSSRLYWADLKTLLSEKLNSIE FADTIKQLSQNTYTPREAGSQKDESLAYYIENQFHEFKFSKVWRDEHYVKIQVKSSIGQN MVTIVQSNGNLDPVESPEGYVAFSKPTEVSGKLVHANFGTKKDFEELSYSVNGSLVIVR AGEITFAEKVANAQSFNAIGVLIYMDKNKFPVVEADLALFGHAHLGTGDPYTPGFPSFN HTQFPPSQSSGLPNIPVQTISRAAAEKLFGKMEGSCPARWNIDSSCKLELSQNQNVKLIV KNVLKERRILNIFGVIKGYEEPDRYVVVGAQRD ALGAGVAAK S S VGTGLLLKLAQ VF SD MISKDGFRPSRSIIFASWTAGDFGAVGATEWLEGYLSSLHLKAFTYINLDKVVLGTSNFK VSASPLLYTLMGKIMQDVKHPVDGKSLYRDSNWISKVEKLSFDNAAYPFLAYSGIPAVSFCFCEDADYPYLGTRLDTYEALTQKVPQLNQMVRTAAEVAGQLIIKLTHDVELNLDYE MYNSKLL SFMKDLNQFKTDIRDMGLSLQWLYS ARGD YFRAT SRLTTDFHNAEKTNRF V MREINDRIMKVEYHFLSPYVSPRESPFRHIFWGSGSHTLSALVENLKLRQKNITAFNETLF RNQLALATWT1QGVANALSGD1WNIDNEF hTfR-ApD-6His; SEQ ID NO: 79HHHHHHHHGKPIPNPLLGLDSTGGGGSDSAQNSVIIVDKNGRLVYLVENPGGYVAYSK AATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGGGGGGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDS TCRMVTSESKNVKLTVS cyTfR-ECD-6His; SEQ ID NO: 80HHHHHHCKGVEPKTECERLAGTESPAREEPEEDFPAAPRLYWDDLKRKLSEKLDTTDFT STIKLLNENLYVPREAGSQKDENLALYIENQFREFKLSKVWRDQHFVKIQVKDSAQNSVI IVDKNGGLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLDSPVNGSIVIVRA GKITFAEKVANAESLNAIGVLIYMDQTKFPIVKADLSFFGHAHLGTGDPYTPGFPSFNHT QFPPSQSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCKMVTSENKSVKLTVS NVLKETKILNIFGVIKGFVEPDHYVVVGAQRDAWGPGAAKSSVGTALLLKLAQMFSDM VLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKV SASPLLYTLIEKTMQDVKHPVTGRSLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERIPELNKVARAAAEVAGQFVIKLTHDTELNLDYERY NSQLLLFLRDLNQYRADVKEMGLSLQWLYSARGDFFRATSRLTTDFRNAEKRDKFVM KKLNDRVMRVEYYFLSPYVSPKESPFRHVFWGSGSHTLSALLESLKLRRQNNSAFNETL FRNQLALATWTIQGAANALSGDVWDIDNEFhTfR-ECD-6His; SEQ ID NO: 81HHHHHHCKGVEPKTECERLAGTESPVREEPGEDFPAARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREFKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARAAAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARGDFFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFL SP YVSPKE SPFRHVFWGSGSHTLP ALLENLK LRKQNNG AFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF

Claims

CLAIMS1. An antibody or antigen-binding fragment thereof that binds human transferrin receptor (TfR) comprising: a heavy chain variable region (HCVR) comprising heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), and a light chain variable region (LCVR) comprising light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3), and wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are selected from the group consisting of: a) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 13; b) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 16; c) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 17; and d) HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 3, HCDR3 comprises SEQ ID NO: 6, LCDR1 comprises SEQ ID NO: 9, LCDR2 comprises SEQ ID NO: 11, and LCDR3 comprises SEQ ID NO: 18.

2. The antibody or antigen-binding fragment thereof of claim 1 comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the LCVR and HCVR are selected from the group consisting of: a) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 22; b) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 25; c) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 26; and d) HCVR comprises SEQ ID NO: 19 and LCVR comprises SEQ ID NO: 27.

3. The antibody of claim 2 comprising a Heavy chain (HC) and a Light chain (LC), wherein the HC and LC are selected from the group consisting of:a) HC of SEQ ID NO: 28 and LC of SEQ ID NO: 37; b) HC of SEQ ID NO: 29 and LC of SEQ ID NO: 37; c) HC of SEQ ID NO: 33 and LC of SEQ ID NO: 39; and d) HC of SEQ ID NO: 36 and LC of SEQ ID NO: 39.

4. The antibody of claim 2 comprising two Heavy chains (HC) and two Light chains (LC), wherein the HC and LC are selected from the group consisting of: a) HC of SEQ ID NO: 28 and LC of SEQ ID NO: 37; b) HC of SEQ ID NO: 29 and LC of SEQ ID NO: 37; c) HC of SEQ ID NO: 33 and LC of SEQ ID NO: 39; and d) HC of SEQ ID NO: 36 and LC of SEQ ID NO: 39.

5. The antibody of claim 2 comprising two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein the HC and LC are selected from the group consisting of: a) HCA of SEQ ID NO:30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 37; b) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 42; c) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 43; and d) HCA of SEQ ID NO: 30, HCB of SEQ ID NO: 31, and LC of SEQ ID NO: 44.

6. The antibody of any one of claims 1-5, wherein the antibody or antigen-binding fragment thereof binds an epitope comprising one or more residues in LFGNMEGDCPSDWKTDSTCR (SEQ ID NO: 45) of TfR.

7. The antigen-binding fragment of any one of claims 1-6, wherein the antigenbinding fragment is a Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, scFv-Fc, Diabody, scFab, scFv-CH3, Fv, scFa, disulfide-linked Fvs (sdFv), or a Fd fragment.

8. The antibody or antigen-binding fragment thereof of any one of claims 1-7, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising cysteine at residue 124 (according to the EU Index numbering).

9. The antibody or antigen-binding fragment thereof of any one of claims 1-7 further comprising a half-life extender.

10. The antibody or antigen-binding fragment thereof claim 9, wherein the half-life extender is selected from an immunoglobulin Fc region or a VHH that binds human serum albumin (HSA).

11. The antibody or antigen-binding fragment thereof of claim 9 or 10, wherein the half-life extender is an immunoglobulin Fc region.

12. The antibody or antigen-binding fragment thereof of claim 9 or 10, wherein the half-life extender is a VHH that binds human serum albumin (HSA).

13. The antibody of claim 1 or claim 2, wherein the antibody comprises one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 28 and the LC comprises SEQ ID NO: 37.

14. The antibody of claim 1 or claim 2, wherein the antibody comprises one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 29 and the LC comprises SEQ ID NO: 37.

15. The antibody of claim 1 or claim 2, wherein the antibody comprises one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 33 and the LC comprises SEQ ID NO: 39.

16. The antibody of claim 1 or claim 2, wherein the antibody comprises one heavy chain (HC) and one light chain (LC), and wherein the HC comprises SEQ ID NO: 36 and the LC comprises SEQ ID NO: 39.

17. The antibody of claim 5, wherein the antibody comprises two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 37.

18. The antibody of claim 5, wherein the antibody comprises two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 42.

19. The antibody of claim 5, wherein the antibody comprises two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 43.

20. The antibody of claim 5, wherein the antibody comprises two variants of Heavy chain (HCA and HCB) and a Light chain (LC), wherein HCA comprises SEQ ID NO: 30, HCB comprises SEQ ID NO: 31, and LC comprises SEQ ID NO: 44.

21. A nucleic acid molecule encoding for the antibody or antigen-binding fragment thereof of claims 1-20.

22. A vector comprising the nucleic acid molecule of claim 21.

23. A mammalian cell comprising the nucleic acid molecule of claim 21.

24. The mammalian cell of claim 23, wherein the mammalian cell is capable of expressing the antibody or fragment thereof.

25. A composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-20 and a carrier, diluent, or excipient.

26. A pharmaceutical composition comprising a) a conjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1-20 and a payload or a therapeutic agent; and b) pharmaceutically acceptable carrier, diluent, or excipient.

27. A method of treating a CNS disease in a patient in need thereof, the method comprising administering to the patient an effective amount of i) a conjugate comprising the antibody or antigen-binding fragment thereof of claims 1-20 and a payload or a therapeutic agent, or ii) the pharmaceutical composition of claim 26.

28. A method of treating or reducing pain in a patient in need thereof, the method comprising administering to the patient an effective amount of i) a conjugate comprising the antibody or antigen-binding fragment thereof of claims 1-20 and a payload or a therapeutic agent, or ii) the pharmaceutical composition of claim 26.

29. A method of making a conjugate, the method comprising conjugating the antibody or antigen-binding fragment thereof of claims 1-20 to a therapeutic agent or a payload.

30. A method of delivering a therapeutic agent or a payload to dorsal root ganglion (DRG) of a patient in need thereof, the method comprising administering an effective amount of a conjugate to the patient, wherein the conjugate comprises the antibody or antigen-binding fragment thereof of any one of claims 1-20 and a therapeutic agent or a payload.

31. Use of the antibody or antigen-binding fragment thereof of any one of claims 1-20 in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain.

32. Use of the pharmaceutical composition of claim 26 in the manufacture of a medicament for i) treating a CNS disease or ii) treating or reducing pain.

33. The antibody or antigen-binding fragment thereof of any one of claims 1-20 for use in treatment of a CNS disease in a patient in need thereof.

34. The antibody or antigen-binding fragment thereof of any one of claims 1-20 for use in treatment or reduction of pain in a patient in need thereof.

35. The pharmaceutical composition of claim 26 for use in the treatment of a CNS disease or ii) in the treatment or reduction of pain.

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