Anti-transferrin receptor 1 (Anti-TFR1) antibodies, compositions, and methods for use in TFR1-mediated delivery of therapeutic payloads

Abstract

[000435] The present disclosure provides anti-transferrin receptor 1 (anti-TfRl) antibodies. In embodiments, the anti-TfRl antibodies can be deployed as targeting agents for delivery of conjugated therapeutic payloads to cells expressing TfRl. The anti-TfRl delivery agents bind specifically to TfRl and facilitate receptor-mediated internalization of conjugated, complexed, or fused therapeutic payloads, including nucleic acid molecules (e.g., antisense oligonucleotides, siRNAs) and therapeutic proteins (e.g., antibodies, enzymes). In preferred embodiments, the anti-TfRl delivery agents do not significantly activate TfRl-dependent signaling and function as inert shuttles for payload delivery. The disclosure encompasses anti-TfRl antibodies and fragments thereof, payload-delivery agent complexes and conjugates, compositions, polynucleotides and vectors encoding the anti-TfRl antibodies, cells comprising such components, and methods for TfRl -mediated delivery of therapeutic payloads to target cells. The delivery platform enables efficient intracellular delivery of diverse therapeutic modalities that would otherwise exhibit poor cell permeability, expanding their therapeutic potential across various diseases and conditions.

Description

PCT APPLICATION ANTI- TRANSFERRIN RECEPTOR 1 (ANTI-TFR1) ANTIBODIES, COMPOSITIONS, AND METHODS FOR USE IN TFR1-MEDIATED DELIVERY OF THERAPEUTIC PAYLOADSRELATED APPLICATIONS

[0001] This application claims the benefit under 35 U. S. C. § 119(e) of U. S.Provisional Application No. 63 / 756101, filed on February 8, 2025, the entire contents of which is hereby incorporated by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (A136170026WO00-SEQ-GJM.xml; Size: 292,246 bytes; and Date of Creation: February 6, 2026) is herein incorporated by reference in its entirety.TECHNICAL FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to anti-transferrin receptor 1 antibodies (anti-TfRl antibodies) and antibody fragments thereof. In some embodiments, these antibodies serve as delivery agents for TfRl -mediated delivery of payloads, such as therapeutic payloads, such as, nucleic acid molecules (e.g. ASO) and therapeutic proteins (e.g. monospecific, bispecific, and multispecific antibodies), and diagnostic agents. The disclosure also provides composition and methods for TfRl -mediated delivery of payloads to cells of interest and other uses thereof. This disclosure also provides related polynucleotides and vectors encoding the anti-TfRl antibodies and cells comprising the same.BACKGROUND

[0004] Many promising therapeutic agents, including nucleic acid-based therapeutics such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), as well as protein-based therapeutics such as antibodies and enzymes, face significant challenges in achieving efficient intracellular delivery. The cell membrane represents a substantial barrier to the uptake of these typically large, charged, or hydrophilic molecules, limiting their therapeutic efficacy even when they possess potent activity against intracellular targets.

[0005] The transferrin receptor 1 (TfRl), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds iron-bound transferrin (Tf) and plays a crucial role in cellular iron uptake by internalization through receptor-mediated 1#14904047v2PCT APPLICATION endocytosis to acidic vesicles. There, the iron-transferrin complex is released from the receptor (TfRl) and becomes disassociated, whereafter the iron becomes available to the cell and the unbound transferrin and TfRl are recycled back to the cell surface. Iron is vital for various cellular functions, including DNA synthesis and cell proliferation. Due to its widespread expression and constitutive internalization, TfRl has been explored as a potential route for delivering therapeutic and / or diagnostic agents into cells. However, many existing TfRl -targeting approaches may activate receptor signaling or interfere with normal transferrin binding and iron homeostasis, potentially leading to undesired biological effects.

[0006] There remains a need for improved delivery agents that can efficiently shuttle therapeutic and / or diagnostic payloads into TfRl-expressing cells via receptor-mediated TfRl -dependent endocytosis without significantly disrupting normal TfRl function or activating unwanted signaling pathways. The present disclosure addresses these needs by providing novel anti-TfRl antibodies and antibody fragments which in some embodiments can function as inert delivery agents for a broad range of therapeutic payloads.SUMMARY

[0007] The present disclosure relates to anti-transferrin receptor 1 (anti-TfRl) antibodies and antibody fragments thereof. In various embodiments, these antibodies may be deployed as delivery agents for TfRl-mediated delivery of therapeutic payloads (e.g., nucleic acid molecules such as ASOs and siRNAs; therapeutic proteins such as monospecific, bispecific, and multispecific antibodies) and diagnostic agents. The disclosure further provides compositions and methods for TfRl-mediated payload delivery to target cells, as well as related polynucleotides, vectors, and cells.

[0008] The present disclosure addresses the need for improved intracellular delivery of a payloads by providing novel anti-transferrin receptor 1 (anti-TfRl) antibodies and antibody fragments that function as highly efficient delivery agents for therapeutic or diagnostic payloads. The anti-TfRl delivery agents of the invention bind specifically to TfRl expressed on target cells and facilitate receptor-mediated internalization of conjugated payloads, including but not limited to antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), therapeutic proteins, antibodies, and targeted protein degradation agents. The delivery agents when conjugated with a payload (e.g. a therapeutic or diagnostic payload) is defined herein as a “delivery platform” or “delivery system.” In preferred embodiments, the anti-TfRl delivery agents of the herein delivery systems are inert, i.e. do not or do not substantially modulate TfRl -dependent signaling and thereby functioning solely as shuttles 2#14904047v2PCT APPLICATION for payload delivery without themselves exhibiting therapeutic activity. Accordingly, in certain embodiments, inert anti-TfRl antibodies minimize potential interference with normal TfRl biological function, such as transferrin binding and iron homeostasis. By exploiting the natural endocytic pathway of TfRl while remaining inert themselves as to TfRl-mediated signaling, the delivery agents of the disclosure enable efficient intracellular delivery of diverse therapeutic or diagnostic modalities to target cells, thereby overcoming the substantial barrier posed by the cell membrane and expanding the therapeutic potential of payload molecules that would otherwise exhibit poor cell permeability.

[0009] Accordingly, in one aspect, the disclosure provides improved TfRl antibodies or fragments thereof for use as delivery agents which may be conjugated to a therapeutic agent or payload of interest, such as, but not limited to, an antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), therapeutic protein, antibody, or a targeted protein degradation agent to provide a delivery system of the disclosure (i.e. the delivery agent conjugated to a payload).

[0010] In various embodiments, the anti-TfRl antibodies that may be used as a delivery agent may include antibodies described in Table X herein (e.g. Ab.l, Ab.2, Ab.3, Ab.4, Ab.5, Ab.6, Ab.7, Ab.8, Ab.9, Ab.10, Ab.ll, Ab.12, Ab.13, Ab.14, Ab.15, Ab.16, Ab.17, Ab.18, Ab.19, Ab.20, Ab.21, Ab.22, Ab.23, Ab.24, Ab.25, and Ab.26), or a variant of any one of the antibodies of Table X, wherein said variant antibodies may comprise at least one VH, HC, VL, or LC region having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or up to 100% sequence identity the corresponding sequence identifiers for the VH, HC, VL, and LC regions of Table X.

[0011] In still some embodiments, the anti-TfRl antibodies that may be used as a delivery agent herein may comprise one or more amino acid sequences described in Table I.

[0012] In yet some embodiments, the anti-TfRl antibodies that may be used as a delivery agent herein may comprise one or more amino acid sequences described in Table II.

[0013] In still some embodiments, the anti-TfRl antibodies for use as a target agent may comprise:(i) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124-130, and(ii) a heavy chain, and optional wherein the heavy chain comprises an amino acid sequence that is selected from the group consisting of SEQ ID NOs: 66-91.3#14904047v2PCT APPLICATION

[0014] In yet some embodiments, the anti-TfRl antibodies for use as a target agent may comprise:(i) a light chain, and(ii) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-91, and wherein the light chain comprises an amino acid sequence that is selected from the group consisting of SEQ ID NOs: 124-130.

[0015] In further embodiments, the anti-TfRl antibodies for use as a target agent may comprise:(i) a light chain comprising an amino acid sequence that is selected from the group consisting of SEQ ID NOs: 124-130, and(ii) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-91.

[0016] In still further embodiments, the anti-TfRl antibodies for use as a target agent may comprise:(i) a variable light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 96-102,(ii) a variable light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103-109, and (iii) a variable light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 110-116, and (iv) variable heavy chain CDR1, CDR2, and CDR3.

[0017] In still further embodiments, the anti-TfRl antibodies for use as a target agent may comprise:(i) a variable light chain CDR1, CDR2, and CDR3, and(ii) a variable heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-12,(iii) a variable heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-20, and (iv) a variable light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21-40.

[0018] In still further embodiments, the anti-TfRl antibodies for use as a target agent may comprise:4#14904047v2PCT APPLICATION (i) a variable light chain amino acid sequence comprising SEQ ID NO:122 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 41,(ii) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 42,(iii) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 43,(iv) a variable light chain amino acid sequence comprising SEQ ID NO:118 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 44,(v) a variable light chain amino acid sequence comprising SEQ ID NO:120 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 45,(vi) a variable light chain amino acid sequence comprising SEQ ID NO:118 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 47,(vii) a variable light chain amino acid sequence comprising SEQ ID NO:118 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 48,(viii) a variable light chain amino acid sequence comprising SEQ ID NO:118 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 52,(ix) a variable light chain amino acid sequence comprising SEQ ID NO:120 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 50,(x) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 49,(xi) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 55,5#14904047v2PCT APPLICATION (xii) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 56,(xiii) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 54,(xiv) a variable light chain amino acid sequence comprising SEQ ID NO:122 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 46,(xv) a variable light chain amino acid sequence comprising SEQ ID NO:122 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 51,(xvi) a variable light chain amino acid sequence comprising SEQ ID NO:123 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 53,(xvii) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 57,(xviii) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 58,(xix) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 59,(xx) a variable light chain amino acid sequence comprising SEQ ID NO:123 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 60,(xxi) a variable light chain amino acid sequence comprising SEQ ID NO:121 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 61,(xxii) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 62,6#14904047v2PCT APPLICATION (xxiii) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 64,(xxiv) a variable light chain amino acid sequence comprising SEQ ID NO:117 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 64,(xxv) a variable light chain amino acid sequence comprising SEQ ID NO:120 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 63, or(xxvi) a variable light chain amino acid sequence comprising SEQ ID NO:119 and a variable heavy chain amino acid sequence comprising SEQ ID NO: 65.

[0019] In various embodiments, the antibodies of any of the above paragraphs can be in the format of a full-length IgG, a Fab fragment, a F(ab') fragment, a F(ab’)2 fragment, a scFv, or aFv.

[0020] In various embodiments, the antibodies of any of the above paragraphs can of the isotype of IgGl, IgG2, IgG3, or IgG4.

[0021] In one aspect, the present disclosure relates to the development of anti-TfRl antibodies or proteins having an antigen-binding portion of an anti-TfRl antibody that specifically recognize and bind TfRl. As used herein, the term “antibody” — which is defined in the definition section — includes proteins having an antigen-binding portion of an anti-TfRl antibody.

[0022] The disclosure provides additional non-limiting embodiments described by the following numbered paragraphs, as follows.1. An antibody or an antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment comprises:a. a heavy chain variable (VH) domain comprising a heavy chain complementarity determining region (HC CDR1) having the sequence of SEQ ID NO: 4, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 24, and a light chain variable (VL) domain comprising a light chain complementarity determining region (LC CDR1) having the sequence of SEQ ID NO: 101, a LC CDR2 having the sequence of SEQ ID NO: 104, and a LC CDR3 having the sequence of SEQ ID NO: 111; b. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 6, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID 7#14904047v2PCT APPLICATION NO: 31, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 100, a LC CDR2 having the sequence of SEQ ID NO: 106, and a LC CDR3 having the sequence of SEQ ID NO: 114;c. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 9, a HC CDR2 having the sequence of SEQ ID NO: 19, and a HC CDR3 having the sequence of SEQ ID NO: 37, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 96, a LC CDR2 having the sequence of SEQ ID NO: 109, and a LC CDR3 having the sequence of SEQ ID NO: 116;d. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 11, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 28, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 97, a LC CDR2 having the sequence of SEQ ID NO: 104, and a LC CDR3 having the sequence of SEQ ID NO: 111; ore. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 5, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 26, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 101, a LC CDR2 having the sequence of SEQ ID NO: 105, and a LC CDR3 having the sequence of SEQ ID NO: 111.2. The antibody or antigen-binding fragment of paragraph 1, comprising:a. a VH having the sequence of SEQ ID NO: 44 and a VL having the sequence of SEQ ID NO: 118;b. a VH having the sequence of SEQ ID NO: 54 and a VL having the sequence of SEQ ID NO: 121;c. a VH having the sequence of SEQ ID NO: 60 and a VL having the sequence of SEQ ID NO: 123;d. a VH having the sequence of SEQ ID NO: 63 and a VL having the sequence of SEQ ID NO: 120; ore. a VH having the sequence of SEQ ID NO: 47 and VL having the sequence of SEQ ID NO: 118.3. The antibody or antigen-binding fragment of paragraph 1 or paragraph 2, further comprising:8#14904047v2PCT APPLICATION a. a heavy chain (HC) having the sequence of SEQ ID NO: 69 and a light chain (LC) having the sequence of SEQ ID NO: 125;b. a HC having the sequence of SEQ ID NO: 79 and a LC having the sequence of SEQ ID NO: 128;c. a HC having the sequence of SEQ ID NO: 85 and a LC having the sequence of SEQ ID NO: 130;d. a HC having the sequence of SEQ ID NO: 88 and a LC having the sequence of SEQ ID NO: 127; ore. a HC having the sequence of SEQ ID NO: 72 and a LC having the sequence of SEQ ID NO: 125.4. The antibody or antigen binding fragment of any of paragraphs 1-3, wherein the antibody or antigen-binding fragment is selected from:a. a full-length immunoglobulin G (IgG),b. a Fab fragment,c. a monovalent Fab-Fc constructd. a F(ab') fragment,e. a F(ab')2 fragment,f. a single-chain variable fragment (scFv),g. a variable fragment (Fv),h. a single-domain antibody (nanobody),i. a diabody, orj. a triabody.5. A composition comprising the antibody or antigen-binding fragment of any of the preceding paragraphs and a therapeutic agent.6. The composition of paragraph 5, wherein the therapeutic agent is selected from a double stranded RNA, oligonucleotide, peptide, small molecule, antibody or antigen binding fragment thereof, or a combination thereof.7. The composition of paragraph 5 or paragraph 6, comprising an antibody-oligonucleotide conjugate (AOC) comprising an antibody according to any one of paragraphs 1-4.9#14904047v2PCT APPLICATION8. The composition of paragraph 5 or paragraph 6, comprising a bispecific antibody, wherein the bispecific antibody comprises an antibody according to any one of paragraphs 1-4.9. The composition of paragraph 5 or paragraph 6, comprising a fusion protein comprising an antibody according to any one of paragraphs 1-4.10. An isolated nucleic acid encoding the antibody or antigen-binding fragment thereof of any of the preceding paragraphs.11. A composition comprising:a. A TfRl-binding domain that is an anti-TfRl antibody or antigen-binding fragment thereof of any of the preceding paragraphs;b. An oligonucleotide that is complementary to at least a portion of a target mRNA; and c. A linker that conjugates at least one amino acid residue of the anti-TfRl antibody or antigen-binding fragment thereof to a nucleotide position selected from the 3’- or 5-end of the oligonucleotide.12. The composition of paragraph 11, wherein the oligonucleotide is an antisense oligonucleotide (ASO).13. The composition of paragraph 11 or paragraph 12, wherein the linker is cleavable linker.14. The composition of any of paragraphs 11-13, wherein the linker comprises a Val-Cit moiety or an MCC moiety.15. The composition of paragraph 11, wherein the mRNA target is selected from a CNS, PNS, neuromuscular or cardiac muscle target.16. The composition of paragraph any one of paragraphs 11-15, wherein the mRNA target is transcribed from a gene selected from the group consisting of SMN2, SNCA, HTT, GFAP, APOE, APP, NEFL, MFN2, DMPK, DMD, SOD1, DUX4, DNMT3A, or APOB.10#14904047v2PCT APPLICATION17. The composition of any one of paragraphs 11-15, wherein the mRNA target encodes a gene product selected from the group consisting of SMN2, alpha- synuclein, huntingtin (HTT), STMN2, GFAP, apolipoprotein E4 (ApoE4), tau protein, and amyloid precursor protein (APP), neurofilament light chain (NEFL), PMP22, MGN22, MPZ, sodium channel proteins, DMPK, dystrophin, SOD1, DUX4, IGHMBP2, GYSI, DMN2, macrophage inflammatory targets, DNA methyltransferase 3 A, or apolipoprotein B.18. A pharmaceutical composition comprising the composition of any of the preceding paragraphs, and a pharmaceutically acceptable carrier.19. A multi- specific binding molecule comprising:a. A first binding domain according to any one of paragraphs 1-4; andb. one or more additional binding arms second binding domain that specifically binds a therapeutically effective target.20. The multi-specific binding molecule of paragraph 19, wherein:a. A first heavy chain comprises a first VH sequence and a first constant Fc fragment; andb. A second heavy chain comprises a second VH sequence and a second constant Fc fragment.21. The multi-specific binding molecule of paragraph 29, wherein the therapeutically effective target is selected from a central nervous system (CNS), peripheral nervous system (PNS), neuromuscular, or cardiac muscle target.22. The multi-specific binding molecule of any one of paragraphs 19-21, wherein the therapeutically effective target is selected from epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), alpha-synuclein, huntingtin, a sodium channel protein, a macrophage inflammatory target, or DNMT3A.23 An isolated nucleic acid encoding the multi- specific binding molecule of any of the preceding paragraphs.11#14904047v2PCT APPLICATION 24. A method of delivering an antibody or oligonucleotide across the blood-brain barrier (BBB) of a subject in need thereof, comprising administering to the subject a complex comprising the multi-specific binding molecule of any of the preceding paragraphs, or the composition of any of the preceding paragraphs.25. The method of paragraph 24, the method comprising treating or detecting a disorder, in a subject in need thereof, by administering to the subject the composition of any of the preceding paragraphs, or the pharmaceutical composition of paragraphs.26. The method of paragraph 25, wherein the disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, epilepsy, autism spectrum disorders, multiple sclerosis, myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy, neuromuscular disorders, spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy, spinal muscular atrophy with respiratory distress type 1, cardiovascular diseases, cardiac dysfunction, hypercholesterolemia, atherosclerosis, dyslipidemia, and cardiovascular disease risk.

[0023] The foregoing and other aspects, implementations, acts, functionalities, features and embodiments of the present teachings can be more fully understood from the following description in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments, and together with the written description, serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein.

[0025] FIG. 1A shows a schematic depicting the biological process of transferrin binding to TfRl, followed by TfRl-mediated endocytosis, iron release in the endosomal body, and recycling of the transferrin and TfRl to the cell surface.

[0026] FIG. IB shows the structure of TfRl in panel A. Panel B shows the formation of diferric transferrin / TfRl complex at the surface of a cell that expresses the receptor. (A) This receptor is a type II receptor found on the cell surface as a homodimer consisting of two monomers linked by disulfide bonds at cysteine (Cys) residues 89 and 98. The TfRl contains an intracellular domain, a transmembrane domain, and a large extracellular domain. There is 12#14904047v2PCT APPLICATION an O-linked glycosylation site at threonine (Thr) 104 ( ▲ ) and three N-linked glycosylation sites on asparagine (Asn) residues 251, 317, and 727 (•). The extracellular domain of the TfRl consists of three subdomains: apical (A), helical (H), and protease-like domain (P). (B) TfRl consists of a dimer on the surface of the cell. Each receptor monomer binds one Tf molecule that consists of lobes (the N- and C-lobes). Each lobe binds one iron atom. Diferric Tf, also known as holo-Tf, contains two atoms of iron and binds to the receptor with high affinity.

[0027] FIG. 1C shows the general structure of an IgG immunoglobulin as an embodiment of the antibodies contemplated herein, and which is further annotated to indicate the position of the disclosed exemplary sequences from Tables I and II herein. The herein disclosed antibodies may be formatted as IgG immunoglobulins but are not limited thereto as described herein (and may include antibody fragments of any configuration (e.g. see FIG. ID), bispecific antibodies or antibody fragments, multispecific antibodies or antibody fragments, drug-antibody conjugates). The isotype IgG molecule consists of four polypeptide chains (two heavy chains and two light chains) joined together by disulfide bridges. The light chain consists of a variable light (VL) constant light (CL) region, and the heavy chain consists of one VH chain linked to three constant regions (CHI, CH2, and CH3). The Fc region consisting of the disulfide hinge, CH2, and CH3 consisting of the disulfide hinge, CH2, and CH3 is important for mediating immune system effector functions, and Protein-A and -G binding. Abbreviations: Fab, fragment antigen binding; Fc, fragment crystallizable; IgG, immunoglobulin G; Ag, antigen.

[0028] FIG. ID depicts the general structures for IgG, IgM, and IgA immunoglobulins in panel A in mice, rats, and humans. Without limitation, the herein disclosed antibodies may be formatted as IgG, IgM, or IgA immunoglobulins in various embodiments. Panel B depicts the general structures for mouse, mouse / human chimeric, humanized, and human IgG antibodies. The herein disclosed antibodies may be formatted in each of these configurations in various embodiments. Panel C depicts a non-limiting set of alternative structures of antibodies or antigen binding fragments, including IgGl, IgG3, IgG3-_Av, scFv, bivalent scFv, monovalent Fab-Fc (e.g. see FIG. 1 J) and scFv-Fc. The herein disclosed antibodies may be formatted in each of these configurations in various embodiments, as well as other not shown.

[0029] FIG. IE provides a schematic of an antibody-drug conjugate comprising an anti-TfRl antibody and a payload (e.g., a cytotoxin agents, immune- stimulant agents, or ASO agents), wherein the payload is covalently joined to the antibody by a linker (e.g., a cleavable 13#14904047v2PCT APPLICATION linker or a non-cleavable linker), the antibody may be in any format (e.g., antibody fragments), and may be designed to target a single antigen (e.g., TfRl), or multiple antigens (e.g., TfRl and a target antigen on or within a cell, such as a therapeutic target).

[0030] FIG. IF provides a schematic depicting the use of a bispecific antibody of the present disclosure for immune cell activation against cancer cells. Here, the antibody is designed with an anti-TfRl arm which is capable of binding to a TfRl expressed on the surface of a cancer cell target. The other arm of the antibody targets an antigen on an immune cell, such as a cytotoxic T cell (e.g., wherein the anti-immune cell antigen binding arm is designed to bind to a T cell antigen which results in immunoactivation of the T cell against the cancer cell). Such antibodies may also be configured to included one or more therapeutic agents coupled to thereto in the form of a antibody-drug conjugate (ADCs). Such ADC may comprise agents such as small molecules, peptides, and ASOs. Such agents may have one more therapeutic activities, such as cytotoxicity and / or immunoregulatory functions.

[0031] FIG. 1G provides a schematic depicting the use of a bispecific antibody of the present disclosure for targeting a therapeutic target in a cell via shuttling of the bispecific antibody into the cell via the TfRl. Such bispecific antibodies may be designed with an anti-TfRl arm which is capable of binding to a TfRl expressed on the surface of a target cell of interest that expresses a therapeutic target. The other arm of the bispecific antibody binds to the therapeutic target. Such target cells may include any cell that expresses TfRl, including but not limited to CNS cell, PNS cells, neuromuscular cells, metabolic cells, and cardiac cells. Such antibodies may also be configured to included one or more therapeutic agents coupled to thereto in the form of a antibody-drug conjugate (ADCs). Such ADC may comprise agents such as small molecules, peptides, and ASOs. Such agents may have one more therapeutic activities, such as cytotoxicity and / or immunoregulatory functions.

[0032] FIG. 1H provides a schematic depicting the use of a bispecific antibody of the present disclosure for targeting a therapeutic target specifically in the brain via shuttling of the bispecific antibody across the blood-brain barrier (BBB) and into the brain wherein the bispecific antibody may bind to its therapeutic target. Such bispecific antibodies may be designed with an (a) anti-TfRl arm which is capable of binding to a TfRl expressed on the surface of an endothelial cell of the blood-brain barrier. The other arm (b) of the bispecific antibody binds to the therapeutic target that is expressed in the brain (“the therapeutic target arm”). Such antibodies may also be configured to included one or more therapeutic agents coupled to thereto in the form of a antibody-drug conjugate (ADCs). Such ADC may comprise agents such as small molecules, peptides, and ASOs. Such agents may have one 14#14904047v2PCT APPLICATION more therapeutic activities, such as cytotoxicity and / or immunoregulatory functions.

[0033] FIG. II provides a schematic depicting the use of a bispecific antibody of the present disclosure for targeting a extracellular antigen or a cell-surface antigen for endocytotic degradation. Such bispecific antibodies may be designed with an (a) anti-TfRl arm which is capable of binding to a TfRl expressed on the surface of an target cell that expresses an antigen of interest either on the cell surface or extracellularly. The other arm (b) of the bispecific antibody binds to the antigen of interest. The antigen of interest is then shuttled inside of the target cell via TfRl-mediated endocytosis into an endosome which leads to the destruction of the bound antigen of interest. Such antibodies may also be configured to included one or more therapeutic agents coupled to thereto in the form of a antibody-drug conjugate (ADCs). Such ADC may comprise agents such as small molecules, peptides, and ASOs. Such agents may have one more therapeutic activities, such as cytotoxicity and / or immunoregulatory functions.

[0034] FIG. 1 J provides a schematic depicting the use of a particular embodiment an anti-TfRl antibody of the present disclosure, namely a monovalent Fab-Fc format. In the embodiment shown, the antibodies comprise a heterodimeric knob-in-hole Fc used to express a subset of the TfRl antibodies / Such antibodies may be configured with three amino acid chains: (a) a light chain comprising a variable light (“VL”) region and a light chain constant region (“C”); (b) a heavy chain comprising a variable heavy (“VH”) region and a constant region (“C”), and an Fc region; and (c) an “empty” Fc region. In embodiments, the VH / VL regions are configured to bind to TfRl. In embodiments, the L chain, H chain, VL, VH, and CDR sequences in both the VH and VL regions may comprising any of the corresponding sequences provided in Tables I (exemplary heavy chain sequences) and II (exemplary light chain sequences). In some embodiments, the empty Fc domain may comprise a purification tag, such as a His-6 tag. In addition, the Fc domains may include one or more mutations, such knob-in-hole mutations (e.g., “knob” mutations (k) such as T366W, S354C mutations relative to isotype IgG numbering, or at an equivalent position in the Fc domains of any of the herein disclose full heavy chain sequences of Table I, and “hole” mutations (h) such as T366S, L368A, Y407V, Y349C mutations relative to isotype IgG numbering, or at an equivalent position in the Fc domains of any of the herein disclose full heavy chain sequences of Table I. The monovalent Fab-Fc format may also comprise a covalent linkage (1), such as a disulfide bridge, that couples the light chain to the heavy chain.

[0035] FIG. 2A provides binding kinetic measurements (ka and kd) against recombinant human TfRl as measured on a Carterra LSA instrument for the set of discovered TfRl 15#14904047v2PCT APPLICATION antibodies and two comparator antibodies (anti-TfRl Comp. A and anti-TfRl Comp. B) against TfRl. Each dot represents a single anti-TfRl clone. The diagonal lines represent equilibrium binding constant values for each clone calculated as kd / ka.

[0036] FIG. 2B provides binding kinetic measurements (ka and kd) against recombinant cynomolgus macaque (cyno) TfRl as measured on a Carterra LSA instrument for the set of discovered TfRl antibodies and two comparator antibodies against TfRl (anti-TfRl Comp. A and anti-TfRl Comp. B). Each dot represents a single anti-TfRl clone. The diagonal lines represent equilibrium binding constant values for each clone calculated as kd / ka.

[0037] FIG. 3A provides exemplary binding traces and calculated values for association (ka) and dissociation (kd) kinetics of seven exemplary anti-TfRl antibodies (Ab.26, Ab.14, Ab.15, Ab.l, Ab.6, Ab.8, and Ab.5 of Table X) from the Carterra LSA experiment measuring binding to recombinant human TfRl presented in Figure 2A

[0038] FIG. 3B provides exemplary binding traces and calculated values for association (ka) and dissociation (kd) kinetics of seven exemplary anti-TfRl antibodies (Ab.26, Ab.14, Ab.15, Ab.l, Ab.6, Ab.8, and Ab.5 of Table X) from the Carterra LSA experiment measuring binding to recombinant human TfRl presented in Figure 2 A

[0039] FIG. 4 provides a summary of cell binding for each discovered TfRl antibody of Table X against two cell lines that endogenously express human TfRl (LN-229 and HEK) and two cell lines engineered to express either human (ATX-D3102) or cynomolgus macaque (ATX-D3580) TfRl. TfRl antibodies were incubated with cells at a single 100 nM concentration and binding measured by flow cytometry with a fluorescently labeled antihuman IgG secondary. Mean fluorescence intensity (MFI) values are reported for each TfRl binding clone compared to two comparator anti-TfRl antibodies (Comp A and Comp B) and an isotype control.

[0040] FIG. 5A provides a summary of the purity of each discovered anti-TfRl antibody of Table X as measured by capillary electrophoresis (CE-SDS). Each dot represents an individual clones that binds TfRl and the dashed line represents a cut-off of 90% purity.

[0041] FIG. 5B provides a summary of the purity of each discovered anti-TfRl antibody of Table X as measured by size exclusion chromatography (SEC) that can detect the presence of aggregates or degradation species. Each dot represents an individual clones that binds TfRl and the dashed line represents a cut-off of 90% purity.

[0042] FIG. 5C provides a summary of the thermal stability or melting temperature of each discovered anti-TfRl antibody of Table X as measured by differential scanning fluorimetry (DSF). Each dot represents an individual clone that binds TfRl with higher 16#14904047v2PCT APPLICATION values indicating a more stable antibody, and the dashed line represents a cut-off of 58°C

[0043] FIG. 5D provides a summary of the aggregation propensity of each discovered anti-TfRl antibody of Table X as measured by AC- SINS. Each dot represents an individual clone that binds TfRl with lower values in the assay indicating a clone that is less likely to aggregate.

[0044] FIG. 5E provides a summary of the polyreactivity of each discovered anti-TfRl antibody of Table X as measured by a BVP-ELISA assay. Each dot represents an individual clone that binds TfRl with lower values in the assay indicating a clone that is less likely to have polyreactive binding to non-TfRl proteins.

[0045] FIG. 6A provides a cross-blocking experiment performed on the Carterra LSA in which each pair of discovered TfRl antibodies of Table X was tested to determine if both antibodies are able to simultaneously bind to TfRl (indicating that they bind to nonoverlapping epitopes) or are unable to simultaneously bind to TfRl (indicating that they bind to overlapping epitopes). Each row represents an immobilized antibody of Table X in the assay and each column represents the corresponding soluble antibody of Table X used in the assay. Red colored squares indicate combinations that are unable to bind TfRl simultaneously (and thus where the tested antibody pairs from Table X bind to overlapping epitopes thereby blocking one another from binding to TfRl), green colored squares indicate combinations that are able to bind TfRl simultaneously (indicating each of the antibodies from Table X tested in combination each bind to non- overlapping epitopes thus both are able to separately bind to TfRl), and yellow colored squares represent combinations where the data are inconclusive.

[0046] FIG. 6B provides a summary of the Carterra LSA cross -blocking experiment presented in Figure 6A. Each circle represents an individual TfRl binding antibody where binding was measured in both an immobilized and soluble format in Figure 6A, while squares represent clones where binding was only measured in a soluble format. Lines between clones indicate that they bind to an overlapping epitope on TfRl as indicated by an inability to simultaneously bind TfRl in the Carterra LSA assay. Solid lines indicate that cross -blocking was measured in both orientations (either antibody immobilized), while dashed lines indicate that cross -blocking was only measured in one orientation. Antibody clones (circles or squared) are clustered with other antibody clones that had the most similar cross -blocking profile indicating that they bind to a similar epitope on TfRl. (a) represents Comp B anti-TfRl antibody which is an intermediate blocker (5.6 nM KD, no mouse cross), (b) represents Ab.20 of Table X which is a non-ligand blocker (0.7 nM KD, weak mouse cross), (c)17#14904047v2PCT APPLICATION represents Comp A anti-TfRl antibody which is an non-ligand blocker (1.5 nM KD, mouse cross), (d) Ab.17 of Table X is an intermediate blocker (4.8 nM KD, mouse cross), (e) a group of Table X antibodies which are ligand-blockers (ligand blockers, 6-40 nM KD, Mixed mouse cross), (f) Abl did not show Cyno cross reactivity, (h) shows that the majority of Abs from Table X are non-ligand blockers which is desired to avoid disrupting Tf trafficking. Non-ligand blockers include Ab.4, AB.5, Ab.6, Ab.7, Ab.9, Ab.10, Ab.11, Ab.12, AB.13, Ab.14, Ab.15, Ab.21, Ab.22, Ab.23, Ab.24, Ab.25 (single VH clonotypes with diverse LC’s; non-ligand bloxkers; subset have mouse cross -reactivity; range of hTfR affinities from 1-100 nM). (g) mixed blocking antibodies from Table X (10-100 nM Kd, no mouse cross).

[0047] FIG. 7 provided exemplary ligand-blocking sensograms for Ab.19 and Ab.20 (although the others were tested as well, data summarized in FIG. 8). The figure provides exemplary traces from a Carterra LSA experiment to determine if discovered anti-TfRl antibodies Ab.19 and Ab.20 of Table X compete with the endogenous ligand transferrin (Tf) for binding to TfRl. Immobilized antibodies were first bound to soluble TfRl, followed by incubation with soluble Tf ligand. A second increase in the binding signal after adding Tf indicates that the antibody and Tf ligand are able to simultaneously bind to TfRl due to binding non-overlapping epitopes, while the lack of an increase after the addition of Tf indicates that the antibody competes for TfRl binding with the Tf ligand.

[0048] FIG. 8 provides a summary of the cross -blocking and ligand blocking experiments described in FIG. 6 A, 6B, and 7. Each circle or square represents an individual TfRl binding clone color coded as competitive binding with the Tf ligand (red), non-competitive binding with the Tf ligand (green), or inconclusive data (yellow).

[0049] FIG. 9 provides an overall summary of the discovered TfRl binding antibodies of Table X including binding kinetics, cell binding, epitope binning, ligand blocking, and developability profile.

[0050] FIG. 10 provides binding kinetic measurements (ka and kd) against recombinant human TfRl and cynomolgus monkey TfRl as measured on a Carterra LSA instrument for the set of discovered TfRl antibodies and four comparator antibodies against TfRl, all expressed as monovalent Fab-Fc fusion proteins. Each dot represents a single anti-TfRl clone. The diagonal lines represent equilibrium binding constant values for each clone calculated as kd / ka.

[0051] FIG. 11 provides a summary of cell binding for each discovered TfRl antibody produced as a monovalent Fab-Fc protein against two cell lines that endogenously express human TfRl (LN-229 and HEK) and one cell line engineered to express cynomolgus18#14904047v2PCT APPLICATION macaque (ATX-D3580) TfRl. TfRl antibodies were incubated with cells at a range of concentrations from 0.0006 to 100 nM and binding measured by flow cytometry with a fluorescently labeled anti-human IgG secondary. Mean fluorescence intensity (MFI) values at each concentration are reported for each TfRl binding clone compared to an isotype control.

[0052] FIG. 12 provides a table summarizing the develop ability measurements for each TfRl antibody produced as a monovalent Fab Fc proteins of FIG. 1J including thermal stability (DSF), aggregation propensity (AC-SINS), and polyreactivity (BVP-ELISA and HEK-IMP). For each row number, the monovalent Fab-Fc antibody is identified with a nomenclature that references the parent Ab from Table X. For example, in row 1, the M. Ab.26 monovalent Fab-Fc antibody is derived from the Ab.26 of Table X. This means that the monovalent M. Ab.26 antibody comprises (a) a LC (or “L”) of SEQ ID NO: 126, (b) a HC (or “H”) of SEQ ID NO: 71, (c) and an empty Fc region, wherein the HC chain of SEQ ID NO: 71 in the Fc region and the empty Fc region each comprise knob-in-hole mutations, such as knob mutations T366W, S354C and hole mutations T366S, L368A, Y407V, and Y349C relative to IgG isoform numbering, or at an equivalent position. Any of the other Table X anti-TfRl antibodies can be configured as a monovalent Fab-Fc variant having the structure of FIG. 1 J based on the sequences from Table X.

[0053] FIG. 13 provides in vitro cellular internalization measurements reported as area under the curve (AUC) for each TfRl antibody of Table X which have been formed as a monovalent Fab-Fc protein in accordance with FIG. 1J at either 1.1 or 10 pg / mL in HEK293 or LN-229 cells that endogenously express human TfRl. Internalization was measured on an Incucyte instrument using Human FabFluor-pH sensitive dye.

[0054] FIGs. 14A and 14B summarizes in vitro cellular internalization measurements reported as area under the curve (AUC) for each TfRl antibody produced as a monovalent Fab-Fc protein at 1.1, 3.3, or 10 pg / mL in HEK293 (FIG. 14A) or LN-229 (FIG. 14B) cells that endogenously express human TfRl. Internalization was measured on an Incucyte instrument using Human FabFluor-pH sensitive dye.

[0055] FIG. 15A summarizes in vitro cellular internalization using flow cytometry analysis of antibody binding to cells for TfRl antibodies produced as a monovalent Fab-Fc protein. Histograms show median fluorescence intensity (MFI) across cell populations, where the x-axis represents cell count and the Y-axis represents MFI. Anti-TfRl antibodies were tested to evaluate binding in cells from huTfR-C57BL / 6 or wild-type C57BL / 6 mice.19#14904047v2PCT APPLICATION

[0056] FIGs. 15B and 15C provide a summary of cell binding for TfRl antibodies produced as monovalent Fab-Fc protein in erythroid (TERI 19+) and non-erythroid (TERI 19-) cell subsets. Bar graphs show frequency of huTfR staining in cells within TERI 19+ and TERI 19- cell populations.

[0057] FIGs. 16A-16F show exemplary images and summaries of biodistribution for each TfRl antibody produced as a monovalent Fab-Fc protein as expressed in mouse brain, liver, and skeletal muscle tissues. FIGs. 16A-16C show representative images of ex vivo tissue from mouse brain, liver, and skeletal muscle, where epi-fluorescence indicates the presence of antibody measured as radiant efficiency |p / sec / cm2 / sr| / |p W / cm2|. FIGs. 16D-16F show summaries of average radiant efficiency | p / sec / cm2 / sr| / |p W / cm2| for each TfRl antibody produced as a monovalent Fab-Fc protein in mouse brain, liver, and skeletal muscle tissues. Statistical significance was determined using one-way ANOVA followed by Tukey's multiple comparison test. Asterisks denote significance levels: *p < 0.05, **p < 0.01, ***p < 0.001, **p < 0.0001.

[0058] FIG. 17 provides a summary of antibody oligonucleotide conjugates (AOC) and their corresponding components of TfRl antibody produced as a monovalent Fab-Fc protein, payload oligos, release mechanism linkers, conjugation technology used, and target Oligonucleotide-antibody ratio (OAR).

[0059] FIG. 18A and 18B provide schematics depicting antibody oligonucleotide conjugates (AOC) wherein a monovalent antibody clone is attached to either a MCC and ValCit linker, and a Malatl gapmer.

[0060] FIGs. 19A-19E summarize antibody oligonucleotide conjugate (AOC) purity based on small angle X-ray scattering (SAXs) analysis for AOC4 and AOC6 (FIG. 19A), AOC1 and AOC3 (FIG. 19B), AOC7 and AOC8 (FIG. 19C), AOC9 and AOC 10 (FIG. 19D), and AOC 11 (isotype control) (FIG. 19E) where the y-axis shows absorbance at 280nm / mAU and the x-axis shows time / min. Graphs show the absorbance of AOCs with different numbers of linked oligonucleotides, labeled as oligo to antibody ratio (OAR) OAR 0, OAR 1, and OAR 2.

[0061] FIG. 20 provides a summary of in vitro characterization of TfRl binders. Antibody binding in HEK293T cells, internalization AUC (lOug / mL), and international rate are provided for each TfRl antibody produced as monovalent Fab-Fc proteins.

[0062] FIG. 21 provides a summary table of components of antibody oligonucleotide conjugates (AOCs) including TfRl antibodies produced as monovalent Fab-Fc protein, linkers (MCC or ValCit), and oligo to antibody ratio (OAR).20#14904047v2PCT APPLICATION

[0063] FIG. 22 provides a summary of in vitro AOC internalization where each AOC corresponds to an antibody and internalization AUC, linker type, oligo to antibody ratio (OAR), and % of knockdown following AOC uptake by gymnosis and AOC uptake by transfection.

[0064] FIG. 23 summarizes in vitro internalization of antibody oligonucleotide conjugates (AOC) and knock down of MALAT1 following transfection with 5nM or 25nM of each AOC. Knock down of MALAT1 is measured as % remaining mRNA (normalized to PBS control).

[0065] FIG. 24A and 24B summarize in vitro internalization of antibody oligonucleotide conjugates (AOC) and knock down of MALAT1 following gymnosis. FIG. 24A shows knock down of MALAT1 following gymnosis with O.lpM or 1 pM of each AOC. FIG. 24B shows knock down of MALAT1 following gymnosis with O.lpM of each AOC. Knock down of MALAT1 is measured as % remaining mRNA (normalized to PBS control).

[0066] FIG. 25 summarizes in vivo knockdown of MALAT1 by AOC1 - AOC11 compared to negative controls when AOC1 - AOC11 are delivered 2 times weekly at 1.5 mg / kg of MALAT1 oligonucleotide. indicates a p-value of < 0.05, “**” indicates a p-value of < 0.01, and “***” indicates a p-value of < 0.001.DETAILED DESCRIPTIONI. Overview

[0067] The present disclosure provides novel anti-transferrin receptor 1 (anti-TfRl) antibodies and antibody fragments. In embodiments, the anti-TfRl antibodies can be deployed as highly efficient delivery agents for the targeted intracellular delivery of therapeutic or diagnostic payloads. The anti-TfRl delivery agents described herein address a fundamental challenge in modem therapeutics: the difficulty of delivering biologically active molecules across cell membranes and into intracellular compartments where they can exert their intended effects. Many promising therapeutic agents, including nucleic acid-based therapeutics (e.g., antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs)), proteins, antibodies, and targeted protein degradation agents, exhibit limited cellular uptake due to their size, charge, or hydrophilicity, thereby limiting their therapeutic efficacy even when they possess potent activity against intracellular targets.

[0068] The anti-TfRl delivery agents of the present disclosure overcome these limitations by exploiting the natural endocytic pathway of transferrin receptor 1 (TfRl), a cell surface receptor that is highly expressed on many cell types and undergoes constitutive receptor- 21#14904047v2PCT APPLICATION mediated endocytosis. The delivery agents bind specifically to TfRl expressed on target cells and facilitate receptor-mediated internalization of conjugated, complexed, or fused payloads into the intracellular compartment. When a delivery agent is coupled to a payload (e.g., a therapeutic or diagnostic payload), the resulting construct is referred to herein as a "delivery platform," "delivery system," or "payload-delivery agent complex," or similar terms.

[0069] In preferred embodiments, the anti-TfRl delivery agents function as inert shuttles that do not, or do not substantially, modulate TfRl -dependent signaling pathways. These inert delivery agents bind to TfRl and facilitate cellular uptake without triggering significant activation of TfRl -mediated signaling cascades, thereby minimizing potential interference with normal TfRl biological functions such as transferrin binding and iron homeostasis. By remaining functionally inert with respect to TfRl signaling while efficiently promoting receptor-mediated endocytosis, the delivery agents enable targeted intracellular delivery of diverse therapeutic or diagnostic modalities without the confounding effects that might arise from activation of TfRl -dependent cellular processes. This approach expands the therapeutic potential of payload molecules that would otherwise exhibit poor cell permeability and provides a generally applicable platform for intracellular delivery across a broad range of therapeutic applications.

[0070] The present disclosure provides anti-TfRl antibodies and antibody fragments for use as delivery agents. These delivery agents may be conjugated to, complexed with, fused to, or otherwise associated with a therapeutic or diagnostic payload of interest to provide a delivery system of the disclosure. Therapeutic payloads that may be delivered using the anti-TfRl delivery agents include, but are not limited to, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNAs (mRNAs), guide RNAs, therapeutic proteins, enzymes, antibodies (including monospecific, bispecific, and multispecific antibodies), peptides, small molecule drugs, targeted protein degradation agents (e.g., PROTACs, molecular glues), gene editing proteins (e.g., Cas nucleases, base editors), radioisotopes, imaging agents, and combinations thereof.

[0071] In various embodiments, the anti-TfRl antibodies that may be used as delivery agents include the antibodies described in Table X herein, including but not limited to Ab.l, Ab.2, Ab.3, Ab.4, Ab.5, Ab.6, Ab.7, Ab.8, Ab.9, Ab.10, Ab.ll, Ab.12, Ab.13, Ab.14, Ab.15, Ab.16, Ab.17, Ab.18, Ab.19, Ab.20, Ab.21, Ab.22, Ab.23, Ab.24, Ab.25, and Ab.26. In some embodiments, the delivery agents comprise variant antibodies having at least one VH, HC, VL, or LC region with at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or up to 100% sequence identity to the 22#14904047v2PCT APPLICATION corresponding VH, HC, VL, or LC region sequences provided in Table X, wherein the variant antibodies retain the ability to bind TfRl and facilitate receptor-mediated internalization of payloads.

[0072] In some embodiments, the anti-TfRl antibodies that may be used as delivery agents comprise one or more amino acid sequences described in Table I. In some embodiments, the anti-TfRl antibodies that may be used as delivery agents comprise one or more amino acid sequences described in Table II. In further embodiments, the anti-TfRl antibodies comprise complementarity-determining region (CDR) sequences, framework region sequences, variable domain sequences, or constant domain sequences as specifically disclosed herein, including combinations and permutations thereof.

[0073] Accordingly, in various aspects, the present disclosure, at least in part, is based on the development of antibodies and variants that specifically bind TfRl.II. TfRl (Transferrin Receptor 1)

[0074] The transferrin receptor 1 (TfRl), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds iron-bound transferrin (Tf) and plays a crucial role in cellular iron uptake by internalization through receptor-mediated endocytosis to acidic vesicles. There, the iron-transferrin complex is released from the receptor (TfRl) and becomes disassociated, whereafter the iron becomes available to the cell and the unbound transferrin and TfRl are recycled back to the cell surface. Iron is vital for various cellular functions, including DNA synthesis and cell proliferation.

[0075] TfRl is constitutively expressed at the cell plasma membrane of tissues that are constantly renewed, such as precursors of blood cells in the bone marrow, hepatocytes in the liver, keratinocytes in the epidermis, enterocytes in intestinal epithelium, and skeletal muscle cells particularly during muscle repair and regeneration. In addition, it has been reported that TfRl is overexpressed in cancer cells. TfRl has also been reported to be expressed in cells of the central and peripheral nervous systems (CNS / PNS). Further TfRl has been found to drive receptor-mediated transcytosis across the blood-brain barrier (BBB), thereby establishing TfRl -targeting as a potential approach for treating diseases of the central and peripheral nervous systems.

[0076] Given TfRl’s cell surface and extracellular accessibility, its rapid endocytosis and recycling properties, and its ability to cross the BBB, TfRl has become a highly attractive target for delivery of medicines to cells to treat a variety of diseases, including cancers / proliferative disorders, muscle disorders (e.g., cardiac and skeletal muscle disorders), liver disorders, and CNS / PNS disorders. In one approach, agents (e.g., small molecules,23#14904047v2PCT APPLICATION therapeutic proteins, antisense oligonucleotides (ASOs), or siRNAs) may be coupled or otherwise conjugated to transferrin (which binds to TfRl) or to antibodies that bind to TfRl (e.g., a drug-antibody conjugates). In this way, therapeutic agents may be shuttled into diseased cells (e.g., cancer cells) through uptake by TfRl-mediated endocytosis. Another therapeutic approach involving TfRl involves the use of bispecific antibodies that bind to TfRl and a second target (e.g., a target of the CNS or a cancer cell target), for example, as discussed in Kanodia et al., “Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain,” CPT Pharmacometrics Syst Pharmacol, 2016, 5(5): 283-291.

[0077] This disclosure relates to the development of anti-TfRl antibodies or proteins having an antigen-binding portion of an anti-TfRl antibody that specifically recognize and bind TfRl.

[0078] As further background, TfRl (also known as CD71, IMD46, T9, TFR, TFR1, TR, TRFR, and p90) is a type II transmembrane glycoprotein consisting of 760 amino acids that are linked by two disulfide bonds to form a 180-kDa homodimer that plays a crucial role in the regulation of iron uptake and cell growth (BOMFORD and MUNRO. Hepatology. 5:870-875, 1985). See FIG. 1. When diferric transferrin (TO binds to TfRl on cell surface, the holo-Tf-TfRl complex is internalized via clathrin-coated pits and is delivered into acidic endosomes, where the iron-Tf-TfRl complex undergoes conformational change triggered by low pH, and iron is subsequently released and transported to the cytosol. The apo-Tf / TfRl complex is then recycled back to the cell surface where apo-Tf dissociates from the receptor (WARD. Invest Radiol. 22:74-83, 1987; DANIELS et al. Clin Immunol. 121:144-158, 2006).

[0079] In general, TfRl is expressed at low levels on most normal cells. Increased expression is observed on cells with a high rate of proliferation, including those of the basal epidermis, intestinal epithelium, and certain activated immune cells. However, high expression is also observed on cells with a high need of iron, such as placental trophoblasts and erythroid progenitors due to the high requirement of iron for heme synthesis. In addition, cells of the vascular endothelium of the brain capillaries that compose the blood-brain barrier (BBB) also express high levels of the receptor TfRl expression is increased on rapidly proliferating cells, such as precursors of blood cells, hepatocytes, keratinocytes, in which iron is highly required for heme synthesis, whereas its expression is decreased or absent on nondividing cells.

[0080] TfRl is also overexpressed in primary and metastatic cancer cells of lymphocytes, pancreas, stomach, colon, lung, breast, bladder, and skin origins (GATTER et al. J Clin 24#14904047v2PCT APPLICATION Pathol. 36:539-545, 1983; FAULK et al. Lancet. 2:390-392, 1980; SUTHERLAND et al. Proc Natl Acad Sci USA 78:4515-4519, 1981; DANIELS et al. Clin Immunol. 121:144-158, 2006; JEONG et al. Biochem Biophys Res Commun. 471:373-379, 2016; PEER et al. Nat Nanotechnol. 2:751-760, 2007; QIAN et al. Pharmacol Rev. 54:561-587, 2002;RICHARDSON et al. Biochim Biophys Acta Gen Subj. 1790:702-717, 2009). Since cancer cells seem to be more sensitive to iron deprivation, targeting on Tf or TfRl by blocking their binding or interfering with internalization of the holo-Tf / TfRl complex can cause iron deprivation and thus kill malignant cells.

[0081] An exemplary amino acid sequence of the human TfRl protein is (NCBI Ref. Seq. No. NP_001121620.1):1 MMDQARSAFS NLFGGEPLSY TRFSLARQVD GDNSHVEMKL AVDEEENADN NTKANVTKPK 61 RCSGSICYGT IAVIVFFLIG FMIGYLGYCK GVEPKTECER LAGTESPVRE EPGEDFPAAR 121 RLYWDDLKRK LSEKLDSTDF TGTIKLLNEN SYVPREAGSQ KDENLALYVE NQFREFKLSK 181 VWRDQHFVKI QVKDSAQNSV IIVDKNGRLV YLVENPGGYV AYSKAATVTG KLVHANFGTK 241 KDFEDLYTPV NGSIVIVRAG KITFAEKVAN AESLNAIGVL IYMDQTKFPI VNAELSFFGH 301 AHLGTGDPYT PGFPSFNHTQ FPPSRSSGLP NIPVQTISRA AAEKLFGNME GDCPSDWKTD 361 STCRMVTSES KNVKLTVSNV LKEIKILNIF GVIKGFVEPD HYVWGAQRD AWGPGAAKSG 421 VGTALLLKLA QMFSDMVLKD GFQPSRSIIF ASWSAGDFGS VGATEWLEGY LSSLHLKAFT 481 YINLDKAVLG TSNFKVSASP LLYTLIEKTM QNVKHPVTGQ FLYQDSNWAS KVEKLTLDNA 541 AFPFLAYSGI PAVSFCFCED TDYPYLGTTM DTYKELIERI PELNKVARAA AEVAGQFVIK 601 LTHDVELNLD YERYNSQLLS FVRDLNQYRA DIKEMGLSLQ WLYSARGDFF RATSRLTTDF 661 GNAEKTDRFV MKKLNDRVMR VEYHFLSPYV SPKESPFRHV FWGSGSHTLP ALLENLKLRK 721 QNNGAFNETL FRNQLALATW TIQGAANALS GDVWDIDNEF

[0082] TfRl may refer to any native TfRl from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed TfRl as well as any form or isomer of TfRl that results from processing in the cell. The term also encompasses naturally occurring variants of TfRl, e.g., splice variants or allelic variants. In some embodiments, the TfRl herein is human TfRl (“hTfRl”) comprising the above amino acid sequence. In another embodiment, the TfRl herein is primate TfR (“pTfRl”) comprising the amino acid sequence as set forth in Genbank reference AFD 18260.1. For comparison, the mouse TfRl sequence may be found in Genbank reference AAH54522.1.

[0083] The anti-TfRl antibody described herein may also bind to a fragment of a human TfRl and / or to any isoform of TfRl. The fragment of TfRl can be generated by removing a portion of the N-terminus, the C-terminus, or an internal region. The fragment can also be formed from noncontiguous regions of the protein relative to the wildtype amino acid 25#14904047v2PCT APPLICATION sequence. The length of the fragment can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 96%, 97%, 98%, 99%, or up to just under 100% of the length of the wildtype human TfRl protein.III. DefinitionsAdministering:

[0084] As used herein, the terms “administering” or “administration” means to provide an antibody or a composition thereof to a subject in a manner that is physiologically and / or pharmacologically useful (e.g., to treat a condition in the subject).Affinity Matured Antibody:

[0085] “Affinity Matured Antibody” is used herein to refer to an antibody with one or more alterations in one or more CDRs or framework residues, which result in an improvement in the affinity (e.g., KD, kd or ka) of the antibody for a target antigen compared to a parent antibody, which does not possess the alteration(s). Exemplary affinity matured antibodies will have nanomolar or even picomolar affinities for the target antigen. A variety of procedures for producing affinity matured antibodies are known in the art, including the screening of a combinatory antibody library that has been prepared using bio-display. For example, Marks et al., BioTechnology, 10: 779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and / or framework residues is described by Barbas et al., Proc. Nat. Acad. Sci. USA, 91: 3809-3813 (1994); Schier et al., Gene, 169: 147-155 (1995); Yelton et al., J. Immunol., 155: 1994-2004 (1995); Jackson et al., J. Immunol., 154(7): 3310-3319 (1995); and Hawkins et al, J. Mol. Biol., 226: 889-896 (1992). Selective mutation at selective mutagenesis positions and at contact or hypermutation positions with an activity-enhancing amino acid residue is described in U. S. Pat. No.6,914,128 Bl.Antibody:

[0086] As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one site, e.g., paratope, that specifically binds to an antigen. In some embodiments, an antibody comprises a paratope. In some embodiments, a paratope comprises one or more complementarity determining regions (CDRs). In some embodiments, an antibody is a chimeric antibody, e.g., a mouse-human chimeric antibody. In some embodiments, an antibody is a humanized antibody. In some some embodiments, an antibody is a fully human antibody. In still some embodiments, an antibody is a polyclonal antibody. In some embodiments, an antibody is a monoclonal antibody. In yet some26#14904047v2PCT APPLICATION embodiments, an antibody is a bi-specific antibody. In still some embodiments, an antibody is a multi-specific antibody.

[0087] In some embodiments, an antibody is a full-length antibody. In some embodiments, an antibody may be an antibody fragment that comprises an antigen or epitope binding region, such as Fab, Fab', F(ab')2, Fv, Fd, rlgG, single chain (scFv) or sc(Fv)2, mutants thereof, fusion proteins comprising an antibody portion, diabodies, a nanobody derived from a camelid antibody, a nanobody derived from shark antibody, single domain antigen binding (SDAB) molecules, a VH or VL domain, or a VHH domain, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody can include any protein having an antigen-binding portion of an anti-TfRl antibody.

[0088] In a particular embodiment, the disclosed antibodies (e.g., those identified in Table X) may be formatted as a monovalent Fab-Fc fragment as depicted in FIG. 1 J, as an example. Such antibodies may be configured with three amino acid chains: (a) a light chain comprising a variable light (“VL”) region and a light chain constant region (“C”); (b) a heavy chain comprising a variable heavy (“VH”) region and a constant region (“C”), and an Fc region; and (c) an “empty” Fc region. In embodiments, the VH / VL regions are configured to bind to TfRl. In embodiments, the L chain, H chain, VL, VH, and CDR sequences in both the VH and VL regions may comprising any of the corresponding sequences provided in Tables I (exemplary heavy chain sequences) and II (exemplary light chain sequences). In some embodiments, the empty Fc domain may comprise a purification tag, such as a His-6 tag. In addition, the Fc domains may include one or more mutations, such knob-in-hole mutations (e.g., “knob” mutations (k) such as T366W, S354C mutations relative to isotype IgG numbering, or at an equivalent position in the Fc domains of any of the herein disclose full heavy chain sequences of Table I, and “hole” mutations (h) such as T366S, L368A, Y407V, Y349C mutations relative to isotype IgG numbering, or at an equivalent position in the Fc domains of any of the herein disclose full heavy chain sequences of Table I. The monovalent Fab-Fc format may also comprise a covalent linkage (1), such as a disulfide bridge, that couples the light chain to the heavy chain. The Examples demonstrate the characteristics of exemplary monovalent Fab-Fc antibodies described herein, but the Examples are not limited to those described. Any of the Table X antibodies can be converted into such format, and / or another suitable format.27#14904047v2PCT APPLICATION

[0089] An antibody can be an antibody from any class of antibody, such as IgD, IgE, IgG, IgA, or IgM (or a sub-class thereof), but does not need not be of any particular class. The antibody may also comprise components from multiple classes. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2.

[0090] Antibodies described herein can be murine, rat, human, or any other origin, including chimeric or humanized antibodies and including such antibodies generated by affinity maturation. In some examples, the antibody may comprise a naturally occurring constant region or a modified constant region, such as a constant region that is immunologically inert, e.g., does not trigger complement mediated lysis, or does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC).

[0091] In some embodiments, an antibody comprises a framework having a human germline sequence. In another embodiment, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgGl, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgAl, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH), and / or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant domain, e.g., an Fc region. An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein can be an alpha (a), delta (A), epsilon (E), gamma (y) or mu (p) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (a), delta (A), epsilon (E), gamma (y) or mu (p) heavy chain. In one embodiment, an antibody described herein may comprise a human gamma 1 CHI, CH2, and / or CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (y) heavy chain constant region, such as any known in the art. Nonlimiting examples of human constant region sequences have been described in the art, e.g., see U. S. Pat. No. 5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%,28#14904047v2PCT APPLICATION 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein.

[0092] In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation (i.e., a process in which SUMO proteins are covalently attached to specific lysine residues in target proteins, thereby regulating various aspects of protein function including transcription, subcellular localization, DNA repair and cell cycle), and / or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to an antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (addition by covalent bonding of a glycosylphophatidylinositol (GPI) anchor and is a common post-translational modification that localizes proteins to cell membranes), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecule are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, or a phospholipid unit. In some embodiments, an antibody is a construct that comprises a polypeptide comprising one or more antigen binding fragments of the disclosure linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Examples of linker polypeptides have been reported (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123).

[0093] Still further, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058).

[0094] Further, an antibody may also be in the form of a conjugate wherein the antibody is coupled to a payload either directly or by a linker. The antibody can be an anti-TfRl antibody, or a multispecific anti-TfRl antibody that targets one or more additional antigens (e.g., a target cell protein). The payload can be a therapeutic payload (e.g., as in a drug- 29#14904047v2PCT APPLICATION antibody conjugate or ADC), such as a small molecule drug, therapeutic peptide, therapeutic nucleic acid (such as an oligonucleotide-antibody conjugate), or other biological agent, such as a cytotoxic anti-cancer agent (e.g., microtubule inhibitors or DNA damaging agents). In various embodiments, the linker can conjugate the payload to the antibody and preferably is designed such that it remains stable during circulation. In some embodiments, the linker is a cleavable linker (e.g., acid labile linker, disulfide or enzyme dipeptide) or the linker is a non-cleavable linker (e.g., thioether, hindered disulfide). The payload can also be an immune modulating agent which modulates the immune system in some way via immune stimulation or immune inhibition. Antibody conjugates can involve full length antibodies or an antibody fragment, such as any of the aforementioned antibody fragments.

[0095] Still further, in some embodiments, an antibody may be described as a recombinant antibody. As used herein, the term “recombinant antibody” refers to an antibody (e.g. a chimeric, humanized, or human antibody or antigen-binding fragment thereof) that is expressed by a recombinant host cell comprising nucleic acid encoding the antibody.Examples of "host cells" for producing recombinant antibodies include: (1) mammalian cells, for example, Chinese Hamster Ovary (CHO), COS, myeloma cells (including YO and NSO cells), baby hamster kidney (BHK), Hela and Vero cells; (2) insect cells, for example, sf9, sf21 and Tn5; (3) plant cells, for example plants belonging to the genus Nicotiana (e.g.Nicotiana tabacum); (4) yeast cells, for example, those belonging to the genus Saccharomyces ( e.g. Saccharomyces cerevisiae) or the genus Aspergillus ( e.g. Aspergillus niger); ( 5) bacterial cells, for example Escherichia coli cells or Bacillus subtilis cells, etc.

[0096] An "antigen-binding fragment" of an antibody is a molecule that comprises a portion of a full-length antibody which is capable of detectably binding to the antigen, typically comprising one or more portions of at least the VH region. Antigen-binding fragments include multivalent molecules comprising one, two, three, or more antigen-binding portions of an antibody, and single-chain constructs wherein the VL and VH regions, or selected portions thereof, are joined by synthetic linkers or by recombinant methods to form a functional, antigen-binding molecule. Antigen-binding fragments can also be a single-domain antibody (sdAb), also known as a nanobody, which is an antibody fragment consisting of a single monomeric variable antibody domain (VHH). While some antigen-binding fragments of an antibody can be obtained by actual fragmentation of a larger antibody molecule (e.g., enzymatic cleavage), most are typically produced by recombinant techniques. The antibodies of the disclosure can be prepared as full length antibodies or antigen-binding fragments thereof. Examples of antigen-binding fragments include Fab, Fab', F(ab)2, F(ab')2, F(ab)3, Fv 30#14904047v2PCT APPLICATION (typically the VL and VH domains of a single arm of an antibody), single-chain Fv (scFv, see e.g., Bird et al., Science 1988; 242:423-426; and Huston et al. PNAS 1988; 85:5879-5883), dsFv, Fd (typically the VH and CHI domain), and dAb (typically a VH domain) fragments: VH, VL, VHH, and V-NAR domains: monovalent molecules comprising a single VH and a single VL chain: minibodies, diabodies, triabodies, tetrabodies, and kappa bodies (see, e.g., Ill et al., Protein Eng 1997: 10:949-57); camel IgG; IgNAR; as well as one or more isolated CDRs or a functional paratope, where the isolated CDRs or antigen-binding residues or polypeptides can be associated or linked together so as to form a functional antibody fragment. Various types of antibody fragments have been described or reviewed in, e.g., Holliger and Hudson, Nat Biotechnol 2005; 23: 1126-1136; W02005040219, and published U. S. Patent Applications 20050238646 and 20020161201. Antibody fragments can be obtained using conventional recombinant or protein engineering techniques, and the fragments can be screened for antigen-binding or other function in the same manner as are intact antibodies.

[0097] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of full-length antibodies (see, e.g., orimoto et al., Journal of Biochemical and Biophysical Methods, 24: 107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., Bio / Technology,10: 163-167 (1992)). According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. In some embodiments, the antibody of choice is a single chain Fv fragment (scFv). See WO 1993 / 16185; US. Pat. No. 5,571,894; and U. S. Pat No.5, 587, 458. The antibody fragment may also be a "linear antibody", e.g., as described in U. S. Pat No. 5,641,870, for example. Such linear antibody fragments can be monospecific or bispecific.Antibody-Oligonucleotide Conjugate:

[0098] As used herein, the term “antibody-oligonucleotide conjugate” (“AOC”) refers to type of delivery system described herein (i.e. an anti-TfRl antibody conjugated to a therapeutic payload) wherein the therapeutic payload is one or more oligonucleotides. In embodiments, the anti-TfRl antibody and the one or more oligonucleotide payloads are directly or indirectly associated with one another. Such association may be covalent or non-covalent interaction and may occur through one or more linker moieties, adapters, carriers, or intermediary components.31#14904047v2PCT APPLICATION

[0099] The anti-TfRl antibody may be a full-length antibody or any antigen-binding fragment or derivative thereof, including but not limited to monoclonal antibodies, multispecific antibodies, bispecific antibodies, single-domain antibodies, antibody fragments, or engineered antibody formats.[000100] The oligonucleotides may be single-stranded or double-stranded and may comprise DNA, RNA, or nucleic acid analogs. Exemplary oligonucleotides include, but are not limited to, antisense oligonucleotides (ASOs), microRNAs (miRNAs, small interfering RNAs (siRNAs) (e.g. which may inhibit or modulate the activity of a pathogenic RNA), messenger RNAs (mRNAs), aptamers, guide RNAs, or combinations thereof. In some embodiments, the oligonucleotide modulates the expression or activity of a target nucleic acid or protein, encodes a therapeutic or cytotoxic polypeptide, or serves a regulatory, diagnostic, or targeting function.[000101] The oligonucleotide may comprise naturally occurring and / or chemically modified nucleotides, including modifications to the nucleobase, sugar, and / or internucleoside linkage, and may include one or more conjugation handles or functional groups to facilitate association with the antibody.[000102] An AOC may comprise one or more oligonucleotides per antibody, and the oligonucleotide(s) may be functionally active or inactive in the conjugated state.Approximately:[000103] As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).Bispecific Antibody:[000104] As used herein, the term “bispecific antibody” refers to a type of multispecific antibody comprising two different antigen binding sites, e.g., paratopes, that have different antigen binding specificities. For example, in one embodiment, a bispecific antibody is a polypeptide that includes two different antigen binding sites in which each antigen binding site binds to a different epitope of the same antigen. In some embodiments, a bispecific antibody is a polypeptide that includes two different antigen binding sites in which each site binds to a different antigen. In some embodiments, a bispecific antibody comprises two 32#14904047v2PCT APPLICATION different sets of immunoglobulin variable domains, each of which set binds to a different epitope or group of epitopes. In some embodiments, at least one antigen to which an antigen binding site of a bispecific antibody specifically binds is a complex.[000105] Typically, each of the two antigen binding sites is present within an “arm” of a bispecific antibody, e.g., an antibody comprising a first arm that binds to TfRl and a second arm that binds to a target protein (e.g., a T cell receptor or surface antigen, a cancer cell antigen, a CNS protein). In some embodiments, an arm of a bispecific antibody is configured as a monospecific antibody, e.g., a full-length IgG or a fragment thereof. In some embodiments, a bispecific antibody comprises two arms, one or each of which is configured as an Fv region that confers specificity to distinct antigen residues. In some embodiments, a bispecific antibody comprises two arms of the same configuration, e.g., a Fab, a Fab’, a scFv, or any other suitable format. In some embodiments, a bispecific antibody comprises two arms of two different configurations, e.g., a Fab on one arm and a scFv on the other arm. In some embodiments, a bispecific antibody does not comprise an Fc region. In some embodiments, the two arms of a bispecific antibody are linked directly. In some embodiments, the two arms of a bispecific antibody are linked by a linker.[000106] In some embodiments, a bispecific antibody comprises an Fc region, e.g., a dimeric Fc or a monomeric Fc. In some embodiments, a bispecific antibody comprises a monomeric Fc. In some embodiments, a bispecific antibody comprises one arm linked to one end (e.g., the N terminal) of a monomeric Fc and a second arm linked to the other end (e.g., the C terminal) of the monomeric Fc (see, e.g., Shan et al., “In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance”, Communications Biology, Vol. 4, Article No. 1048 (2021)). In some embodiments, a bispecific antibody comprises a dimeric Fc region. In some embodiments, a bispecific antibody comprises two arms that are oriented symmetrically around an Fc region (e.g., each Fc monomer of a dimeric Fc region is linked to one arm). In some embodiments, a bispecific antibody comprises two distinct heavy chains and two distinct light chains, with each heavy chain / light chain pair having different antigen binding specificity. In some embodiments, a bispecific antibody comprises two arms that are oriented asymmetrically around an Fc (e.g., the two arms of the bispecific antibody are linked to one of the monomers of a dimeric Fc region). In some embodiments, because bispecific antibodies are capable of binding two different targets, they can be used as scaffolds to recruit or redirect cells to antigenic targets, e.g., to recruit immune cells to cancer cells.33#14904047v2PCT APPLICATION [000107] In some embodiments, a bispecific antibody contains a first antigen binding site that specifically binds to TfRl and a second antigen binding site (e.g. a peptide: MHC complex, cancer cell antigen, or T cell receptor). In some embodiments, a bispecific antibody comprises a second antigen binding site specifically binds to a T cell antigen. In some embodiments, the T cell antigen is a CD3 complex or a portion thereof, e.g., CD38, CD3E, CD3y, a CD3E / 8 heterodimer, or a CD3E / y heterodimer. In some embodiments, a bispecific antibody comprises a first antigen binding site that binds to TfRl and a second binding site that specifically binds to a T cell antigen (e.g., CD3).[000108] In various embodiments, the second antigen binding site or arm of a bispecific antibody disclosed herein which binds to a target other than TfRl may be regarded as the therapeutic payload itself as contemplated herein. In certain such embodiments, the bispecific antibody serves a dual function: (i) the first arm that binds to TfRl facilitates targeted delivery and cellular internalization via TfRl-mediated endocytosis, and (ii) the second arm that binds to a target other than TfRl provides the therapeutic activity. In further embodiments, a bispecific antibody may be further conjugated to, complexed with, or otherwise associated with one or more additional therapeutic agents or payloads, thereby creating a multifunctional therapeutic construct that combines TfRl-mediated delivery, target- specific binding via the second arm, and the biological activity of the additional therapeutic agent(s). Non-limiting examples of additional therapeutic agents that may be conjugated to a bispecific antibody include small molecule drugs (e.g., cytotoxic agents, kinase inhibitors, chemotherapeutic agents, oncology drugs, nucleic acid molecules (e.g., ASOs, siRNAs), peptides, additional proteins, radioisotopes, imaging agents, or targeted protein degradation molecules. In some embodiments, the additional therapeutic agent conjugated to the bispecific antibody is a cytotoxic small molecule, and the resulting construct functions analogously to an antibody-drug conjugate (ADC) but with the added benefit of TfRl-mediated cellular uptake and delivery.Blood-Brain Barrier (BBB):[000109] As used herein, the term "blood- brain barrier" or " BBB" refers to a physiological barrier between the peripheral circulation and the brain and spinal cord which is primarily formed by tight junctions within the brain capillary endothelial plasma membranes, creating a tight barrier that regulates the exchange of molecules between the peripheral circulation and the central nervous system (CNS). The BBB can restrict the transport of even very small molecules such as urea (60 Da) into the brain. As used herein, the term “BBB” includes34#14904047v2PCT APPLICATION related CNS barriers with similar restrictive and transport-regulating functions. Examples include, but are not limited to the BBB within the brain, the blood-spinal cord barrier, within the spinal cord, and the blood-retinal barrier within the retina, all of which are contiguous capillary barriers, within the CNS. The BBB also encompasses the blood-CSF barrier (choroid plexus) where the barrier is comprised of ependymal cells rather than capillary endothelial cells.Blood-Brain Barrier Receptor (R / BBB):[000110] As used herein, the term "blood-brain barrier receptor" (abbreviated " R / BBB") refers to a membrane-associated receptor expressed on cells of the BBB that is capable of mediating cellular uptake, transcytosis, or transport of endogenous ligands across the BBB, and that may be leveraged to facilitate transport of molecules into or across the BBB or be used to transport exogenously administered molecules. An exemplary R / BBB herein is transferrin receptor 1 (TfRl).CDR:[000111] As used herein, the term " CDR" refers to the complementarity determining region within antibody variable sequences. A typical antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or the contact definition, all of which are well known in the art. See, e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No.91-3242; IMGT®, the international ImMunoGeneTics information system® imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P., Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P., Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [[Epub]], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33: D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37: D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43: D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia,35#14904047v2PCT APPLICATION C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, a CDR may refer to the CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the same amino acid sequence of that CDR as determined by the same method, for example, the IMGT definition.[000112] In certain embodiments, there are three CDRs in each of the variable regions of a heavy chain and a light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term " CDR set" as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-portions of CDRs may be designated as LC CDR1, LC CDR2 and LC CDR3 or HC CDR1, HC CDR2 and HC CDR3 where the " LC" and the " HC" designate the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although preferred embodiments use Kabat or Chothia defined CDRs.[000113] In certain embodiments, the CDRs of an antibody may have different amino acid sequences when different definition systems are used (e.g., the IMGT definition, the Kabat definition, or the Chothia definition). A definition system annotates each amino acid in a given antibody sequence (e.g., VH or VL sequence) with a number, and numbers corresponding to the heavy chain and light chain CDRs are provided in Table 2. The CDRs listed in Tables I- IV are defined in accordance with the Kabat definition. One skilled in the36#14904047v2PCT APPLICATION art is able to derive the CDR sequences using the different numbering systems for an anti-TfRl antibody provided in Tables LIV.Table 2. CDR DefinitionsIMGT1Kabat2Chothia3HC CDR1 27-38 31-35 26-32HC CDR2 56-65 50-65 53-55HC CDR3 105-116 / 117 95-102 96-101LC CDR1 27-38 24-34 26-32LC CDR2 56-65 50-56 50-52LC CDR3 105-116 / 117 89-97 91-961IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999)2Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No. 91-32423Chothiaet al., J. Mol. Biol. 196:901-917 (1987)CDR-Grafted Antibody:[000114] The term " CDR-grafted antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and / or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.Central Nervous System (CNS):[000115] The term "central nervous system" or " CNS" refers to the complex of nerve tissues that control bodily function, and includes the brain and spinal cord.Chemotherapeutic Agent:[000116] As used herein, a "chemotherapeutic agent" refers to a chemical compound useful in the treatment of proliferative disorders, such as cancers (e.g., cancers expressing CD22). These agents can be, e.g., alkylating agents, such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan and piposulfane; aziridines such as benzodopa, carbocuone, meturedopa and uredopa; ethylene imines and methylamelamines, including altretamine, triethylene methamine, triethylene phosphoramide, triethylene-thiophosphoramide and trimethylolomelamine; acetogenins (especially bulatacin and bulatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL); beta-lapacona;37#14904047v2PCT APPLICATION lapacol; Colchicines; betulinic acid; a camptothecin (which includes the synthetic analog topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR), acetylcamptothecin, scopolectin and 9-aminocamptothecin); Bryostatin; Callistatin; CC-1065 (including its synthetic analogs of adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (which include the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictiina, -pongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamidea, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics, such as enediin antibiotics (e.g., calicheamicin, especially gammall calicheamicin and omegall calicheamicin (see, for example, Agnew, Chem Inti. Ed. Engl., 33: 183-186 (1994)); dynemycin, including dynemycin A; a esperamycin; as well as neocarzinostatin chromophore and chromophores of related chromoprotein antibiotics), aclacinomisins, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorrubicin, 6-diazo-5-oxo- L-norleucine, doxorubicin (including morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, chelamicin, rodrububicin, streptonigrin, streptozocin, tubercidin, ubenimex, zino statin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, tiamiprin, thioguanine; analogues of pyrimidine such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocythabin, floxuridine; androgens such as calusterone, dromostanolone propionate, epithio stand, mepitiostane, testolactone; antisuprenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid enhancer such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabuchil; bisantrene; edatraxate; defofamin; demecolcine; diazicuone; elfornitin; eliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainin; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofirano; spirogermanium;38#14904047v2PCT APPLICATION tenuazonic acid; triazicuone; 2,2 2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine), urethane, vindesine (ELDISINE, FILDESIN), dacarbazine, manomustine, mitobronitol, mitolactol, pipobroman, gacitosin, arabinoside (" Ara-C"), thiotepa, taxoids, for example, paclitaxel (TAXOL, Bristol-Myers Squibb Oncology, Princeton, NJ), Cremophor-free ABRAXANE ™, nanoparticle formulation modified with paclitaxel albumin (American Pharmaceutical Partners, Schaumberg, Illinois), and docetaxel (TAXOTERE®; Rhone-Poulenc Rorer, Antony, France); chloranbuchil; gemcitabine (GEMZAR); 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovina; vinorrelbine (NAVELBINE®); novan trone; edatrexate; Daunomycin; aminopterin; ibandronate;Topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; as well as combinations of two or more of the foregoing such as CHOP, an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone; CVP, an abbreviation for a combination therapy of cyclophosphamide, vincristine and prednisolone; and FOLFOX, an abbreviation for an oxaliplatin treatment regimen (ELOXATIN ™) combined with 5-FU and leucovorin.[000117] In the context of the present disclosure, and in some embodiments, the bispecific and multispecific antibodies described herein may be conjugated to one or more such chemotherapeutic agents. The additional therapeutic agent conjugated to the bi- or multispecific antibodies may function analogously to an antibody-drug conjugate (ADC) but with the added benefit of TfRl -mediated cellular uptake and delivery.Chimeric Antibody:[000118] The term “chimeric antibody” refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.Drug-Like:[000119] The term “drug-like,” as used herein, refers to an anti-TfRl antibody that has been engineered in a sequence and molecular format suitable for incorporation into a therapeutic product intended for clinical development, without requiring fundamental re-engineering of the antibody scaffold.39#14904047v2PCT APPLICATION [000120] In some embodiments, a drug-like antibody exhibits properties consistent with use in a clinical development context, including but not limited to favorable expression, stability, purity, aggregation, and polyreactive profiles, and compatibility with standard manufacturing, formulation, and conjugation workflows. The term “drug-like” does not require that the antibody has undergone regulatory approval or completed clinical testing.Compete:[000121] The term “compete”, as used herein with regard to an antibody, means that a first antibody binds to an epitope of a protein (e.g., CD22) in a manner sufficiently similar to the binding of a second antibody, such that the result of binding of the first antibody with its epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. The alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody, can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope. However, where each antibody detectably inhibits the binding of the other antibody with its epitope or ligand, whether to the same, greater, or lesser extent, antibodies are said to “Cross-compete” or “cross block” with each other for binding of their respective epitope(s). In some embodiments, antibodies that compete or cross-compete bind to the same or overlapping epitopes. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate that such competing and / or cross-competing antibodies are encompassed and can be useful for the methods and / or compositions provided herein.Complementary:[000122] As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleotides or two sets of nucleotides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleotides or two sets of nucleotides. For example, if a base at one position of an oligonucleotide is capable of hydrogen bonding with a base at the corresponding position of a target nucleic acid (e.g., an mRNA), then the bases are considered to be complementary to each other at that position. Base pairings may include both canonical Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairings, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil-type bases (U), that 40#14904047v2PCT APPLICATION cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T.Conjugated:[000123] As used herein, the term “conjugated” refers to two or more entities that are directly or indirectly associated with one another. The association may be covalent or noncovalent and may occur through one or more linker moieties, adapters, carrier or intermediary components. Conjugation may include, but is not limited to, direct chemical linkage or noncovalent binding. Conjugation may be reversible or irreversible.Conservative Amino Acid Substitution:[000124] As used herein, a “conservative amino acid substitution” refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for altering polypeptide sequence known to one of ordinary skill in the art such as are found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F. M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions made amongst amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.Cross-Reactive:[000125] As used herein and in the context of a targeting agent (e.g., antibody), the term “cross-reactive,” refers to the ability of the agent to specifically bind to corresponding antigens from more than species or biological class. In some embodiments, a cross -reactive agent specifically binds to orthologous forms of the same target antigen, including orthologs from human and one or more non-human species. Cross -reactivity may include binding to homologous, paralogous, or orthologous forms of an antigen that share structural or sequence similarity. Cross -reactive binding does not require identical binding affinity, avidity, or epitope recognition across the different antigens.Cytotoxic Agent:[000126] As used herein, the term “cytotoxic agent” refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. Such agents are well known in the art, and include, e.g., radioactive isotopes (e.g., At211, I131, I125, Y90, Re186,41#14904047v2PCT APPLICATION Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and the various anti-tumor or anti-cancer agents described below.[000127] In the context of the present disclosure, and in some embodiments, the bispecific and multispecific antibodies described herein may be conjugated to one or more such cytotoxic agents. The additional cytotoxic agent conjugated to the bi- or multispecific antibodies may function analogously to an antibody-drug conjugate (ADC) but with the added benefit of TfRl -mediated cellular uptake and delivery.Delivery Agent[000128] As used herein, the term “delivery agent” refers to an anti-TfRl antibody or antibody fragment of the invention that serves as a molecular vehicle or shuttle for transporting a payload (e.g., a therapeutic payload or a diagnostic payload) to TfRl-expressing target cells. A delivery agent binds specifically to transferrin receptor 1 (TfRl) expressed on the surface of target cells and facilitates receptor-mediated internalization and intracellular delivery of an associated therapeutic payload through TfRl-mediated endocytosis.[000129] The delivery agent functions primarily to enable cellular uptake and intracellular access of the payloads (e.g., the therapeutic or diagnostic payloads) that would otherwise have limited or no ability to cross cell membranes or reach intracellular compartments. In some embodiments, the delivery agent does not itself possess therapeutic activity and functions solely as a delivery vehicle. In some embodiments, the delivery agent does not result in any significant activation of TfRl -dependent signaling pathways, thereby minimizing interference with normal TfRl biological functions such as transferrin binding and iron homeostasis.[000130] As used herein, a delivery agent that does not “significantly activate” TfRl signaling or TfRl -dependent signaling pathways refers to a delivery agent that, upon binding to TfRl, does not induce substantial modulation of cellular processes or signaling cascades mediated by TfRl beyond the normal basal level of TfRl activity when not being induced by its natural transferrin ligand under normal physiological conditions. In some embodiments, a delivery agent that does not significantly activate TfRl signaling induces less than about 42#14904047v2PCT APPLICATION 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, or less than about 5% of the signaling activity induced by a positive control TfRl agonist or TfRl-activating antibody under comparable conditions. In some embodiments, a delivery agent that does not significantly activate TfRl signaling does not substantially increase TfRl phosphorylation, does not substantially activate downstream kinase cascades (e.g., MAPK, PI3K / AKT pathways), does not substantially alter iron uptake beyond normal transferrin-mediated levels, and / or does not substantially affect TfRl expression levels or turnover. In some embodiments, the delivery agent binds to an epitope on TfRl that is distinct from the transferrin binding site and does not significantly interfere with normal transferrin binding or iron homeostasis. In some embodiments, lack of significant TfRl signaling activation by a delivery agent described herein (e.g., an anti-TfRl antibody described herein) is determined by measuring one or more of the following parameters: receptor phosphorylation (e.g., by Western blot, phospho-ELISA), downstream signaling pathway activation (e.g., ERK1 / 2 phosphorylation, AKT phosphorylation), changes in gene expression profiles, cellular proliferation assays, or functional assays measuring iron uptake or cellular iron levels. In some embodiments, a delivery agent that does not significantly activate TfRl signaling exhibits a signaling activation profile that is statistically indistinguishable from vehicle control or untreated cells, or differs by less than 2-fold, less than 1.5-fold, or less than 1.2-fold from baseline.Delivery Platform or Delivery System:[000131] As used herein, the term “delivery platform” or equivalently “delivery system” refers to the combination of an anti-TfRl antibody or antibody fragment (i.e., the “delivery agent” as defined herein) with its associated a payload (e.g. a therapeutic payload). Other suitable equivalent terms that may be used herein include “payload-delivery agent complex,” “antibody-payload conjugate,” “anti-TfRl conjugate,” “anti-TfRl complex,” or similar terms. As applied to this disclosure, the delivery platform may be referred specifically to an “anti-TfRl antibody delivery platform” and likewise the term delivery system may be referred to as an “anti-TfRl antibody delivery system.”Developability:[000132] As used herein, the term “developability” refers to the extent to which a polypeptide, such as an antibody or antibody fragment, possesses characteristics favorable for its manufacture, formulation, storage, and clinical use. Attributes of developability include, but are not limited to: high expression in eukaryotic cells, solubility, low viscosity, resistance to aggregation, high chemical and thermal stability, long serum half-life, low clearance rate,43#14904047v2PCT APPLICATION and minimal nonspecific or polyspecific binding. Developability may be assessed using a suite of biophysical and biochemical assays including, but not limited to, PSR (polyspecificity reagent) binding, AC-SINS (affinity-capture self-interaction nanoparticle spectroscopy), HIC (hydrophobic interaction chromatography), SEC (size-exclusion chromatography), DLS (dynamic light scattering), DSF (differential scanning fluorimetry), CIC (cross -interaction chromatography), and others. A developability profile may refer to the composite score or assessment derived from these assays and can be used to compare or rank antibody candidates.Effective Amount:[000133] As used herein, “an effective amount” refers to the amount of each active agent (e.g., anti-TfRl antibody) required to confer a desired effect (e.g., a therapeutic effect on the subject), either alone or in combination with one or more other active agents. In some embodiments, the therapeutic effect is reduced TfRl level or activity and / or alleviated disease conditions (e.g., treatment of a cancer with an ADC embodiment that delivers an anticancer agent to a cancer cell target).Framework:[000134] As used herein, the term “framework” or “framework sequence” refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (LC CDR1, LC CDR2, and LC CDR3 of light chain and HC CDR1, HC CDR2, and HC CDR3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four subregions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred to by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region. Human heavy chain and light chain acceptor sequences are known in the art. In one embodiment, the acceptor sequences known in the art may be used in the antibodies disclosed herein. These regions are shown in the general schematic of FIG. 1C.Fusion Protein[000135] As used herein, the term “fusion protein” refers to a single polypeptide chain comprising two or more distinct protein domains or functional moieties that are joined 44#14904047v2PCT APPLICATION together through peptide bonds, typically produced by expression of a single recombinant nucleic acid construct. A fusion protein is created by joining the coding sequences of two or more genes or gene fragments in-frame such that the resulting polypeptide is translated as a single continuous chain.[000136] In the context of the present disclosure, a fusion protein may comprise an anti-TfRl antibody or antibody fragment (e.g., scFv, Fab, VHH, single-domain antibody) linked to a therapeutic protein, therapeutic peptide, or other functional domain. The anti-TfRl antibody or antibody fragment serves as a targeting domain that facilitates TfRl -mediated delivery, internalization, transcytosis, and / or tissue targeting of the therapeutic protein or functional domain. In some embodiments, the therapeutic protein or functional domain serves as the therapeutic payload to be delivered to TfRl -expressing cells.Human Antibody:[000137] The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.Humanized Antibody:[000138] The term “humanized antibody” refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and / or VL sequence has been altered to be more “human-like”, i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding nonhuman CDR sequences. In one embodiment, humanized anti-TfRl antibodies and antigen binding portions are provided. Such antibodies may be generated by obtaining murine anti-TfRl monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in Kasaian et al PCT publication No. WO 2005 / 123126 A2.45#14904047v2PCT APPLICATION [000139] Humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Antibodies may have Fc regions modified as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs derived from one or more CDRs from the original antibody. Humanized antibodies may also involve affinity maturation.[000140] In some embodiments, humanization is achieved by grafting the CDRs (e.g., as shown in Table 1) into the human variable domains (e.g., IGKV1-NL1*01 and IGHV1-3*01 human variable domain). In some embodiments, the anti-TfRl antibody of the present disclosure is a humanized variant comprising one or more amino acid substitutions (e.g., in the VH framework region) as compared with any one of the VHs listed in Table 1, and / or one or more amino acid substitutions (e.g., in the VL framework region) as compared with any one of the VLs listed in Table 1.Internalization Profile:[000141] An “internalization profile”, as used herein, refers to a depiction (e.g., a graph, a map, etc.) of how, when, and how much of an anti-TfRl antibody is taken up by cells expressing TfRl via receptor-mediated endocytosis to acidic vesicles. Non-limiting examples of methods for generating internalization profiles that may be used herein include: antibody internalization assays, including Incucyte®-based assays, flow cytometry, and livecell imaging assays, including, confocal microscopy, and imaging of endosomal or lysosomal markers.Isolated Antibody:46#14904047v2PCT APPLICATION [000142] An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds TfRl is substantially free of antibodies that specifically bind antigens other than TfRl). In some embodiments, an isolated antibody that specifically binds TfRl does not demonstrate cross-reactivity to other antigens. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.Kabat Numbering:[000143] The terms " Kabat numbering", " Kabat definitions” and " Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S.Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.Multispecific Antibody:[000144] As used herein, the term “multispecific antibody” refers to a polypeptide or a complex (e.g., two or more covalently linked polypeptides) comprising at least two distinct immunoglobulin variable domains or at least two different sites, e.g., paratopes, that specifically bind to one or more antigens. For example, in one embodiment, a multispecific antibody is a polypeptide that includes at least two different sites in which each site binds to a different epitope of the same antigen. In some embodiments, a multispecific antibody is a polypeptide that includes at least two different sites in which each site binds to a different antigen. In some embodiments, an antigen to which a site of a multispecific antibody specifically binds is a complex (e.g., a peptide complexed with a single chain HLA-A2 molecule).[000145] A multi-specific antibody may be bispecific, trispecific, or higher-order multispecific. A multispecific antibody may comprise one or more polypeptide chains and may be formed as a single polypeptide, multiple covalently linked polypeptides, or a non-covalent complex.47#14904047v2PCT APPLICATION [000146] In some embodiments, a multi- specific antibody comprises a first antigen-binding site that specifically binds to transferrin receptor 1 (TfRl) and one or more additional antigen-binding sites that specifically bind to one or more target molecules distinct from TfRl. The TfRl-binding site may facilitate cellular uptake, internalization, transcytosis, tissue targeting, and / or delivery of the multispecific antibody and / or an associated therapeutic payload.[000147] The one or more target molecules bound by the additional antigen-binding site(s) may include, but are not limited to, cell-surface proteins, soluble proteins, tissue- or disease-associated antigens, peptide major histocompatibility complexes (peptide: MHC), or other biologically relevant molecular targets. In some embodiments, the multispecific antibody does not substantially modulate the biological function of TfRl.[000148] Each antigen-binding site may be present within an “arm” of the multispecific antibody. The arms may independently be configured as full-length antibodies, antigenbinding fragments, or engineered antibody formats, including but not limited to Fab, Fab’, scFv, Fv, single-domain antibodies, or other suitable antigen-binding domains. The antigenbinding sites may have the same or different configurations and may be directly linked or indirectly linked via one or more linker moieties.[000149] A multispecific antibody may comprise an Fc region or may be Fc-free. When present, the Fc region may be monomeric or dimeric. In some embodiment, a multispecific antibody comprises a monomeric Fc with different antigen-binding sites linked to different termini of the Fc. In some embodiments, a multispecific antibody comprises a dimeric Fc region, with antigen-binding sites arranged symmetrically or asymmetrically relative to the Fc. In some embodiments, the multispecific antibody comprises two or more distinct heavy chains and / or two or more distinct light chains, wherein different heavy chain / light chain pairs confer different antigen-binding specificities.[000150] In various embodiments, one or more antigen binding sites or arms of a multispecific antibody disclosed herein which bind to a target or targets other than TfRl may be regarded as the therapeutic payload itself as contemplated herein. In certain such embodiments, the multispecific antibody serves multiple functions: (i) a first arm that binds to TfRl facilitates targeted delivery and cellular internalization via TfRl -mediated endocytosis, and (ii) one or more additional arms that bind to one or more targets other than TfRl provide the therapeutic activity. In further embodiments, a multispecific antibody may be further conjugated to, complexed with, or otherwise associated with one or more additional therapeutic agents or payloads, thereby creating a multifunctional therapeutic 48#14904047v2PCT APPLICATION construct that combines TfRl -mediated delivery, target-specific binding via the one or more additional arms, and the biological activity of the additional therapeutic agent(s). Nonlimiting examples of additional therapeutic agents that may be conjugated to a multispecific antibody include small molecule drugs (e.g., cytotoxic agents, kinase inhibitors, chemotherapeutic agents, oncology drugs), nucleic acid molecules (e.g., ASOs, siRNAs), peptides, additional proteins, radioisotopes, imaging agents, or targeted protein degradation molecules. In some embodiments, the additional therapeutic agent conjugated to the multispecific antibody is a cytotoxic small molecule, and the resulting construct functions analogously to an antibody-drug conjugate (ADC) but with the added benefit of TfRl-mediated cellular uptake and delivery and, optionally, additional target-specific binding through one or more non-TfRl -binding arms.Recombinant Antibody:[000151] The term "recombinant antibody", as used herein, is intended to include all antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more details in this disclosure), including, for example, antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H. R., (1997) TIB Tech.15:62-70; Azzazy H., and Highsmith W. E., (2002) Clin. Biochem. 35:425-445; Gavilondo J. V., and Larrick J. W. (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann S-A., and Green L. L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. In some embodiments, recombinant human antibodies are provided herein. In certain embodiments, such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. One embodiment of the disclosure provides fully human antibodies capable of binding human TfRl which can be generated using techniques 49#14904047v2PCT APPLICATION well known in the art, such as, but not limited to, using human Ig phage libraries such as those disclosed in Jermutus et al., PCT publication No. WO 2005 / 007699 A2.Selective:[000152] As used herein, the term “selective” or “selectively” refers to the ability of a molecule to produce an effect (e.g., inhibit, antagonize, agonize, etc.) in relation to its target molecule compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that this molecule is capable of inhibiting its target molecule to a degree that is distinguishable from a reference molecule in an inhibition assay or other inhibitory context. For example, with respect to an inhibitor, the term, “selectively inhibits”, refers to the ability of the inhibitor to inhibit its target molecule with a degree that is distinguishable from a reference molecule that is not substantially inhibited in an inhibition assay, e.g., to an extent that permit selective inhibition of the target molecule, as described herein. Once the reaction is terminated, the signal produced by inhibiting the target molecule can be measured. The half maximal inhibitor concentration for the target molecule and the reference molecule can be calculated. In some embodiments, a molecule described herein selectively binds to a target molecule. In some embodiments, a molecule described herein selectively binds TfRl.Specifically Binds:[000153] As used herein, the term “specifically binds” refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish the binding partner from an appropriate control in a binding assay or other binding context. With respect to an antibody, the term, “specifically binds”, refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or avidity, compared with an appropriate reference antigen or antigens, that enables the antibody to be used to distinguish the specific antigen from others, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a KD for binding the target of at least about 10’4M, 10’5M, 10’6M, 10’7M, 10’8M, 10’9M, IO10M, 10’11M, 1012M, 1013M, or less. In some embodiments, an antibody specifically binds a TfRl. Subject:[000154] As used herein, the term “subject” refers to a mammal. In some embodiments, a subject is a human. In some embodiments, a subject is a patient, e.g., a human patient that has or is suspected of having a disease.Therapeutic Agent or Therapeutic Payload:50#14904047v2PCT APPLICATION [000155] As used herein, the terms “therapeutic agent” or “therapeutic payload” or “payload” can be used interchangeably and refer to any molecule, compound, or composition that possesses biological activity capable of providing a therapeutic, prophylactic, or diagnostic benefit when delivered to a target cell, tissue, or organism. A therapeutic agent or payload may exert its effect through various mechanisms, including but not limited to modulation of gene expression, protein function, enzymatic activity, receptor binding, immune system modulation, cellular signaling, metabolic pathways, or replacement of a deficient or absent endogenous molecule.[000156] In the context of the present disclosure, a therapeutic agent or payload is the biologically active molecule, compound, or composition that is conjugated to, complexed with, fused to, or otherwise associated with an anti-TfRl antibody or antibody fragment of the invention. The anti-TfRl antibody or antibody fragment serves as a delivery agent or shuttle that facilitates TfRl -mediated cellular uptake, internalization, and intracellular delivery of the therapeutic payload to TfRl-expressing cells. The payload represents the cargo or active agent that is being delivered, while the anti-TfRl antibody or antibody fragment functions as the delivery agent or shuttle.[000157] The combination of an anti-TfRl antibody or antibody fragment with its associated therapeutic payload may be referred to as a “delivery system” or “delivery platform”, or equivalent terms such as “payload-delivery agent complex,” “antibody-payload conjugate,” “anti-TfRl conjugate,” “anti-TfRl complex,” or similar terms (each of which are define herein). Such fusion proteins and anti-TfRl conjugates enable targeted delivery of the therapeutic payload to TfRl-expressing cells and facilitate intracellular access of payloads that would otherwise have limited or no ability to cross cell membranes.Treatment:[000158] As used herein, the term “treating” or “treatment” refers to the application or administration of a delivery system disclosed herein (which, as defined herein, includes an anti-TfRl antibody conjugated to a therapeutic payload) or pharmaceutical composition comprising a delivery platform disclosed herein to a subject, who has a target disease or disorder (e.g., cancer expressing TfRl), a symptom of the disease / disorder, or a predisposition toward the disease / disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom of the disease, or the predisposition toward the disease or disorder. Alleviating a target disease / disorder includes delaying or preventing the development or progression of the disease, or reducing disease severity. Therapeutic payloads when delivered via anti-TfRl antibodies or antibody51#14904047v2PCT APPLICATION fragments of the invention (i.e. the delivery systems described herein), may be used for the treatment, prevention, or diagnosis of a wide range of diseases and conditions, including but not limited to cancer, autoimmune diseases, inflammatory diseases, genetic disorders, lysosomal storage diseases, metabolic disorders, infectious diseases, cardiovascular diseases, neurological diseases, central nervous system disorders, neurodegenerative diseases, hematological disorders, ophthalmic diseases, and rare diseases.Tunable or Tunability:[000159] As used herein, the term "tunable" or "tunability" refers to a characteristic of the anti-TfRl antibodies disclosed herein, which have been engineered to exhibit a range of distinct properties, enabling optimization for specific applications. The tunability of the disclosed anti-TfRl antibodies and conjugates arises from the availability of multiple variants within the disclosed collection, each exhibiting a different property profile. This diversity enables the selection of an antibody or conjugate best suited for a particular therapeutic, prophylactic, or diagnostic use based on the requirements of that application. Non-limiting examples of properties that vary among the disclosed antibodies or conjugates, and which may be evaluated in the selection process, include binding affinity, avidity, epitope specificity, internalization kinetics, receptor trafficking pathway (e.g., favoring recycling versus lysosomal degradation), pharmacokinetics (e.g., serum half-life, tissue distribution), immunogenicity, effector function, payload release kinetics, developability, manufacturability, thermal stability, chemical stability, and binding specificity. The disclosed antibodies having tunable properties may be characterized and evaluated using assays designed to measure any one or more of the above properties, thereby enabling selection of a specific antibody for a specific application. Thus, the disclosure provides a tunable platform wherein different applications (e.g., CNS delivery, cancer therapy, lysosomal storage disease treatment) can be addressed by selecting the appropriate anti-TfRl antibody or conjugate from the disclosed repertoire based on the desired property profile. Anti-TfRl antibodies Exemplary anti-TfRl antibodies[000160] The following tables (Tables X and I- IV) provide amino acid and nucleic acid sequences for 26 exemplary IgGl anti-TfRl antibodies identified in accordance with the Examples. In embodiments, the anti-TfRl antibodies can be deployed as highly efficient delivery agents for the targeted intracellular delivery of therapeutic or diagnostic payloads. The anti-TfRl delivery agents described herein address a fundamental challenge in modern therapeutics: the difficulty of delivering biologically active molecules across cell membranes and into intracellular compartments where they can exert their intended effects.52#14904047v2PCT APPLICATION [000161] Each antibody comprises an IgGl format which consists of four polypeptide chains (two heavy chains (HC) and two light chains (LC)) joined together by disulfide bridges. The LC consists of a variable light (VL) constant light (CL) region, and the heavy chain consists of one VH chain linked to three constant regions (CHI, CH2, and CH3). The Fc region is important for mediating immune system effector functions, and Protein-A and -G binding.[000162] For each of the 26 antibodies, the tables include the following sequences:• 26 Heavy chains (full length): SEQ ID NOs: 66-91;• 7 Light chains (full length): SEQ ID NOs: 124- 130;• 7 Variable light chain regions: SEQ ID NOs: 117-123;• 25 Variable heavy chain regions: SEQ ID NOs: 41-65;• 7 Variable light chain CDRls: SEQ ID NOs: 96-102;• 7 Variable light chain CDR2s: SEQ ID NOs: 103-109;• 7 Variable light chain CDRs3: SEQ ID NOs: 110-116;• 12 Variable heavy chain CDRls: SEQ ID NOs: 1-12;• 9 Variable heavy chain CDR2s: SEQ ID NOs: 13-20;• 20 Variable heavy chain CDR3s: SEQ ID NOs: 21-40, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the above sequences;• Corresponding nucleotide sequences encoding variable heavy chain regions for each exemplary antibody Nos. 1-26 (SEQ ID NOs: 131-156);• Corresponding nucleotide sequences encoding full length heavy chains for each exemplary antibody Nos. 1-26 (SEQ ID NOs: 157-182);• Corresponding nucleotide sequences encoding variable light chain regions for each exemplary antibody Nos. 1-26 (SEQ ID NOs: 183-208); and• Corresponding nucleotide sequences encoding full length light chains for each exemplary antibody Nos. 1-26 (SEQ ID NOs: 209-234).53#14904047v2PCT APPLICATION Table X, Summary of sequence identifiers (SEQ ID NOs:) for the amino acid sequences of Tables I (heavy chain sequences) and II (light chain sequences)VHCDR1 VHCDR2 VHCDR3 VH HC VLCDR1 VLCDR2 VLCDR3 VL LC Ab. No.1-13 14-20 21-40 41-65 66-90 96-102 103-109 110-116 117-123 124-130 Ab.l 1 15 21 41 66 98 107 115 122 129 Ab.2 2 14 22 42 67 100 106 114 121 128 Ab.3 3 18 23 43 68 102 108 110 117 124 Ab.4 4 16 24 44 69 101 104 111 118 125 Ab.5 4 16 24 44 70 101 105 113 120 127 Ab.6 5 16 26 47 72 101 105 111 118 125 Ab.7 5 17 27 48 73 101 105 113 118 125 Ab.8 6 16 27 52 77 101 105 113 118 125 Ab.9 5 16 28 50 75 97 104 111 120 127 Ab.10 5 16 28 49 74 100 106 114 121 128 Ab.11 6 16 32 55 80 100 106 114 121 128 Ab.12 6 16 33 56 81 100 106 114 121 128 Ab.13 6 16 31 54 79 100 106 114 121 128 Ab.14 5 16 25 46 71 98 107 115 122 129 Ab.15 6 16 29 51 76 98 107 115 122 129 Ab.16 6 16 30 53 78 96 109 116 123 130 Ab.17 13 16 34 57 82 100 106 114 121 128 Ab.18 7 17 35 58 83 102 108 110 117 124 Ab.19 8 18 36 59 84 102 108 110 117 124 Ab.20 9 19 37 60 85 96 109 116 123 130 Ab.21 10 16 38 61 86 100 106 114 121 128 Ab.22 11 16 39 62 87 102 108 110 117 124 Ab.23 11 16 28 64 89 102 108 110 117 124 Ab.24 11 16 28 46 90 102 108 110 117 124 Ab.25 11 16 28 63 88 97 104 111 120 127Ab.26 12 20 40 65 71 99 103 112 119 126#14904047v2PCT APPLICATION Table I. Heavy chain amino acid sequencesColumn A: VHCDR1 heavy chain (SEQ ID NOs: 1-13) (VHCDR1)Column B: VHCDR2 heavy chain (SEQ ID NOs: 14-20) (VHCDR2)Column C: VHCDR3 heavy chain (SEQ ID NOs: 21-40) (VHCDR2)Column D: (VH) heavy chain variable region (SEQ ID NOs: 41-65)Column E: full length heavy chain (HC) sequences IgGl-Agly-Fc AA (full length heavy chain sequence) (SEQ ID NOs: 66-90) for each antibody protein Nos. 1-26, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the Table I sequences.No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full1 DYWMS 1 NIKQDGSERYYV 15 SRGFFDY 21 EVQLVESGGGLVQP 41 E VQLVE S GGGLVQP GGS LRL S CAAS GF TF S D 66DSVKG GGSLRLSCAASGFT YWMSWVRQAPGKGLEWVANIKQDGSERYYVD FSDYWMSWVRQAPG S VKGRF T I S RDNAKN S L YLQMN S LRAED T AV KGLEWVANIKQDGS YYCARSRGFFD YWGQGTPVTVS SASTKGP SV ERYYVDSVKGRFTI FPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SRDNAKNSLYLQMN SWNSGALTSGVHTFPAVLQSSGLYSLSSWT SLRAEDTAVYYCAR VPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SRGFFDYWGQGTPV SCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TVSS TLMI SRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYASTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full2 NYAIS 2 GIIPIFGTANYA 14 GGYIYGY 22 Q VQ L VQ S GAE VKKP 42 QVQLVQSGAEVKKPGASVKVSCKASGGTFSN 67QKFQD ERRYFDL GASVKVSCKASGGT YAISWVRQAPGQGLEWMGGIIPIFGTANYAQ FSNYAISWVRQAPG KFQDRVTI TADESTSTAYMELS SLTSEDTAV QGLEWMGGIIPIFG YYCARGGYIYGYERRYFDLWGRGTLVTVSSA TANYAQKFQDRVTI STKGPSVFP LAP SSKSTSGGTAALGC L VKD Y TADESTSTAYMELS FPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLTSEDTAVYYCAR SLSSWTVPSSSLGTQTYICNVNHKPSNTKV GGYIYGYERRYFDL DKRVEPKSCDKTHTCPPCPAPELLGGPSVFL WGRGTLVTVSS FPPKPKDTLMI SRTPEVTCVWDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYASTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPG3 NYNMN 3 SISSSSTYIYYA 18 DSSIAAF 23 EVQLVESGGGLVKP 43 EVQLVESGGGLVKPGGSLRLSCAASGFTFSN 68DSVQG GGFDP GGSLRLSCAASGFT YNMNWLRQAP GKGLE WVS SISSSSTYI Y YAD FSNYNMNWLRQAPG S VQGRF T I S RDNAKN S L YLQMN S LRAED T AV KGLEWVSSISSSST YYCARDSSIAAFGGFDPWGQGSLVTVSSAST YIYYADSVQGRFTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SRDNAKNSLYLQMN EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SLRAEDTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK DSSIAAFGGFDPWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGSLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full4 SGNWW 4 EIYHSGSTNYNP 16 EGGYSVY 24 QVQLQESGPGLVKP 44 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 69 S SLKS GPFDY SGTLSLTCAVSGGS GNWWSWVRQPPGKGLEWIGEI YHSGSTNYNP ISSGNWWSWVRQPP SLKSRVTISIDNSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSVYGPFDYWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDNSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSVYGPFDYWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG5 SGNWW 4 EIYHSGSTNYNP 16 EGGYSVY 24 QVQLQESGPGLVKP 44 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 70 S SLKS GPFDY SGTLSLTCAVSGGS GNWWSWVRQPPGKGLEWIGEI YHSGSTNYNP ISSGNWWSWVRQPP SLKSRVTISIDNSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSVYGPFDYWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDNSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSVYGPFDYWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full6 SSNWW 5 EIYHSGSTNYNP 16 EGGYSNY 26 QVQLQESGPGLVKP 47 QVQLQESGPGLVKPSGTLSLTCAVSGDSISS 72 N SLKS GWFDP SGTLSLTCAVSGDS SNWWNWVRQPPGKGLEWIGEI YHSGSTNYNP ISSSNWWNWVRQPP SLKSRVTISIDNSKNHFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCTREGGYSNYGWFDPWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDNSKNHFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCTR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNYGWFDPWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG7 SSNWW 5 EIYHSGNTNYNP 17 EGGYSVY 27 QVQLQESGPGLVKP 48 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 73 N SLKS GDFDY SGTLSLTCAVSGGS SNWWNWVRQPPGKGLEWIGEI YHSGNTNYNP ISSSNWWNWVRQPP SLKSRVTISIDKSKNQFSLKVRSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSVYGDFDYWGQGTLVTVSSAST NTNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDKSKNQFSLKVR EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSVYGDFDYWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full8 SSNWW 6 EIYHSGSTNYNP 16 EGGYSVY 27 QVQLQESGPGLVKP 52 QVQLQESGPGLVKPSETLSLTCAVSGGSISS 77 S SLKS GDFDY SETLSLTCAVSGGS SNWWSWVRQPPGKGLEWIGEI YHSGSTNYNP ISSSNWWSWVRQPP SLKSRVTISVDKSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSVYGDFDYWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSVYGDFDYWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG9 SSNWW 5 EIYHSGSTNYNP 16 EGGYSNR 28 QVQLQESGPGLVKP 50 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 75 N SLKS GPYDI SGTLSLTCAVSGGS SNWWNWVRQPPGKGLEWIGEI YHSGSTNYNP ISSSNWWNWVRQPP SLKSRVTISVDKSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full10 SSNWW 5 EIYHSGSTNYNP 16 EGGYSNR 28 QVQLQESGPGLVKP 49 QVQLQESGPGLVKPSETLSLTCTVSGGSISS 74 N SLKS GPYDI SETLSLTCTVSGGS SNWWNWVRQPPGRGLEWIGEI YHSGSTNYNP ISSSNWWNWVRQPP SLKSRVTISIDKSKNQFSLKLSSVTAADTAL GRGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTALYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG11 SSNWW 6 EIYHSGSTKYNP 16 EGGYSTH 32 QVQLQESGPGLVKP 55 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 80 S SLKS GAFDI SGTLSLTCAVSGGS SNWWSWVRQPPGKGLEWIGEI YHSGSTKYNP ISSSNWWSWVRQPP SLKSRVTISVDKSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSTHGAFDIWGQGTMVTVSSAST STKYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSTHGAFDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full12 SSNWW 6 EIYHSGTTNYNP 16 EGGYSAY 33 QVQLQESGPGLVKP 56 QVQLQESGPGLVKPSGTLSLTCAVSGDSISS 81 S SLKS GPFDY SGTLSLTCAVSGDS SNWWSWVRQPPGKGLEWIGEI YHSGTTNYNP ISSSNWWSWVRQPP SLKSRVTISVDTSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSAYGPFDYWGQGTLVTVSSAST TTNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDTSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSAYGPFDYWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG13 SSNWW 6 EIYHSGSTNYNP 16 EGGYSIY 31 QVQLQESGPGLVKP 54 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 79 S SLKS EGFDP SGTLSLTCAVSGGS SNWWSWVRQSPGKGLEWIGEI YHSGSTNYNP ISSSNWWSWVRQSP SLKSRVTISIDNSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG Y YCAREGGYS I YEGFDP WGQGTQVTVS SAS T STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDNSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSIYEGFDPWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTQVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full14 SSNWW 5 EIYHSGSTNYNP 16 EGGYSNY 25 QVQLQESGPGLVKP 46 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 71 N SLKS EAFDI SGTLSLTCAVSGGS SNWWNWVRQPPGKGLEWIGEI YHSGSTNYNP ISSSNWWNWVRQPP SLKSRVTISVDIPNNQFSLKLTSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSNYEAFDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDIPNNQFSLKLT EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNYEAFDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG15 SSNWW 6 EIYHSGSTNYNP 16 EGGYSTY 29 QVQLQESGPGLVKP 51 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 76 S SLKS EAFDI SGTLSLTCAVSGGS SNWWSWVRQPPGKGLEWIGEI YHSGSTNYNP ISSSNWWSWVRQPP SLKSRVTISIDNSKNQFSLNLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSTYEAFDIWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDNSKNQFSLNLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSTYEAFDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full16 SSNWW 6 EIYHSGSINYNP 16 YRGWFDP 30 QVQLQESGPGLVKP 53 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 78 S SLKS SGTLSLTCAVSGGS SNWWSWVRQPPGKGLEWIGEI YHSGSINYNP ISSSNWWSWVRQPP SLKSRVTISVDKSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG Y YCAGYRGWFDP WGQGTLVTVS S AS TKGP SV SINYNPSLKSRVTI FPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SVDKSKNQFSLKLS SWNSGALTSGVHTFPAVLQSSGLYSLSSWT SVTAADTAVYYCAG VPSSSLGTQTYICNVNHKPSNTKVDKRVEPK YRGWFDPWGQGTLV SCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TVSS TLMI SRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYASTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG17 SSNWW 13 EIYHSGTTNYNP 16 GEWELDY 34 QVQLQESGPGLVKP 57 QVQLQESGPGLVKPSGTLSLTCAVSGGSISS 82 T SLKS SGTLSLTCAVSGGS SNWWTWVRQPPGRGLEWIGEI YHSGTTNYNP ISSSNWWTWVRQPP SLKSRVTISVDKSKNQFSLKLNSVTAADTAV GRGLEWIGEI YHSG YYCAGGEWELD YWGQGTLVTVS SASTKGP SV TTNYNPSLKSRVTI FPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SVDKSKNQFSLKLN SWNSGALTSGVHTFPAVLQSSGLYSLSSWT SVTAADTAVYYCAG VPSSSLGTQTYICNVNHKPSNTKVDKRVEPK GEWELDYWGQGTLV SCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TVSS TLMI SRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYASTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full18 SYDIN 7 WMNPDSGNTGYA 17 YYGDYYY 35 Q VQ L VQ S GAE VKKP 58 QVQLVQSGAEVKKPGASMKVSCKASGYTFTS 83QRFQG YYYMDV GASMKVSCKASGYT YDINWVRQATGQGLEWMGWMNPDSGNTGYAQ FTSYDINWVRQATG RFQGRVTMTRNTSISTAYMELSSLRSEDTAV QGLEWMGWMNPDSG YYCARYYGDYYYYYYMDVWGKGTTVTVSSAS NTGYAQRFQGRVTM TKGP S VFP LAP S S KS T S GGTAALGC LVKD YF TRNTSISTAYMELS PEPVTVSWNSGALTSGVHTFPAVLQSSGLYS SLRSEDTAVYYCAR LSSWTVPSSSLGTQTYICNVNHKPSNTKVD YYGDYYYYYYMDVW KRVEPKSCDKTHTCPPCPAPELLGGPSVFLF GKGTTVTVSS PPKPKDTLMI SRTPEVTCVWDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYASTYRWSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG19 SYGMH 8 SISSSSTYIYYA 18 DSSIAAF 36 EVQLVESGGGLVQP 59 E VQLVE S GGGLVQP GGS LRL S CAAS GF TF S S 84DSVQG GGFDP GGSLRLSCAASGFT YGMHWVRQAP GKGLE WVS SISSSSTYI Y YAD FSSYGMHWVRQAPG S VQGRF T I S RDNAKN S L YLQMN S LRAED T AV KGLEWVSSISSSST YYCARDSSIAAFGGFDPWGQGSLVTVSSAST YIYYADSVQGRFTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SRDNAKNSLYLQMN EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SLRAEDTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK DSSIAAFGGFDPWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGSLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full20 SYWMH 9 RINNDGSSRSYA 19 PPYSGSY 37 EVQLVESGGDLLQP 60 EVQLVESGGDLLQPGRSLRLSCAASGFTFSS 85DSVKG FDAFDI GRSLRLSCAASGFT YWMHWVRQAP GKGLE WVS RI NNDGS S RS YAD F S S Y WMH WVRQ AP G SVKGRFTI SRDNAKNTLYLQMNSLRAEDTAV KGLEWVSRINNDGS YYCARPPYSGSYFDAFDIWGQGTMVTVSSAS SRSYADSVKGRFTI TKGP S VFP LAP S S KS T S GGTAALGC LVKD YF SRDNAKNTLYLQMN PEPVTVSWNSGALTSGVHTFPAVLQSSGLYS SLRAEDTAVYYCAR LSSWTVPSSSLGTQTYICNVNHKPSNTKVD PPYSGSYFDAFDIW KRVEPKSCDKTHTCPPCPAPELLGGPSVFLF GQGTMVTVSS PPKPKDTLMI SRTPEVTCVWDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYASTYRWSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG21 TSNWW 10 EIYHSGSTNYNP 16 EGGYSNR 38 QVQLQESGPGLVKP 61 QVQLQESGPGLVKP SGTLSLTCAVSGGS I ST 86 N SLKS GAFDI SGTLSLTCAVSGGS SNWWNWVRQPPGKGLEWIGEI YHSGSTNYNP ISTSNWWNWVRQPP SLKSRVTISVDTSKNQFSLKLSSVTAADTAV GKGLEWIGEI YHSG YYCAREGGYSNRGAFDIWGQGTLVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDTSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGAFDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTLVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full22 TSNWW 11 EIYHSGSTNYNP 16 EGGYSNR 39 QVQLQESGPGLVKP 62 QVQLQESGPGLVKP SETLSLTCTVSGGS I ST 87 T SLKS GPYDI SETLSLTCTVSGGS SNWWTWVRQTPGRGLEWIGEI YHSGSTNYNP ISTSNWWTWVRQTP SLKSRVTISIDKSKNQFSLKLSSVTAADTAL GRGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTALYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG23 TSNWW 11 EIYHSGSTNYNP 16 EGGYSNR 28 QVQLQESGPGLVKP 64 QVQLQESGPGLVKP SGTLSLTCAVSGGS IGT 89 T SLKS GPYDI SGTLSLTCAVSGGS SNWWTWVRQTPGRGLEWIGEI YHSGSTNYNP IGTSNWWTWVRQTP SLKSRVTISIDKSKNQFSLKLSSVTAADTAV GRGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDKSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTAVYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full24 TSNWW 11 EIYHSGSTNYNP 16 EGGYSNR 28 QVQLQESGPGLVKP 46 QVQLQESGPGLVKP SGTLSLTCAVSGGS I ST 90 T SLKS GPYDI SGTLSLTCAVSGGS SNWWTWVRQTPGRGLEWIGEI YHSGSTNYNP ISTSNWWTWVRQTP SLKSRVTISIDRSKNQFSLKLSSVTAADTAL GRGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGTMVTVSSAST STNYNPSLKSRVTI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SIDRSKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTALYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG25 TSNWW 11 EIYHSGSTNYNP 16 EGGYSNR 28 QVQLQESGPGLVKP 63 QVQLQESGPGLVKP SGTLSLTCAVSGGS I ST 88 T SLKS GPYDI SGTLSLTCAVSGGS SNWWTWVRQTPGRGLEWIGEI YHSGSTNYNP ISTSNWWTWVRQTP SLKSRVAI SVDTAKNQFSLKLS SVTAADTAL GRGLEWIGEI YHSG YYCAREGGYSNRGPYDIWGQGIMVTVSSAST STNYNPSLKSRVAI KGP S VFP LAP S S KS T S GGTAALGC LVKD YFP SVDTAKNQFSLKLS EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SVTAADTALYYCAR SSWTVPSSSLGTQTYICNVNHKPSNTKVDK EGGYSNRGPYDIWG RVEPKSCDKTHTCPPCPAPELLGGPSVFLFP QGTMVTVSS PKPKDTLMI SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION No. A SID (A) B SID (B) C SID (C) D SID (D) E SID ( VHCDR1 VHCDR2 VHCDR3 VH chain HC full26 TYGIN 12 WISAYNGNTNYA 20 GMYNWNY 40 Q VQ L VQ S GAE VKKP 65 QVQLVQSGAEVKKPGASVKVSCKASGYTFTT 71QKLQG PFDY GASVKVSCKASGYT YGINWVRQAPGQGLEWMGWI SAYNGNTNYAQ FTTYGINWVRQAPG KLQGRVTMTTDTSTSTAYMELRSLRSEDTAV QGLEWMGWISAYNG YYCARGMYNWNYPFDYWGQGTLVTVSSASTK NTNYAQKLQGRVTM GP S VFP LAP S S KS T S GGTAALGC LVKD YFP E TTDTSTSTAYMELR PVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SLRSEDTAVYYCAR S WTVP S S S LGTQT YI CNVNHKP SNTKVDKR GMYNWNYPFDYWGQ VEPKSCDKTHTCPPCPAPELLGGPSVFLFPP GTLVTVSS KPKDTLMI SRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRWSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG#14904047v2PCT APPLICATION Table II: Light chain amino acid sequencesColumn A: VLCDR1 (SEQ ID NOs: 96-102) (VLCDR1)Column B: VLCDR2 (SEQ ID NOs: 103-109) (VLCDR2)Column C: VLCDR3 (SEQ ID NOs: 110-116) (VLCDR3)Column D: light chain variable region (VL) (SEQ ID NOs: 117-123)Column E: full length light chain (LC) sequences (Kappa LC AA (full length light chain) (SEQ ID NOs: 124-130) for each antibody protein Nos. 1-26, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the Table II sequences.A E N SID (A) B SID (B) C SID (C) Do. SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full1 RASQS 98 KASSLES 107 QQYNSYS 115 DIQMTQSPSTLSAS 122 DIQMTQSPSTLSASVGDRVTITCRASQSISS 129 ISSWL WT VGDRVTITCRASQS WLAWYQQKPGKAPKLLIYKASSLESGVPSRF A ISSWLAWYQQKPGK SGSGSGTEFTLTISSLQPDDFATYYCQQYNS APKLLIYKASSLES YSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTE LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLQPDDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYNSYSWTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKVEIK#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full2 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK3 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full4 QASQD 101 DASNLET 104 QQYDNLP 111 DIQMTQSPSSLSAS 118 DIQMTQSPSSLSASVGDRVTITCQASQDISN 125 ISNYL YT VGDRVTITCQASQD YLNWYQQKPGKAPKLLIYDASNLETGVPSRF N ISNYLNWYQQKPGK SGSGSGTDFTFTISSLQPEDIATYYCQQYDN APKLLIYDASNLET LPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTFTISSLQPEDIA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYDNLPYTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKLEIK5 RASQS 101 DASNRAT 105 QQRSNWP 113 EIVLTQSPATLSLS 120 EIVLTQSPATLSLSPGERATLSCRASQSVSS 127 VSSYL LT PGERATLSCRASQS YLAWYQQKPGQAPRLLI YDASNRATGIPARF A VSSYLAWYQQKPGQ SGSGSGTDFTLTISSLEPEDFAVYYCQQRSN APRLLIYDASNRAT WPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ GIPARFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLEPEDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY VYYCQQRSNWPLTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full6 RASQS 101 DASNRAT 105 QQRSNWP 111 EIVLTQSPATLSLS 118 EIVLTQSPATLSLSPGERATLSCRASQSVSS 125 VSSYL LT PGERATLSCRASQS YLAWYQQKPGQAPRLLI YDASNRATGIPARF A VSSYLAWYQQKPGQ SGSGSGTDFTLTISSLEPEDFAVYYCQQRSN APRLLIYDASNRAT WPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ GIPARFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLEPEDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY VYYCQQRSNWPLTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GGGTKVEIK7 RASQS 101 DASNRAT 105 QQRSNWP 113 EIVLTQSPATLSLS 118 EIVLTQSPATLSLSPGERATLSCRASQSVSS 125 VSSYL LT PGERATLSCRASQS YLAWYQQKPGQAPRLLI YDASNRATGIPARF A VSSYLAWYQQKPGQ SGSGSGTDFTLTISSLEPEDFAVYYCQQRSN APRLLIYDASNRAT WPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ GIPARFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLEPEDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY VYYCQQRSNWPLTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full8 RASQS 101 DASNRAT 105 QQRSNWP 113 EIVLTQSPATLSLS 118 EIVLTQSPATLSLSPGERATLSCRASQSVSS 125 VSSYL LT PGERATLSCRASQS YLAWYQQKPGQAPRLLI YDASNRATGIPARF A VSSYLAWYQQKPGQ SGSGSGTDFTLTISSLEPEDFAVYYCQQRSN APRLLIYDASNRAT WPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQ GIPARFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLEPEDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY VYYCQQRSNWPLTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GGGTKVEIK9 QASQD 97 DASNLET 104 QQYDNLP 111 DIQMTQSPSSLSAS 120 DIQMTQSPSSLSASVGDRVTITCQASQDISN 127 ISNYL YT VGDRVTITCQASQD YLNWYQQKPGKAPKLLIYDASNLETGVPSRF N ISNYLNWYQQKPGK SGSGSGTDFTFTISSLQPEDIATYYCQQYDN APKLLIYDASNLET LPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTFTISSLQPEDIA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYDNLPYTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKLEIK#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full10 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK11 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full12 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK13 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B S C D E No. ID (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full14 RASQS 98 KASSLES 107 QQYNSYS 115 DIQMTQSPSTLSAS 122 DIQMTQSPSTLSASVGDRVTITCRASQSISS 129 ISSWL WT VGDRVTITCRASQS WLAWYQQKPGKAPKLLIYKASSLESGVPSRF A ISSWLAWYQQKPGK SGSGSGTEFTLTISSLQPDDFATYYCQQYNS APKLLIYKASSLES YSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTE LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLQPDDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYNSYSWTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKVEIK15 RASQS 98 KASSLES 107 QQYNSYS 115 DIQMTQSPSTLSAS 122 DIQMTQSPSTLSASVGDRVTITCRASQSISS 129 ISSWL WT VGDRVTITCRASQS WLAWYQQKPGKAPKLLIYKASSLESGVPSRF A ISSWLAWYQQKPGK SGSGSGTEFTLTISSLQPDDFATYYCQQYNS APKLLIYKASSLES YSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTE LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLQPDDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYNSYSWTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKVEIK#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full16 KSSQS 96 WASTRES 109 QQYYSTP 116 DIVMTQSPDSLAVS 123 DIVMTQSPDSLAVSLGERATINCKSSQSVLY 130 VLYSS YT LGERATINCKSSQS SSNNKNYLAWYQQKPGQPPKLLIYWASTRES NNKNY VLYSSNNKNYLAWY GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY LA QQKPGQPPKLLIYW CQQYYSTPYTFGQGTKLEIKRTVAAPSVFIF ASTRESGVPDRFSG PPSDEQLKSGTASWCLLNNFYPREAKVQWK SGSGTDFTLTISSL VDNALQSGNSQESVTEQDSKDSTYSLSSTLT QAEDVAVYYCQQYY LSKADYEKHKVYACEVTHQGLSSPVTKSFNR STPYTFGQGTKLEI GECK17 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full18 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC19 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full20 KSSQS 96 WASTRES 109 QQYYSTP 116 DIVMTQSPDSLAVS 123 DIVMTQSPDSLAVSLGERATINCKSSQSVLY 130 VLYSS YT LGERATINCKSSQS SSNNKNYLAWYQQKPGQPPKLLIYWASTRES NNKNY VLYSSNNKNYLAWY GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY LA QQKPGQPPKLLIYW CQQYYSTPYTFGQGTKLEIKRTVAAPSVFIF ASTRESGVPDRFSG PPSDEQLKSGTASWCLLNNFYPREAKVQWK SGSGTDFTLTISSL VDNALQSGNSQESVTEQDSKDSTYSLSSTLT QAEDVAVYYCQQYY LSKADYEKHKVYACEVTHQGLSSPVTKSFNR STPYTFGQGTKLEI GECK21 RASQS 100 GASSRAT 106 QQYGSSP 114 EIVLTQSPGTLSLS 121 EIVLTQSPGTLSLSPGERATLSCRASQSVSS 128 VSSSY LT PGERATLSCRASQS SYLAWYQQKPGQAPRLLI YGASSRATGIPDR LA VSSSYLAWYQQKPG FSGSGSGTDFTLTISRLEPEDFAVYYCQQYG QAPRLLIYGASSRA SSPLTFGGGTKVEIKRTVAAPSVFIFPPSDE TGIPDRFSGSGSGT QLKSGTASWCLLNNFYPREAKVQWKVDNAL DFTLTISRLEPEDF QSGNSQESVTEQDSKDSTYSLSSTLTLSKAD AVYYCQQYGSSPLT YEKHKVYACEVTHQGLSSPVTKSFNRGEC FGGGTKVEIK#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full22 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC23 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC#14904047v2PCT APPLICATION A SID (A) B SI C D E No. D (B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full24 RSSQS 102 LGSNRAS 108 MQALQTP 110 DIVMTQSPLSLPVT 117 DIVMTQSPLSLPVTPGEPASISCRSSQSLLH 124 LLHSN YT PGEPASISCRSSQS SNGYNYLDWYLQKPGQSPQLLIYLGSNRASG GYNYL LLHSNGYNYLDWYL VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC D QKPGQSPQLLIYLG MQALQTP YTFGQGTKLEIKRTVAAPSVFIFP SNRASGVPDRFSGS PSDEQLKSGTASWCLLNNFYPREAKVQWKV GSGTDFTLKISRVE DNALQSGNSQESVTEQDSKDSTYSLSSTLTL AEDVGVYYCMQALQ SKADYEKHKVYACEVTHQGLSSPVTKSFNRG TPYTFGQGTKLEIK EC25 QASQD 97 DASNLET 104 QQYDNLP 111 DIQMTQSPSSLSAS 120 DIQMTQSPSSLSASVGDRVTITCQASQDISN 127 ISNYL YT VGDRVTITCQASQD YLNWYQQKPGKAPKLLIYDASNLETGVPSRF N ISNYLNWYQQKPGK SGSGSGTDFTFTISSLQPEDIATYYCQQYDN APKLLIYDASNLET LPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTFTISSLQPEDIA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQYDNLPYTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKLEIK#14904047v2PCT APPLICATION A SID (A) B SID ( C D E No. B) SID (C) SID (D) SID (E LHCDR1 LHCDR2 LHCDR3 VL chain LC Full26 RASQS 99 AASSLQS 103 QQSYSTP 112 DIQMTQSPSSLSAS 119 DIQMTQSPSSLSASVGDRVTITCRASQSISS 126 ISSYL YT VGDRVTITCRASQS YLNWYQQKPGKAPKLLIYAASSLQSGVPSRF N ISSYLNWYQQKPGK SGSGSGTDFTLTISSLQPEDFATYYCQQSYS APKLLIYAASSLQS TPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQ GVPSRFSGSGSGTD LKSGTASWCLLNNFYPREAKVQWKVDNALQ FTLTISSLQPEDFA SGNSQESVTEQDSKDSTYSLSSTLTLSKADY TYYCQQSYSTPYTF EKHKVYACEVTHQGLSSPVTKSFNRGEC GQGTKLEIK#14904047v2PCT APPLICATION Table III: Heavy chain nucleotide sequencesColumn A: heavy chain variable region (VH) (SEQ ID NOs: 131-156)Column B: full length heavy chain sequences (SEQ ID NOs: 157-182) for each antibody protein Nos. 1-26, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the Table III sequences.No. A SID B SID (A) (B) 1 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGG 131 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTC 157 TCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTGACTAT CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTGACTATTGGA TGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTG TGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAAC GC C AAC AT AAAGC AAGAT GGAAGT GAGAGAT AT T AT GT GGAC T C T GT G AT AAAGC AAGAT GGAAGT GAGAGAT AT TAT GT GGAC T C T GT GAAGGGC C G AAGGGC CGATTCACCATCTC C AGAGAC AAC GC C AAGAAT TCACTGTAT ATTCACCATCTC C AGAGAC AAC GC C AAGAAT TCACTGTATCT GC AAAT GA C T GC AAAT GAAC AGC C T GAGAGC C GAGGAC AC GGCTGTGTATTACTGT AC AGC C T GAGAGC C GAGGAC AC GGCTGTGTATTACTGTGC GAGAT C T AGG GCGAGATCTAGGGGCTTTTTTGACTACTGGGGCCAGGGAACCCCGGTC GGCTTTTTTGACTACTGGGGCCAGGGAACCCCGGTCACCGTCTCCTCAGC ACCGTCTCCTCA TAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGA CCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCT GAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCA CACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTG TGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAAT GT GAAC C AC AAAC C T T C AAAT AC AAAAGT GGAT AAAC GC GT AGAAC C GAA ATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGC TTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTA ATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCA CGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTAC AC AAT GC T AAGAC T AAAC C T C GC GAGGAGC AGT AC GC C T C GAC C T AT C GT GTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGA ATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAA C C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C C AGGT GT AT AC T C T T CCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCT GGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACG GT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GT C C T GGAT AGC GAC GGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCA GCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT83#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 2 CAGGTGCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCC 132 CAGGTGCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTC 158 TCAGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTAT AGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTATGCTA GCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATG TCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGG GGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTC ATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGACAG C AGGAC AGAGT C AC GAT T AC C GC GGAC GAAT C C AC GAGC AC AGC C T AC AGT C AC GAT T AC C GC GGAC GAAT C C AC GAGC AC AGC C T AC AT GGAGC T GT ATGGAGCTGTCCAGCCTGACATCTGAGGACACGGCCGTGTATTACTGT C C AGC C T GAC AT C T GAGGAC AC GGCCGTGTATTACTGTGC GAGAGGGGGA GC GAGAGGGGGAT AC AT CTATGGTTAC GAGC GAC GGTACTTCGATCTC TACATCTATGGTTACGAGCGACGGTACTTCGATCTCTGGGGCCGTGGCAC TGGGGCCGTGGCACCCTGGTCACCGTCTCCTCA CCTGGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCT TGGCCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGC CTTGTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGG GGCGCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGG GCTTGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGC ACTCAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGT GGATAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGC CATGCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCG C C GAAGC C T AAAGAT AC TCTAATGATCAGCCGTACGC C AGAGGT GAC AT G TGTCGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGT ATGTTGATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAG CAGTACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCA AGATTGGCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCAC TTCCGGCCCCAATC GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGA GAACCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAA TCAAGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTG CTGTTGAATGGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACG CCACCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGAC TGTAGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTA T GC AT GAAGC GT T AC AT AAT C AC T AC AC GC AGAAAT C T C T T AGT C T T T C ACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 3 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGG 133 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTC 159 TCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTAT CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTATAACA AACATGAACTGGCTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTC TGAACTGGCTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCC TCATCCATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTG ATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGCAGGGCCG CAGGGCCGATTCACCATCTC C AGAGAC AAC GC C AAGAAC TCACTGTAT ATTCACCATCTC C AGAGAC AAC GC C AAGAAC TCACTGTATCT GC AAAT GA C T GC AAAT GAAC AGC C T GAGAGC C GAGGAC AC AGC TGTCTATTACTGT AC AGC C T GAGAGC C GAGGAC AC AGC TGTCTATTACTGTGC GAGAGAC T C G GC GAGAGAC T C GAGT AT AGC AGC TTTCGGGGGGTTC GAC CCCTGGGGC AGTATAGCAGCTTTCGGGGGGTTCGACCCCTGGGGCCAGGGATCCCTGGT CAGGGATCCCTGGTCACTGTCTCCTCA CACTGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 4 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 134 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 160 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTGGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTGGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC CAT AT C AAT AGAC AAT T C C AAGAAC CAGTTCTCC AGTCACCATAT C AAT AGAC AAT T C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCGTGTATTACTGTGC GAGAGAGGGA GC GAGAGAGGGAGGAT AT AGT GT C TACGGCCCCTTT GAC TACTGGGGC GGATATAGTGTCTACGGCCCCTTTGACTACTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT86#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 5 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 135 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 161 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTGGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTGGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC CAT AT C AAT AGAC AAT T C C AAGAAC CAGTTCTCC AGTCACCATAT C AAT AGAC AAT T C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCGTGTATTACTGTGC GAGAGAGGGA GC GAGAGAGGGAGGAT AT AGT GT C TACGGCCCCTTT GAC TACTGGGGC GGATATAGTGTCTACGGCCCCTTTGACTACTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT87#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 6 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 136 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 162 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCAGCAGTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATAGGG ATAGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC CAT AT C AAT AGAC AAT T C C AAGAAC CACTTCTCC AGTCACCATAT C AAT AGAC AAT T C C AAGAAC CACTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTACGAGAGAGGGG AC GAGAGAGGGGGGC T AC AGT AAC TACGGATGGTTC GAC CCCTGGGGC GGCTACAGTAACTACGGATGGTTCGACCCCTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT88#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 7 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 137 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 163 ACCCTGTCCCTCACATGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACATGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG AT T GGGGAAAT C T AT C AT AGT GGGAAC AC C AAC T AC AAC C C GT C C C T C GAAATCTATCATAGTGGGAACACCAACTACAACCCGTCCCTCAAGAGTCG AAGAGT C GAGT C AC C AT AT C AAT AGAC AAGT C C AAGAAC C AGT T C T C C AGT C AC CAT AT C AAT AGAC AAGT C C AAGAAC C AGT T C T C C C T GAAGGT GA CTGAAGGTGAGGTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GGTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAAGGA GCGAGAGAAGGAGGGTATAGCGTGTATGGGGATTTTGACTACTGGGGC GGGTATAGCGTGTATGGGGATTTTGACTACTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT89#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 8 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAG 138 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGAC 164 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGTAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGTAGTAGTAATT AATTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCGTGTATTACTGTGC GAGAGAAGGA GC GAGAGAAGGAGGGT AT AGC GT GT AT GGGGATTTT GAC T AC T GGGGA GGGTATAGCGTGTATGGGGATTTTGACTACTGGGGACAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 9 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 139 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 165 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCGTGTATTACTGTGC GAGAGAGGGA GCGAGAGAGGGAGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGA GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGACAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 10 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAG 140 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGAC 166 ACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAGGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAGGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC C AT AT C AAT AGAC AAGT C C AAGAAC C AGT T C T C C AGTCACCATAT C AAT AGAC AAGT C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCCTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCCTGTATTACTGTGC GAGAGAGGGA GCGAGAGAGGGAGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGC GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGCCAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT92#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 11 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 141 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 167 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAAGTACAACCCGTCCCTC GAAATCTATCATAGTGGGAGCACCAAGTACAACCCGTCCCTCAAGAGTCG AAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGTTCTGTGACCGCCGCGGACACGGCCGTGTATTATTGT GTTCTGTGACCGCCGCGGACACGGCCGTGTATTATTGTGCGAGAGAGGGG GCGAGAGAGGGGGGGTACAGCACCCACGGGGCTTTTGATATCTGGGGC GGGTACAGCACCCACGGGGCTTTTGATATCTGGGGCCAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 12 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 142 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 168 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGACTCCATCAGCAGTAGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAGATCTATCATAGTGGGACCACCAACTACAACCCGTCCCTC GAGATCTATCATAGTGGGACCACCAACTACAACCCGTCCCTCAAGAGTCG AAGAGTCGAGTCACCATATCAGTTGACACGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTTGACACGTCCAAGAACCAGTTCTCCCTGAAACTGA CTGAAACTGAGCTCTGTGACCGCCGCGGACACGGCCGTATATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCGTATATTACTGTGC GAGAGAGGGA GC GAGAGAGGGAGGAT AT AGT GC TTACGGCCCCTTT GAC TACTGGGGC GGATATAGTGCTTACGGCCCCTTTGACTACTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 13 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 143 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 169 ACCCTGTCCCTCACTTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACTTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAGTTGGGTCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGTCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAATCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAT C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC CAT AT C AAT AGAC AAT T C C AAGAAC CAGTTCTCC AGTCACCATAT C AAT AGAC AAT T C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTATATTACTGT GCTCTGTGACCGCCGCGGACACGGCCGTATATTACTGTGCGAGAGAGGGG GCGAGAGAGGGGGGCTACAGTATCTACGAGGGGTTCGACCCCTGGGGC GGCTACAGTATCTACGAGGGGTTCGACCCCTGGGGCCAGGGAACCCAGGT CAGGGAACCCAGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 14 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 144 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 170 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAGTAGACATTCCCAATAACCAGTTCTCC AGTCACCATATCAGTAGACATTCCCAATAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGACTTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT CTTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAGGGG GC GAGAGAGGGGGGC T AC AGT AAC T AC GAGGC TTTTGATATCTGGGGC GGCTACAGTAACTACGAGGCTTTTGATATCTGGGGCCAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 15 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 145 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 171 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC CAT AT C AAT AGAC AAC T C C AAGAAC CAGTTCTCC AGTCACCATAT C AAT AGAC AAC T C C AAGAAC CAGTTCTCCCT GAAC C T GA CTGAACCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAGGGT GC GAGAGAGGGT GGAT AT AGT AC C T AC GAGGC TTTTGATATCTGGGGC GGATATAGTACCTACGAGGCTTTTGATATCTGGGGCCAGGGAACCCTGGT CAGGGAACCCTGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT97#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 16 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 146 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 172 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAATGG GGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAATGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCATCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AT C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTAGACAAGTCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGGGCTACAGA GCGGGCTACAGAGGGTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTC GGGTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACTGTCTCCTCAGC ACTGTCTCCTCA TAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGA CCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCT GAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCA CACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTG TGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAAT GT GAAC C AC AAAC C T T C AAAT AC AAAAGT GGAT AAAC GC GT AGAAC C GAA ATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGC TTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTA ATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCA CGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTAC AC AAT GC T AAGAC T AAAC C T C GC GAGGAGC AGT AC GC C T C GAC C T AT C GT GTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGA ATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAA C C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C C AGGT GT AT AC T C T T CCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCT GGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACG GT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GT C C T GGAT AGC GAC GGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCA GCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 17 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 147 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 173 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAGTAACT AACTGGTGGACTTGGGTCCGCCAGCCCCCAGGGAGGGGGCTGGAGTGG GGTGGACTTGGGTCCGCCAGCCCCCAGGGAGGGGGCTGGAGTGGATTGGG AT T GGGGAAAT C T AT C AT AGT GGGAC C AC C AAC T AC AAC C C GT C C C T C GAAAT C T AT C AT AGT GGGAC C AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATTTCAGTAGACAAGTCCAAGAACCAGTTCTCC AGTCACCATTT C AGT AGAC AAGT C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAACTCTGTGACCGCCGCGGACACGGCCGTGTATTATTGT ACTCTGTGACCGCCGCGGACACGGCCGTGTATTATTGTGCGGGAGGGGAG GCGGGAGGGGAGTGGGAGCTTGACTACTGGGGCCAGGGAACCCTGGTC TGGGAGCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGC ACCGTCTCCTCA TAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGTCCAGCAAATCGA CCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAAGATTATTTCCCT GAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGACAAGTGGTGTGCA CACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATAGCCTCAGCTCTG TGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACGTATATTTGCAAT GT GAAC C AC AAAC C T T C AAAT AC AAAAGT GGAT AAAC GC GT AGAAC C GAA ATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGGCACCTGAACTGC TTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCTAAAGATACTCTA ATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGTTGACGTGTCCCA CGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATGGTGTAGAGGTAC AC AAT GC T AAGAC T AAAC C T C GC GAGGAGC AGT AC GC C T C GAC C T AT C GT GTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCTTAACGGCAAAGA ATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCCCAATCGAGAAAA C C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C C AGGT GT AT AC T C T T CCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATCCCTTACGTGTCT GGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAATGGGAATCGAACG GT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GT C C T GGAT AGC GAC GGCTCATTTTTTCTGTATAGCAAACTGACTGTAGATAAATCACGGTGGCA GCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 18 CAGGTGCAGCTGGTGCAATCTGGAGCTGAGGTGAAGAAGCCTGGGGCC 148 CAGGTGCAGCTGGTGCAATCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTC 174 TCAATGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAGTTAT AATGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAGTTATGATA GATATCAACTGGGTGCGACAGGCCACTGGACAGGGGCTTGAGTGGATG TCAACTGGGTGCGACAGGCCACTGGACAGGGGCTTGAGTGGATGGGATGG GGAT GGAT GAAC C C T GAC AGT GGT AAC AC AGGC TAT GC AC AGAGAT T C ATGAACCCTGACAGTGGTAACACAGGCTATGCACAGAGATTCCAGGGCAG C AGGGC AGAGT C AC C AT GAC C AGGAAC AC C T C C AT AAGC AC AGC C T AC AGT C AC CAT GAC C AGGAAC AC C T C CAT AAGC AC AGC C T AC AT GGAGC T GA AT GGAGC T GAGC AGC C T GAGAT C T GAGGAC AC GGCCGTGTATTACTGT GCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGGTACTAC GCGAGGTACTACGGTGACTACTACTACTACTACTACATGGACGTCTGG GGTGACTACTACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCAC GGCAAAGGGACCACGGTCACCGTCTCCTCA GGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGG CCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTT GTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGC GCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCT TGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACT CAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGA TAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCAT GCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCG AAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGT CGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATG T T GAT GGT GT AGAGGT AC AC AAT GC T AAGAC T AAAC C T C GC GAGGAGC AG TACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGA T T GGC T T AAC GGC AAAGAAT AT AAGT GC AAGGT AAGC AAT AAAGC AC T T C CGGCCCCAATC GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAA CCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCA AGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTG T T GAAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C A CCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGT AGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGC AT GAAGC GT T AC AT AAT C AC T AC AC GC AGAAAT C T C T T AGT C T T T C AC C CGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 19 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGG 149 GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTC 175 TCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTAT CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCA GGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTC TGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTCTCATCC TCATCCATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTG ATTAGTAGTAGTAGTACTTACATATACTACGCAGACTCAGTGCAGGGCCG CAGGGCCGATTCACCATCTC C AGAGAC AAC GC C AAGAAC TCACTGTAT ATTCACCATCTC C AGAGAC AAC GC C AAGAAC TCACTGTATCT GC AAAT GA C T GC AAAT GAAC AGC C T GAGAGC C GAGGAC AC AGC TGTCTATTACTGT AC AGC C T GAGAGC C GAGGAC AC AGC TGTCTATTACTGTGC GAGAGAC T C G GC GAGAGAC T C GAGT AT AGC AGC TTTCGGGGGGTTC GAC CCCTGGGGC AGTATAGCAGCTTTCGGGGGGTTCGACCCCTGGGGCCAGGGATCCCTGGT CAGGGATCCCTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 20 GAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTGCTACAGCCTGGCAGG 150 GAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTGCTACAGCCTGGCAGGTC 176 TCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTAC CCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTACTGGA TGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGAGTGGGTC TGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGAGTGGGTCTCACGT TCACGTATTAATAATGATGGGAGTAGTAGAAGCTACGCGGACTCCGTG AT T AAT AAT GAT GGGAGT AGT AGAAGC T AC GC GGAC T C C GT GAAGGGC C G AAGGGC CGATTCACCATATC T AGAGAC AAC GC C AAGAAC AC GC T GT AT ATTCACCATATC T AGAGAC AAC GC C AAGAAC AC GCTGTATCT GC AAAT GA CTGCAAATGAACAGTCTGAGAGCCGAGGACACGGCTGTGTATTACTGT AC AGT C T GAGAGC C GAGGAC AC GGCTGTGTATTAC T GT GC AAGAC C T C C G GCAAGACCTCCGTATAGTGGGAGCTACTTTGATGCTTTTGATATCTGG TATAGTGGGAGCTACTTTGATGCTTTTGATATCTGGGGCCAAGGGACAAT GGCCAAGGGACAATGGTCACCGTCTCCTCA GGTCACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGG CCCCGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTT GTGAAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGC GCTGACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCT TGTATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACT CAGACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGA TAAACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCAT GCCCGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCG AAGCCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGT CGTGGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATG T T GAT GGT GT AGAGGT AC AC AAT GC T AAGAC T AAAC C T C GC GAGGAGC AG TACGCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGA T T GGC T T AAC GGC AAAGAAT AT AAGT GC AAGGT AAGC AAT AAAGC AC T T C CGGCCCCAATC GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAA CCCCAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCA AGTATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTG T T GAAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C A CCCGTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGT AGATAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGC AT GAAGC GT T AC AT AAT C AC T AC AC GC AGAAAT C T C T T AGT C T T T C AC C CGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 21 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 151 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 177 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGTAACT AACTGGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG GGTGGAATTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCCTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C C T C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC AGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT GCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGGGAGGGA GCGAGGGAGGGAGGCTACAGTAACCGTGGTGCTTTTGATATCTGGGGC GGCTACAGTAACCGTGGTGCTTTTGATATCTGGGGCCAAGGGACATTGGT CAAGGGACATTGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 22 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAG 152 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGAC 178 ACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCACTAGT CCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCACTAGTAACT AACTGGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGG GGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC C AT AT C AAT AGAC AAGT C C AAGAAC C AGT T C T C C AGTCACCATAT C AAT AGAC AAGT C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCCTGTATTACTGT GC T C T GT GAC C GC C GC GGAC AC GGCCCTGTATTACTGTGC GAGAGAGGGA GCGAGAGAGGGAGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGC GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGCCAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 23 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 153 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 179 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCGGCACTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCGGCACTAGTAACT AACTGGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGG GGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGT C GAGT C AC C AT AT C AAT AGAC AAGT C C AAGAAC C AGT T C T C C AGTCACCATAT C AAT AGAC AAGT C C AAGAAC CAGTTCTCCCT GAAGC T GA CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT GCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAGGGG GCGAGAGAGGGGGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGA GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGACAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCCTCA CACCGTCTCCTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 24 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 154 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 180 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGTAACT AACTGGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGG GGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCGTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C GT C C C T C AAGAGT C G AAGAGTCGAGTCACCATATCAATAGACAGGTCCAAGAACCAGTTCTCC AGT C AC C AT AT C AAT AGAC AGGT C C AAGAAC C AGT T C T C C C T GAAGC T GA CTGAAGCTGAGTTCTGTGACCGCCGCGGACACGGCCCTGTATTACTGT GT T C T GT GAC C GC C GC GGAC AC GGCCCTGTATTACTGTGC GAGAGAGGGA GCGAGAGAGGGAGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGA GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGACAAGGGACAATGGT CAAGGGACAATGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 25 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGG 155 CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGGGAC 181 ACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGT CCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCACTAGTAACT AACTGGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGG GGTGGACTTGGGTCCGCCAGACCCCAGGGAGGGGGCTGGAGTGGATTGGG ATTGGGGAAATCTATCATAGTGGGAGCACCAACTACAACCCCTCCCTC GAAAT C T AT C AT AGT GGGAGC AC C AAC T AC AAC C C C T C C C T C AAGAGT C G AAGAGTCGAGTCGCCATATCAGTAGACACGGCCAAGAACCAGTTCTCC AGTCGCCATATCAGTAGACACGGCCAAGAACCAGTTCTCCCTGAAGCTGA CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCCTGTATTACTGT GC T C T GT GAC C GC T GC GGAC AC GGCCCTGTATTACTGTGC GAGAGAGGGA GCGAGAGAGGGAGGCTACAGTAACCGTGGTCCTTATGATATCTGGGGA GGCTACAGTAACCGTGGTCCTTATGATATCTGGGGACAAGGGATAATGGT CAAGGGATAATGGTCACCGTCTCTTCA CACCGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCC CGTCCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTG AAAGATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCT GACAAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGT ATAGCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAG ACGTATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAA ACGCGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCC CGGCACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAG CCTAAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGT GGTTGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTG ATGGTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTAC GCCTCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTG GCTTAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGG C C C C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C CAGGTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGT ATCCCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTG AAT GGGAAT C GAAC GGT C AGC C GGAGAAT AAT T AT AAAAC AAC GC C AC C C GTCCTGGATAGCGACGGCTCATTTTTTCTGTATAGCAAACTGACTGTAGA TAAATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGT#14904047v2PCT APPLICATION No. A SID B SID (A) (B) 26 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCC 156 CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTC 182 TCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTAT AGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCACCTATGGTA GGTATCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATG TCAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGG GGAT GGAT C AGC GC T T AC AAT GGT AAC AC AAAC T AT GC AC AGAAGC T C AT C AGC GC T T AC AAT GGT AAC AC AAAC TAT GC AC AGAAGC T C C AGGGC AG C AGGGC AGAGT C AC CAT GAC C AC AGAC AC AT C C AC GAGC AC AGC C T AC AGT C AC C AT GAC C AC AGAC AC AT C C AC GAGC AC AGC C T AC AT GGAGC T GA AT GGAGC T GAGGAGC C T GAGAT C C GAGGAC AC GGCCGTGTATTACTGT GGAGC C T GAGAT C C GAGGAC AC GGCCGTGTATTACTGTGC GAGAGGGAT G GC GAGAGGGAT GT AT AAC T GGAAC TACCCTTTT GAC TACTGGGGCCAG T AT AAC T GGAAC T AC C C T T T T GAC T AC T GGGGC C AGGGAAC C C T GGT C AC GGAACCCTGGTCACCGTCTCTTCA CGTCTCTTCAGCTAGCACTAAAGGGCCTTCTGTATTTCCCTTGGCCCCGT CCAGCAAATCGACCTCGGGAGGGACAGCCGCCCTGGGTTGCCTTGTGAAA GATTATTTCCCTGAGCCAGTTACCGTAAGTTGGAACAGTGGGGCGCTGAC AAGTGGTGTGCACACGTTTCCTGCCGTCCTGCAATCATCGGGCTTGTATA GCCTCAGCTCTGTGGTCACTGTCCCAAGTTCATCGCTGGGCACTCAGACG TATATTTGCAATGTGAACCACAAACCTTCAAATACAAAAGTGGATAAACG CGTAGAACCGAAATCGTGTGATAAAACTCACACATGCCCGCCATGCCCGG CACCTGAACTGCTTGGTGGTCCCAGCGTGTTCCTGTTCCCGCCGAAGCCT AAAGATACTCTAATGATCAGCCGTACGCCAGAGGTGACATGTGTCGTGGT TGACGTGTCCCACGAAGATCCCGAAGTTAAGTTCAATTGGTATGTTGATG GTGTAGAGGTACACAATGCTAAGACTAAACCTCGCGAGGAGCAGTACGCC TCGACCTATCGTGTCGTGAGCGTTCTGACCGTCCTTCACCAAGATTGGCT TAACGGCAAAGAATATAAGTGCAAGGTAAGCAATAAAGCACTTCCGGCCC C AAT C GAGAAAAC C AT T T C C AAGGC C AAAGGT C AAC C AAGAGAAC C C C AG GTGTATACTCTTCCGCCTTCTCGTGAGGAAATGACTAAAAATCAAGTATC CCTTACGTGTCTGGTTAAAGGTTTTTATCCTAGCGATATTGCTGTTGAAT GGGAATCGAACGGTCAGCCGGAGAATAATTATAAAACAACGCCACCCGTC C T GGAT AGC GAC GGC T C AT T T T T T C T GT AT AGC AAAC T GAC T GT AGAT AA ATCACGGTGGCAGCAGGGCAATGTATTCAGTTGCTCCGTTATGCATGAAGCGTTACATAATCACTACACGCAGAAATCTCTTAGTCTTTCACCCGGTTable IV: Light chain nucleotide sequencesColumn A: light chain variable region (VL) (SEQ ID NOs: 183-208)Column B: full length light chain nucleotide sequences (SEQ ID NOs: 209-234) for each antibody protein Nos. 1-26, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or up to 100% sequence identity with any of the Table IV sequences.108#14904047v2PCT APPLICATIONSID SIDNo. A B(A) (B) 1 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAG 183 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACA 209 GAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAG GAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTG C T GGT T GGC C T GGT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C TAT AAGGC GT C T CTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGT AGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAG TCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAG AAT T C AC T C T C AC C AT C AGC AGC C T GC AGC C T GAT GAT T T T GC AAC T T AT T A C C T GC AGC C T GAT GAT T T T GC AAC T T AT T AC T GC C AAC AGT AT AAT CTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTG AGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA GAAATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT2 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 184 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 210 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 3 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 185 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 211 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC T AT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C T AT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T A AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGT CCGGTCACAAAATCGTTTAACCGCGGTGAGTGT4 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAG 186 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAA 212 GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAG GAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTG C T AC T T AGC C T GGT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C GT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C C T CAT C TAT GAT GC AT C C CTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGT AACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG TCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA CCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGC CTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTG AAC TGGCCTCTCACTTTCGGC GGAGGGAC C AAGGT GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C TAAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT110#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 5 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 187 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACA 213 GAGAC AGAGT C AC CATCACTTGCCAGGC GAGT C AGGAC AT T AGC AA GAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTAAATTG CTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTC GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C T AC GAT GC AT C C C T GAT C T AC GAT GC AT C C AAT T T GGAAAC AGGGGT C C C AT C AAGGT AATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAG TCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAG AT T T T AC T T T C AC C AT C AGC AGC C T GC AGC C T GAAGAT AT T GC AAC AT AT T A CCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGAT CTGTCAACAGTATGATAATCTCCCGTACACTTTTGGCCAGGGGACCAAGCTG AAT C T C C C GT AC AC T T T T GGC C AGGGGAC C AAGC T GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT6 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAG 188 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAA 214 GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAG GAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTG C T AC T T AGC C T GGT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C GT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C C T CAT C TAT GAT GC AT C C CTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGT AACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG TCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA CCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGC CTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTG AAC TGGCCTCTCACTTTCGGC GGAGGGAC C AAGGT GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT111#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 7 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAG 189 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAA 215 GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAG GAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTG C T AC T T AGC C T GGT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C GT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C C T CAT C TAT GAT GC AT C C CTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGT AACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG TCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA CCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGC CTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTG AAC TGGCCTCTCACTTTCGGC GGAGGGAC C AAGGT GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT8 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAG 190 GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAA 216 GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAG GAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTG C T AC T T AGC C T GGT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C GT AC C AAC AGAAAC C T GGC C AGGC T C C C AGGC T C C T CAT C TAT GAT GC AT C C CTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGT AACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG TCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAG ACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTA CCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGC CTGTCAGCAGCGTAGCAACTGGCCTCTCACTTTCGGCGGAGGGACCAAGGTG AAC TGGCCTCTCACTTTCGGC GGAGGGAC C AAGGT GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT112#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 9 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 191 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACA 217 GAGAC AGAGT C AC CATCACTTGCCAGGC GAGT C AGGAC AT T AGC AA GAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTAAATTG CTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTC GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C T AC GAT GC AT C C C T GAT C T AC GAT GC AT C C AAT T T GGAAAC AGGGGT C C C AT C AAGGT AATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAG TCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAG AT T T T AC T T T C AC C AT C AGC AGC C T GC AGC C T GAAGAT AT T GC AAC AT AT T A CCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGAT CTGTCAACAGTATGATAATCTCCCGTACACTTTTGGCCAGGGGACCAAGCTG AAT C T C C C GT AC AC T T T T GGC C AGGGGAC C AAGC T GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT10 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 192 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 218 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 11 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 193 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 219 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAA TCGTTTAACCGCGGTGAGTGT12 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 194 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 220 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T CAT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT114#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 13 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 195 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 221 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAA TCGTTTAACCGCGGTGAGTGT14 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAG 196 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACA 222 GAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAG GAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTG C T GGT T GGC C T GGT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C TAT AAGGC GT C T CTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGT AGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAG TCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAG AAT T C AC T C T C AC C AT C AGC AGC C T GC AGC C T GAT GAT T T T GC AAC T T AT T A C C T GC AGC C T GAT GAT T T T GC AAC T T AT T AC T GC C AAC AGT AT AAT CTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTG AGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA GAAATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT115#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 15 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAG 197 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACA 223 GAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAG GAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTG C T GGT T GGC C T GGT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C TAT AAGGC GT C T CTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGT AGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAG TCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAG AAT T C AC T C T C AC C AT C AGC AGC C T GC AGC C T GAT GAT T T T GC AAC T T AT T A C C T GC AGC C T GAT GAT T T T GC AAC T T AT T AC T GC C AAC AGT AT AAT CTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTG AGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA GAAATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT16 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 198 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGA 224 GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATA GGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAA C AGC T C C AAC AAT AAGAAC T AC T T AGC T T GGT AC C AGC AGAAAC C A T AAGAAC TACTTAGCTTGGTAC C AGC AGAAAC C AGGAC AGC C T C C T AAGC T G GGAC AGC C T C C T AAGC T GC T C AT T T AC T GGGC AT C T AC C C GGGAAT CTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTG CCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTT GCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA CACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTAT AGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTT TACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGA GGCCAGGGGACCAAGCTGGAGATCAAACGTACGGTAGCTGCCCCTTCAGTTT C C AAGC T GGAGAT C AAA TTATCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGT TTGCCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTC GAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GA CTATGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCC AGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT116#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 17 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 199 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 225 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAA TCGTTTAACCGCGGTGAGTGT18 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 200 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 226 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC T AT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C T AT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C TA AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT117#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 19 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 201 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 227 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC T AT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C T AT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T A AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGT CCGGTCACAAAATCGTTTAACCGCGGTGAGTGT20 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGG 202 GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGA 228 GCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATA GGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAA C AGC T C C AAC AAT AAGAAC T AC T T AGC T T GGT AC C AGC AGAAAC C A T AAGAAC TACTTAGCTTGGTAC C AGC AGAAAC C AGGAC AGC C T C C T AAGC T G GGAC AGC C T C C T AAGC T GC T C AT T T AC T GGGC AT C T AC C C GGGAAT CTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTG CCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTT GCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA CACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTAT AGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTT TACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGA GGCCAGGGGACCAAGCTGGAGATCAAACGTACGGTAGCTGCCCCTTCAGTTT C C AAGC T GGAGAT C AAA TTATCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGT TTGCCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTC GAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GA CTATGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCC AGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT118#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 21 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGG 203 GAGATTGTACTTACTCAGAGTCCGGGAACTCTTTCCCTGTCTCCGGGAGAGC 229 GAGAGCGGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAG GGGCCACGCTGAGCTGCCGCGCCTCACAGTCAGTCTCTAGCTCATATCTCGC CTCATATCTCGCATGGTACCAACAAAAGCCTGGCCAAGCCCCGAGG AT GGT AC C AAC AAAAGC C T GGC C AAGC C C C GAGGT T GC T C AT T T AC GGAGC C TTGCTCATTTACGGAGCCTCCTCTCGCGCGACGGGCATACCCGACA TCCTCTCGCGCGACGGGCATACCCGACAGGTTTAGTGGAAGCGGGTCAGGGA GGTTTAGTGGAAGCGGGTCAGGGACGGACTTTACGCTGACAATCTC CGGACTTTACGCTGACAATCTCTAGGCTTGAACCCGAAGACTTCGCCGTGTA TAGGCTTGAACCCGAAGACTTCGCCGTGTACTACTGTCAACAGTAT CTACTGTCAACAGTATGGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAA GGCTCTAGCCCCCTCACGTTTGGGGGTGGTACTAAAGTAGAAATCA GTAGAAATCAAGCGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGT AG CTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAA TTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAG T C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT ATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TAT GAAAAAC AT AA AGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAA TCGTTTAACCGCGGTGAGTGT22 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 204 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 230 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC T AT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C T AT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C TA AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT119#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 23 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 205 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 231 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC T AT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C T AT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T A AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGT CCGGTCACAAAATCGTTTAACCGCGGTGAGTGT24 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C G 206 GAC AT AGT AAT GAC GC AAAGC C C T C T T AGT C T C C C GGT AAC AC C C GGAGAAC 232 GAGAACCAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCA CAGCGTCCATATCCTGCCGATCCAGTCAGTCTCTGTTGCACTCTAACGGGTA CTCTAACGGGTACAACTATCTTGACTGGTATCTTCAAAAACCGGGA C AAC TAT C T T GAC T GGT AT C T T C AAAAAC C GGGAC AGT C AC C AC AAT T GC T C CAGTCACCACAATTGCTCATATATCTTGGATCTAACCGCGCCTCCG ATATATCTTGGATCTAACCGCGCCTCCGGGGTGCCCGACCGATTTTCCGGCA GGGTGCCCGACCGATTTTCCGGCAGTGGGAGTGGCACGGATTTCAC GT GGGAGT GGC AC GGAT T T C AC T C T C AAAAT AT C C C GC GT AGAAGC GGAGGA TCTCAAAATATCCCGCGTAGAAGCGGAGGACGTTGGTGTTTATTAT CGTTGGTGTTTATTATTGCATGCAAGCCTTGCAGACTCCCTATACCTTTGGG T GC AT GC AAGC C T T GC AGAC T C C C TAT AC C T T T GGGC AAGGGAC AA CAAGGGACAAAGCTGGAAATAAAGCGTACGGTAGCTGCCCCTTCAGTTTTTA AGC T GGAAAT AAAG TCTTTCCGCCGTCTGACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTG CCTGCTGAATAATTTTTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGAC AAT GC T T T GC AGT C GGGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C TA AAGAT TCCACATATTCACTCAGCTCCACCCTTACACT GAGC AAAGC C GAC TA TGAAAAACATAAAGTTTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT120#14904047v2PCT APPLICATION SID SIDNo. A B(A) (B) 25 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 207 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACA 233 GAGAC AGAGT C AC CATCACTTGCCAGGC GAGT C AGGAC AT T AGC AA GAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTAAATTG CTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTC GT AT C AGC AGAAAC C AGGGAAAGC C C C T AAGC T C C T GAT C T AC GAT GC AT C C C T GAT C T AC GAT GC AT C C AAT T T GGAAAC AGGGGT C C C AT C AAGGT AATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAG TCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAG AT T T T AC T T T C AC C AT C AGC AGC C T GC AGC C T GAAGAT AT T GC AAC AT AT T A CCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATGAT CTGTCAACAGTATGATAATCTCCCGTACACTTTTGGCCAGGGGACCAAGCTG AAT C T C C C GT AC AC T T T T GGC C AGGGGAC C AAGC T GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCG TTTAACCGCGGTGAGTGT26 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAG 208 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACA 234 GAGAC AGAGT C AC CATCACTTGCC GGGC AAGT C AGAGC AT T AGC AG GAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTG CTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTC GTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCC CTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGT AGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAG TCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAG AT T T C AC T C T C AC C AT C AGC AGT C T GC AAC C T GAAGAT T T T GC AAC T T AC T A T C T GC AAC C T GAAGAT T T T GC AAC T T AC T AC T GT C AAC AGAGT T AC CTGTCAACAGAGTTACAGTACCCCGTACACTTTTGGCCAGGGGACCAAGCTG AGT AC C C C GT AC AC T T T T GGC C AGGGGAC C AAGC T GGAGAT C AAA GAGATCAAACGTACGGTAGCTGCCCCTTCAGTTTTTATCTTTCCGCCGTCTG ACGAGCAGTTAAAATCCGGGACCGCTTCTGTAGTTTGCCTGCTGAATAATTT TTATCCGCGTGAGGCTAAAGTACAATGGAAAGTCGACAATGCTTTGCAGTCG GGAAAT T C AC AGGAAAGT GT T AC GGAGC AGGAT T C T AAAGAT T C C AC AT AT T C AC T C AGC T C C AC C C T T AC AC T GAGC AAAGC C GAC TAT GAAAAAC AT AAAGT TTACGCATGTGAGGTGACGCACCAAGGATTATCCAGTCCGGTCACAAAATCGTTTAACCGCGGTGAGTGT121#14904047v2PCT APPLICATION IV. Antibody formats, sequence variations, and modifications[000163] In some embodiments, the anti-TfRl antibody can be a full-length IgG, a Fab fragment, a F(ab’) fragment, a scFv, or a Fv. In some embodiments, an antibody comprises a heavy chain constant region of the isotype IgGl, IgG2, IgG3, or IgG4. In some embodiments, an antibody is a chimeric antibody, e.g., a mouse-human chimeric antibody. In some embodiments, an antibody is a humanized antibody. In some embodiments, an antibody is a fully human antibody. In some embodiments, an antibody is a polyclonal antibody. In some embodiments, an antibody is a monoclonal antibody. In yet some embodiments, an antibody is a bi-specific antibody. In some embodiments, an antibody is a multi-specific antibody. In still some embodiments, the antibody can be a synthetic antibody. In yet some embodiments, the antibody can be obtained via a phage-display screening methodology. In some embodiments, the antibody can be obtained by introducing TfRl antigen into an antibody-production animal, e.g., a mouse, and screening for anti-TfRl antibodies. In such cases, the CDR sequences may be obtained and introduced into a human antibody framework to generate a chimeric antibody having a human framework with mouse CDRs. In still some embodiments, any chimeric antibody such generated can be humanized using known methodologies.[000164] Also within the scope of the present disclosure are functional variants of any of the exemplary anti-TfRl antibodies as disclosed herein. A functional variant may contain one or more amino acid residue variations in the VH and / or VL, or in one or more of the HC CDRs and / or one or more of the LC CDRs as relative to the reference antibody, while retaining substantially similar binding and biological activities (e.g., substantially similar binding affinity, binding specificity, or a combination thereof) as the reference antibody.[000165] In some embodiments, an anti-TfRl antibody of the disclosure have one or more CDRs (e.g., HC CDR or LC CDR) sequences substantially similar to any of the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 sequences from one of an anti-TfRl antibody selected from Tables I- IV. In some embodiments, the position of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) region of an antibody described herein can vary by one, two, three, four, five, or six amino acid positions so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). For example, in some embodiments, the position defining a CDR of any antibody described herein can vary by shifting the N-terminal and / or C- 122#14904047v2PCT APPLICATION terminal boundary of the CDR by one, two, three, four, five, or six amino acids, relative to the CDR position of any one of the antibodies described herein, so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived). In another embodiment, the length of one or more CDRs along the VH (e.g., HC CDR1, HC CDR2, or HC CDR3) and / or VL (e.g., LC CDR1, LC CDR2, or LC CDR3) region of an antibody described herein can vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the binding of the original antibody from which it is derived).[000166] Accordingly, in some embodiments, a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described herein (e.g., CDRs from an anti-TfRl antibody selected from Tables LIV) so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described herein (e.g., CDRS from an anti-TfRl antibody selected from Tables LIV) so long as immuno specific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRS from an anti- TfRl antibody selected from Tables LIV) so long as immuno specific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs from an anti- TfRl antibody 123#14904047v2PCT APPLICATION selected from Tables I-IV) so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the amino portion of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRs from any of the anti-TfRl antibodies selected from Tables I- IV) so long as immuno specific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived). In some embodiments, the carboxy portion of a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and / or LC CDR3 described herein can be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., CDRS from an anti-TfRl antibody selected from Tables I-IV) so long as immuno specific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived).[000167] Any method can be used to ascertain whether immuno specific binding to TfRl (e.g., human TfRl) is maintained, for example, using binding assays and conditions described in the art.[000168] In some examples, an anti- TfRl antibody of the disclosure has one or more CDR (e.g., HC CDR or LC CDR) sequences substantially similar to any one of an anti- TfRl antibody selected from Tables I- IV. For example, antibodies may include one or more CDR sequence(s) from an anti-TfRl antibody selected from Tables I-IV containing up to 5, 4, 3, 2, or 1 amino acid residue variations as compared to the corresponding CDR region in any one of the CDRs provided herein (e.g., CDRs from an anti-TfRl antibody selected from Tables I-IV) so long as immunospecific binding to TfRl (e.g., human TfRl) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived).[000169] In some embodiments, any of the amino acid variations in any of the CDRs provided herein may be conservative variations. Conservative variations can be introduced into the CDRs at positions where the residues are not likely to be involved in interacting with a TfRl protein (e.g., a human TfRl protein), for example, as determined based on a crystal 124#14904047v2PCT APPLICATION structure. Some aspects of the disclosure provide anti-TfRl antibodies that comprise one or more of the heavy chain variable (VH) and / or light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein include one or more of the HC CDR sequences (e.g., HC CDR1, HC CDR2, and HC CDR3) provided herein, for example, any of the CDR-H sequences provided in any one of the anti-TfRl selected from Tables LIV. In some embodiments, any of the VL domains provided herein include one or more of the CDR-L sequences (e.g., LC CDR1, LC CDR2, and LC CDR3) provided herein, for example, any of the LC CDR sequences provided in any one of an anti-TfRl antibody selected from Tables LIV.[000170] In some embodiments, an anti-TfRl antibody of the disclosure includes any antibody that includes a heavy chain variable domain and / or a light chain variable domain of any one of an anti-TfRl antibody selected from Tables LIV, and variants thereof. In some embodiments, anti-TfRl antibodies of the disclosure include any antibody that includes the heavy chain variable and light chain variable pairs of any anti-TfRl antibodies selected from Tables LIV.[000171] Aspects of the disclosure provide anti-TfRl antibodies having a heavy chain variable (VH) and / or a light chain variable (VL) domain amino acid sequence homologous to any of those described herein. In some embodiments, the anti-TfRl antibody comprises a heavy chain variable sequence or a light chain variable sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the heavy chain variable sequence and / or any light chain variable sequence of any one of an anti-TfRl antibody selected from Tables LIV. In some embodiments, the homologous heavy chain variable and / or a light chain variable amino acid sequences do not vary within any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) may occur within a heavy chain variable and / or a light chain variable sequence excluding any of the CDR sequences provided herein. In some embodiments, an anti-TfRl antibody provided herein comprise a heavy chain variable sequence and a light chain variable sequence that comprises a framework sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of any anti-TfRl antibodies selected from Tables LIV.125#14904047v2PCT APPLICATION [000172] In some embodiments, the anti-TfRl antibody of the present disclosure is a humanized antibody (e.g., a humanized variant containing one or more CDRs of Tables LIV). In some embodiments, the anti-TfRl antibody of the present disclosure comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2, and a LC CDR3 that are the same as the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 shown in Tables LIV, and comprises a humanized heavy chain variable region and / or a humanized light chain variable region.[000173] In some embodiments, the anti-TfRl antibody of the present disclosure is a humanized antibody comprising a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VH of an anti-TfRl antibody listed in Tables LIV.Alternatively or in addition, the anti-TfRl antibody of the present disclosure is a humanized antibody comprising a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VL of any one of an anti-TfRl antibody listed in Tables LIV.[000174] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a HC CDR1, a HC CDR2, and a HC CDR3 that collectively are at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the HC CDR1, HC CDR2, and HC CDR3 of Tables LIV. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a LC CDR1, a LC CDR2, and a LC CDR3 that collectively are at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the to the LC CDR1, LC CDR2, and LC CDR3 of Tables I-IV.[000175] In some embodiments, the anti-TfRl antibody of the present disclosure comprises: a HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR1 having the amino acid sequence of SEQ ID NOs: 1-12; a HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR2 having the amino acid sequence of SEQ ID NOs: 13-20; and / or a HC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR3 having the amino acid sequence of SEQ ID NOs: 21-40. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises: a LC CDR1 having no more than 3 amino acid 126#14904047v2PCT APPLICATION variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the LC CDR1 having the amino acid sequence of SEQ ID NOs: 96-102; a LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the LC CDR2 having the amino acid sequence of SEQ ID NOs: 103-109; and / or a LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the LC CDR3 having the amino acid sequence of SEQ ID NOs: 110-116.[000176] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NOs: 124-130.[000177] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VH as set forth in SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VL as set forth in SEQ ID NOs: 124-130. In some embodiments, the number of amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) may occur within a VH of SEQ ID NOs: 66-91 and / or a VL of SEQ ID NOs: 124-130 excluding any of the CDR sequences therein. In some embodiments, an anti-TfRl antibodies provided herein comprise a heavy chain variable sequence that comprises a framework sequence that that contains no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation to the framework sequence of a VH of SEQ ID NOs: 66-91, and / or a light chain variable sequence that comprises a framework sequence that that contains no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation to the framework sequence of a VL of SEQ ID NOs: 124-130.[000178] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH as set forth in SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at 127#14904047v2PCT APPLICATION least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VL as set forth in SEQ ID NOs: 124-130. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) may occur within a VH of SEQ ID NOs: 66-91, and / or a VL of SEQ ID NOs: 124-130 excluding any of the CDR sequences therein. In some embodiments, an anti-TfRl antibody provided herein comprise a heavy chain variable sequence that is at least 75%, (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of a VH of SEQ ID NOs: 66-91, and / or a light chain variable sequence that comprises a framework sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of a VL of SEQ ID NOs: 124-130.[000179] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a HC CDR1, HC CDR2 and HC CDR3 of a heavy chain variable domain having the amino acid sequence of SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a LC CDR1, LC CDR2 and LC CDR3 of a light chain variable domain having the amino acid sequence of SEQ ID NOs: 124-130.[000180] In some embodiments, according to the Kabat definition system, the anti-TfRl antibody of the present disclosure comprises a HC CDR1 having the amino acid sequence of SEQ ID NOs: 1-12, a HC CDR2 having the amino acid sequence of SEQ ID NOs: 13-20, a HC CDR3 having the amino acid sequence of SEQ ID NOs: 21-40, a LC CDR1 having the amino acid sequence of SEQ ID NOs: 96-102, a LC CDR2 having the amino acid sequence of SEQ ID NOs: 103-109, and a LC CDR3 having the amino acid sequence of SEQ ID NOs: 103-109.[000181] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a HC CDR1, a HC CDR2, and a HC CDR3, which collectively contains no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2, or 1 amino acid variation) as compared with the HC CDR1 having the amino acid sequence of SEQ ID NOs: 1-12, HC CDR2 having the amino acid sequence of SEQ ID NOs: 13-20, and HC CDR3 having the amino acid sequence of SEQ ID NOs: 21-40. “Collectively,” as used anywhere in the present disclosure, means that the total number of amino acid variations in all of the three heavy chain CDRs is within 128#14904047v2PCT APPLICATION the defined range. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a LC CDR1, a LC CDR2, and a LC CDR3, which collectively contains no more than 5 amino acid variations (e.g., no more than 5, 4, 3, 2 or 1 amino acid variation) as compared with the LC CDR1 having the amino acid sequence of SEQ ID NOs: 96-102, LC CDR2 having the amino acid sequence of SEQ ID NOs: 103-109, and LC CDR3 having the amino acid sequence of SEQ ID NOs: 110-116.[000182] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a HC CDR1, a HC CDR2, and a HC CDR3 that collectively are at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the HC CDR1 having the amino acid sequence of SEQ ID NOs: 1-12, HC CDR2 having the amino acid sequence of SEQ ID NOs: 13-20, and HC CDR3 having the amino acid sequence of SEQ ID NOs: 21-40. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a LC CDR1, a LC CDR2, and a LC CDR3 that collectively are at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the to the LC CDR1 having the amino acid sequence of SEQ ID NOs: 96-102, LC CDR2 having the amino acid sequence of SEQ ID NOs: 103-109, and LC CDR3 having the amino acid sequence of SEQ ID NOs: 110-116.[000183] In some embodiments, the anti-TfRl antibody of the present disclosure comprises: a HC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR1 having the amino acid sequence of SEQ ID NOs: 1-12; a HC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR2 having the amino acid sequence of SEQ ID NOs: 13-20; and / or a HC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the HC CDR3 having the amino acid sequence of SEQ ID NOs: 21-40. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises: a LC CDR1 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the LC CDR1 having the amino acid sequence of SEQ ID NOs: 96-102; a LC CDR2 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the LC CDR2 having the amino acid sequence of SEQ ID NOs: 103-109; and / or a LC CDR3 having no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid129#14904047v2PCT APPLICATION variation) as compared with the LC CDR3 having the amino acid sequence of SEQ ID NOs: 110-116.[000184] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VH as set forth in SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a VL containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VL as set forth in SEQ ID NOs: 124-130. In some embodiments, the number of amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) may occur within a VH of SEQ ID NOs: 66-91 and / or a VL of SEQ ID NOs: 124-130 excluding any of the CDR sequences therein. In some embodiments, an anti-TfRl antibodies provided herein comprise a heavy chain variable sequence that comprises a framework sequence that that contains no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation to the framework sequence of a VH of SEQ ID NOs: 66-91, and / or a light chain variable sequence that comprises a framework sequence that that contains no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation to the framework sequence of a VL of SEQ ID NOs: 124-130.[000185] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a VH comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the VH as set forth in SEQ ID NOs: 66-91. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a VL comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL as set forth in SEQ ID NOs: 124-130. In some embodiments, the degree of sequence variation (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) may occur within a VH of SEQ ID NOs: 66-91, and / or a VL of SEQ ID NOs: 124-130 excluding any of the CDR sequences therein. In some embodiments, an anti-TfRl antibody provided herein comprise a heavy chain variable sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of a VH of SEQ ID NOs: 66-91,130#14904047v2PCT APPLICATION and / or a light chain variable sequence that comprises a framework sequence that is at least 75% (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the framework sequence of a VL of SEQ ID NOs: 124-130.[000186] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables I- IV or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 7. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables I- IV or any variants thereof and a heavy chain constant region that contains no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables LIV or any variants thereof and a heavy chain constant region set forth in Tables LIV.[000187] In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region contains no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region set forth in Tables LIV.[000188] Examples of IgG heavy chain and light chain amino acid sequences of an anti-TfRl antibody described are provided in Tables LIV above.[000189] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the heavy chain as set forth in Tables LIV. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a light chain containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the light chain as set forth in Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain 131#14904047v2PCT APPLICATION comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to Tables LIV. Alternatively or in addition, the anti-TfRl antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the amino acid sequence of Tables LIV. Alternatively or in addition, the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of Tables LIV.[000190] In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables LIV or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables LIV or any variants thereof and a heavy chain constant region that contains no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the VH as listed in Tables LIV or any variants thereof and a heavy chain constant region set forth in Tables LIV.[000191] In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region contains no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a light chain comprising the VL as listed in Tables LIV or any variants thereof and a light chain constant region set forth in Tables LIV.[000192] Examples of IgG heavy chain and light chain amino acid sequences of an anti-TfRlantibody described are provided in Tables LIV above.[000193] In some embodiments, the anti-TfRl antibody of the present disclosure comprises a heavy chain containing no more than 20 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the heavy chain as set forth in Tables LIV. Alternatively or in addition, the anti-TfRl antibody of the present disclosure comprises a light chain containing no more than 20 amino 132#14904047v2PCT APPLICATION acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the light chain as set forth in Tables I- IV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to Tables LIV. Alternatively or in addition, the anti-TfRl antibody described herein comprises a light chain comprising an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to Tables LIV. In some embodiments, the anti-TfRl antibody described herein comprises a heavy chain comprising the amino acid sequence of Tables LIV. Alternatively or in addition, the anti-TfRl antibody described herein comprises a light chain comprising the amino acid sequence of Tables LIV.[000194] An anti-TfRl antibody described herein can be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (such as Fab, F(ab'), F(ab')2, Fv), single chain antibodies, bispecific antibodies, multispecific antibodies, or nanobodies. In some embodiments, the anti-TfRl antibody described herein is a scFv. In some embodiments, the anti-TfRl antibody described herein is a scFv-Fab (e.g., scFv fused to a portion of a constant region). Provided herein, in some embodiments, is a bispecific antibody. In some embodiments, the first antigen binding site of the bispecific antibody specifically binds TfRl. In some embodiments, the second antigen binding site specifically binds a T cell antigen. In some antibodies, the T cell antigen is a CD3 complex or a portion thereof.[000195] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are not likely to be involved in interacting with a target antigen (e.g., TfRl), for example, as determined based on a crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an anti-TfRl antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or antigen-dependent cellular cytotoxicity.[000196] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U. S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI 133#14904047v2PCT APPLICATION domain can be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of an antibody or to facilitate linker conjugation.[000197] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or CH3 domain (residues 341-447 of human IgGl) and / or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat) to increase or decrease the affinity of an antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of an antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U. S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.[000198] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of an antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U. S. Pat. Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.[000199] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the half-life of the anti-TfRl antibody in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of an antibody in vivo.[000200] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of an antibody in vivo. In some embodiments, antibodies can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of 134#14904047v2PCT APPLICATION human IgGl) and / or the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the constant region of the IgGl of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U. S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as " YTE mutant" has been shown to display fourfold increased half-life as compared to wild-type versions of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat.[000201] In some embodiments, one, two or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the anti-TfRl antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U. S. Pat. Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating antibody thereby increasing tumor localization. See, e.g., U. S. Pat. Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R L et al., (2001) J Biol Chem 276: 6591-604).[000202] In some embodiments, one or more amino in the constant region of an anti-TfRl antibody described herein can be replaced with a different amino acid residue such that the antibody has altered Clq binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U. S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody dependent135#14904047v2PCT APPLICATION cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fey receptor. This approach is described further in International Publication No. WO 00 / 42072.[000203] In some embodiments, the heavy and / or light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or composite human antibodies or antigen-binding fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibodies derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will maintain the ability to specifically bind TfRl, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to TfRlrelative to the original antibody from which it is derived.[000204] In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing ‘Adair’ mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline resulting in an IgGl-like hinge sequence.Accordingly, any antibodies may include a stabilizing ‘Adair’ mutation.[000205] In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to an antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody is fully or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by 136#14904047v2PCT APPLICATION enzymatic means. In some embodiments, an antibody is glycosylated in vitro or inside a cell, which may optionally be deficient in an enzyme in the N- or O- glycosylation pathway, e.g. a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application Publication WO2014065661, published on May 1, 2014, entitled, “Modified antibody, antibodyconjugate and process for the preparation thereof’.[000206] In some embodiments, any one of an anti-TfRl antibody described herein may comprise a signal peptide in the heavy and / or light chain sequence (e.g., a N-terminal signal peptide). In some embodiments, the anti-TfRl antibody described herein comprises any one of the VH and VL sequences, any one of the IgG heavy chain and light chain sequences, or any one of the F(ab') heavy chain and light chain sequences described herein, and further comprises a signal peptide (e.g., a N-terminal signal peptide).[000207] In some embodiments, any one of the antibodies described herein is a multispecific antibody that specifically binds TfRl and one or more additional target antigens. In some embodiments, an antibody is a bispecific antibody that specifically binds to TfRl and one additional target antigen, e.g., a therapeutically relevant target. In some embodiments, the multispecific antibody or bispecific antibody can be obtained by known technology in the art. In some embodiments, the one or more additional targets include but are not limited to CD3, CD4, CD8, CD20, CD19, CD21, CD23, CD46, CD80, HLA-DR, CD74, CD22, CD14, CD15, CD16, CD123, TCR gamma / delta, NKp46, or KIR.[000208] The anti-TfRl antibodies may be configured in bispecific or multispecific format to bind to TfRl with one affinity arm, and a second antigen, such as a T cell antigen, which may include CD3 (without being bound by theory, CD3 is involved in activating cytotoxic T-cells and T-helper cells), CD4 (without being bound by theory, CD4 initiates the early phase of T-cell activation. May function as an important mediator of indirect neuronal damage in infectious and immune-mediated CNS diseases), CD8 (without being bound by theory, CD27, CD8 is involved in T cell signaling and cytotoxic T cell-antigen interactions), CD28 (without being bound by theory, CD28 is involved in co-stimulation of T cells), CD44 (leukocyte rolling, homing and aggregation), CD45 (involved in B- and T-cell receptor-mediated activation), CD62L, CD127, CD137, CD152, CD183, CD184, CD185, CD194, CD197, CD365, IFNy receptor, TNFa receptor, IL-2 receptor, IL-4 receptor, IL-6 receptor, IL-10 receptor, IL-12 receptor, IL-17A receptor, IL-18 receptor, and IL-21 receptor.[000209] The anti-TfRl antibodies may be configured in bispecific or multispecific format to bind to TfRl with one affinity arm, and a second antigen, such as a B cell antigen which may 137#14904047v2PCT APPLICATION include CD5, CD10, CD34, Pax5, CD117, CD38, CD20, CD24, CD34, CD38, CD93, IL-3R, IL-7Ra, IL-4Ra, CD21, CD40, CD19, and others.[000210] In some embodiments, the antibodies described herein are conjugated directly or indirectly to one or more molecular payloads or labels. For example, in some embodiments, antibodies described herein are conjugated to molecular payload, e.g., a molecular payload providing a therapeutic benefit for a subject, e.g., an antibody-oligonucleotide conjugate (AOC), an antibody-drug conjugate (ADC). In some embodiments, a molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity capable of modulating the activity or function of a gene, protein, and / or nucleic acid, e.g., in a cell. In some embodiments, the molecular payload is a cytotoxic agent or a chemotherapeutic agent. In some embodiments, antibodies described herein are conjugated directly or indirectly to a detectable label, e.g., for diagnostic purposes.[000211] In some embodiments, the present disclosure also provides fusion proteins comprising an anti-TfRl antibody described herein fused directly or indirectly (e.g., via a linker) to one or more polypeptide or protein.[000212] In the case of immunoconjugates disclosed herein (e.g. anti-TfRl antibodies conjugated to a heterologous molecule such as a therapeutic agent), the immunoconjugates may include a linker. A "linker" as used herein is a structure that covalently or non-covalently connects the anti-TfR antibody to heterologous molecule. In certain embodiments, a linker is a peptide. In some embodiments, a linker is a chemical linker.V. Anti-TfRl antibodies as tunable delivery agents[000213] In embodiments, anti-TfRl antibodies provided herein are tunable as defined above. Non-limiting examples of properties that are tunable for a particular application include: binding affinity, avidity, epitope bound, internalization profile, developability, manufacturability, stability, and specificity.[000214] In some embodiments, an anti-TfRl antibody provided herein is tunable with respect to its binding affinity for TfRl. The anti-TfRl antibodies disclosed herein in Tables LIV may be further modified to tune or adjust the strength of anti-TfRl / TfRl interaction. Antibody affinity refers to the strength of the binding interaction between an antibody and its antigen (e.g. between an anti-TfRl an...

Claims

PCT APPLICATION CLAIMS1. An antibody or an antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment comprises:a. a heavy chain variable (VH) domain comprising a heavy chain complementarity determining region (HC CDR1) having the sequence of SEQ ID NO: 4, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 24, and a light chain variable (VL) domain comprising a light chain complementarity determining region (LC CDR1) having the sequence of SEQ ID NO: 101, a LC CDR2 having the sequence of SEQ ID NO: 104, and a LC CDR3 having the sequence of SEQ ID NO: 111;b. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 6, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 31, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 100, a LC CDR2 having the sequence of SEQ ID NO: 106, and a LC CDR3 having the sequence of SEQ ID NO: 114;c. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 9, a HC CDR2 having the sequence of SEQ ID NO: 19, and a HC CDR3 having the sequence of SEQ ID NO: 37, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 96, a LC CDR2 having the sequence of SEQ ID NO: 109, and a LC CDR3 having the sequence of SEQ ID NO: 116;d. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 11, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 28, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 97, a LC CDR2 having the sequence of SEQ ID NO: 104, and a LC CDR3 having the sequence of SEQ ID NO: 111; ore. a VH comprising a HC CDR1 having the sequence of SEQ ID NO: 5, a HC CDR2 having the sequence of SEQ ID NO: 16, and a HC CDR3 having the sequence of SEQ ID NO: 26, and a VL comprising a LC CDR1 having the sequence of SEQ ID NO: 101, a LC CDR2 having the sequence of SEQ ID NO: 105, and a LC CDR3 having the sequence of SEQ ID NO: 111.220#14904047v2PCT APPLICATION2. The antibody or antigen-binding fragment of claim 1, comprising:a. a VH having the sequence of SEQ ID NO: 44 and a VL having the sequence of SEQ ID NO: 118;b. a VH having the sequence of SEQ ID NO: 54 and a VL having the sequence of SEQ ID NO: 121;c. a VH having the sequence of SEQ ID NO: 60 and a VL having the sequence of SEQ ID NO: 123;d. a VH having the sequence of SEQ ID NO: 63 and a VL having the sequence of SEQ ID NO: 120; ore. a VH having the sequence of SEQ ID NO: 47 and VL having the sequence of SEQ ID NO: 118.

3. The antibody or antigen-binding fragment of claim 1 or claim 2, further comprising:a. a heavy chain (HC) having the sequence of SEQ ID NO: 69 and a light chain (LC) having the sequence of SEQ ID NO: 125;b. a HC having the sequence of SEQ ID NO: 79 and a LC having the sequence of SEQ ID NO: 128;c. a HC having the sequence of SEQ ID NO: 85 and a LC having the sequence of SEQ ID NO: 130;d. a HC having the sequence of SEQ ID NO: 88 and a LC having the sequence of SEQ ID NO: 127; ore. a HC having the sequence of SEQ ID NO: 72 and a LC having the sequence of SEQ ID NO: 125.

4. The antibody or antigen binding fragment of any of claims 1-3, wherein the antibody or antigen-binding fragment is selected from:221#14904047v2PCT APPLICATION a. a full-length immunoglobulin G (IgG),b. a Fab fragment,c. a monovalent Fab-Fc constructd. a F(ab') fragment,e. a F(ab')2 fragment,f. a single-chain variable fragment (scFv),g. a variable fragment (Fv),h. a single-domain antibody (nanobody),i. a diabody, orj. a triabody.

5. A composition comprising the antibody or antigen-binding fragment of any of the preceding claims and a therapeutic agent.

6. The composition of claim 5, wherein the therapeutic agent is selected from a double stranded RNA, oligonucleotide, peptide, small molecule, antibody or antigen binding fragment thereof, or a combination thereof.

7. The composition of claim 5 or claim 6, comprising an antibody-oligonucleotide conjugate (AOC) comprising an antibody according to any one of claims 1-4.

8. The composition of claim 5 or claim 6, comprising a bispecific antibody, wherein the bispecific antibody comprises an antibody according to any one of claims 1-4.

9. The composition of claim 5 or claim 6, comprising a fusion protein comprising an antibody according to any one of claims 1-4.222#14904047v2PCT APPLICATION10. An isolated nucleic acid encoding the antibody or antigen-binding fragment thereof of any of the preceding claims.

11. A composition comprising:a. A TfRl-binding domain that is an anti-TfRl antibody or antigen-binding fragment thereof of any of the preceding claims;b. An oligonucleotide that is complementary to at least a portion of a target mRNA; andc. A linker that conjugates at least one amino acid residue of the anti-TfRl antibody or antigen-binding fragment thereof to a nucleotide position selected from the 3’- or 5-end of the oligonucleotide.

12. The composition of claim 11, wherein the oligonucleotide is an antisense oligonucleotide (ASO).

13. The composition of claim 11 or claim 12, wherein the linker is cleavable linker.

14. The composition of any of claims 11-13, wherein the linker comprises a Val-Cit moiety or an MCC moiety.

15. The composition of claim 11, wherein the mRNA target is selected from a CNS, PNS, neuromuscular or cardiac muscle target.

16. The composition of claim any one of claims 11-15, wherein the mRNA target is transcribed from a gene selected from the group consisting of SMN2, SNCA, HTT, GFAP, APOE, APP, NEFL, MFN2, DMPK, DMD, SOD1, DUX4, DNMT3A, or APOB.223#14904047v2PCT APPLICATION17. The composition of any one of claims 11-15, wherein the mRNA target encodes a gene product selected from the group consisting of SMN2, alpha- synuclein, huntingtin (HTT), STMN2, GFAP, apolipoprotein E4 (ApoE4), tau protein, and amyloid precursor protein (APP), neurofilament light chain (NEFL), PMP22, MGN22, MPZ, sodium channel proteins, DMPK, dystrophin, SOD1, DUX4, IGHMBP2, GYSI, DMN2, macrophage inflammatory targets, DNA methyltransferase 3A, or apolipoprotein B.

18. A pharmaceutical composition comprising the composition of any of the preceding claims, and a pharmaceutically acceptable carrier.

19. A multi-specific binding molecule comprising:a. A first binding domain according to any one of claims 1-4; andb. one or more additional binding arms second binding domain that specifically binds a therapeutically effective target.

20. The multi-specific binding molecule of claim 19, wherein:a. A first heavy chain comprises a first VH sequence and a first constant Fc fragment; andb. A second heavy chain comprises a second VH sequence and a second constant Fc fragment.

21. The multi-specific binding molecule of claim 29, wherein the therapeutically effective target is selected from a central nervous system (CNS), peripheral nervous system (PNS), neuromuscular, or cardiac muscle target.

22. The multi-specific binding molecule of any one of claims 19-21, wherein the therapeutically effective target is selected from epidermal growth factor receptor (EGFR),224#14904047v2PCT APPLICATION human epidermal growth factor 2 (HER2), alpha-synuclein, huntingtin, a sodium channel protein, a macrophage inflammatory target, or DNMT3A.23 An isolated nucleic acid encoding the multi- specific binding molecule of any of the preceding claims.

24. A method of delivering an antibody or oligonucleotide across the blood-brain barrier (BBB) of a subject in need thereof, comprising administering to the subject a complex comprising the multi-specific binding molecule of any of the preceding claims, or the composition of any of the preceding claims.

25. The method of claim 24, the method comprising treating or detecting a disorder, in a subject in need thereof, by administering to the subject the composition of any of the preceding claims, or the pharmaceutical composition of claims.

26. The method of claim 25, wherein the disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, epilepsy, autism spectrum disorders, multiple sclerosis, myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy, neuromuscular disorders, spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy, spinal muscular atrophy with respiratory distress type 1, cardiovascular diseases, cardiac dysfunction, hypercholesterolemia, atherosclerosis, dyslipidemia, and cardiovascular disease risk.225#14904047v2

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