Anti-TfR:payload fusions and methods of using same

Abstract

Provided, in part, are fusion proteins comprising an anti-human transferrin receptor antigen binding protein and an anti-human transferrin receptor antigen binding protein (e.g., in scFv, Fab, or antibody format) that can be fused to a payload for delivery of the payload to a target tissue (e.g., across the blood-brain barrier and into the brain). The payload includes, for example, an alpha-glucosidase (GAA) polypeptide. With these fusions, methods are provided for treating various diseases, e.g., glycogen storage diseases such as Pompe disease, with such molecules.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Application No. 63 / 393,719, filed July 29, 2022, which is incorporated herein by reference in its entirety for all purposes. (Reference to sequence listing submitted as a text file via EFS WEB) The sequence listing set forth in file 598882SEQLIST.xml is 573 kilobytes, was created on July 26, 2023, and is incorporated herein by reference. [Background technology]

[0002] Iron delivery to the brain is achieved through the binding and intracellular transport of the iron-binding protein transferrin (Tf). The Tf receptor (TfR) is the target of several studies for drug delivery to the brain. For example, approaches include the use of Tf-decorated liposomes used for the delivery of contrast agents and DNA (Sharma et al., (2013) Cell penetrating peptide tethered biligand liposomes for delivery to the brain in vivo: biodistribution and transfection. J. Control. Release 167, 1-10), or the use of an iron-mimetic peptide as a ligand (Staquicini et al., (2011)). A correlation between increased antibody affinity and lysosomal degradation has also been suggested (Bien-Ly et al., (2014) Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 211, 233-244), supporting the idea that lower antibody affinity helps transported complexes avoid intracellular degradation. Bien-Ly et al. found that a bispecific antibody against TfR and beta-secretase (BACE1) crossed the blood-brain barrier (BBB) and effectively reduced brain amyloid beta levels, but high-affinity binding to TfR also caused a dose-dependent reduction in brain TfR levels. Similarly, Moos & Morgan (2001) compared the ability of an anti-TfR antibody, OX26, and transferrin to cross the rat BBB and found that while the antibody exhibits a high-affinity antibody-antigen interaction with TfR that is not easily reversed, OX26 does not recirculate from the brain like transferrin, because that of Tf is readily reversed depending on pH and the iron content of Tf (Restricted transport of anti-transferrin receptor antibody (OX26) through the blood-brain barrier in the rat, J Neurochem 2001 Oct;79(1):119-29). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Sharma et al.,(2013)Cell penetrating peptide tethered bi-ligand liposomes for delivery to brain in vivo:biodistribution and transfection.J.Control.Release 167,1-10 [Non-patent document 2] the use of an iron-mimetic peptide as ligand(Staquicini et al.,(2011) [Non-patent document 3] Bien-Ly et al.,(2014)Transferrin receptor(TfR)trafficking determines brain uptake of TfR antibody affinity variants.J.Exp.Med.211,233-244 [Non-patent document 4] Restricted transport of anti-transferrin receptor antibody(OX26)through the blood-brain barrier in the rat,J Neurochem 2001 Oct;79(1):119-29 Summary of the Invention [Means for solving the problem]

[0004] In one aspect, provided is an antigen binding protein that specifically binds to the transferrin receptor, or an antigenic fragment or variant thereof. Some such antigen binding proteins include: (i) an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172, 182, 192, 202, 212, 222, 232, 242, 252, 262, 272, 282, 292, 302, or 312 (or a variant thereof); and / or (ii) a LCVR comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, or 317 (or a variant thereof). Optionally, the antigen binding protein is fused to a payload. Some such antigen binding proteins include: (1) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof). (3) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (4) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof). (5) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); (6) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (7) an LCVR comprising an HCVR having an HCDR1, HCDR2, and HCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising an LCVR having an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof); (8) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof);(9) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (10) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (11) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof), and (11) an LCVR comprising an HCVR comprising an HCDR3 and an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (12) an LCVR comprising an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof) and an LCVR comprising an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (13) an HCVR comprising an amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof). (12) an HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR having the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR having the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof); (13) an LCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR having the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR having the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof); (14) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (14) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (15) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof);(16) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof), and LCDR1 and LCDR2 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof). and LCDR3; (18) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (19) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof). (20) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (21) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207; (21) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof); (22) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (23) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof);(24) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (25) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (26) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof). and HCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof), (26) an LCVR comprising the HCVR comprising the HCDR1, HCDR2, and HCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof), and an LCVR comprising the LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof), (27) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof). (27) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (28) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (29) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 282; (30) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof);(31) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 (or a variant thereof), and / or (32) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). Some such antigen binding proteins comprise a HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and a LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof).

[0005] Some such antigen binding proteins include: (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 9 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof). (c) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof);(e) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (f) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); (g) an amino acid sequence set forth in SEQ ID NO: 63 (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (i) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof);(G) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (H) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (I) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (II) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); (K) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 1 04 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (l) HCVR comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof);(n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof); and an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); (o) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (q) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183 (or a variant thereof); (t) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 193 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 195 (or a variant thereof); (u) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 203 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (v) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 (or a variant thereof); (w) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and an LCVR comprising an amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof); (x) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 233 (or a variant thereof). (y) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof), and an LCVR comprising an amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); (z) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 253 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 255 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); (aa) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof); (ab) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof); an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof); (ac) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 283 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); (ad) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 293 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 295 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 303 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 305 (or a variant thereof), and an LCVR comprising an amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof); and / or HCVRs comprising (at) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 313 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 315 (or a variant thereof); and LCVRs comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof).

[0006] Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof).Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof).

[0007] Some such antigen binding proteins comprise an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof).

[0008] Some such antigen binding proteins include: (i) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (ii) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (iii) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (iv) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (v) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); (vi) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof); and (vii) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62. (viii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (ix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (x) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (xi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (xii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (xiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof);(xiv) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof); (xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (xv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof); (xvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (xvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (xix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof) and an amino acid sequence set forth in SEQ ID NO: 187 ( (xx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (xxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (xxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (xxiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof);(xxvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof); (xxvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (xxix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); (xxx) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof), (xxx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof), (xxxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 (or a variant thereof), and / or (xxxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof).

[0009] Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof).

[0010] Some such antigen binding proteins comprise an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof).

[0011] In some such antigen-binding proteins, the transferrin receptor is a human transferrin receptor or a variant thereof. Some such antigen-binding proteins are antibodies or antigen-binding fragments thereof. Some such antigen-binding proteins are Fabs. Some such antigen-binding proteins are scFvs, optionally comprising a fragment of -(GGGGS) m-(SEQ ID NO: 426), wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and optionally the scFv variable region is connected by a peptide linker that is -(GGGGS) n -(SEQ ID NO:426), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some such antigen binding proteins, the scFv comprises the amino acid sequence set forth in SEQ ID NO:443 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO:440 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO:429 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO:433 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO:442 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO:438 (or a variant thereof). In some such antigen binding proteins, the scFv comprises the amino acid sequence set forth in SEQ ID NO:443 (or a variant thereof).

[0012] Also provided is an antigen binding protein, or antigenic fragment or variant thereof, that specifically binds to the transferrin receptor, and that comprises (a) an epitope comprising the sequence LLNE (SEQ ID NO: 525) and / or an epitope comprising the sequence TYKEL (SEQ ID NO: 507), (b) an epitope comprising the sequence DSTDFTGT (SEQ ID NO: 526), and / or an epitope comprising the sequence VKHPVTGQF (SEQ ID NO: 527), and / or an epitope comprising the sequence IERIPEL ( (c) an epitope comprising the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529), (d) an epitope comprising the sequence FEDL (SEQ ID NO: 519), (e) an epitope comprising the sequence IVDKNGRL (SEQ ID NO: 530), (t) an epitope comprising the sequence IVDKNGRLVY (SEQ ID NO: 531), (g) an epitope comprising the sequence DQTKF (SEQ ID NO: 532), (h) an epitope comprising the sequence LVENPGGY (SEQ ID NO: 533). (i) an epitope comprising the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope comprising the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope comprising the sequence TYKEL (SEQ ID NO: 507); G) an epitope comprising the sequence KRKLSEKLDST an epitope comprising the sequence DFTGTIKL (SEQ ID NO: 508), and / or an epitope comprising the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or an epitope comprising the sequence LIERIPENKVARAAAE (SEQ ID NO: 510); (k) an epitope comprising the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) an epitope comprising the sequence GTKKDFEDL (SEQ ID NO: 512); (m) an epitope comprising the sequence SVIIVDKNGRL VYLVENPGGYV AYSK (SEQ ID NO: 513); (n) an epitope comprising the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514), and / or an epitope comprising the sequence DQTKFPIVNAEL (SEQ ID NO: 515), and / or an epitope comprising the sequence TYKELIERIPELNK (SEQ ID NO: 516);(o) an epitope comprising the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope comprising the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) an epitope comprising the sequence SVIIVDKNGRL VYLVENPGGYV AY (SEQ ID NO: 517), (q) an epitope comprising the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope comprising the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), (r) an epitope comprising the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope comprising the sequence LVENPGYVAYSKAATVTGKL (SEQ ID NO: 520), and / or an epitope comprising the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or an epitope comprising the sequence ISRAAAEKL (SEQ ID NO: 522), and / or an epitope comprising the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or an epitope comprising the sequence FCEDT an epitope comprising DYPYLGTTMDT (SEQ ID NO: 524); (s) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or an epitope contained within or overlapping with the sequence TYKEL (SEQ ID NO: 507); (t) an epitope contained within or overlapping with the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or an epitope contained within or overlapping with the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or the sequence LIERIPELNKV (u) an epitope contained within or overlapping with the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (v) an epitope contained within or overlapping with the sequence GTKKDFEDL (SEQ ID NO: 512); (w) an epitope contained within or overlapping with the sequence SVIIVDKNGRL VYLVENPGGYVAYSK (SEQ ID NO: 513);(x) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope contained within or overlapping with the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (y) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (z) the sequence SVIIVDKNGRL (aa) an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope contained within or overlapping with the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), and (ab) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope contained within or overlapping with the sequence LVENPGYVAYSKAATVTGKL (SEQ ID NO: 520); and / or an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or an epitope contained within or overlapping with the sequence ISRAAAEKL (SEQ ID NO: 522), and / or an epitope contained within or overlapping with the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or an epitope contained within or overlapping with the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524), or an antigenic fragment or variant thereof. In some such antigen binding proteins, the antigen binding protein binds to one or more epitopes of hTfR selected from (a) an epitope consisting of the sequence LLNE (SEQ ID NO: 525) and / or an epitope consisting of the sequence TYKEL (SEQ ID NO: 507), (b) an epitope consisting of the sequence DSTDFTGT (SEQ ID NO: 526),and / or an epitope consisting of the sequence VKHPVTGQF (SEQ ID NO: 527), and / or an epitope consisting of the sequence IERIPEL (SEQ ID NO: 528), (c) an epitope consisting of the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529), (d) an epitope consisting of the sequence FEDL (SEQ ID NO: 519), (e) an epitope consisting of the sequence IVDKNGRL (SEQ ID NO: 530), (f) an epitope consisting of the sequence IVDKNGRLVY (SEQ ID NO: 531), (g) an epitope consisting of the sequence DQTKF (SEQ ID NO: 532), (h) an epitope consisting of the sequence LVENPGGY (SEQ ID NO: 533), and / or an epitope consisting of the sequence PIVNAEL SF (SEQ ID NO: 534) and / or an epitope consisting of the sequence PYLGTTMDT (SEQ ID NO: 535), (i) an epitope consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope consisting of the sequence TYKEL (SEQ ID NO: 507), G) an epitope consisting of the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or an epitope consisting of the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or an epitope consisting of the sequence LIERIPELNKV (k) an epitope consisting of the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511), (l) an epitope consisting of the sequence GTKKDFEDL (SEQ ID NO: 512), (m) an epitope consisting of the sequence SVIIVDKNGRL VYLVENPGGYVAYSK (SEQ ID NO: 513), (n) an epitope consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope consisting of the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516), (o) an epitope consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516), (p) an epitope consisting of the sequence SVIIVDKNGRL an epitope consisting of VYLVENPGGYVAY (SEQ ID NO: 517);(q) an epitope consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope consisting of the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), and (r) an epitope consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope consisting of the sequence LVENPGYVAYSKAATVTGKL (SEQ ID NO: 520), and / or an epitope consisting of the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or an epitope consisting of the sequence ISRAAAEKL (SEQ ID NO: 522), and / or an epitope consisting of the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or an epitope consisting of the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524).

[0013] In some such antigen-binding proteins, the antigen-binding protein is selected from a humanized antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a murine antibody or antigen-binding fragment thereof, a CH1meric antibody or antigen-binding fragment thereof, a monovalent Fab', a bivalent Fab2, a F(ab)'3 fragment, a single-chain fragment variable (scFv), a bis-scFv, an (scFv)2, a diabody, a bivalent antibody, a one-armed antibody, a minibody, a nanobody, a triabody, a tetrabody, a disulfide stabilized Fv (dsFv), a single-domain antibody (sdAb), an Ig NAR, a single heavy chain antibody, a bispecific antibody or binding fragment thereof, a bi-specific T-cell engager (BiTE), a triabody, or a chemically modified derivative thereof.

[0014] In another aspect, provided is a fusion protein comprising any of the above antigen binding proteins fused to a payload. In another aspect, provided is a fusion protein comprising an antigen binding protein that specifically binds to the transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload, wherein the antigen binding protein has a K D or higher affinity. In some such fusion proteins, the antigen-binding protein has a K of about 41 nM. D or greater affinity. In some such fusion proteins, the antigen-binding protein binds to the human transferrin receptor with a K of about 3 nM. D or greater affinity. In some such fusion proteins, the antigen-binding protein binds to the human transferrin receptor with a K of about 3 nM. D or binds to the human transferrin receptor with greater affinity, or the antigen-binding protein has a K of about 0.45 nM to 3 nM. DThe fusion proteins bind to the human transferrin receptor at a specific site. In some such fusion proteins, the payload is one or more antibodies or antigen-binding fragments thereof, proteins, enzymes, or viral vectors containing one or more polynucleotides or oligonucleotides; or a human alpha-glucosidase polypeptide (hGAA) or a variant thereof. In some such fusion proteins, the payload is a lysosomal storage disease therapeutic agent (LSD-TA); or a polypeptide or polypeptide encoded by a human gene designated in any one of Tables C-N, or a variant thereof. In some such fusion proteins, the payload is miglustat, eliglustat, α-galactosidase A; ceramidase; β-glucosidase; saposin-C activator; acid sphingomyelinase; β-galactosidase; β-hexosaminidase A and B; β-hexosaminidase A; GM2-activator protein; GM3 synthase; arylsulfatase A; sphingolipid activator; α-iduronidase; iduronidase-2-sulfatase; heparan N-sulfatase; N-arylsulfatase; LSD-TA is cetyl-α-glucosaminidase; acetyl-CoA; α-glucosamide N-acetyltransferase; N-acetylglucosamine-6-sulfatase; N-acetylgalactosamine-6-sulfate sulfatase; β-galactosidase; N-acetylgalactosamine-4-sulfatase (arylsulfatase B); β-glucuronidase; hylauronidase; α-fucosidase 2; or lysosomal acid lipase.

[0015] Some such fusion proteins contain a heavy chain variable region (HCVR or VVR). H ) and a light chain variable region (LCVR or VL and an antigen binding protein that specifically binds to the human transferrin receptor fused to an alpha-glucosidase polypeptide (GAA), wherein the V H and V L Fab having a K of approximately 0.65 nM D or a fusion protein that binds to the human transferrin receptor with greater affinity, such that when the fusion protein is administered to a mouse expressing the human transferrin receptor in the brain, the mouse achieves a molar ratio of mature GAA protein in the brain to serum GAA protein of about 1:1 or greater when normalized to the ratio in a mouse expressing the mouse transferrin receptor administered 8D3.

[0016] In some such fusion proteins, the antigen-binding protein is a Fab. In some such fusion proteins, the antigen-binding protein is a single-chain fragment variable region (scFv). In some such fusion proteins, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof), or the amino acid sequence set forth in SEQ ID NO: 405 (or a variant thereof). In some such fusion proteins, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof).

[0017] In some such fusion proteins, the antigen binding protein is an antibody or antigen-binding fragment thereof. In some such fusion proteins, the antigen binding protein is an scFv comprising domains arranged in the following orientation: N-heavy chain variable region-light chain variable region-GAA protein-C. In some such fusion proteins, the antigen binding protein is an scFv comprising domains arranged in the following orientation: N-light chain variable region-heavy chain variable region-GAA protein-C. In some such fusion proteins, the antigen binding protein is an scFv, and the scFv and GAA are connected by a peptide linker. In some such fusion proteins, the scFv and GAA are connected by a peptide linker. m -(SEQ ID NO: 426), and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some such fusion proteins, the antigen binding protein is an scFv, and the scFv variable regions are connected by a peptide linker. In some such fusion proteins, the scFv variable regions are connected by a peptide linker. n -(SEQ ID NO: 426), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some such fusion proteins, the fusion protein is about 1 x 10 -7 K of M D or binds to the human transferrin receptor with higher affinity.

[0018] Some such fusion proteins include (i) HCDR1 and HCDR2 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 222, 232, 242, 252, 482, 262, 272, 282, 292, 302, 483, or 312 (or a variant thereof); and HCDR3, and / or (ii) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, or 484 (or a variant thereof).

[0019] In some such fusion proteins, the fusion protein comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) and an alpha-glucosidase polypeptide (GAA), H , V L , and GAA, (i) V L -V H -GAA, (ii)V H -V L -GAA, (iii)V L -[(GGGGS)3 (SEQ ID NO: 538)]-V H -[(GGGGS)2 (SEQ ID NO: 537)]-GAA, or (iv) V H -[(GGGGS)3 (SEQ ID NO: 538)]-V L -[(GGGGS)2 (SEQ ID NO: 537)]-GAA.

[0020] Some such fusion proteins comprise the amino acid sequence set forth in a member selected from the group consisting of SEQ ID NOs:392-423, SEQ ID NO:321 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO:500) signal sequence), SEQ ID NO:322 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO:500) signal sequence), SEQ ID NO:323 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO:500) signal sequence), and SEQ ID NO:324 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO:500) signal sequence), or a variant thereof.

[0021] In some such fusion proteins, the antigen-binding protein, when not fused to a GAA polypeptide, does not block more than 50% of the binding of a human transferrin receptor C-terminal fragment to human holo-transferrin that occurs in the absence of such a single-chain fragment variable region (scFv), antibody, or antigen-binding fragment. In some such fusion proteins, blocking is measured in an enzyme-linked immunosorbent assay (ELISA) plate assay in which the binding of a human transferrin receptor extracellular domain fused to a His6-myc-myc tag is pre-bound to the scFv, antibody, or antigen-binding fragment and then contacted with holo-transferrin that has been immobilized to the plate surface by binding of a plate-bound anti-holo-transferrin antibody. In some such fusion proteins, the binding of holo-transferrin to the human transferrin receptor extracellular domain in the absence of an scFv, antibody, or antigen-binding fragment is measured at a concentration of about 300 pM of human transferrin receptor extracellular domain.

[0022] Some such fusion proteins or antigen-binding proteins specifically bind to the human transferrin receptor and have one or more of the following characteristics: Affinity (K) for binding to human TfR at 25°C in a surface plasmon resonance format of approximately 41 nM or higher affinity D ), Affinity (K) for binding to monkey TfR at 25°C in a surface plasmon resonance format of approximately 0 nM (no detectable binding) or higher affinity D ), K for binding to monkey TfR at 25°C in a surface plasmon resonance format of 0–278 D / K for binding to human TfR D ] ratio, Blockade of hTfR binding to human holo-Tf when in Fab format (IgG1) by approximately 3-13% Approximately 6-13% of scFv (V K -V H ) format, blocking hTfR binding to human holo-Tf; Approximately 11-26% of scFv (V H -V L ) format, blocking hTfR binding to human holo-Tf; when in the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), results in a ratio of mature hGAA protein in the brain (normalized to that of the positive control 8D3:GAA scFv) of about 1-2; when in an anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), results in a ratio of mature hGAA protein in the brain parenchyma (normalized to that of the positive control 8D3:GAA scFv) of about 0.1 to 1.2; when in an anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), exhibits a ratio of mature hGAA protein in the quadriceps muscle (normalized to that of the positive control 8D3:GAA scFv) of about 0.67, 1.80, 1.78, or 7.74 (about 1-2); when in an anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), results in a ratio of mature hGAA protein in the brain parenchyma (normalized to that of the positive control 8D3:GAA scFv) of about 0.1 to 1.2; when in the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), delivers mature hGAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps; when in the anti-hTfR scFv:hGAA format, reduces glycogen stores in the cerebrum, cerebellum, spinal cord, heart, and / or quadriceps muscle when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA); containing an antigen-binding protein fused to GAA reduces glycogen levels in the cerebellum of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least about 90% compared to those in untreated mice; reduces glycogen levels in the quadriceps muscles of mice that express the human transferrin receptor but lack functional endogenous GAA by at least about 89% compared to those of untreated mice, when the antigen binding protein is fused to GAA; and / or When administered to mice expressing the human transferrin receptor, it does not cause abnormal iron homeostasis.

[0023] In another aspect, provided is a pharmaceutical composition comprising any of the above fusion proteins or antigen binding proteins and a pharmaceutically acceptable carrier.

[0024] In another aspect, provided are compositions or kits comprising any of the above fusion proteins or antigen-binding proteins or pharmaceutical compositions in association with an additional therapeutic agent. In some such compositions or kits, the additional therapeutic agent is selected from alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), avalglucosidase alfa, levalbuterol, an antibacterial agent, cortisone, prednisone, a bisphosphonate, and a palivizumab. In some such compositions or kits, the additional therapeutic agent is selected from a beta2-adrenergic agonist, a steroid, a bisphosphonate, an infectious disease treatment, a vaccine, and a pneumococcal vaccine.

[0025] In another aspect, provided is a conjugate comprising any of the above fusion proteins or antigen-binding proteins linked to a human transferrin receptor polypeptide or an antigenic fragment thereof.

[0026] In another aspect, provided is an isolated polynucleotide encoding any of the above fusion proteins or antigen binding proteins. Some such polynucleotides are set forth in SEQ ID NOs: 1, 6, 11, 16, 21, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 76, 81, 86, 91, 96, 101, 106, 111, 116, 121, 126, 131, 136, 141, 146, 151, 156, 161, 166, 171, 176, 181, 186, 191, 201, 206, 206, 211, 212, 214, 216, 218, 219, 220, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 256, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 71, 176, 181, 186, 191, 196, 201, 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 271, 276, 281, 286, 291, 296, 301, 306, 311, and / or 316. Some such polynucleotides include (1) the nucleotide sequence set forth in SEQ ID NO:1 and SEQ ID NO:6, (2) the nucleotide sequence set forth in SEQ ID NO:11 and SEQ ID NO:16, (3) the nucleotide sequence set forth in SEQ ID NO:21 and SEQ ID NO:26, (4) the nucleotide sequence set forth in SEQ ID NO:31 and SEQ ID NO:36, (5) the nucleotide sequence set forth in SEQ ID NO:41 and SEQ ID NO:46, (6) the nucleotide sequence set forth in SEQ ID NO:51 and SEQ ID NO:56, (7) the nucleotide sequence set forth in SEQ ID NO:61 and SEQ ID NO:66, (8) the nucleotide sequence set forth in SEQ ID NO:71 and SEQ ID NO:76, (9) the nucleotide sequence set forth in SEQ ID NO:81 and SEQ ID NO:86, (10) the nucleotide sequence set forth in SEQ ID NO:91 and SEQ ID NO:96, and (11) the nucleotide sequence set forth in SEQ ID NO:10. (12) the nucleotide sequence set forth in SEQ ID NO: 111 and SEQ ID NO: 116, (13) the nucleotide sequence set forth in SEQ ID NO: 121 and SEQ ID NO: 126, (14) the nucleotide sequence set forth in SEQ ID NO: 131 and SEQ ID NO: 136, (15) the nucleotide sequence set forth in SEQ ID NO: 141 and SEQ ID NO: 146, (16) the nucleotide sequence set forth in SEQ ID NO: 151 and SEQ ID NO: 156, (17) the nucleotide sequence set forth in SEQ ID NO: 161 and SEQ ID NO: 166, (18) the nucleotide sequence set forth in SEQ ID NO: 171 and SEQ ID NO: 176, (19) the nucleotide sequence set forth in SEQ ID NO: 181 and SEQ ID NO: 186, (20) the nucleotide sequence set forth in SEQ ID NO: 191 and SEQ ID NO: 196,(21) The nucleotide sequences set forth in SEQ ID NO: 201 and SEQ ID NO: 206, (22) The nucleotide sequences set forth in SEQ ID NO: 211 and SEQ ID NO: 216, (23) The nucleotide sequences set forth in SEQ ID NO: 221 and SEQ ID NO: 226, (24) The nucleotide sequences set forth in SEQ ID NO: 231 and SEQ ID NO: 236, (25) The nucleotide sequences set forth in SEQ ID NO: 241 and SEQ ID NO: 246, (26) The nucleotide sequences set forth in SEQ ID NO: 251 and SEQ ID NO: 256, (27) The nucleotide sequences set forth in SEQ ID NO: 261 and SEQ ID NO: 266, (28) The nucleotide sequences set forth in SEQ ID NO: 271 and SEQ ID NO: 276, (29) The nucleotide sequences set forth in SEQ ID NO: 281 and SEQ ID NO: 286, (30) The nucleotide sequences set forth in SEQ ID NO: 291 and SEQ ID NO: 296, (31) The nucleotide sequences set forth in SEQ ID NO: 301 and SEQ ID NO: 306, and / or (32) The nucleotide sequences set forth in SEQ ID NO: 311 and SEQ ID NO: 316.

[0027] In another aspect, provided is a vector comprising any of the above polynucleotides.

[0028] In another aspect, provided is a host cell comprising any of the above fusion proteins, antigen binding proteins, polynucleotides, or vectors. Some such host cells are Chinese hamster ovary (CHO) cells.

[0029] In another aspect, provided are methods for making any of the above fusion proteins or antigen-binding proteins, comprising culturing a host cell comprising a polynucleotide encoding the fusion protein or antigen-binding protein in a culture medium under conditions favorable for expression of the fusion protein or antigen-binding protein. Some such methods comprise: (a) introducing the polynucleotide into the host cell; (b) culturing the host cell under conditions favorable for expression of the fusion protein or antigen-binding protein; (c) optionally isolating the fusion protein or antigen-binding protein from the culture medium and / or host cell; and (d) optionally chemically conjugating the antigen-binding protein to a payload. In another aspect, provided are fusion proteins or antigen-binding proteins that are the product of such methods.

[0030] In another aspect, provided is a container or injection device containing any of the above fusion proteins or antigen binding proteins.

[0031] In another aspect, provided are methods for administering any of the above fusion proteins or antigen binding proteins to a subject, comprising introducing the protein into the subject. In some such methods, the fusion protein or antigen binding protein is introduced into the subject parenterally.

[0032] In another aspect, provided is a method for treating or preventing a lysosomal storage disease in a subject in need thereof, comprising administering to the subject an effective amount of any of the above fusion proteins, wherein the payload is a lysosomal storage disease therapeutic agent (LSD-TA). In some such methods, the lysosomal storage disorder is selected from the group consisting of Fabry disease, Farber lipogranulomatosis, Gaucher disease type I, Gaucher disease (type II or type III), Niemann-Pick disease (type A or type B), GM1-gangliosidosis, GM2-gangliosidosis (Sandhoff disease), GM2-gangliosidosis (Tay-Sachs disease), GM2-gangliosidosis (GM2 activator deficiency), GM3-gangliosidosis, metachromatic leukodystrophy, sphingolipid activator deficiency, MPS I (Scheie, Hurler-Scheie, or Hurler disease), MPS II (Hunter disease), MPS IHA (Sanfilippo type A), MPS IIIB (Sanfilippo type B), MPS IIIC (Sanfilippo type C), MPS HID (Sanfilippo type D), MPS IVA (Morquio syndrome type A), MPS The LSD may be selected from the group consisting of: MPS IVB (Morquio syndrome type B), MPS VI (Maroteaux-Lamy syndrome), MPS VII (Sly disease), MPS IX, Pompe disease (glycogen storage disease type II), or lysosomal acid lipase deficiency (LAL-D, Wolman disease). In some such methods, one or more signs or symptoms of the LSD in the subject are alleviated after administering the fusion protein or antigen binding protein.

[0033] In another aspect, provided are methods for treating or preventing glycogen storage disease (GSD) in a subject in need thereof, comprising administering to the subject an effective amount of any of the above fusion proteins. In some such methods, the glycogen storage disease is Pompe disease. In some such methods, the Pompe disease is the classic infantile-onset form of Pompe disease. In some such methods, the Pompe disease is the non-classic infantile form of Pompe disease. In some such methods, the Pompe disease is the late-onset form of Pompe disease. In some such methods, the subject has a GAA genotype selected from the group consisting of ASP91ASN; MET318THR; GLU521LYS; GLY643ARG; ARG725TRP; IVSIAS,TG,-13; LYS903DEL; LEU299ARG; SER529VAL; ASP645GLU; GLU689LYS; EX18DEL; PRO545LEU; I-BP DEL,525T; ARG854TER; ALA237VAL; GLY293ARG; and IVS6AS,GC,-1.

[0034] In some such methods, the subject is administered the fusion protein in association with an additional therapeutic agent. In some such methods, the additional therapeutic agent is selected from alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), avalglucosidase alfa, levalbuterol, an antibiotic, cortisone, prednisone, a bisphosphonate, and palivizumab. In some such methods, the additional therapeutic agent is selected from a beta2-adrenergic agonist, a steroid, a bisphosphonate, an infectious disease treatment, a vaccine, and a pneumococcal vaccine. In some such methods, the subject is 1 year old or younger, Difficulty eating and not gaining weight Poor head and neck control, Turning over and sitting up later than expected, difficulty breathing, lung infections, Enlarged and thickened heart Heart defects, an enlarged liver, and Experiencing symptoms ranging from an enlarged tongue

[0035] In some such methods, the subject is an adult; weakness in the legs, trunk, and / or arms; ·shortness of breath, lung infections, Difficulty breathing while sleeping Spinal curvature, Enlarged liver, Enlarged tongue, as well as · Experiencing symptoms ranging from stiffness in the joints.

[0036] In some such methods, one or more signs or symptoms of GSD in the subject are alleviated after administering the fusion protein or antigen binding protein.

[0037] In another aspect, provided are methods for delivering a payload to a tissue or cell type within a subject, comprising administering to the subject an antigen-binding protein that specifically binds to the transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload. In some such methods, the payload is one or more antibodies or antigen-binding fragments thereof, proteins, enzymes, or viral vectors containing one or more polynucleotides or oligonucleotides. In some such methods, the payload is a human GAA protein or variant thereof. In some such methods, the tissue is brain / spinal cord / CNS, eye, skeletal muscle, adipose tissue, blood / bone marrow, breast, lung / bronchi, colon, uterus, esophagus, heart, kidney, liver, lymph node, ovary, pancreas, placenta, prostate, rectum, skin, peripheral blood mononuclear cells (PBMCs), small intestine, spleen, stomach, testis, peripheral nervous system, and / or bone / cartilage / joint. In some such methods, the cell type and tissue associated with the cell type are [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0038] In some such methods, the method comprises puncturing the body of a subject with a needle of a syringe and injecting into the body of the subject an antigen binding protein that specifically binds to a transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload, In some such methods, the subject is suffering from a muscle wasting condition, a metabolic disease, sarcopenia, or cachexia.

[0039] In another aspect, provided is a method of expressing in a cell a fusion protein comprising an antigen binding protein that specifically binds to a transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload, the method comprising: (a) administering to the cell a gene therapy vector comprising any of the above polynucleotides, wherein the isolated polynucleotide encodes the fusion protein; (b) allowing the isolated polynucleotide to integrate into a genomic locus of the cell; and (c) causing the cell to produce the fusion protein.

[0040] In some such methods, the method further comprises administering to the cell a nuclease agent or one or more polynucleotides encoding the nuclease agent, wherein the nuclease agent cleaves the nuclease target site in the genomic locus, and the isolated polynucleotide is integrated into the genomic locus. In some such methods, the nuclease agent comprises a clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated (Cas) system, a zinc finger nuclease (ZFN), or a transcription activator-like effector nuclease (TALEN). In some such methods, the cell is in vivo in the subject. In some such methods, the cell is ex vivo. In some such methods, the gene therapy vector is a viral vector, a naked polynucleotide, or a polynucleotide complex, optionally wherein the polynucleotide complex is a lipid nanoparticle containing the polynucleotide. In some such methods, the gene therapy vector is a viral vector selected from the group consisting of retrovirus, adenovirus, herpes simplex virus, poxvirus, vaccinia virus, lentivirus, or adeno-associated virus. In some such methods, the gene therapy vector is an adeno-associated virus (AAV) vector, optionally wherein the gene therapy vector is an AAV2 / 8 chimera and / or AAV pseudotyped for liver. In some such methods, the genomic locus is a safe harbor locus.In some such methods, the genomic locus is at or proximal to a locus selected from the group consisting of the EESYR locus, the SARS locus, position 188,083,272 on human chromosome 1 or a non-human mammalian ortholog thereof, position 3,046,320 on human chromosome 10 or a non-human mammalian ortholog thereof, position 67,328,980 on human chromosome 17 or a non-human mammalian ortholog thereof, chromosomal adeno-associated virus site 1 (AAVS1), a naturally occurring integration site of the AAV virus on human chromosome 19 or a non-human mammalian ortholog thereof, the chemokine receptor 5 (CCR5) gene, a chemokine receptor gene encoding an HIV-1 co-receptor, the mouse Rosa26 locus or a non-mouse mammalian ortholog thereof, and the albumin (alb) locus. In some such methods, the cell is a human cell. In some such methods, the cell is a liver cell.

[0041] Provided herein are antigen-binding proteins that can be fused to a payload, having one or more of the following characteristics: (1) an affinity (K) for binding to human TfR at 25°C in a surface plasmon resonance format with an affinity of about 41 nM or greater; D ), (2) affinity (K) for binding to monkey TfR at 25°C in a surface plasmon resonance format of 0 nM (no detectable binding) or higher affinity D ), (3) K for binding to monkey TfR at 25°C in a surface plasmon resonance format of 0–278 D / K for binding to human TfR D ] ratio, (4) about 3-13% blocking of hTfR binding to human holo-Tf when in Fab format (IgG1), (5) about 6-13% blocking of hTfR binding to human holo-Tf when in scFv (V K -V H ) format, (6) blocking of hTfR binding to human holo-Tf by approximately 11-26% H -V L(7) when comprising an antigen binding protein fused to GAA, when in an anti-hTfR scFv:hGAA format, it exhibits a ratio of mature hGAA protein in the brain (normalized to that of the positive control 8D3:GAA scFv) of about 1 to 2 when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA); (8) when comprising an antigen binding protein fused to GAA, when in an anti-hTfR scFv:hGAA format, it exhibits a ratio of mature hGAA protein in the brain parenchyma (normalized to that of the positive control 8D3:GAA scFv) of about 0.1 to 1.2 when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA); (9) when comprising an antigen binding protein fused to GAA, it exhibits a ratio of mature hGAA protein in the brain parenchyma (normalized to that of the positive control 8D3:GAA scFv) of about 0.1 to 1.2 when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA). When in the scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), they exhibit a ratio of mature hGAA protein (normalized to that of the positive control 8D3:GAA scFv) of about 0.67, 1.80, 1.78, or 7.74 (about 1-2) in the quadriceps muscle; (10) when comprising an antigen binding protein fused to GAA, when in the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), they exhibit a ratio of mature hGAA protein (normalized to that of the positive control 8D3:GAA scFv) of about 0.1-1 in the brain parenchyma.(11) when comprising an antigen binding protein fused to GAA, when in an anti-hTfR scFv:hGAA format, delivers mature hGAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA); (12) when comprising an antigen binding protein fused to GAA, delivers mature hGAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA). When in the scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), it reduces glycogen stores in the cerebrum, cerebellum, spinal cord, heart, and / or quadriceps muscle; (13) when comprising an antigen binding protein fused to GAA, it reduces glycogen levels in the cerebellum of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least about 90% compared to those of untreated mice; (14) when comprising an antigen binding protein fused to GAA, it reduces glycogen levels in the quadriceps muscle of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least about 89% compared to those of untreated mice; and / or (15) when administered to mice expressing the human transferrin receptor, it does not cause abnormal iron homeostasis.

[0042] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind to a transferrin receptor (e.g., a human transferrin receptor), comprising: (i) an HC comprising an amino acid sequence set forth in SEQ ID NO: 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 222, 232, 242, 252, 482, 262, 272, 282, 292, 302, 483, or 312 (or a variant thereof). and / or (ii) a heavy chain variable region comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, or 484 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof is selected from the group consisting of: (1) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (3) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof);(4) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof), and LCDR1 and LCDR2 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); and LCDR3, (6) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof), (7) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof). (8) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (9) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 ( (10) an LCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising an LCDR1, HCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (11) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof);(11) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (12) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (13) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof). and HCDR3 of an LCVR having the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof), (14) an LCVR having the HCDR1, HCDR2, and HCDR3 of an HCVR having the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR having the LCDR1, LCDR2, and LCDR3 of an LCVR having the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof), (15) an LCVR having the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof). (16) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (17) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (17) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); (18) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof);(19) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof); (20) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof), and LCDR1 and LCDR2 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof). and LCDR3; (21) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (22) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof). (23) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (24) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof), and an amino acid sequence set forth in SEQ ID NO: 237. (25) an LCVR comprising an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising an LCVR comprising an HCDR1, HCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); (26) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof);(27) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof); (28) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (29) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof); and an LCDR of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof). (30) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof); (31) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof) and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (32) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises: (23) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof); and an LCDR1 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof);(25) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises: (23) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof); , HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises (25) an HCVR comprising the HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising the LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises (14) an HCVR comprising the HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR comprising the LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises (18) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises (27) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises (28) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof).

[0043] In one embodiment, the antibody or antigen-binding fragment comprises: (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 9 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof). (c) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof);(e) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (f) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); (g) an amino acid sequence set forth in SEQ ID NO: 63 (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (i) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof);(G) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (H) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (I) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (II) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); (K) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 1 04 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (l) HCVR comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof);(n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof); and an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); (o) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (q) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183 (or a variant thereof); (t) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 193 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 195 (or a variant thereof); (u) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 203 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (v) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 (or a variant thereof); (w) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof); and an LCVR comprising an LCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof); (x) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 233 (or a variant thereof); (y) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); (z) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 253 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 255 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); (aa) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof); (ab) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof); an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof); (ac) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 283 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); (ad) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 293 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 295 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 303 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 305 (or a variant thereof), and an LCVR comprising an amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof); and / or (af) an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 313 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 315 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (w) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof);or (y) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises (w) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (y) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof);and an LCVR comprising an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises (aa) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (ab) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof).

[0044] In one embodiment, the antibody or antigen-binding fragment is selected from the group consisting of: (i) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (ii) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (iii) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (iv) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (v) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); (vi) a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof) and a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof); and (vii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62. (viii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (ix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (x) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (xi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (xii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (xiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof);(xiv) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof); (xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (xv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof); (xvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (xvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (xix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof) and an amino acid sequence set forth in SEQ ID NO: 187 ( (xx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (xxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (xxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (xxiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof);(xxvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof); (xxvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (xxix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: (xxx) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof), (xxx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof), (xxxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 or 488 (or a variant thereof), and / or (xxxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof). See, for example, Figure 1. In one embodiment, the antibody or antigen-binding fragment comprises: (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof), or (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises:(xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises (xxvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises (xxviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof).

[0045] In one embodiment, the antigen-binding fragment comprises an scFv. In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof). In one embodiment, the antigen-binding fragment comprises an scFv. In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 433 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 442 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 438 (or a variant thereof).

[0046] Provided herein are heavy chain variable regions (V H ) and the light chain variable region (V L), which specifically binds to the human transferrin receptor (e.g., about 1×10), fused to a payload such as alpha-glucosidase polypeptide (GAA). -7 K D or higher affinity), an antibody (e.g., an IgG, e.g., IgG1, IgG2, IgG3, or IgG4), or an antigen-binding fragment thereof (e.g., Fab), wherein the Fab has a K of about 0.65 nM. D or the V that binds to the human transferrin receptor with higher affinity H and V L wherein the fusion protein is anti-hTfR:GAA, and when administered to a mouse expressing human transferrin receptor in the brain, the mouse achieves a molar ratio of mature GAA protein in the brain to serum GAA protein of about 1:1 or greater in the mouse, when normalized to that ratio in a mouse expressing mouse transferrin receptor administered 8D3. For example, if the fusion protein is scN, the scFv comprises domains arranged in the following orientation: N-heavy chain variable region-light chain variable region-GAA protein-C or N-light chain variable region-heavy chain variable region-payload protein-C (where "N-" indicates the amino terminus of the polypeptide and "C-" indicates the carboxy terminus of the polypeptide). In one embodiment, the scFv and payload, e.g., GAA, are connected by a peptide linker such as -(GGGGS)m- (SEQ ID NO: 426), where m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, the scFv variable regions are connected by a peptide linker such as -(GGGGS)n- (SEQ ID NO: 426), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0047] In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof), or comprises the amino acid sequence set forth in SEQ ID NO: 405 (or a variant thereof). In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof). In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 405 (or a variant thereof).

[0048] In one embodiment, the anti-hTfR:payload fusion protein comprises (i) an HCDR1, HCDR2, HCDR3, HCDR4, HCDR5, HCDR6, HCDR7, HCDR8, HCDR9, HCDR10, HCDR11, HCDR12, HCDR13, HCDR14, HCDR15, HCDR16, HCDR17, HCDR18, HCDR19 ...1, HCDR12, HCDR13, HCDR14, HCDR15, and / or (ii) a heavy chain variable region comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, or 484 (or a variant thereof). In one embodiment, the fusion protein comprises: (1) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (3) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (4) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof);(5) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (6) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); (7) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof); and HCDR3, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof); (7) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof); (8) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof). (9) an HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR having the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR having the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof); (10) an LCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR having the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof); (11) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof);(12) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (13) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and LCDR1 and LCDR2 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof). and LCDR3; (14) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (15) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof). (16) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (17) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof), and an amino acid sequence set forth in SEQ ID NO: 167. (18) an LCVR comprising an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising an LCVR comprising an HCDR1, HCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (19) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof);(20) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof); (21) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (22) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof). and HCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof), (22) an LCVR comprising the HCVR comprising the HCDR1, HCDR2, and HCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof), and an LCVR comprising the LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof), (23) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof). (23) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (24) an LCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (25) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242; (26) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); (27) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof);(27) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (28) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (29) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof); (30) SEQ ID NO: 292 (or a variant thereof) and LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof); (31) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof) and LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (32) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) and LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof). In one embodiment, the fusion protein comprises: (23) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); or (25) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof);and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises (23) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). and LCDR3. In one embodiment, the fusion protein comprises (25) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises (14) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the fusion protein comprises (18) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the fusion protein comprises (27) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the fusion protein comprises (28) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof).

[0049] In one embodiment, the fusion protein comprises: (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 9 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof). (c) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof);(e) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (f) an HCVR comprising an HCDR1 having the amino acid sequence set forth in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); (g) an amino acid sequence set forth in SEQ ID NO: 63 (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (i) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof);(G) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (H) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (I) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); (II) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); (K) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 1 04 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (l) HCVR comprising HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and LCVR comprising LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof);(n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof); and an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); (o) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (q) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183 (or a variant thereof); (t) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 193 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 195 (or a variant thereof); (u) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 203 (or a variant thereof);HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 (or a variant thereof), SEQ ID NO: (w) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof); an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof); (x) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 233 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 235 (or a variant thereof); (y) an HCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof); and an LCVR comprising an LCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising an amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); (z) an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 253 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 255 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); (aa) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof); (ab) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof); an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof); (ac) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 283 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); (ad) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 293 (or a variant thereof);an HCVR comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof) and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 295 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 303 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 305 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof); and / or (af) an LCVR comprising an HCDR1 comprising an amino acid sequence set forth in SEQ ID NO: 313 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 315 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof). In one embodiment, the fusion protein comprises: (w) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof);or (y) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the fusion protein comprises (w) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof). In one embodiment, the fusion protein comprises: (y) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the fusion protein comprises: (n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof);and an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof). In one embodiment, the fusion protein comprises (aa) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof). In one embodiment, the fusion protein comprises (ab) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof).

[0050] In one embodiment, the fusion protein comprises: (i) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (ii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (iii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (iv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (v) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); (vi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof); or (vii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof). (viii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (ix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (x) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (xi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (xii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (xiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof);(xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (xv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof); (xvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (xvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (xix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 (or a variant thereof); (xx) an amino acid sequence set forth in SEQ ID NO: 192 ( (xxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (xxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (xxiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); (xxvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 (or a variant thereof);(xxvii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (xxix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof) and an amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof). ant), (xxx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof), (xxxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 or 488 (or a variant thereof), and / or (xxxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 (or a variant thereof). In one embodiment, the fusion protein comprises (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof), or (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxiiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof);and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the fusion protein comprises (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the fusion protein comprises (xxvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the fusion protein comprises (xxviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof).

[0051] Provided herein are heavy chain variable regions (V H ) and the light chain variable region (V L ) and a payload such as alpha glucosidase polypeptide (GAA), H , V L , and the payload, e.g., GAA, is (i) V L -V H -payload, (ii) V H -V L -Payload, (iii)V L -[(GGGGS)(SEQ ID NO:538)]-V H -[(GGGGS)2(SEQ ID NO:537)]-payload, or (iv) V H [(GGGGS)3(SEQ ID NO:538)]-V L-[(GGGGS)2 (SEQ ID NO: 537)]-payload. For example, in one embodiment, the fusion protein comprises (i) the amino acid sequence set forth in SEQ ID NO: 321 (or a mature polypeptide thereof), (ii) the amino acid sequence set forth in SEQ ID NO: 322 (or a mature polypeptide thereof), (iii) the amino acid sequence set forth in SEQ ID NO: 323 (or a mature polypeptide thereof), (iv) the amino acid sequence set forth in SEQ ID NO: 324 (or a mature polypeptide thereof), (v) amino acids 30 to 1168 of SEQ ID NO: 321, (vi) amino acids 30 to 1171 of SEQ ID NO: 322, (vii) amino acids 30 to 1164 of SEQ ID NO: 323, or (viii) amino acids 30 to 1166 of SEQ ID NO: 324. In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof) or comprises the amino acid sequence set forth in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 433 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 442 (or a variant thereof). In one embodiment, the scFv comprises the amino acid sequence set forth in SEQ ID NO: 438 (or a variant thereof). In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof) or the amino acid sequence set forth in SEQ ID NO: 405 (or a variant thereof). In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 408 (or a variant thereof). In one embodiment, the fusion protein comprises the amino acid sequence set forth in SEQ ID NO: 405 (or a variant thereof). In one embodiment, the fusion protein (e.g., the Fab of the fusion protein) comprises the amino acid sequence set forth in a member selected from the group consisting of SEQ ID NOs: 392-423 fused to a payload, e.g., a GAA polypeptide.In one embodiment, an anti-TfR:GAA fusion protein single-chain fragment variable region (scFv), antibody, or antigen-binding fragment thereof that is not fused to a GAA polypeptide does not block more than 50% of the binding of a human transferrin receptor C-terminal fragment to human holo-transferrin that occurs in the absence of such single-chain fragment variable region (scFv), antibody, or antigen-binding fragment, e.g., the blocking is measured in an enzyme-linked immunosorbent assay (ELISA) plate assay in which binding of a human transferrin receptor C-terminal fragment fused to His6-myc-myc is contacted with holo-transferrin that has been pre-bound to the scFv, antibody, or antigen-binding fragment and then immobilized to the surface of a plate by binding of an anti-holo-transferrin antibody that is bound to the plate, e.g., the binding of holo-transferrin to human transferrin receptor C in the absence of the scFv, antibody, or antigen-binding fragment is measured at a concentration of human transferrin receptor C-terminal fragment of about 300 pM.

[0052] Also provided are compositions comprising the anti-hTfR:GAA fusion proteins provided herein, e.g., pharmaceutical compositions comprising the fusion proteins disclosed herein and a pharmaceutically acceptable carrier. Kits comprising the fusion proteins disclosed herein are also provided. Also provided are such compositions or kits further comprising an additional therapeutic agent (e.g., alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), avalglucosidase alfa, levalbuterol, antibacterial agents, cortisone, prednisone, bisphosphonates, and palivizumab, beta2-adrenergic agonists, steroids, bisphosphonates, infectious disease treatments, vaccines, and / or pneumococcal vaccines).

[0053] Also provided is a conjugate comprising an anti-hTfR:GAA fusion protein disclosed herein linked to a human transferrin receptor polypeptide or an antigenic fragment thereof.

[0054] Also provided are, for example, SEQ ID NOs: 1, 6, 11, 16, 21, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 76, 81, 86, 91, 96, 101, 106, 111, 116, 121, 126, 131, 136, 141, 146, 151, 156, 161, 166, 171, 176, 181, 186, 191, 196, 201 , 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 271, 276, 281, 286, 291, 296, 301, 306, 311, and / or 316. For example, (1) the nucleotide sequence set forth in SEQ ID NO: 1 and SEQ ID NO: 6, (2) the nucleotide sequence set forth in SEQ ID NO: 11 and SEQ ID NO: 16, (3) the nucleotide sequence set forth in SEQ ID NO: 21 and SEQ ID NO: 26, (4) the nucleotide sequence set forth in SEQ ID NO: 31 and SEQ ID NO: 36, (5) the nucleotide sequence set forth in SEQ ID NO: 41 and SEQ ID NO: 46, (6) the nucleotide sequence set forth in SEQ ID NO: 51 and SEQ ID NO: 56, (7) the nucleotide sequence set forth in SEQ ID NO: 61 and SEQ ID NO: 66, (8) the nucleotide sequence set forth in SEQ ID NO: 71 and SEQ ID NO: 76, (9) the nucleotide sequence set forth in SEQ ID NO: 81 and SEQ ID NO: 86, (10) the nucleotide sequence set forth in SEQ ID NO: 91 and SEQ ID NO: 96, and (11) the nucleotide sequence set forth in SEQ ID NO: 101 and SEQ ID NO: 106. Sequence, (12) the nucleotide sequence set forth in SEQ ID NO: 111 and SEQ ID NO: 116, (13) the nucleotide sequence set forth in SEQ ID NO: 121 and SEQ ID NO: 126, (14) the nucleotide sequence set forth in SEQ ID NO: 131 and SEQ ID NO: 136, (15) the nucleotide sequence set forth in SEQ ID NO: 141 and SEQ ID NO: 146, (16) the nucleotide sequence set forth in SEQ ID NO: 151 and SEQ ID NO: 156, (17) the nucleotide sequence set forth in SEQ ID NO: 161 and SEQ ID NO: 166, (18) the nucleotide sequence set forth in SEQ ID NO: 171 and SEQ ID NO: 176, (19) the nucleotide sequence set forth in SEQ ID NO: 181 and SEQ ID NO: 186, (20) the nucleotide sequence set forth in SEQ ID NO: 191 and SEQ ID NO: 196, (21) the nucleotide sequence set forth in SEQ ID NO: 201 and SEQ ID NO: 206,(22) A polynucleotide comprising any one or more of the nucleotide sequences set forth in SEQ ID NOs: 211 and 216, (23) the nucleotide sequences set forth in SEQ ID NOs: 221 and 226, (24) the nucleotide sequences set forth in SEQ ID NOs: 231 and 236, (25) the nucleotide sequences set forth in SEQ ID NOs: 241 and 246, (26) the nucleotide sequences set forth in SEQ ID NOs: 251 and 256, (27) the nucleotide sequences set forth in SEQ ID NOs: 261 and 266, (28) the nucleotide sequences set forth in SEQ ID NOs: 271 and 276, (29) the nucleotide sequences set forth in SEQ ID NOs: 281 and 286, (30) the nucleotide sequences set forth in SEQ ID NOs: 291 and 296, (31) the nucleotide sequences set forth in SEQ ID NOs: 301 and 306, and / or (32) the nucleotide sequences set forth in SEQ ID NOs: 311 and 316. A vector, e.g., an expression vector, comprising a polynucleotide encoding the fusion protein disclosed herein is provided. Also provided are host cells (Chinese Hamster Ovary (CHO) cells) containing the fusion proteins, polynucleotides, and / or vectors.

[0055] Also provided are methods for producing the anti-hTfR:GAA fusion proteins disclosed herein, comprising culturing host cells (e.g., CHO cells) containing a polynucleotide encoding the fusion protein in a culture medium under conditions favorable for expression of the fusion protein, e.g., (a) introducing the polynucleotide into the host cells, (b) culturing the host cells under conditions favorable for expression of the fusion protein, and (c) optionally isolating the fusion protein from the culture medium and / or the host cells. Such fusion proteins that are the products of such methods are provided.

[0056] Also provided herein are methods for administering (e.g., parenterally, e.g., intravenously) an anti-hTfR:GAA fusion protein disclosed herein, optionally in association with an additional therapeutic agent, to a subject (e.g., having GSD, and / or a GAA genotype selected from the group consisting of ASP91ASN; MET318THR; GLU521LYS; GLY643ARG; ARG725TRP; IVSIAS,TG,-13; LYS903DEL; LEU299ARG; SER529VAL; ASP645GLU; GLU689LYS; EX18DEL; PRO545LEU; I-BP DEL,525T; ARG854TER; ALA237VAL; GLY293ARG; and IVS6AS,GC,-1). Also provided herein is a method for treating or preventing glycogen storage disease (e.g., Pompe disease, e.g., classic infantile-onset form of Pompe disease, non-classic infantile form of Pompe disease, or late-onset form of Pompe disease) in a subject in need thereof (e.g., having a GAA genotype selected from the group consisting of ASP91ASN; MET318THR; GLU521LYS; GLY643ARG; ARG725TRP; IVSIAS,TG,-13; LYS903DEL; LEU299ARG; SER529VAL; ASP645GLU; GLU689LYS; EX18DEL; PRO545LEU; I-BP DEL,525T; ARG854TER; ALA237VAL; GLY293ARG; and IVS6AS,GC,-1), comprising administering to the subject an effective amount of a fusion protein disclosed herein, optionally in association with an additional therapeutic agent. In one embodiment, the subject is under 1 year of age and is experiencing symptoms selected from: difficulty feeding, not gaining weight, poor head and neck control, rolling over and sitting up slower than expected, difficulty breathing, lung infections, an enlarged and thickened heart; heart defects, an enlarged liver, and an enlarged tongue. In one embodiment, the subject is an adult and is experiencing symptoms selected from: weakness of the legs, trunk, and / or arms, shortness of breath, lung infections, difficulty breathing during sleep, curvature of the spine, an enlarged liver, an enlarged tongue, and stiff joints.

[0057] Also provided herein are methods for delivering a payload (e.g., one or more antibodies or antigen-binding fragments thereof, proteins, enzymes, or viral vectors containing one or more polynucleotides or oligonucleotides), e.g., GAA, to a tissue within a subject's body (e.g., cartilage, brain, cerebral cortex; cerebellum; hippocampus; caudate nucleus; parathyroid glands; adrenal glands; bronchi; lungs; oral mucosa; esophagus; stomach; duodenum; small intestine; colon; rectum; liver; gallbladder; pancreas; kidneys; urinary bladder; testes; epididymis; prostate; vagina; ovaries; fallopian tubes; endometrium; cervix; placenta; breast; muscle, cardiac muscle; skeletal muscle, smooth muscle, muscular endothelial vasculature; soft tissue; skin; cecum; lymph nodes; tonsils; and / or bone marrow), comprising administering to the subject an antigen-binding protein that specifically binds to the transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload. For example, the method may include puncturing the body of a subject with a needle of a syringe and injecting into the body of the subject an antigen binding protein that specifically binds to a transferrin receptor, or an antigenic fragment or variant thereof, fused to a payload. [Brief explanation of the drawings]

[0058] [Figure 1] The amino acid sequences of various anti-human transferrin receptor scFv molecules provided herein in the Vk-3XG4S (SEQ ID NO: 538)-VH format.

[0059] [Figure 2A] Anti-human TfR scFv antibody clones deliver GAA to the cerebrum of TfR mice. Anti-human TfR:GAA molecules 69261, 69329, 12839, 12841, 12843, and 12845 (Figure 2A), 69348, 12795, 12799, 12801, 12850, and 12798 (Figure 2B), and 12802, 69340, 12847, 12848, 69307, and 69323 (Figure 2C) were tested. Each lane represents one mouse. Delivery by HDD. Quantification is shown in Table 4-1. [Figure 2B]Anti-human TfR scFv antibody clones deliver GAA to the cerebrum of TfR mice. Anti-human TfR:GAA molecules 69261, 69329, 12839, 12841, 12843, and 12845 (Figure 2A), 69348, 12795, 12799, 12801, 12850, and 12798 (Figure 2B), and 12802, 69340, 12847, 12848, 69307, and 69323 (Figure 2C) were tested. Each lane represents one mouse. Delivery by HDD. Quantification is shown in Table 4-1. [Figure 2C] Anti-human TfR scFv antibody clones deliver GAA to the cerebrum of TfR mice. Anti-human TfR:GAA molecules 69261, 69329, 12839, 12841, 12843, and 12845 (Figure 2A), 69348, 12795, 12799, 12801, 12850, and 12798 (Figure 2B), and 12802, 69340, 12847, 12848, 69307, and 69323 (Figure 2C) were tested. Each lane represents one mouse. Delivery by HDD. Quantification is shown in Table 4-1.

[0060] [Figure 3] A subset of anti-hTFRC antibodies (12798, 12850, 69323, 12841, 12843, 12845, 12847, 12848, 12799, 69307, and 12839) delivered mature GAA to the brain parenchyma in the scfv:GAA format (delivered by HDD). Lane E corresponds to the endothelium, and lane P corresponds to the parenchyma. The affinity ratio for mfTfR:human TfR is shown below the image (mf refers to cynomolgus monkey). Quantification is shown in Tables 4-2 and 4-3.

[0061] [Figure 4] Anti-hTFRC antibodies (12799, 12843, 12847, and 12839) delivered mature GAA in the scfv:GAA format to the brain parenchyma (AAV8 episomal liver depot gene therapy). Lane E corresponds to the endothelium, and lane P corresponds to the parenchyma. Quantification is shown in Table 4-4.

[0062] [Figure 5] Episomal AAV8 liver-depot anti-hTFRC scfv:GAA antibody delivered GAA protein to the CNS (cerebellum, cerebrum, spinal cord), heart, and muscle (quadriceps) in Gaa- / - / Tfrchum mice, as quantified in Tables 4-5.

[0063] [Figure 6] Episomal AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12839, 12843, and 12847) rescued glycogen stores in the central nervous system (CNS) (cerebellum, cerebrum, and spinal cord), heart, and muscle (quadriceps) in Gaa- / - / Tfrchum mice, as quantified in Tables 4-6.

[0064] [Figure 7A] Episomal AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12847, 12843, and 12799) rescued glycogen stores in the brain (thalamus (Figure 7A), cortex (Figure 7B), and hippocampal CAI (Figure 7C)), and muscle (quadriceps (Figure 7D)) in Gaa- / - / Tfrchum mice. [Figure 7B] Episomal AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12847, 12843, and 12799) rescued glycogen stores in the brain (thalamus (Figure 7A), cortex (Figure 7B), and hippocampal CAI (Figure 7C)), and muscle (quadriceps (Figure 7D)) in Gaa- / - / Tfrchum mice. [Figure 7C] Episomal AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12847, 12843, and 12799) rescued glycogen stores in the brain (thalamus (Figure 7A), cortex (Figure 7B), and hippocampal CAI (Figure 7C)), and muscle (quadriceps (Figure 7D)) in Gaa- / - / Tfrchum mice. [Figure 7D]Episomal AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12847, 12843, and 12799) rescued glycogen stores in the brain (thalamus (Figure 7A), cortex (Figure 7B), and hippocampal CAI (Figure 7C)), and muscle (quadriceps (Figure 7D)) in Gaa- / - / Tfrchum mice.

[0065] [Figure 8] Albumin insertion of anti-hTFRC 12847 scfv:GAA delivers mature GAA protein to the CNS and muscle of Pompe model mice.

[0066] [Figure 9] Albumin insertion of anti-hTFRC 12847 scfv:GAA rescues glycogen stores in the CNS and muscle of Pompe model mice. One-way ANOVA (*p<0.01; **=p<0.001; ***=p<0.0001).

[0067] [Figure 10] GAA activity in serum after AAV delivery—Cas9-mediated insertion of anti-TfR1:GAA or anti-CD63:GAA into the cynomolgus monkey albumin locus. Vehicle alone was used as a negative control. One unit of GAA activity is defined as the amount of enzyme that produces 1.0 μmol of 4-MU per minute at pH 4.5 and 37°C. Error bars are SEM. N=1 for vehicle, N=2-4 for all others.

[0068] [Figure 11] Albumin insertion of anti-hTFRC 12847 scfv:GAA delivers mature GAA protein to the CNS and muscle of cynomolgus monkeys. For bar graphs, mature GAA was quantified by Western blot of tissue lysates, and error bars are SD.

[0069] [Figure 12]The figure shows the interactions of Mammarenavirus machupoense GPI protein (PDB 3KAS), human ferritin (PDB 6GSR), Plasmodium vivax Sal-I PvRBP2b protein (PDB 6D04), human HFE protein (PDB 1DE4), and human transferrin (PDB I SUV) molecules superimposed on two TfR molecules in the symmetry unit. Only one copy of Mammarenavirus machupoense GPI protein and human ferritin is shown in the symmetry unit to reduce the complexity of the diagram for clarity.

[0070] [Figure 13] Hydrogen-Deuterium Exchange (HDX) mass spectrometry (Hydrogen-Deuterium Exchange) protection for the antibodies tested in the HDX-MS experiments shows that they can be assigned to five regions in the TfR (PDB I SUV).

[0071] [Figure 14] The TfR regions protected by REGN17513 are shown, representing antibodies that induce HDX protection in the TfR apical domain, which overlaps with the Mammarenavirus machupoense GPI protein, human ferritin, and Plasmodium vivax PvRBP2b protein binding sites.

[0072] [Figure 15] The TfR regions protected by REGN17510 are shown, representing an antibody with HDX protection in the TfR apical domain that is not shared by other TfR binding partners shown in FIG.

[0073] [Figure 16] The TfR regions protected by REGN17515 are shown, representing an antibody with HDX protection in the TfR apical domain that shares binding sites with human ferritin and Plasmodium vivax Sal-1 PvRBP2b protein.

[0074] [Figure 17] The TfR regions protected by REGN17514 are shown, representing an antibody that has HDX protection in the TfR protease-like domain and shares a binding site with the Plasmodium vivax Sal-1PvRBP2b protein.

[0075] [Figure 18] 18 shows the TfR region protected by REGN17508, representing an antibody with HDX protection in the TfR protease-like domain, a region not utilized by other TfR-interacting molecules shown in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0076] I. Overview Provided herein are anti-transferrin receptor antigen-binding proteins. Also provided are anti-transferrin receptor antigen-binding proteins fused to a payload. Such fusions are useful, for example, for delivering payloads to various tissues in the body, including the brain. For example, an anti-TfR:GAA fusion protein is provided, which exhibits high affinity for the transferrin receptor and excellent blood-brain barrier penetration. Surprisingly, fusions exhibiting high binding affinity for TfR crossed the BBB more efficiently than low-affinity binders. It was found that high-affinity antibodies conferred the best delivery to the CNS and muscle in the anti-hTFRscfv:payload (e.g., GAA) format. This contrasts with previous findings with monovalent and bivalent anti-TFR antibodies, in which low-affinity antibodies crossed the BBB more effectively. The fusions disclosed herein are capable of efficiently delivering GAA to the brain and are therefore effective treatments for glycogen storage diseases such as Pompe disease.

[0077] There may be employed herein conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being fully explained in the literature. For example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein referred to as "Sambrook, et al., 1989"), DNA Cloning: A Practical Approach, Volumes I and II (DNGlover ed.1985), Oligonucleotide Synthesis (MJGait ed.1984), Nucleic Acid Hybridization(BDHames&S.J.HIgG1ns,eds.(1985)), Transcription And Translation(BDHames&S.J.HIgG1ns,eds.(1984)), Animal Cell Culture(RIFreshney,ed.(1986)), Immobilized Cells And Enzymes(IRL Press, (1986)), B. Perbal, A Practical Guide To Molecular See Cloning (1984), FMA Usubel, et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0078] Polynucleotides include DNA and RNA. Provided herein is any polynucleotide disclosed herein operably linked to a promoter or other expression control sequence.

[0079] A symptom is a manifestation of a disease that is apparent to the patient, while a sign is a manifestation of a disease that is perceived by a physician. A complete or partial reduction of a sign or symptom can be referred to as alleviation of the sign or symptom.

[0080] An oligonucleotide is a polynucleotide up to about 30 nucleotides in length, for example, about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length.

[0081] Transferrin receptor 1 (TfR) is a membrane receptor involved in regulating iron supply to cells through binding of transferrin, a major iron carrier protein. Transferrin receptor 1 is expressed from the TFRC gene. Transferrin receptor 1 may also be referred to herein as TFRC. Because iron is essential for maintaining ribonucleotide reductase activity, the only enzyme catalyzing the conversion of ribonucleotides to deoxyribonucleotides, this receptor plays an important role in regulating cell proliferation. Preferably, the TfR is human TfR (hTfR). See, for example, accession numbers NP_001121620.1, BAD92491.1, and NP_001300894.1, and Ensembl entry: ENSG00000072274. Human transferrin receptor 1 is expressed in several tissues, including, but not limited to, the cerebral cortex, cerebellum, hippocampus, caudate nucleus, parathyroid glands, adrenal glands, bronchi, lungs, oral mucosa, esophagus, stomach, duodenum, small intestine, colon, rectum, liver, gallbladder, pancreas, kidney, urinary bladder, testis, epididymis, prostate, vagina, ovaries, fallopian tubes, endometrium, cervix, placenta, breast, cardiac muscle, smooth muscle, soft tissue, skin, cecum, lymph nodes, tonsils, and bone marrow. See also the tissues and cell types in Table B herein. A related transferrin receptor is transferrin receptor 2 (TfR.2). Human transferrin receptor 2 shares approximately 45% sequence identity with human transferrin receptor 1. Trinder & Baker, Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol. 2003 Mar;35(3):292-6. Unless otherwise stated, transferrin receptor as used herein generally refers to transferrin receptor 1 (e.g., human transferrin receptor 1) (CD71).

[0082] Human transferrin (Tf) is a single-chain, 80 kDa member of the anion-binding superfamily of proteins. Transferrin is a 698-amino acid precursor divided into a 19-amino acid signal sequence and a 679-amino acid mature segment, typically containing 19 intrachain disulfide bonds. The N- and C-terminal flanking regions (or domains) bind ferric iron through interactions with obligate anions (e.g., bicarbonate) and four amino acids (His, Asp, and two Tyr). Apotransferrin (or iron-free transferrin) first binds a single atom of iron at the C-terminus, followed by subsequent iron binding by the N-terminus to form holotransferrin (diferric Tf, holo-Tf). Through its C-terminal iron-binding domain, holotransferrin interacts with TfR on the cell surface, where it is internalized into acidifying endosomes. Iron dissociates from the Tf molecule within these endosomes and is transported to the cytosol as ferrous iron. In addition to TfR, transferrin has been reported to bind to cubrin, IGFBP3, microbial iron-binding proteins, and liver-specific TfR2.

[0083] The blood-brain barrier (BBB) is located within the brain's microvasculature and regulates the passage of molecules from the blood to the brain. Burkhart et al., Accessing targeted nanoparticles to the brain: the vascular route. Curr Med Chem. 2014;21(36):4092-9. Transcellular passage through brain capillary endothelial cells can occur via: 1) cell entry by leukocytes; 2) carrier-mediated influx of glucose, e.g., via glucose transporter 1 (GLUT-1), amino acids, e.g., via L-type amino acid transporter 1 (LAT-1), and small peptides, e.g., via organic anion-transporting peptide-B (OATP-B); 3) paracellular passage of small hydrophobic molecules; 4) adsorptive-mediated transcytosis of, e.g., albumin and cationized molecules; 5) passive diffusion of lipid-soluble nonpolar solutes, including CO2 and O2; and 5) receptor-mediated transcytosis of, e.g., insulin via the insulin receptor and Tf via the TfR. Johnsen et al.,Targeting the transferrin receptor for brain drug delivery,Prog Neurobiol.2019 Oct;181:101665. II. Anti-Human Transferrin Receptor Antigen Binding Proteins and Fusions

[0084] Provided are antigen-binding proteins, such as antibodies, and antigen-binding fragments thereof, such as Fabs and scFvs, that specifically bind to the transferrin receptor, preferably human transferrin receptor 1 (anti-hTfR). For example, in one embodiment, the anti-hTfR is in the form of a fusion protein. The fusion protein comprises an anti-hTfR antigen-binding protein fused to a specific payload (anti-hTfR:payload). The anti-hTfR can efficiently cross the blood-brain barrier (BBB), thereby delivering the fused payload to the brain.

[0085] Antigen binding proteins that specifically bind to the transferrin receptor (e.g., human transferrin receptor (e.g., REGN2431) or monkey transferrin receptor (e.g., REGN2054)) and fusions thereof, e.g., tags such as His6 and / or myc, have a K of about 20 nM at about 25°C, e.g., in a surface plasmon resonance assay. D or with greater affinity. Such antigen binding proteins may be referred to as "anti-TfR." In some embodiments, the antigen binding protein has a K of about 0.41 nM. D In some embodiments, the antigen binding protein binds to the human transferrin receptor with an affinity of about 3 nM or greater. D In some embodiments, the antigen binding protein binds to the human transferrin receptor with an affinity of about 0.45 nM to 3 nM or greater. D In some embodiments, a Fab having an HCVR and an LCVR binds to the human transferrin receptor with a K of about 0.65 nM. D or greater affinity. In some embodiments, the fusion proteins disclosed herein bind to the human transferrin receptor at a concentration of about 1 x 10 -7 K D or binds to the human transferrin receptor with greater affinity.

[0086] In one embodiment, the anti-hTfR scFv:payload or anti-TfR:payload scFv fusion protein comprises an scFv comprising a variable region arrangement such as LCVR-HCVR or HCVR-LCVR, where the HCVR and LCVR are optionally connected by a linker, and the scFv is optionally connected to a payload (e.g., GAA or a variant thereof) by a linker (e.g., LCVR-(Gly4Ser)1 (SEQ ID NO: 538)-HCVR-(Gly4Ser)2 (SEQ ID NO: 537))-payload (e.g., mature human GAA), or LCVR-(Gly4Ser)3 (SEQ ID NO: 538)-HCVR-(Gly4Ser)2 (SEQ ID NO: 537))-payload (e.g., mature human GAA)) (Gly4Ser = SEQ ID NO: 426).

[0087] The anti-hTfR:payload optionally comprises a signal peptide linked to an antigen binding protein that specifically binds to transferrin receptor (TfR), preferably human transferrin receptor (hTfR), which is fused (optionally by a linker) to a payload such as GAA or a variant thereof. In one embodiment, the signal peptide is the mROR signal sequence (e.g., mROR signal sequence-LCVR-(Gly4Ser)3 (SEQ ID NO: 538)-HCVR-(Gly4Ser)2 (SEQ ID NO: 537))-payload (e.g., mature human GAA), or LCVR-(Gly4Ser)3 (SEQ ID NO: 538)-HCVR-(Gly4Ser)2 (SEQ ID NO: 537))-payload (e.g., mature human GAA)) (Gly4Ser = SEQ ID NO: 426).

[0088] The terms "fused" or "tethered" with respect to a fusion polypeptide refer to polypeptides that are directly or indirectly linked (eg, via, for example, a linker or other polypeptide).

[0089] In one embodiment, the assignment of amino acids to each framework or CDR domain in an immunoglobulin is based on the amino acid sequence found in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; th ed. NIH Puhl. No. 91-3242 (1991), Kabat (1978) Adv. Prot. Chem. 32:1-75, Kabat et al., (1977) J. Biol. Chem. 252:6609-6616, Chothia, et al., (1987) J Mol. Biol. 196:901-917, or Chothia, et al., (1989) Nature 342:878-883. Thus, provided herein are compounds that are capable of reacting with V H CDR and V L and antibodies and antigen-binding fragments comprising the CDRs of V H and V Lcomprises an amino acid sequence as set forth herein (see, for example, the sequences in Table A or variants thereof), and the CDRs are as defined according to Kabat and / or Chothia.

[0090] Provided herein are antibodies that specifically bind to human transferrin receptor 1. As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds. In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V"). H ") (e.g., SEQ ID NOs: 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 222, 232, 242, 252, 482, 262, 272, 282, 292, 302, 483, and / or 312, or variants thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "VVR"). L ") (e.g., SEQ ID NOs: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, and / or 484, or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 222 or 242, or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L") (e.g., SEQ ID NO: 227 or 247, or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 222 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 227 or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 242 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 247 or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 132 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 137 or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 172 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 177, or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H") (e.g., comprising SEQ ID NO: 262 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 267 or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., comprising SEQ ID NO: 272 or a variant thereof) and a heavy chain constant region (e.g., human IgG, human IgG1, or human IgG4), and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "V L ") (e.g., SEQ ID NO: 277 or a variant thereof) and a light chain constant region (e.g., human kappa or human lambda). H and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), which are interspersed with more conserved regions, called framework regions (FRs). H and V L comprises three CDRs and four FRs. The anti-TfR antibodies disclosed herein can also be fused to a payload, such as GAA or a variant thereof.

[0091] The anti-TfR antigen-binding proteins provided herein can be antigen-binding fragments of antibodies that can be tethered to a payload. The term "antigen-binding portion" or "antigen-binding fragment" of an antibody, as used herein, refers to an immunoglobulin molecule that binds to an antigen but does not contain all of the sequence of a complete antibody (preferably, the complete antibody is an IgG). Non-limiting examples of antigen-binding fragments include (i) Fab fragments, (ii) F(ab')2 fragments, (iii) Fd fragments, (iv) Fv fragments, (v) single-chain Fv (scFv) molecules, and (vi) dAb fragments, which consist of amino acid residues that mimic the hypervariable regions (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) of an antibody or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, and small modular immunopharmaceuticals (SMIPs) are also encompassed by the term "antigen-binding fragment" as used herein.

[0092] As mentioned, the anti-TfR antigen binding proteins provided herein can be scFvs that can be tethered to a payload. scFvs (single-chain fragment variable regions) are composed of heavy (V H ) domain and light (V L) domain variable regions (in either order), which are preferably linked together by a flexible linker (e.g., a peptide linker). The length of the flexible linker used to link both V regions can be important for ensuring correct folding of the polypeptide chain. Previously, it has been estimated that a peptide linker needs to span 3.5 nm (35 Å) between the carboxy terminus of one variable domain and the amino terminus of the other domain without affecting the ability of the domains to fold and form an intact antigen-binding site (Huston et al., Protein engineering of single-chain Fv analogs and fusion proteins. Methods in Enzymology. 1991;203:46-88). In one embodiment, the linker comprises an amino acid sequence of such length that it separates the variable domains by approximately 3.5 nm.

[0093] In some embodiments, the anti-TfR antigen binding proteins described herein comprise monovalent or "one-arm" antibodies. As used herein, a monovalent or "one-arm" antibody refers to an immunoglobulin protein comprising a single variable domain. For example, a one-arm antibody may comprise a single variable domain within a Fab, which is linked to at least one Fc fragment. In certain embodiments, a one-arm antibody comprises a polypeptide comprising: (i) a heavy chain comprising a heavy chain constant region and a heavy chain variable region; (ii) a light chain comprising a light chain constant region and a light chain variable region; and (iii) an Fc fragment or truncated heavy chain. In certain embodiments, the Fc fragment or truncated heavy chain contained in a separate polypeptide is a "dummy Fc," which refers to an Fc fragment that is not linked to an antigen-binding domain. The one-arm antibodies of the present disclosure may comprise any of the HCVR / LCVR pairs or CDR amino acid sequences set forth in Table A herein. One-arm antibodies comprising a full-length heavy chain, a full-length light chain, and an additional Fc domain polypeptide can be constructed using standard methodology (see, e.g., WO2010151792, incorporated herein by reference in its entirety), where the heavy chain constant region differs from the Fc domain polypeptide by at least two amino acids (e.g., H95R and Y96F according to the IMGT exon numbering system, or H435R and Y436F according to the EU numbering system). Such modifications are useful in the purification of monovalent antibodies (see, e.g., WO2010151792).

[0094] An antigen-binding fragment of an antibody, in one embodiment, comprises at least one variable domain. A variable domain may be of any size or amino acid composition and generally comprises at least one CDR adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H Domain and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H-V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may be a monomeric V dimer. H or V L It may contain domains.

[0095] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in the antigen-binding fragments of antibodies described herein include: (i) a V H -CH1, (ii) V H -CH2, (iii) V H -CH3, (iv)V H -CH1-CH2, (v) V H -CH1-CH2-CH3, (vi) V H -CH2-CH3, (vii)V H -CL, (viii)V L -CH1, (ix)V L -CH2, (x)V L -CH3, (xi)V L -CH1-CH2, (xii) V L -CH1-CH2-CH3, (xiii)V L -CH2-CH3, and (xiv) V L -CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains can be either directly linked to each other or can be linked by a complete or partial hinge or linker region. The hinge region can consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which provides a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies described herein can be linked to each other and / or to one or more monomeric V H or V LThe present disclosure includes antigen-binding fragments of antigen-binding proteins, such as antibodies, described herein.

[0096] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are further discussed herein. The present disclosure includes monospecific as well as multispecific (e.g., bispecific) antigen-binding fragments comprising one or more variable domains from the antigen-binding proteins specifically described herein.

[0097] The term "specifically binds" or "binds specifically" refers to an affinity of at least about 10 as measured by a real-time label-free biolayer interferometry assay, e.g., at 25°C or 37°C, e.g., an Octet® HTX biosensor, or by surface plasmon resonance, e.g., BIACORE™, or by solution affinity ELISA. -9 K of M (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM) D "Anti-TfR" refers to an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that has binding affinity to an antigen, such as a human TfR protein, a mouse TfR protein, or a monkey TfR protein, represented as "anti-TfR." The present disclosure includes antigen-binding proteins that specifically bind to a TfR protein. "Anti-TfR" refers to an antigen-binding protein (or other molecule), such as an antibody or antigen-binding fragment thereof, that specifically binds to TfR.

[0098] "Isolated" antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free from other biological molecules from the cell or cell culture in which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials such as cell debris and growth medium. Isolated antigen binding proteins may also be at least partially free from expression system components such as biological molecules from the host cell or its growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such biological molecules (e.g., trace or insignificant amounts of impurities may remain), or the absence of water, buffers or salts, or components of a pharmaceutical formulation that comprises the antigen binding protein (e.g., antibody or antigen-binding fragment).

[0099] The present disclosure includes antigen binding proteins, e.g., antibodies or antigen-binding fragments, that bind to the same epitope as the antigen binding proteins described herein. In some embodiments, provided are antigen binding proteins, or antigenic fragments thereof, or receptors thereof, that specifically bind to the transferrin receptor, and include (a) an epitope comprising the sequence LLNE (SEQ ID NO: 525) and / or an epitope comprising the sequence TYKEL (SEQ ID NO: 507), (b) an epitope comprising the sequence DSTDFTGT (SEQ ID NO: 526) and / or an epitope comprising the sequence VKHPVTGQF (SEQ ID NO: 527) and / or an epitope comprising the sequence IERIPEL (SEQ ID NO: 528), (c) an epitope comprising the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529), (d) an epitope comprising the sequence FEDL (SEQ ID NO: 519), (e) an epitope comprising the sequence IVDKNGRL (SEQ ID NO: 530), (f) an epitope comprising the sequence IVDKNGRL VY (SEQ ID NO: 531), (g) an epitope comprising the sequence DQTKF (SEQ ID NO: 532), (h) an epitope comprising the sequence LVENPGGY (SEQ ID NO: 533), and / or an epitope comprising the sequence PIVNAELSF (SEQ ID NO: 534), and / or an epitope comprising the sequence PYLGTTMDT (SEQ ID NO: 535), (i) an epitope comprising the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope comprising the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or an epitope comprising the sequence TYKEL (SEQ ID NO: 507), G) an epitope comprising the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or an epitope comprising the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or an epitope comprising the sequence LIERIPELNKV (k) an epitope comprising the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) an epitope comprising the sequence GTKKDFEDL (SEQ ID NO: 512); (m) an epitope comprising the sequence SVIIVDKNGRL(n) an epitope comprising the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope comprising the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope comprising the sequence TYKELIERIPELNK (SEQ ID NO: 516); (o) an epitope comprising the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope comprising the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) an epitope comprising the sequence SVIIVDKNGRL (q) an epitope comprising the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope comprising the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518); (r) an epitope comprising the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope comprising the sequence LVENPGYVAYSKAATVTGKL (SEQ ID NO: 520), and / or an epitope comprising the sequence TYMDQTKFPTVNAELSF (SEQ ID NO: 521), and / or an epitope comprising the sequence ISRAAAEKL (SEQ ID NO: 522), and / or an epitope comprising the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or an epitope comprising the sequence an epitope comprising the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524); (s) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or an epitope contained within or overlapping with the sequence TYKEL (SEQ ID NO: 507); (t) an epitope contained within or overlapping with the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or an epitope contained within or overlapping with the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or the sequence LIERIPELNKV(u) an epitope contained within or overlapping with the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (v) an epitope contained within or overlapping with the sequence GTKKDFEDL (SEQ ID NO: 512); (w) an epitope contained within or overlapping with the sequence SVIIVDKNGRL VYLVENPGGYV (x) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope contained within or overlapping with the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (y) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (z) the sequence SVIIVDKNGRL (aa) an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope contained within or overlapping with the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), and (bb) an epitope contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope contained within or overlapping with the sequence LVENPGYV AYSKAATVTGKL (SEQ ID NO: 520), and / or an epitope contained within or overlapping with the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or an epitope contained within or overlapping with the sequence ISRAAAEKL (SEQ ID NO: 522), and / or the sequence VTSESKNVKL.an antigen binding protein, or antigenic fragment thereof, or a receptor thereof, that binds to one or more epitopes of hTfR selected from an epitope contained within or overlapping with TVSNVLKE (SEQ ID NO: 523) and / or an epitope contained within or overlapping with the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524). In some embodiments, provided is an antigen binding protein comprising: (a) an epitope consisting of the sequence LLNE (SEQ ID NO: 525) and / or an epitope consisting of the sequence TYKEL (SEQ ID NO: 507); (b) an epitope consisting of the sequence DSTDFTGT (SEQ ID NO: 526), and / or an epitope consisting of the sequence VKHPVTGQF (SEQ ID NO: 527), and / or an epitope consisting of the sequence IERIPEL (SEQ ID NO: 528); (c) an epitope consisting of the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529); (d) an epitope consisting of the sequence FEDL (SEQ ID NO: 519); (e) an epitope consisting of the sequence IVDKNGRL (SEQ ID NO: 530); VY (SEQ ID NO: 531), (g) an epitope consisting of the sequence DQTKF (SEQ ID NO: 532), (h) an epitope consisting of the sequence LVENPGGY (SEQ ID NO: 533), and / or an epitope consisting of the sequence PIVNAELSF (SEQ ID NO: 534), and / or an epitope consisting of the sequence PYLGTTMDT (SEQ ID NO: 535), (i) an epitope consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or an epitope consisting of the sequence TYKEL (SEQ ID NO: 507), G) an epitope consisting of the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or an epitope consisting of the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or an epitope consisting of the sequence LIERIPELNKV (k) an epitope consisting of the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) an epitope consisting of the sequence GTKKDFEDL (SEQ ID NO: 512); (m) an epitope consisting of the sequence SVIIVDKNGRL(n) an epitope consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514), and / or an epitope consisting of the sequence DQTKFPIVNAEL (SEQ ID NO: 515), and / or an epitope consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516); (o) an epitope consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) an epitope consisting of the sequence SVIIVDKNGRL (q) an epitope consisting of the sequence TYMDQTKFPTVNAEL (SEQ ID NO: 506) and / or an epitope consisting of the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), and (r) an epitope consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope consisting of the sequence LVENPGYVAYSKAATVTGKL (SEQ ID NO: 520), and / or is an antigen binding protein, comprising an antibody or antigen-binding fragment thereof, that binds to one or more epitopes of hTfR selected from the epitope consisting of the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or the epitope consisting of the sequence ISRAAAEKL (SEQ ID NO: 522), and / or the epitope consisting of the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or the epitope consisting of the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524).

[0100] An antigen is a molecule, such as a peptide (e.g., TfR or a fragment thereof (antigenic fragment)) to which an antibody or antigen-binding fragment thereof binds. The specific region on an antigen that an antibody recognizes and binds to is called an epitope. Antigen-binding proteins (e.g., antibodies) described herein that specifically bind to such antigens are part of the present disclosure.

[0101] The term "epitope" refers to an antigenic determinant (e.g., on TfR) that interacts with a specific antigen-binding site of an antigen-binding protein, e.g., the variable region of an antibody known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. The term "epitope" may also refer to the site on an antigen to which B and / or T cells respond and / or the region of an antigen bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and contain residues that directly contribute to the affinity of the interaction. Epitopes may be linear or conformational, i.e., composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. The epitopes to which the antigen-binding proteins described herein bind can be contained in a fragment of the TfR, such as its extracellular domain. Antigen-binding proteins (e.g., antibodies) described herein that bind to such epitopes are part of the present disclosure.

[0102] Methods for determining the epitope of an antigen-binding protein, such as an antibody or fragment or polypeptide, include alanine scanning mutation analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol. 248:443-63), peptide truncation analysis, crystallographic studies, and NMR analysis. In addition, methods such as epitope excision, epitope extraction, and chemical modification of antigens can be used (Tomer (2000) Prot. Sci. 9:487-496). Another method that can be used to identify amino acids in a polypeptide with which an antigen-binding protein (e.g., an antibody or fragment or polypeptide) interacts is hydrogen / deuterium exchange detected by mass spectrometry. See, for example, Ehring (1999) Analytical Biochemistry 267:252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

[0103] The present disclosure includes antigen binding proteins that compete with the antigen binding proteins described herein for binding to the TfR epitopes discussed herein. As used herein, the term "compete" refers to an antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to an antigen (e.g., TfR) and inhibits or blocks the binding of another antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) to the antigen. Unless otherwise stated, the term also includes competition between two antigen binding proteins, e.g., antibodies, in both orientations, i.e., a first antibody binding to an antigen and blocking binding by a second antibody, and vice versa. Thus, in one embodiment, competition occurs in one such orientation. In certain embodiments, a first antigen binding protein (e.g., an antibody) and a second antigen binding protein (e.g., an antibody) may bind to the same epitope. Alternatively, the first and second antigen-binding proteins (e.g., antibodies) can bind to different, but overlapping or non-overlapping, epitopes, such that binding of one inhibits or blocks binding of the second antibody, for example, through steric hindrance. Competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art, for example, by real-time label-free biolayer interferometry assays. Binding competition between TfR-binding proteins (e.g., monoclonal antibodies (mAbs)) can also be determined using real-time label-free biolayer interferometry assays on an Octet RED384 biosensor (Pall ForteBio Corp.).

[0104] Typically, antibodies or antigen-binding fragments described herein that have been modified in some way retain the ability to specifically bind to TfR, e.g., retain at least 10% of their TfR binding activity (compared to the parent antibody), where that activity is expressed on a molar basis. Preferably, antibodies or antigen-binding fragments described herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the TfR binding affinity of the parent antibody. It is also intended that the antibodies or antigen-binding fragments described herein may include conservative or non-conservative amino acid substitutions (referred to as "conservative variants" or "function-conservative variants" of antibodies) that do not substantially alter their biological activity.

[0105] The anti-TfR antigen-binding proteins provided herein can be monoclonal antibodies or antigen-binding fragments of monoclonal antibodies that can be tethered to a payload. Provided herein are monoclonal anti-TfR antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof, as well as monoclonal compositions comprising a plurality of isolated monoclonal antigen-binding proteins. As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody from a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. A "plurality" of such monoclonal antibodies and fragments in a composition refers to a concentration of identical (i.e., in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts, as discussed above) antibodies and fragments that exceeds the concentration normally present in nature in the blood of a host organism, such as a mouse or human.

[0106] In one embodiment, the anti-TfR antigen binding protein, e.g., antibody or antigen-binding fragment (optionally tethered to a payload), comprises a heavy chain constant domain, e.g., of the IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, and IgG4) or IgM type. In one embodiment, the antigen binding protein, e.g., antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., of the kappa or lambda type. In one embodiment, the V-type TfR antigen binding protein described herein comprises a heavy chain constant domain, e.g., of the IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, and IgG4) or IgM type. H is linked to a human heavy chain constant domain (e.g., IgG) and L is linked to a human light chain constant domain (e.g., kappa). The present disclosure includes antigen binding proteins comprising a variable domain as described herein, which is linked to a heavy and / or light chain constant domain, e.g., as described herein.

[0107] Provided herein are human anti-TfR antigen-binding proteins that can be tethered to a payload. As used herein, the term "human" antigen-binding protein, such as an antibody or antigen-binding fragment, includes antibodies and fragments having variable and constant regions derived from human germline immunoglobulin sequences, whether in a human cell or grafted into a non-human cell (e.g., a mouse cell). See, e.g., U.S. Patent Nos. 850,2018, 6,596,541, or 5,789,215. The anti-TfR human mAbs provided herein 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), e.g., in the CDRs, particularly CDR3. However, the term "human antibody," as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) are grafted onto human FR sequences. The term includes antibodies recombinantly produced in a non-human mammal or in the cells of a non-human mammal. The term is not intended to include natural antibodies isolated directly from a human subject. The present disclosure includes human antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof described herein).

[0108] Provided herein are anti-TfR chimeric antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (which may be tethered to a payload), and methods of use thereof. As used herein, a "chimeric antibody" is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies are from different species. (See, e.g., U.S. Pat. No. 4,816,567, and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855.) The present disclosure includes chimeric antibodies comprising the variable domains described herein and non-human constant domains.

[0109] The term "recombinant" anti-TfR antigen-binding protein, such as an antibody or antigen-binding fragment thereof (which may be tethered to a payload), refers to such molecules made, expressed, isolated, or obtained by techniques or methods known in the art, such as recombinant DNA technology, including, for example, DNA splicing and transgenic expression. This term includes antibodies expressed in non-human mammals (including transgenic non-human mammals, e.g., transgenic mice), or in cells, such as cell expression systems (e.g., CHO cells), or antibodies isolated from a recombinant combinatorial human antibody library. The present disclosure includes recombinant antigen-binding proteins, such as the antibodies and antigen-binding fragments described herein.

[0110] Antigen-binding fragments of antibodies, in one embodiment, include antibodies that are less than the complete antibody, but still specifically bind to an antigen, e.g., TfR, and that include, for example, at least one variable domain. The variable domain may be of any size or amino acid composition and generally includes at least one (e.g., three) CDRs that are adjacent to or in-frame with one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may be formed by non-covalently linking monomeric V dimers. H and / or V L It may contain domains.

[0111] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in the antigen-binding fragments of antibodies described herein include: (i) a VH -CH1, (ii) V H -CH2, (iii) V H -CH3, (iv)V H -CH1-CH2, (v) V H -CH1-CH2-CH3, (vi) V H -CH2-CH3, (vii)V H -CL, (viii)V L -CH1, (ix)V L -CH2, (x)V L -CH3, (xi)V L -CH1-CH2, (xii) V L -CH1-CH2-CH3, (xiii)V L -CH2-CH3, and (xiv) V L -CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains can be either directly linked to each other or can be linked by a complete or partial hinge or linker region. The hinge region can consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which provides a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies described herein can be linked to each other and / or to one or more monomeric V H or V L The present disclosure includes antigen-binding fragments of antigen-binding proteins, such as antibodies, described herein.

[0112] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are further discussed herein. The present disclosure includes monospecific as well as multispecific (e.g., bispecific) antigen-binding fragments comprising one or more variable domains from the antigen-binding proteins specifically described herein.

[0113] "Variant" of a polypeptide, such as an immunoglobulin chain, may be any variant of a reference amino acid sequence described herein (e.g., SEQ ID NOs: 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19, 20, 22, 23, 24, 25, 27, 28, 29, 30, 32, 33, 34, 35, 37, 38, 39, 40, 42, 43, 44, 45, 47, 48, 49, 50, 52, 53, 54, 55, 57, 58, 59, 60, 62, 63, 64, 65, 67, 68, 69, 70, 72, 73, 74, 75, 77, 78, 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 22, 23, 24, 25, 27, 28, 29, 30, 32, 33, 34, , 87, 88, 89, 90, 92, 93, 94, 95, 97, 98, 99, 100, 102, 103, 104, 105, 107, 108, 109, 110, 112, 113, 114, 115, 117, 118, 119, 120, 122, 123, 124, 125, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 8, 129, 130, 132, 133, 134, 135, 137, 138. 139, 140, 142, 143, 144, 145, 147, 148, 149, 150, 152, 153, 154, 155, 157, 158, 159, 160, 162, 163, 164, 165, 167 , 168, 169, 170, 172, 173, 174, 175, 177, 178, 179, 180, 182, 183, 184, 185, 187, 188, 189, 190, 192, 193, 194, 195, 197, 198, 199, 200, 202, 203, 204, 205 , 207, 208, 209, 210, 212, 213, 214, 215, 217, 218, 219, 220, 222, 223, 224, 225, 227, 228, 229, 230, 232, 233, 234, 235, 237, 238, 239, 240, 242, 243, 244 , 245, 247, 248, 249, 250, 252, 253, 254, 255, 257, 258, 259, 260, 262, 263, 264, 265, 267, 268, 269, 270, 272, 273, 274, 275, 277, 278, 279, 280, 282, 283 , 284, 285, 287, 288, 289, 290, 292, 293, 294, 295, 297, 298, 299, 300, 302, 303, 304, 305, 307, 488, 308, 309, 310, 312, 313, 314, 315, 317, 318, 319, 320,321 (optionally not including the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 322 (optionally not including the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 323 (optionally not including the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 324 (optionally not including the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 328 to 423, or 427 to 458) and (e.g., at least 70-99.9%) amino acid sequences that are identical or similar, and when the comparison is performed using the BLAST algorithm, the algorithm parameters are selected to maximize the match between the respective sequences over the entire length of each reference sequence (e.g., expected threshold: 10, word size: 3, maximum matches within query range: 0, BLOSUM 62 matrix, gap cost: presence 11, extension 1, conditional composition score matrix adjustment), and / or refers to a polypeptide comprising an amino acid sequence but having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations (e.g., point mutations, insertions, truncations, and / or deletions).

[0114] Furthermore, a variant of a polypeptide can include a polypeptide, such as an immunoglobulin chain, whose amino acid sequence can comprise the amino acid sequence of a reference polypeptide specifically described herein, except for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, e.g., one or more missense mutations (e.g., conservative substitutions), nonsense mutations, deletions, or insertions. For example, the present disclosure provides immunoglobulin light chains (or V) comprising the amino acid sequence set forth in SEQ ID NOs: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, or 484, but with one or more such mutations. L ) variants, and / or immunoglobulin heavy chains (or V) comprising the amino acid sequence set forth in SEQ ID NOs: 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 222, 232, 242, 252, 482, 262, 272, 282, 292, 302, 483, or 312, but having one or more such mutations. H In one embodiment, the TfR binding protein comprises an immunoglobulin light chain variant comprising CDR-L1, CDR-L2, and CDR-L3, in which one or more (e.g., one, or two, or three) of such CDRs have one or more such mutations (e.g., conservative substitutions), and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2, and CDR-H3, in which one or more (e.g., one, or two, or three) of such CDRs have one or more such mutations (e.g., conservative substitutions).

[0115] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20):5101-5109, Altschul, SF, et al., (1990) J. Mal. Biol. 215:403-410, Gish, W., et al., (1993) Nature Genet. 3:266-272, Madden, TL, et al., (1996) Meth. Enzymol. 266:131-141, Altschul, SF, et al., (1997) Nucleic Acids Res. 25:3389-3402, Zhang, J., et al., (1997) Genome Res. 7:649-656, Wootton, JC, et al. al., (1993) Comput.Chem.17:149-163, Hancock, JMeta / ., (1994) Comput.Appl.Biosci.10:67-70, ALIGNMENT SCORING SYSTEMS: Dayhoff, M.0., et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M. 0. Dayhoff (ed.), pp. 345-352, Natl. Structure,(1978)vol.5,suppl.3.”M.0.Dayhoff(ed.),pp.353-358,Natl.Biomed.Res.Found.,Washington,DC,Altschul,SF,(1991)J.Mol.Biol.219:555-565,States,DJ,etal.,(1991)Methods 3:66-70, Henikoff, S., etal., (1992) Proc. Natl. Acad. Sci.USA 89:10915-10919, Altschul,SF,et al.,(1993)J.Mal.Evol.36:290-300,ALIGNMENT STATISTICS:Karlin,S.,et al.,(1990)Proc.Natl.Acad.Sci.USA 87:2264-2268,Karlin,S.,et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877, Dembo, A., et al., (1994) Ann. Prob.22:2022-2039, and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, NY. .

[0116] For example, "conservatively modified variants" or "conservative substitutions" of immunoglobulin chains described herein refer to variants in which there is a substitution of one or more amino acids in a polypeptide with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation, and rigidity, etc.). Such changes can frequently be made without significantly destroying the biological activity of the antibody or fragment. Those skilled in the art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al., (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224(4 th (See, e.g., J. Am. Chem. Soc. 1999, 14:131-132, 1999). Additionally, substitutions of structurally or functionally similar amino acids are unlikely to significantly disrupt biological activity. The present disclosure includes TfR binding proteins comprising such conservatively modified variant immunoglobulin chains.

[0117] Examples of groups of amino acids with side chains having similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine, 2) aliphatic-hydroxyl side chains: serine and threonine, 3) amide-containing side chains: asparagine and glutamine, 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan, 5) basic side chains: lysine, arginine, and histidine, 6) acidic side chains: aspartic acid and glutamic acid, and 7) sulfur-containing side chains: cysteine and methionine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45.

[0118] The antibodies and antigen-binding fragments described herein include immunoglobulin chains comprising the amino acid sequences (and variants thereof) specifically described herein, as well as cellular and in vitro post-translational modifications to the antibodies or fragments. For example, the present disclosure includes antibodies and antigen-binding fragments thereof that specifically bind to TfR, comprising the heavy and / or light chain amino acid sequences described herein, as well as antibodies and fragments in which one or more asparagine, serine, and / or threonine residues are glycosylated, one or more asparagine residues are deamidated, one or more residues (e.g., Met, Trp, and / or His) are oxidized, the N-terminal glutamine is pyroglutamic acid (pyroE), and / or the C-terminal lysine or other amino acid is deleted.

[0119] In one embodiment, the anti-hTfR:payload, or the anti-hTfR:payload where the payload is human GAA (e.g., in an scFv, Fab, antibody, or antigen-binding fragment thereof format), exhibits one or more of the following characteristics: an affinity (K) for binding to human TfR at 25°C in a surface plasmon resonance format of about 41 nM or higher (e.g., about 1, or 0.1 nM, or about 0.18 to about 1.2 nM, or higher); D ), Affinity (K) for binding to monkey TfR at 25°C in a surface plasmon resonance format of about 0 nM (no detectable binding) or higher affinity (e.g., about 20 nM or higher) D ), K for binding to monkey TfR / human TfR at 25°C in a surface plasmon resonance format of 0 to 278 (e.g., about 17 or 18) D The ratio of When in Fab format (IgG1), about 3, 5, 10, or 13% blocking of binding of hTfR (e.g., Hmm-hTFRC such as REGN2431) to human holo-Tf, e.g., about 45% or less blocking; scFv(V K -V H ) format, about 6, 8, 10, or 13% blocking of binding of hTfR (e.g., Hmm-hTFRC such as REGN2431) to human holo-Tf, e.g., about 45% or less blocking; scFv(V H -V L ) format, about 11, 17, 23, or 26% blocking of hTfR (e.g., Hmm-hTFRC such as REGN2431) binding to human holo-Tf, e.g., about 45% or less blocking; In the case of the anti-hTfR scFv:hGAA format, mice were administered the molecule via HDD (e.g., Tfrc hum / hum or greater than about 1, 0.67, 1.08, 0.91, 0.65, 0.55, 0.50, 0.27, 0.72, 1.05, 0.49, 0.29, 1.29, 1.72, 1.79, 3.08, 1.24, 0.59, or 0.47 (or about 1-2) in a human (e.g., a knock-in mouse) or delivers mature human GAA protein to the brain of a human administered the scFv:hGAA molecule. In the case of the anti-hTfR scFv:hGAA format, mice administered the molecule via HDD (e.g., Tfrchum / hum or a ratio of mature hGAA protein of about 0.44, 0.05, 1.13, or 0.60 (about 0.1 to 1.2) in the brain parenchyma of a human (mice) receiving the scFv:hGAA molecule, normalized to that of the positive control 8D3:GAA scFv. In the case of anti-hTfR scFv:hGAA format, mice administered the molecule via HDD (e.g., Tfrc hum / hum or a ratio of mature hGAA protein of about 0.67, 1.80, 1.78, or 7.74 (about 1-2) in the quadriceps muscle of a human knock-in mouse (normalized to that of the positive control 8D3:GAA scFv), or delivers mature human GAA protein to the quadriceps muscle or other muscle tissue of a human administered the scFv:hGAA molecule. In the case of anti-hTfR scFv:hGAA format, mice administered the molecule via AAV8 liver depot (e.g., Tfrc hum or a ratio of mature hGAA protein of about 0.94, 0.49, 0.61, or 1.90 (about 0.1 to 1.2) in the brain parenchyma of a mouse (mice) expressing 8D3:GAA scFv (normalized to that of the positive control 8D3:GAA scFv), or delivering mature human GAA to the brain parenchyma of a human administered the scFv:hGAA molecule via a virus, e.g., AAV, liver depot, or parenterally delivered in a protein scFv:hGAA fusion format. Anti-hTfR scFv: In the case of hGAA format, mice administered via AAVS liver depot (e.g., Tjrc hum deliver mature hGAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps of mice (e.g., knock-in mice); or deliver mature human GAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps of humans to whom the scFv:hGAA molecule has been administered via a virus, e.g., AAV, liver depot, or parenterally delivered in a protein scFv:hGAA fusion format; Mice administered the molecule via AAV8 liver depot when in anti-hTfR scFv:hGAA format (e.g., Tfrc hum or reducing glycogen stores in the cerebrum, cerebellum, spinal cord, heart, and / or quadriceps of a human (e.g., knock-in mouse) by, for example, at least 75% to greater than 95% or greater than 99%, or reducing glycogen stores in the cerebrum, cerebellum, spinal cord, heart, and / or quadriceps of a human to whom the scFv:hGAA molecule has been administered via a virus, e.g., AAV, liver depot, or parenterally delivered in a protein scFv:hGAA fusion format. Liver-depot AAV8 anti-hTFRC scfv:hGAA treated with hGAA (e.g., 4e11vg / kg AAV8) - / - / Tjrc hum Glycogen levels in tissues (e.g., cerebellum) of mice treated with untreated Gaa - / - / Tjrc hum reduced by at least about 90% (e.g., about 95% or more) compared to mice; Liver-depot AAV8 anti-hTFRC scfv:hGAA treated with hGAA (e.g., 4e11vg / kg AAV8) - / - / Tjrc hum Glycogen levels in tissues (e.g., quadriceps) of mice treated with untreated Gaa - / - / Tjrc hum reduced by at least about 89% (e.g., 90% or 91% or more) compared to mice or humans treated with the fusion, e.g., by parenteral delivery of the fusion protein; Tjrc (e.g., by HDD or AAV8 episomal liver depot) hum When administered to mice, it does not cause abnormal iron homeostasis, e.g., the mice maintain normal serum, heart, liver, and / or spleen iron levels, normal total iron-binding capacity (TIBC), and / or normal hepcidin levels, or when administered to humans, e.g., by parenteral delivery of the fusion protein, For example, in an AAV8 vector,- / - / Tfrc hum / hum When chromosomally inserted (e.g., into the albumin locus) or episomally delivered into a mouse (e.g., mouse), the DNA encoding the fusion causes expression of mature human GAA in the serum, liver, cerebrum, and / or quadriceps muscle; and / or For example, in an AAV8 vector, when chromosomally inserted (e.g., into the albumin locus) or inserted (e.g., into the human or Gaa - / - / Tfrc hum / hum When episomally inserted (into mice), DNA encoding the fusion reduces glycogen levels in the cerebrum and / or quadriceps muscle. * Tjrc hum or Tfrc hum / hum is a homozygous knock-in mouse.

[0120] The amino acid sequences of the domains in the anti-human transferrin receptor antigen binding proteins provided herein are summarized in Table A below. The amino acid sequences of the domains in the fusion anti-human transferrin receptor antigen binding proteins provided herein are also summarized in Table A below. For example, provided herein are anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) that comprise the HCVR and LCVR of a molecule in Table A, or that comprise the CDRs thereof, fused to a payload. In specific examples, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDRs numbered 23 or 25. In specific examples, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDRs numbered 23. In a specific example, anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDR number 14. In a specific example, anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDR number 18. In a specific example, anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDR number 27. In a specific example, anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFvs and Fabs) comprise the HCVR and LCVR of Table A, or comprise CDR number 28.

[0121] [Table A] H31874B HCVR(V H ) Nucleotide sequence [Table 293] HCVR(V H ) Amino acid sequence [Table 294] HCDR1: GFAFSSYA (SEQ ID NO: 3) HCDR2: ISGIGGST (SEQ ID NO: 4) HCDR3: AKGGAARRMEYFQY (SEQ ID NO: 5) LCVR(V L ) Nucleotide sequence [Table 295] LCVR(V L ) Amino acid sequence [Table 296] LCDR1:QGISNY (SEQ ID NO:8) LCDR2:AAS (SEQ ID NO: 9) LCDR3: QKYNSAPLT (SEQ ID NO: 10) 31863B HCVR(V H ) Nucleotide sequence [Table 7] HCVR(V H ) Amino acid sequence [Table 298] HCDR1: GFTFNSYA (SEQ ID NO: 13) HCDR2: IGGSTGNT (SEQ ID NO: 14) HCDR3: AKGGAARRMEYFQH (SEQ ID NO: 15) LCVR(V L ) Nucleotide sequence [Table 9] LCVR(V L ) Amino acid sequence [Table 10] LCDR1:QGISNY (SEQ ID NO: 18) LCDR2: AAS (SEQ ID NO: 19) LCDR3:QNHNSVPLT (SEQ ID NO: 20) 69348 HCVR(V H ) Nucleotide sequence [Table 11] HCVR(V H ) Amino acid sequence [Table 12] HCDR1: GFTFTTYG (SEQ ID NO: 23) HCDR2: IWYDGSNK (SEQ ID NO: 24) HCDR3: TRTHGYTRSSDGFDY (SEQ ID NO: 25) LCVR(V L ) Nucleotide sequence [Table 13] LCVR(V L ) Amino acid sequence [Table 14] LCDR1:QSIRNV (SEQ ID NO: 28) LCDR2: AAS (SEQ ID NO: 29) LCDR3: LQHNFYPLT (SEQ ID NO: 30) 69340 HCVR(V H ) Nucleotide sequence [Table 15] HCVR(V H ) Amino acid sequence [Table 16] HCDR1: GFTFDDKA (SEQ ID NO: 33) HCDR2: ISWNSGTI (SEQ ID NO: 34) HCDR3: AKDGDTSGWYWYGLDV (SEQ ID NO: 35) LCVR(V L ) Nucleotide sequence [Table 17] LCVR(V L ) Amino acid sequence [Table 18] LCDR1: QSVSSY (SEQ ID NO: 38) LCDR2:DVS (SEQ ID NO: 39) LCDR3: QQRSDWPIT (SEQ ID NO: 40) 69331 HCVR(V H ) Nucleotide sequence [Table 19] HCVR(V H ) Amino acid sequence [Table 20] HCDR1: GFTFSVYG (SEQ ID NO: 43) HCDR2: ISHDGNIK (SEQ ID NO: 44) HCDR3: AKDTWNSLDTFDI (SEQ ID NO: 45) LCVR(V L ) Nucleotide sequence [Table 21] LCVR(V L ) Amino acid sequence [Table 22] LCDR1: QGISSY (SEQ ID NO: 48) LCDR2: AAS (SEQ ID NO: 49) LCDR3:QQLNSYPLT (SEQ ID NO:50) 69332 HCVR(V H ) Nucleotide sequence [Table 23] HCVR(V H ) Amino acid sequence [Table 24] HCDR1: GFSLNTYGMF (SEQ ID NO: 53) HCDR2: IHWDDDK (SEQ ID NO: 54) HCDR3: ARGHNNLNYIIH (SEQ ID NO: 55) LCVR(V1) nucleotide sequence [Table 25] LCVR(V L ) Amino acid sequence [Table 26] LCDR1:QGIRND (SEQ ID NO:58) LCDR2: AAS (SEQ ID NO: 59) LCDR3: LQDYNYPFT (SEQ ID NO: 60) 69326 HCVR(V H ) Nucleotide sequence [Table 27] HCVR(V H ) Amino acid sequence [Table 28] HCDR1: GFIFSSYE (SEQ ID NO: 63) HCDR2: ISSGSTI (SEQ ID NO: 64) HCDR3: VSGVVLFDV (SEQ ID NO: 65) LCVR(V L ) Nucleotide sequence [Table 29] LCVR(V L ) Amino acid sequence [Table 30] LCDR1:QSVSSN (SEQ ID NO: 68) LCDR2:SAS (SEQ ID NO: 69) LCDR3: QQYNIWPRT (SEQ ID NO: 70) 69329 HCVR(V H ) Nucleotide sequence [Table 31] HCVR(V H ) Amino acid sequence [Table 32] HCDR1: GFTFSNYW (SEQ ID NO: 73) HCDR2: IKEDGSEK (SEQ ID NO: 74) HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO: 75) LCVR(V L ) Nucleotide sequence [Table 33] LCVR(V L ) Amino acid sequence [Table 34] LCDR1:QGISSW (SEQ ID NO:78) LCDR2: AAS (SEQ ID NO: 79) LCDR3: QKANSFPYT (SEQ ID NO: 80) 69323(REGN16816 anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 35] HCVR(V H ) Amino acid sequence [Table 36] HCDR1: GFTFDDYA (SEQ ID NO: 83) HCDR2: ISWNSGYI (SEQ ID NO: 84) HCDR3: ARGGSTLVRGVKGGYYGMDV (SEQ ID NO: 85) LCVR(V L ) Nucleotide sequence [Table 37] LCVR(V L ) Amino acid sequence [Table 38] LCDR1: QSISSY (SEQ ID NO: 88) LCDR2: AAS (SEQ ID NO: 89) LCDR3: QQSYSIPLT (SEQ ID NO: 90) 69305 HCVR(V H ) Nucleotide sequence [Table 39] HCVR(V H ) Amino acid sequence [Table 40] HCDR1: GFTFSSYG (SEQ ID NO: 93) HCDR2: IWYDGSNK (SEQ ID NO: 94) HCDR3: AGQLDLFFDY (SEQ ID NO: 95) LCVR(V L ) Nucleotide sequence [Table 41] LCVR(V L ) Amino acid sequence [Table 42] LCDR1: QSIDRY (SEQ ID NO: 98) LCDR2:TTS (SEQ ID NO: 99) LCDR3: QQSYSPPLT (SEQ ID NO: 100) 69307(REGN16817 anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 43] HCVR(V H ) Amino acid sequence [Table 44] HCDR1: GFTFSNYW (SEQ ID NO: 103) HCDR2: IKEDGSEK (SEQ ID NO: 104) HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO: 105) LCVR(V L ) Nucleotide sequence [Table 45] LCVR(V L ) Amino acid sequence [Table 46] LCDR1:QGISSW (SEQ ID NO: 108) LCDR2: AAS (SEQ ID NO: 109) LCDR3:QKADSLPYA (SEQ ID NO: 110) 12795B HCVR(V H ) Nucleotide sequence [Table 47] HCVR(V H ) Amino acid sequence [Table 48] HCDR1: GFTFTSYD (SEQ ID NO: 113) HCDR2: ISGSGGNT (SEQ ID NO: 114) HCDR3: TRSHDFGAFDYFDY (SEQ ID NO: 115) LCVR(V L ) Nucleotide sequence [Table 49] LCVR(V L ) Amino acid sequence [Table 50] LCDR1:QGIRDH (SEQ ID NO: 118) LCDR2: AAS (SEQ ID NO: 119) LCDR3: LQYDTYPLT (SEQ ID NO: 120) 12798B(REGN17078 Fab:REGN17072 scFv:REGN16818 anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 51] HCVR(V H ) Amino acid sequence [Table 52] HCDR1: GFTFDDYA (SEQ ID NO: 123) HCDR2: ISWNSATR (SEQ ID NO: 124) HCDR3: AKDMDISLGYYGLDV (SEQ ID NO: 125) LCVR(V L ) Nucleotide sequence [Table 53] LCVR(V L ) Amino acid sequence [Table 54] LCDR1: QTVSSN (SEQ ID NO: 128) LCDR2: GSS (SEQ ID NO: 129) LCDR3: QQYNNWPPYT (SEQ ID NO: 130) 12799B CREGN17079 Fab:REGN17073 scFv:REGN16819anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 55] HCVR(V H ) Amino acid sequence [Table 56] HCDR1: GFSLSTSGVG (SEQ ID NO: 133) HCDR2: IYWNDHK (SEQ ID NO: 134) HCDR3: AHYSGSYSYYYYGLDV (SEQ ID NO: 135) LCVR(V L ) Nucleotide sequence [Table 57] LCVR(V L ) Amino acid sequence [Table 58] LCDR1: QGIASW (SEQ ID NO: 138) LCDR2: AAS (SEQ ID NO: 139) LCDR3: QQANYFPWT (SEQ ID NO: 140) 12801B HCVR(V H ) Nucleotide sequence [Table 59] HCVR(V H ) Amino acid sequence [Table 60] HCDR1: GFTFTSYA (SEQ ID NO: 143) HCDR2: IRGSGGGT (SEQ ID NO: 144) HCDR3: ARSHDYGAFDFFDY (SEQ ID NO: 145) LCVR(V L ) Nucleotide sequence [Table 61] LCVR(V L ) Amino acid sequence [Table 62] LCDR1:QGIRTD (SEQ ID NO: 148) LCDR2: AAS (SEQ ID NO: 149) LCDR3: LQYNSYPLT (SEQ ID NO: 150) 12802B(REGN16820 anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 63] HCVR(V H ) Amino acid sequence [Table 64] HCDR1: GFTFSDYF (SEQ ID NO: 153) HCDR2: ISSTGSTI (SEQ ID NO: 154) HCDR3: TRDNWNYEY (SEQ ID NO: 155) LCVR(V L ) Nucleotide sequence [Table 65] LCVR(V L ) Amino acid sequence [Table 66] LCDR1: QSVSIN (SEQ ID NO: 158) LCDR2: VAS (SEQ ID NO: 159) LCDR3: QQYDIWPYT (SEQ ID NO: 160) 12808B HCVR(V H ) Nucleotide sequence [Table 67] HCVR(V H ) Amino acid sequence [Table 68] HCDR1: GESISSNTYY (SEQ ID NO: 163) HCDR2: IDYSGTT (SEQ ID NO: 164) HCDR3: AREWGNYGYYYGMDV (SEQ ID NO: 165) LCVR(V L ) Nucleotide sequence [Table 69] LCVR(V L ) Amino acid sequence [Table 70] LCDR1:QGIRND (SEQ ID NO: 168) LCDR2: AAS (SEQ ID NO: 169) LCDR3: LSHNSYPWT (SEQ ID NO: 170) 12812B CREGN16821 Anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 71] HCVR(V H ) Amino acid sequence [Table 72] HCDR1: RGTFSSYA (SEQ ID NO: 173) HCDR2: IIPIFGTA (SEQ ID NO: 174) HCDR3: AREKGWNYFDY (SEQ ID NO: 175) LCVR(V L ) Nucleotide sequence [Table 73] LCVR(V L ) Amino acid sequence [Table 74] LCDR1:QGISSW (SEQ ID NO: 178) LCDR2: AAS (SEQ ID NO: 179) LCDR3: QQANSFPRT (SEQ ID NO: 180) 12816B HCVR(V H ) Nucleotide sequence [Table 75] HCVR(V H ) Amino acid sequence [Table 76] HCDR1: GFTFSDYY (SEQ ID NO: 183) HCDR2: ISSSGTTI (SEQ ID NO: 184) HCDR3: AREGYGNDYYYYGIDV (SEQ ID NO: 185) LCVR(V L ) Nucleotide sequence [Table 77] LCVR(V L ) Amino acid sequence [Table 78] LCDR1: QSLLHGNGYNY (SEQ ID NO: 188) LCDR2:LGS (SEQ ID NO: 189) LCDR3: MQALQTPYT (SEQ ID NO: 190) 12833B HCVR(V H ) Nucleotide sequence [Table 79] HCVR(V H ) Amino acid sequence [Table 80] HCDR1: GFTFSSFG (SEQ ID NO: 193) HCDR2: ISYDGSDK (SEQ ID NO: 194) HCDR3: AKENGILTDSYGMDV (SEQ ID NO: 195) LCVR(V L ) Nucleotide sequence [Table 81] LCVR(V L ) Amino acid sequence [Table 82] LCDR1: QSISSY (SEQ ID NO: 198) LCDR2: AAS (SEQ ID NO: 199) LCDR3: QQSYSTPPIT (sequence number 200) 12834B HCVR(V H ) Nucleotide sequence [Table 83] HCVR(V H ) Amino acid sequence [Table 84] HCDR1: GYTFTSYG (SEQ ID NO: 203) HCDR2: ISVYHGNT (SEQ ID NO: 204) HCDR3: AREGYYDFWSGYYPFDY (SEQ ID NO: 205) LCVR(V L ) Nucleotide sequence [Table 85] LCVR(V L ) Amino acid sequence [Table 86] LCDR1: QSISSY (SEQ ID NO: 208) LCDR2: AAS (SEQ ID NO: 209) LCDR3: QQSYSTPPIT (SEQ ID NO: 210) 12835B HCVR(V H ) Nucleotide sequence [Table 87] HCVR(V H ) Amino acid sequence [Table 88] HCDR1: GFTFRNYE (SEQ ID NO: 213) HCDR2: ISSSGNMK (SEQ ID NO: 214) HCDR3: ARDEFPYGMDV (SEQ ID NO: 215) LCVR(V L ) Nucleotide sequence [Table 89] LCVR(V L ) Amino acid sequence [Table 90] LCDR1: QSISSY (SEQ ID NO: 218) LCDR2: AAS (SEQ ID NO: 219) LCDR3: QQSYSTPPIT (SEQ ID NO: 220) 12847B(REGN17083 anti-hTfR Fab:REGN17077 anti-hTfR scFv:REGN16826 anti-hTfR scFv:hGAA) HCVR(V H ) Nucleotide sequence [Table 91] HCVR(V H ) Amino acid sequence

Table 92

Table 93

Table 94

Table 95

Table 96

Table 97

Table 98

Table 105

Table 106

Table 107

Table 108

Table 109

Table 110

[0122] As discussed, anti-hTfR:payload scFv fusion proteins (e.g., 31874B, 31863B, 69348, 69340, 69331, 69332, 69326, 69329, 69323, 69305, 69307, 12795B, 12798B, 12799B, 12801B, 12802B, 12803B, 12804B, 12805B, 12806B, 12807B, 12808B, 12809B, 12810B, 12811B, 12812B, 12813B, 12814B, 12815B, 12816B, 12817B, 12818B, 12819B, 12820B, 12821B, 12822B, 12823B, 12824B, 12825B, 12826B, 12827B, 12828B, 12829B, 12829B, 12829C, 12829D, 12829E, 12829F, 12829F, 12829F, 12829F, 12830B, 12830B, 12831B, 12831C, 12831D, 12831E, 12831F, 12831F, 12831F, 12831F, 12831F, 2808B, 12812B, 12816B, 12833B, 12834B, 12835B, 12847B, 12848B, 12843B, 12844B, 12845B, 12839B, 12841B, 12850B, 69261, or 69263) can be an scFv (e.g., V L and V H ), optionally connected to a linker, and optionally connected to a payload such as GAA or a variant thereof, e.g., (I) the optional signal peptide is the signal peptide from Mus musculus Rorl (e.g., consisting of the amino acids MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)); (II) scFv, (i) a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 222, 232, 242, 252, 482, 262, 272, 282, 292, 302, 483, or 312; and / or (ii) a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 297, 307, 488, 317, or 484; or or the scFv is (1) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 or 462 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 or 463 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (3) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 or 464 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (4) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 or 465 (or a variant thereof); (5) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 or 466 (or a variant thereof); (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 or 467 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 or 468 (or a variant thereof); (7) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 or 492 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 67 or 469 (or a variant thereof); (8) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 or 470 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 or 471 (or a variant thereof); (9) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (10) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 or 472 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (11) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (12) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 or 473 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 or 474 (or a variant thereof); (13) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof); (14) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (15) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 or 475 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 or 476 (or a variant thereof); (16) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (17) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 or 477 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); (18) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 or 478 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 or 479 (or a variant thereof); (20) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 or 480 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (21) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 or 481 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (22) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (24) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); (26) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 or 482 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof); (27) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (28) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 272 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 277 (or a variant thereof); (29) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 282 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 287 (or a variant thereof); (30) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 292 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 297 (or a variant thereof); (31) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 302 or 483 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 307 or 488 (or a variant thereof); (32) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 312 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 317 or 484 (or a variant thereof); or or the scFv is (a) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof), LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 9 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof); (b) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof); (c) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof); (d) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof); (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 49 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof); (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 53 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); (g) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 63 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof); (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 78 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 79 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80 (or a variant thereof); (i) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 85 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 89 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof); (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof); (l) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120 (or a variant thereof); (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 129 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof); (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); (o) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 149 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 183 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 184 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 188 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 189 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 190 (or a variant thereof); (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 193 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 (or a variant thereof); (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 203 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 204 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 (or a variant thereof); (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 214 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 218 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 219 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 220 (or a variant thereof); (w) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 223 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 224 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 228 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 229 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 230 (or a variant thereof); (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 233 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 234 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 235 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 238 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 239 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 240 (or a variant thereof); (y) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 243 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 244 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 245 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 248 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 249 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 250 (or a variant thereof); (z) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 253 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 254 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 255 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 (or a variant thereof); (aa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 263 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 264 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 265 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 268 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 269 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 270 (or a variant thereof); (ab) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 273 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 274 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 275 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 278 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 279 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 280 (or a variant thereof); (ac) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 283 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 284 (or a variant thereof), and HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 285 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 288 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 289 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 290 (or a variant thereof); (ad) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 293 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 294 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 295 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 298 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 299 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 300 (or a variant thereof); (ae) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 303 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 304 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 305 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 308 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 309 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 310 (or a variant thereof); and / or (af) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 313 (or a variant thereof); HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 314 (or a variant thereof), and an HCVR comprising an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 315 (or a variant thereof); LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 318 (or a variant thereof); LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 319 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 320 (or a variant thereof); or the scFv is (i) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2 or 462 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof); (ii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 12 or 463 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 17 (or a variant thereof); (iii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22 or 464 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof); (iv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 or 465 (or a variant thereof); (v) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 47 or 466 (or a variant thereof); (vi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 52 or 467 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 or 468 (or a variant thereof); (vii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62 or 492 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 67 or 469 (or a variant thereof); (viii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 72 or 470 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 or 471 (or a variant thereof); (ix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof); (x) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 92 or 472 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof); (xi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof); (xii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 112 or 473 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 or 474 (or a variant thereof); (xiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof); (xiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof); (xv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 or 475 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 147 or 476 (or a variant thereof); (xvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof); (xvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 162 or 477 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof); (xviii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof); (xix) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 182 or 478 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187 or 479 (or a variant thereof); (xx) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 192 or 480 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 197 (or a variant thereof); (xxi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 202 or 481 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207 (or a variant thereof); (xxii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 212 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 217 (or a variant thereof); (xxiii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 222 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227 (or a variant thereof); (xxiv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 232 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 237 (or a variant thereof); (xxv) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 242 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 247 (or a variant thereof); (xxvi) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 252 or 482 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 257 (or a variant thereof); (xxvii) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 262 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR comprising the amino acid sequence set forth...

Claims

1. An anti-transferrin receptor (TfR) antigen-binding protein, (i) HCVRs including HCDR1, HCDR2, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NOs: 222, 262, 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172, 182, 192, 202, 212, 232, 242, 252, 272, 282, 292, 302, or 312, and / or (ii) An LCVR comprising LCDR1, LCDR2, and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NOs: 227, 267, 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 237, 247, 257, 277, 287, 297, 307, or 317, An antigen-binding protein that is optionally fused to the payload.

2. (1) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 222, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 227, (2) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 262, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 267, (3) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 2, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 7, (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 12, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 17, (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 22, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 27, (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 32, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 37, (7) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 42, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 47, (8) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 52, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 57, (9) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 62, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 67, (10) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 72, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 77, (11) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 82, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 87, (12) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 92, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 97, (13) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 102, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 107, (14) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 112, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 117, (15) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 122, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 127, (16) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 132, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 137, (17) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 142, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 147, (18) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 152, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 157, (19) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 162, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 167, (20) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 172, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 177, (21) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 182, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 187, (22) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 192, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 197, (23) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 202, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 207, (24) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 212, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 217, (25) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 232, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 237, (26) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 242, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 247, (27) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 252, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 257, (28) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 272, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 277, (29) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 282, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 287, (30) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 292, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 297, (31) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 302, and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 307, and / or (32) The anti-TfR antigen-binding protein according to claim 1, comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 312, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO:

317.

3. (1) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 222, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 227, (2) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 262, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 267, (3) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 242, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 247, (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 132, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 137, (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 172, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 177, and / or (6) The anti-TfR antigen-binding protein according to claim 1, comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 272, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO:

277.

4. The anti-TfR antigen-binding protein according to claim 1, comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 222, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO:

227.

5. (a) HCVR comprising HCDR1 comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 223, HCDR2 comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 224, and HCDR3 comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 225, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 228, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

230. (b) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 263, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 264, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 265, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 268, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

270. (c) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 3, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 4, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 5, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 8, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

10. (d) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 13, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 14, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 15, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 18, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

20. (e) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 23, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 24, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 25, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 28, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

30. (f) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 33, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 34, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 35, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 38, LCDR2 containing the amino acid sequence DVS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

40. (g) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 43, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 44, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 45, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 48, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

50. (h) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 53, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 54, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 55, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 58, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

60. (i) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 63, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 64, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 65, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 68, LCDR2 containing the amino acid sequence SAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

70. (j) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 73, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 74, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 75, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 78, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

80. (k) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 83, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 84, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 85, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 88, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

90. (l) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 93, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 94, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 95, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 98, LCDR2 containing the amino acid sequence TTS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

100. (m) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 103, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 104, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 105, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 108, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

110. (n) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in Sequence ID No. 113, HCDR2 containing the amino acid sequence (or variant thereof) described in Sequence ID No. 114, and HCDR3 containing the amino acid sequence (or variant thereof) described in Sequence ID No. 115, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 118, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

120. (o) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 123, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 124, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 125, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 128, LCDR2 containing the amino acid sequence GSS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

130. (p) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 133, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 134, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 135, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 138, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

140. (q) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 143, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 144, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 145, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 148, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

150. (r) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 153, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 154, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 155, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 158, LCDR2 containing the amino acid sequence VAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

160. (s) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 163, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 164, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 165, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 168, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

170. (t) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 173, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 174, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 175, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 178, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

180. (u) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 183, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 184, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 185, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 188, LCDR2 containing the amino acid sequence LGS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

190. (v) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 193, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 194, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 195, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 198, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

200. (w) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 203, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 204, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 205, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 208, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

210. (x) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 213, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 214, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 215, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 218, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

220. (y) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 233, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 234, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 235, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 238, LCDR2 containing the amino acid sequence GAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

240. (z) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 243, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 244, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 245, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 248, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

250. (aa) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 253, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 254, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 255, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 258, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

260. (ab) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 273, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 274, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 275, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 278, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

280. (ac) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 283, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 284, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 285, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 288, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

290. (ad) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 293, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 294, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 295, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 298, LCDR2 containing the amino acid sequence GAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

300. (ae) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 303, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 304, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 305, LCVR including LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 308, LCDR2 containing the amino acid sequence LGS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 310, and / or (af) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 313, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 314, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 315, The anti-TfR antigen-binding protein according to claim 1, comprising LCVR, which includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 318, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

320.

6. (a) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 223, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 224, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 225, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 228, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

230. (b) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 263, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 264, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 265, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 268, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

270. (c) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 243, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 244, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 245, LCVR includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 248, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

250. (d) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 133, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 134, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 135, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 138, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO:

140. (e) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 173, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 174, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 175, LCVR including LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 178, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 180, and / or (f) HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 273, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 274, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 275, The anti-TfR antigen-binding protein according to claim 1, comprising LCVR, which includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 278, LCDR2 containing the amino acid sequence AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

280.

7. HCVR includes HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 223, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 224, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 225, The anti-TfR antigen-binding protein according to claim 1, comprising LCVR, which includes LCDR1 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 228, LCDR2 containing the amino acid AAS (or a variant thereof), and LCDR3 containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

230.

8. (i) an HCVR comprising the amino acid sequence (or a variant thereof) described in SEQ ID NO: 222, and an LCVR comprising the amino acid sequence (or a variant thereof) described in SEQ ID NO: 227 (ii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 262, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 267, (iii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 2, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 7, (iv) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 12, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 17, (v) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 22, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 27, (vi) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 32, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 37, (vii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 42, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 47, (viiii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 52, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 57, (ix) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 62, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 67, (x) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 72, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 77, (xi) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 82, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 87, (xii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 92, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 97, (xiii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 102, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 107, (xiv) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 112, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 117, (xv) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 122, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 127, (xvi) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 132, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 137, (xvii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 142, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 147, (xviiii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 152, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 157, (xix) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 162, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 167, (xx) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 172, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 177, (xxi) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 182, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 187, (xxii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 192, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 197, (xxiii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 202, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 207, (xxiv) HCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 212, and LCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 217, (xxv) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 232, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 237, (xxvi) HCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 242, and LCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 247, (xxvii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 252, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 257, (xxviiii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 272, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 277, (xxix) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 282, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 287, (xxx) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 292, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 297, (xxxi) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 302, LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 307, and / or (xxxii) The anti-TfR antigen-binding protein according to claim 1, comprising an HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 312 and an LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

317.

9. (i) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 222, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 227, (ii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 262, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 267, (iii) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 242, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 247, (iv) HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 132, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 137, (v) an HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 172, an LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 177, and / or (vi) The anti-TfR antigen-binding protein according to claim 1, comprising an HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 272 and an LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

277.

10. The anti-TfR antigen-binding protein according to claim 1, comprising HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 222, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

227.

11. The anti-TfR antigen-binding protein according to claim 1, wherein the transferrin receptor is a human transferrin receptor or a variant thereof.

12. The anti-TfR antigen-binding protein according to claim 1, which is an antibody or an antigen-binding fragment thereof.

13. The anti-TfR antigen-binding protein according to claim 1, which is Fab.

14. scFv, Optionally, the scFv and the payload are -(GGGGS) ｍ - Linked by a peptide linker (SEQ ID NO: 426), where m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, Optionally, the scFv variable region is -(GGGGGS) ｎ The anti-TfR antigen-binding protein according to claim 1, linked by a peptide linker (SEQ ID NO: 426), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

15. The anti-TfR antigen-binding protein according to claim 14, wherein the scFv comprises the amino acid sequence (or a variant thereof) described in SEQ ID NO: 443, the amino acid sequence (or a variant thereof) described in SEQ ID NO: 440, the amino acid sequence (or a variant thereof) described in SEQ ID NO: 429, the amino acid sequence (or a variant thereof) described in SEQ ID NO: 433, the amino acid sequence (or a variant thereof) described in SEQ ID NO: 442, or the amino acid sequence (or a variant thereof) described in SEQ ID NO:

438.

16. The anti-TfR antigen-binding protein according to claim 14, wherein the scFv comprises the amino acid sequence (or a variant thereof) described in SEQ ID NO:

443.

17. An anti-TfR antigen-binding protein, (a) Epitope containing sequence LLNE (sequence number 525) and / or epitope containing sequence TYKEL (sequence number 507), (b) Epitopes containing the sequence DSTDFTGT (SEQ ID NO: 526), ​​and / or epitopes containing the sequence VKHPVTGQF (SEQ ID NO: 527), and / or epitopes containing the sequence IERIPEL (SEQ ID NO: 528), (c) Epitope containing sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529), (d) Epitope containing sequence FEDL (sequence number 519), (e) Epitope containing sequence IVDKNGRL (SEQ ID NO: 530), (f) Epitope containing sequence IVDKNGRLVY (SEQ ID NO: 531), (g) Epitope containing sequence DQTKF (sequence number 532), (h) Epitope containing sequence LVENPGGY (sequence number 533), and / or epitope containing sequence PIVNAELSF (sequence number 534), and / or epitope containing sequence PYLGTTMDT (sequence number 535), (i) an epitope containing the sequence LLINENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or an epitope containing the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or an epitope containing the sequence TYKEL (SEQ ID NO: 507), (j) Epitope containing sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or epitope containing sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or epitope containing sequence LIERIPELNKVARAAAAE (SEQ ID NO: 510), (k) Epitope containing sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511), (l) Epitope containing sequence GTKKDFEDL (sequence number 512), (m) Epitope containing sequence SVIIVDKNGRRLVYLVENPGGYVAYSK (SEQ ID NO: 513), (n) Epitopes containing the sequence LLINENSYVPREAGSQKDEN (SEQ ID NO: 514), and / or epitopes containing the sequence DQTKFPIVNAEL (SEQ ID NO: 515), and / or epitopes containing the sequence TYKELIERIPELNK (SEQ ID NO: 516), (o) Epitope containing sequence LLINENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitope containing sequence TYKELIERIPELNK (SEQ ID NO: 516), (p) Epitope containing sequence SVIIVDKNGRRLVYLVENPGGYVAY (SEQ ID NO: 517), (q) Epitope containing sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or epitope containing sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), (r) Epitopes containing the sequence LLINENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or epitopes containing the sequence LVENPGGYVAYSKAAATVTGKL (SEQ ID NO: 520), and / or epitopes containing the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or epitopes containing the sequence ISRAAAAEKL (SEQ ID NO: 522), and / or epitopes containing the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or epitopes containing the sequence FCEDTDYPYLGTTTMDT (SEQ ID NO: 524), (s) Epitope contained in or overlapping with sequence LLINENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or epitope contained in or overlapping with sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506), and / or epitope contained in or overlapping with sequence TYKEL (SEQ ID NO: 507), (t) Epitopes contained in or overlapping with sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or epitopes contained in or overlapping with sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or epitopes contained in or overlapping with sequence LIERIPELNKVARAAAAE (SEQ ID NO: 510), (u) Epitope contained in or overlapping with sequence LNENSYVPREAGSQKDENL (sequence number 511), (v) Epitopes contained in or overlapping with sequence GTKKDFEDL (sequence number 512), (w) Epitopes contained in or overlapping with sequence SVIIVDKNGRRLVYLVENPGGYVAYSK (SEQ ID NO: 513), (x) Epitope contained in or overlapping with sequence LLINENSYVPREAGSQKDEN (SEQ ID NO: 514), and / or epitope contained in or overlapping with sequence DQTKFPIVNAEL (SEQ ID NO: 515), and / or epitope contained in or overlapping with sequence TYKELIERIPELNK (SEQ ID NO: 516), (y) Epitope contained in or overlapping with sequence LLINENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitopes contained in or overlapping with sequence TYKELIERIPELNK (SEQ ID NO: 516), (z) Epitopes contained in or overlapping with sequence SVIIVDKNGRRLVYLVENPGGYVAY (SEQ ID NO: 517), (aa) Epitope contained in or overlapping with sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or epitopes contained in or overlapping with sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518), (bb) Epitope contained in or overlapping with sequence LLINENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or epitope contained in or overlapping with sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO: 520), and / or epitope contained in or overlapping with sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or sequence ISRAAAA An antigen-binding protein that binds to one or more epitopes of hTfR, selected from the epitopes contained in or overlapping with EKL (SEQ ID NO: 522), and / or the epitopes contained in or overlapping with sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or the epitopes contained in or overlapping with sequence FCEDTDYPYLGTTTMDT (SEQ ID NO: 524).

18. The aforementioned antigen-binding protein (a) an epitope consisting of sequence LLNE (sequence number 525) and / or an epitope consisting of sequence TYKEL (sequence number 507), (b) an epitope consisting of sequence DSTDFTGT (sequence number 526), ​​and / or an epitope consisting of sequence VKHPVTGQF (sequence number 527), and / or an epitope consisting of sequence IERIPEL (sequence number 528), (c) Epitope consisting of sequence LNENSYVPREAGSQKDEN (Sequence ID 529), (d) Epitope consisting of sequence FEDL (sequence number 519), (e) Epitope consisting of sequence IVDKNGRL (sequence number 530), (f) Epitope consisting of sequence IVDKNGRLVY (sequence number 531), (g) Epitope consisting of sequence DQTKF (sequence number 532), (h) An epitope consisting of the sequence LVENPGGY (sequence number 533), and / or an epitope consisting of the sequence PIVNAELSF (sequence number 534), and / or an epitope consisting of the sequence PYLGTTMDT (sequence number 535), (i) an epitope consisting of the sequence LLINENSYVPREAGSQKDENLAL (sequence number 505), and / or an epitope consisting of the sequence IYMDQTKFPIVNAEL (sequence number 506), and / or an epitope consisting of the sequence TYKEL (sequence number 507), (j) An epitope consisting of the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508), and / or an epitope consisting of the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509), and / or an epitope consisting of the sequence LIERIPELNKVARAAAAE (SEQ ID NO: 510), (k) Epitope consisting of sequence LNENSYVPREAGSQKDENL (sequence number 511), (l) Epitope consisting of sequence GTKKDFEDL (sequence number 512), (m) Epitope consisting of sequence SVIIVDKNGRRLVYLVENPGGYVAYSK (Sequence ID 513), (n) an epitope consisting of the sequence LLINENSYVPREAGSQKDEN (sequence number 514), and / or an epitope consisting of the sequence DQTKFPIVNAEL (sequence number 515), and / or an epitope consisting of the sequence TYKELIERIPELNK (sequence number 516), (o) An epitope consisting of the sequence LLINENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516), (p) Epitope consisting of sequence SVIIVDKNGRRLVYLVENPGGYVAY (Sequence ID 517), (q) an epitope consisting of sequence IYMDQTKFPIVNAEL (sequence number 506) and / or an epitope consisting of sequence FGNMEGDCPSDWKTDSTCRM (sequence number 518), and (r) The anti-TfR antigen-binding protein according to claim 17, comprising an antibody or antigen-binding fragment thereof that binds to one or more epitopes of hTfR selected from the epitope consisting of the sequence LLINENSYVPREAGSQKDENLAL (SEQ ID NO: 505), and / or the epitope consisting of the sequence LVENPGGYVAYSKAAATVTGKL (SEQ ID NO: 520), and / or the epitope consisting of the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521), and / or the epitope consisting of the sequence ISRAAAAEKL (SEQ ID NO: 522), and / or the epitope consisting of the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523), and / or the epitope consisting of the sequence FCEDTDYPYLGTTTMDT (SEQ ID NO: 524).

19. The anti-TfR antigen-binding protein according to claim 17, wherein the anti-TfR antigen-binding protein is selected from a humanized antibody or its antigen-binding fragment, a human antibody or its antigen-binding fragment, a mouse antibody or its antigen-binding fragment, a chimeric antibody or its antigen-binding fragment, a monovalent Fab', a bivalent Fab2, an F(ab)'3 fragment, a single-chain fragment variable region (scFv), a bis-scFv, (scFv)2, a diabody, a bivalent antibody, a one-arm antibody, a minibody, a nanobody, a triabody, a tetrabody, a disulfide-stabilized Fv protein (dsFv), a single-domain antibody (sdAb), an Ig NAR, a single heavy-chain antibody, a bispecific antibody or its binding fragment, a bispecific T-cell engager (BiTE), a triplicate antibody, or a chemically modified derivative thereof.

20. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, fused to a payload.

21. A fusion protein comprising an anti-TfR antigen-binding protein fused to a payload, wherein the anti-TfR antigen-binding protein has a K content of approximately 41 nM. Ｄ Alternatively, a fusion protein that binds to the human transferrin receptor with stronger affinity.

22. The aforementioned anti-TfR antigen-binding protein has a K content of approximately 3 nM. Ｄ Alternatively, the anti-TfR antigen-binding protein may bind to the human transferrin receptor with stronger affinity, or the anti-TfR antigen-binding protein may have a K2 of approximately 0.45 nM to 3 nM. Ｄ A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, which binds to a human transferrin receptor, fused to a payload, or the fusion protein according to claim 21.

23. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload which is one or more antibodies or antigen-binding fragments thereof, proteins, enzymes, or viral vectors containing one or more polynucleotides or oligonucleotides; or human alpha-glucosidase polypeptide (hGAA) or a variant thereof; or the fusion protein according to claim 21.

24. The payload is a lysosomal storage disease treatment agent (LSD-TA), and optionally, the payload may be miglustat, eliglustat, α-galactosidase A; ceramidase; β-glucosidase; saposin-C activator; acid sphingomyelinase; β-galactosidase; β-hexosaminidase A and B; β-hexosaminidase A; GM2-activator protein; GM3 synthase; arylsulfatase A; sphingolipid activator; α-iduronidase; iduronidase-2-sulfatase; heparan N-sulf LSD-TA is a lipase that is either an atase; N-acetyl-α-glucosaminidase; acetyl-CoA; α-glucosamide N-acetyltransferase; N-acetylglucosamine-6-sulfatase; N-acetylgalactosamine-6-sulfate-sulfatase; β-galactosidase; N-acetylgalactosamine-4-sulfatase (arylsulfatase B); β-glucuronidase; hylauronidase; α-flucosidase 2; or lysosomal acid lipase. A fusion protein comprising a TfR antigen-binding protein according to any one of claims 1 to 19, which is a polypeptide or a polypeptide encoded by a human gene specified in any one of Tables C to N, or a variant thereof, fused to a payload, or the fusion protein according to claim 21.

25. Heavy chain variable region (HCVR or V Ｈ ) and the light chain variable region (LCVR or V Ｌ ) and, A fusion protein comprising an anti-transferrin receptor (TfR) antigen-binding protein fused to an alpha-glucosidase polypeptide (GAA), Said V Ｈ and V Ｌ Fab having has a K of about 0.65 nM Ｄ or binds to the human transferrin receptor with higher affinity, The fusion protein, when administered to a mouse expressing the human transferrin receptor in its brain, achieves in the mouse a molar ratio of approximately 1:1 or higher of mature GAA protein to serum GAA protein in the brain, normalized to the ratio in a mouse expressing the mouse transferrin receptor administered with 8D3.

26. The fusion protein according to claim 25, wherein the anti-TfR antigen-binding protein is Fab or a single-chain fragment variable region (scFv).

27. The fusion protein according to claim 26, wherein the fusion protein comprises the amino acid sequence (or a variant thereof) described in SEQ ID NO: 408, or the amino acid sequence (or a variant thereof) described in SEQ ID NO:

405.

28. The fusion protein according to claim 26 or 27, wherein the fusion protein comprises the amino acid sequence (or a variant thereof) described in SEQ ID NO:

408.

29. The fusion protein according to claim 25, wherein the anti-TfR antigen-binding protein is an antibody or an antigen-binding fragment thereof.

30. A fusion protein comprising the anti-TfR antigen-binding protein according to any one of claims 1 to 19, fused to a payload, wherein the anti-TfR antigen-binding protein is an scFv containing a domain arranged in the following orientation: N-heavy chain variable region-light chain variable region-GAA protein-C, or the fusion protein according to claim 21 or 25.

31. A fusion protein comprising the anti-TfR antigen-binding protein according to any one of claims 1 to 19, fused to a payload, wherein the anti-TfR antigen-binding protein is an scFv containing a domain arranged in the following orientation: N-light chain variable region-heavy chain variable region-GAA protein-C, or the fusion protein according to claim 21 or 25.

32. A fusion protein comprising the anti-TfR antigen-binding protein according to any one of claims 1 to 19, wherein the anti-TfR antigen-binding protein is scFv, and the scFv and GAA are linked by a peptide linker, fused to a payload, or the fusion protein according to claim 21 or 25.

33. The above scFv and GAA are -(GGGGGS). ｍ The fusion protein according to claim 32, linked by a peptide linker (SEQ ID NO: 426), wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

34. A fusion protein comprising the anti-TfR antigen-binding protein according to any one of claims 1 to 19, wherein the anti-TfR antigen-binding protein is scFv, and the scFv variable region is connected by a peptide linker, fused to a payload, or the fusion protein according to claim 21 or 25.

35. The fusion protein according to claim 34, wherein the scFv variable region is linked by a peptide linker -(GGGGS)n-(SEQ ID NO: 426), where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

36. The aforementioned fusion protein is approximately 1 × 10 ７ M's K Ｄ A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, which binds to a human transferrin receptor with higher affinity, fused to a payload, or the fusion protein according to claim 21 or 25.

37. (i) HCVRs including HCDR1, HCDR2, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NOs: 222, 262, 2, 462, 12, 463, 22, 464, 32, 42, 52, 467, 62, 492, 72, 470, 82, 92, 472, 102, 112, 473, 122, 132, 142, 475, 152, 162, 477, 172, 182, 478, 192, 480, 202, 481, 212, 232, 242, 252, 482, 272, 282, 292, 302, 483, or 312, and / or (ii) A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, fused to a payload, comprising an LCVR comprising an LCVR containing an amino acid sequence (or variant thereof) described in SEQ ID NOs: 227, 267, 7, 17, 27, 37, 465, 47, 466, 57, 468, 67, 469, 77, 471, 87, 97, 107, 117, 474, 127, 137, 147, 476, 157, 167, 177, 187, 479, 197, 207, 217, 237, 247, 257, 277, 287, 297, 307, 488, 317, or 484, comprising an LCVR comprising LCDR1, LCDR2, and LCDR3, or a fusion protein according to claim 21 or 25.

38. Heavy chain variable region (V Ｈ ) and light chain variable region (V Ｌ ), and scFv comprising alpha-glucosidase polypeptide (GAA), and the V Ｈ , V Ｌ , and GAA, (i) V Ｌ -V Ｈ -GAA、 (ii) V Ｈ -V Ｌ -GAA、 (iii) V Ｌ - [(GGGGS) ３ (Sequence ID 538) - V Ｈ - [(GGGGS) ２ (Sequence ID 537) - GAA, or (iv) V Ｈ - [(GGGGS) ３ (Sequence ID 538) - V Ｌ - [(GGGGS) ２ A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, arranged in the manner of (Sequence ID 537)-GAA, fused to a payload, or the fusion protein according to claim 21 or 25.

39. Sequence IDs 392-423, Sequence ID 321 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (Sequence ID 500) signal sequence), Sequence ID 322 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (Sequence ID 500) signal sequence), Sequence ID 323 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (Sequence ID 500) signal sequence) A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, comprising the amino acid sequence described in (0) lacking a signal sequence, and SEQ ID NO: 324 (optionally lacking the N-terminal MHRPRRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), or a variant thereof, selected from the group consisting of the above, or the fusion protein according to claim 21 or 25.

40. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, or the fusion protein according to claim 21 or 25, wherein, if the antigen-binding protein is not fused to a GAA polypeptide, it does not block more than 50% of the binding of the human transferrin receptor C-terminal fragment to human holo-transferrin that occurs in the absence of such a single-chain fragment variable region (scFv), antibody, or antigen-binding fragment.

41. The fusion protein according to claim 40, wherein the blocking is measured in an enzyme-linked immunosorbent assay (ELISA) plate assay, in which the binding of the extracellular domain of the human transferrin receptor fused to the His6-myc-myc tag is pre-bound to the scFv, antibody, or antigen-binding fragment, and then contacts holotransferrin immobilized on the surface of the plate by binding of an anti-holotransferrin antibody bound to the plate.

42. The fusion protein according to claim 40, wherein the binding of the holo-transferrin to the extracellular domain of the human transferrin receptor in the absence of the scFv, antibody, or antigen-binding fragment is measured at a concentration of the extracellular domain of the human transferrin receptor of about 300 pM.

43. The following features: - Affinity (K) for binding to human TfR at 25°C in a surface plasmon resonance format with an affinity of approximately 41 nM or higher. Ｄ ), - Affinity (K) for binding to monkey TfR at 25°C in a surface plasmon resonance format, with an affinity of approximately 0 nM (no detectable binding) or higher. Ｄ ), - K for coupling to sal TfR at 25°C in the surface plasmon resonance format from 0 to 278 Ｄ / Regarding K binding to human TfR Ｄ The ratio of ] - Approximately 3-13% of the hTfR binding to human holo-Tf in the Fab format (IgG1), • Approximately 6-13% of scFv(V) Ｋ -V Ｈ Blocking of hTfR binding to human holo-Tf in the ) format, • Approximately 11-26% of scFv(V) Ｈ -V Ｌ Blocking of hTfR binding to human holo-Tf in the ) format, In the case of the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally, lacking functional endogenous GAA), it exhibits a ratio of approximately 1-2 mature hGAA proteins in the brain (normalized to the positive control 8D3:GAA scFv). In the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally, lacking functional endogenous GAA), it resulted in a ratio of approximately 0.1–1.2 mature hGAA protein in the brain parenchyma (normalized to the positive control 8D3:GAA scFv). In the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally, lacking functional endogenous GAA), the quadriceps femoris muscle exhibits a mature hGAA protein ratio of approximately 0.67, 1.80, 1.78, or 7.74 (approximately 1-2) (normalized to the positive control 8D3:GAA scFv). In the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally, lacking functional endogenous GAA), it resulted in a ratio of approximately 0.1–1.2 mature hGAA protein in the brain parenchyma (normalized to the positive control 8D3:GAA scFv). - In the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA), it delivers mature hGAA protein to the serum, liver, cerebrum, cerebellum, spinal cord, heart, and / or quadriceps femoris muscle. - In the anti-hTfR scFv:hGAA format, when administered to mice expressing the human transferrin receptor (optionally, lacking functional endogenous GAA), it reduces glycogen stored in the cerebrum, cerebellum, spinal cord, heart, and / or quadriceps femoris muscle. - When the TfR antigen-binding protein fused to GAA is included, it reduces glycogen levels in the cerebellum of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least approximately 90% compared to untreated mice. - When the TfR antigen-binding protein fused to GAA is included, it reduces glycogen levels in the quadriceps femoris muscle of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least approximately 89% compared to untreated mice, and / or A fusion protein or anti-TfR antigen-binding protein having one or more of the following characteristics: • When administered to mice expressing the human transferrin receptor, it does not induce abnormal iron homeostasis.

44. A pharmaceutical composition comprising a fusion protein containing an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, or a fusion protein according to any one of claims 21, 25 and 43, or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43, and a pharmaceutically acceptable carrier.

45. A composition or kit comprising a fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, fused to a payload in association with a further therapeutic agent, or a fusion protein according to any one of claims 21, 25 and 43, or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43, or a pharmaceutical composition thereof.

46. The composition or kit according to claim 45, wherein the further therapeutic agent is selected from alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), avalglucosidase alfa, revalbuterol, antibacterial agents, cortisone, prednisone, bisphosphonates, and palivizumab.

47. The composition or kit according to claim 45, wherein the further therapeutic agent is selected from beta-2-adrenergic agonists, steroids, bisphosphonates, infectious disease treatments, vaccines, and pneumococcal vaccines.

48. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19, which is fused to a payload bound to a human transferrin receptor polypeptide or an antigenic fragment thereof, or a complex comprising a fusion protein according to any one of claims 21, 25 and 43, or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43.

49. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, or an isolated polynucleotide encoding a fusion protein according to any one of claims 21, 25 and 43, or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43.

50. ENTER 221, 226, 261, 266, 1, 6, 11, 16, 21, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 76, 81, 86, 91, 96, 101, 106, 111, 116, 121, 126, 131, 136, 141, 146, 151, 156, 161, 166, 171, The polynucleotide according to claim 49, comprising the nucleotide sequence described in 176, 181, 186, 191, 196, 201, 206, 211, 216, 231, 236, 241, 246, 251, 256, 271, 276, 281, 286, 291, 296, 301, 306, 311, and / or 316.

51. (1) Nucleotide sequences according to Sequence ID No. 221 and Sequence ID No. 226, (2) Nucleotide sequences described in SEQ ID NO: 261 and SEQ ID NO: 266, (3) Nucleotide sequences described in SEQ ID NO: 1 and SEQ ID NO: 6, (4) Nucleotide sequences described in SEQ ID NO: 11 and SEQ ID NO: 16, (5) Nucleotide sequences described in Sequence ID No. 21 and Sequence ID No. 26, (6) Nucleotide sequences described in SEQ ID NO: 31 and SEQ ID NO: 36, (7) Nucleotide sequences described in SEQ ID NO: 41 and SEQ ID NO: 46, (8) Nucleotide sequences described in Sequence ID No. 51 and Sequence ID No. 56, (9) Nucleotide sequences described in SEQ ID NO: 61 and SEQ ID NO: 66, (10) Nucleotide sequences described in SEQ ID NO: 71 and SEQ ID NO: 76, (11) Nucleotide sequences described in SEQ ID NO: 81 and SEQ ID NO: 86, (12) Nucleotide sequences described in SEQ ID NO: 91 and SEQ ID NO: 96, (13) Nucleotide sequences described in SEQ ID NO: 101 and SEQ ID NO: 106, (14) Nucleotide sequences described in SEQ ID NO: 111 and SEQ ID NO: 116, (15) Nucleotide sequences described in SEQ ID NO: 121 and SEQ ID NO: 126, (16) Nucleotide sequences described in SEQ ID NO: 131 and SEQ ID NO: 136, (17) Nucleotide sequences described in SEQ ID NO: 141 and SEQ ID NO: 146, (18) Nucleotide sequences described in SEQ ID NO: 151 and SEQ ID NO: 156, (19) Nucleotide sequences described in SEQ ID NO: 161 and SEQ ID NO: 166, (20) Nucleotide sequences described in SEQ ID NO: 171 and SEQ ID NO: 176, (21) Nucleotide sequences described in SEQ ID NO: 181 and SEQ ID NO: 186, (22) Nucleotide sequences described in SEQ ID NO: 191 and SEQ ID NO: 196, (23) Nucleotide sequences described in SEQ ID NO: 201 and SEQ ID NO: 206, (24) Nucleotide sequences described in SEQ ID NO: 211 and SEQ ID NO: 216, (25) Nucleotide sequences described in Sequence ID No. 231 and Sequence ID No. 236, (26) Nucleotide sequences described in SEQ ID NO: 241 and SEQ ID NO: 246, (27) Nucleotide sequences described in Sequence ID No. 251 and Sequence ID No. 256, (28) Nucleotide sequences described in SEQ ID NO: 271 and SEQ ID NO: 276, (29) Nucleotide sequences described in Sequence ID No. 281 and Sequence ID No. 286, (30) Nucleotide sequences described in Sequence ID No. 291 and Sequence ID No. 296, (31) The nucleotide sequences described in SEQ ID NO: 301 and SEQ ID NO: 306, and / or (32) The polynucleotide according to claim 49, comprising the nucleotide sequences described in SEQ ID NO: 311 and SEQ ID NO:

316.

52. A vector comprising the polynucleotide described in claim 49.

53. A host cell comprising a vector comprising a fusion protein or a fusion protein according to any one of claims 21, 25 and 43, which comprises an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; an anti-TfR antigen-binding protein according to any one of claims 1 to 19 or an anti-TfR antigen-binding protein according to claim 43; an isolated polynucleotide encoding an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43, which comprises a fusion protein, a fusion protein according to any one of claims 21, 25 and 43, which comprises an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; or an isolated polynucleotide encoding an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43.

54. The host cell according to claim 53, which is a Chinese hamster ovary (CHO) cell.

55. A method for producing a fusion protein or a fusion protein or an anti-TfR antigen-binding protein according to any one of claims 1 to 19, which is fused to a payload, the method comprising culturing a host cell containing the fusion protein and the anti-TfR antigen-binding protein in a culture medium under conditions favorable for the expression of the fusion protein or the anti-TfR antigen-binding protein.

56. (a) The step of introducing the polynucleotide into a host cell, (b) A step of culturing the host cells under conditions favorable for the expression of the fusion protein or anti-TfR antigen-binding protein, (c) Optionally, the step of isolating the fusion protein or anti-TfR antigen-binding protein from the culture medium and / or host cells, (d) The method of claim 55, comprising the optional step of chemically conjugating the anti-TfR antigen-binding protein to the payload.

57. A fusion protein or anti-TfR antigen-binding protein which is a product of the method according to claim 55.

58. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; a fusion protein according to any one of claims 21, 25 and 43 A container or injection device comprising a fusion protein or anti-TfR antigen-binding protein, which is a product of a method for producing an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43; or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, wherein the method comprises culturing a host cell containing a polynucleotide encoding the fusion protein or anti-TfR antigen-binding protein in a culture medium under conditions favorable for the expression of the fusion protein or anti-TfR antigen-binding protein.

59. A fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; a fusion protein according to any one of claims 21, 25 and 43 A fusion protein or anti-TfR antigen-binding protein which is a product of a method for producing an anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 43; or an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload, wherein the method comprises culturing a host cell containing the fusion protein or anti-TfR antigen-binding protein in a culture medium under conditions favorable for the expression of the fusion protein or anti-TfR antigen-binding protein, the composition being administered to a subject, the administration of the composition comprising introducing the protein into the subject's body.

60. The composition according to claim 59, characterized in that the fusion protein or anti-TfR antigen-binding protein is introduced parenterally into the body of the subject.

61. A composition for treating or preventing lysosomal storage diseases in subjects requiring such treatment, wherein the composition comprises a fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; a fusion protein according to any one of claims 21, 25 and 43; or a fusion protein or anti-TfR antigen-binding protein which is a product of a method for producing an anti-TfR antigen-binding protein according to any one of claims 1 to 19 or 43 fused to a payload, wherein the method comprises culturing a host cell containing a polynucleotide encoding the fusion protein or anti-TfR antigen-binding protein in a culture medium under conditions favorable for the expression of the fusion protein or anti-TfR antigen-binding protein, and the payload is a lysosomal storage disease treatment agent (LSD-TA).

62. The aforementioned lysosomal storage diseases include Fabry disease, Faber lipogranuloma, Gaucher disease type I, Gaucher disease (type II or III), Niemann-Pick disease (type A or B), GM1 gangliosidosis, GM2 gangliosidosis (Sandhoff disease), GM2 gangliosidosis (Tey-Sachs disease), GM2 gangliosidosis (GM2 activator deficiency), GM3 gangliosidosis, metachromatic leukodystrophy, sphingolipid activator deficiency, MPS I (Schaye, Haller-Schaye, or Haller disease), MPS II (Hunter disease), MPS IIIA (Sanfilippo type A), MPS IIIB (Sanfilippo type B), MPS IIIC (Sanfilippo type C), MPS IID (Sanfilippo type D), MPS IVA (Morcchio syndrome type A), MPS The composition according to claim 61, wherein the condition is IVB (Morcchio syndrome type B), MPS VI (Maroto-ramy), MPS VII (Sleigh disease), MPS IX, Pompe disease (glycostored storage disease type II), or lysosomal acid lipase deficiency (LAL-D, Wolmann disease).

63. The composition according to claim 61, wherein one or more signs or symptoms of LSD in the subject are alleviated after administration of the fusion protein or anti-TfR antigen-binding protein.

64. A composition for treating or preventing glycogen storage disease (GSD) in a subject requiring such treatment, comprising a fusion protein comprising an anti-TfR antigen-binding protein according to any one of claims 1 to 19 fused to a payload; a fusion protein according to any one of claims 21, 25 and 43; or a fusion protein or anti-TfR antigen-binding protein which is a product of a method for producing a fusion protein or anti-TfR antigen-binding protein according to any one of claims 1 to 19 or 43 fused to a payload, wherein the method comprises culturing a host cell containing a polynucleotide encoding the fusion protein or anti-TfR antigen-binding protein in a culture medium under conditions favorable for the expression of the fusion protein or anti-TfR antigen-binding protein.

65. The composition according to claim 64, wherein the glycogen storage disease is Pompe disease.

66. The composition according to claim 65, wherein the Pompe disease is the classic infantile form of Pompe disease.

67. The composition according to claim 65, wherein the Pompe disease is a non-classical infantile form of Pompe disease.

68. The composition according to claim 65, wherein the Pompe disease is a late-onset form of Pompe disease.

69. The aforementioned subject is, The composition according to claim 64, having a GAA genotype selected from the group consisting of ASP91ASN;MET318THR;GLU521LYS;GLY643ARG;ARG725TRP;IVS1AS,T-G,-13;LYS903DEL;LEU299ARG;SER529VAL;ASP645GLU;GLU689LYS;EX18DEL;PRO545LEU;I-BPDEL,525T;ARG854TER;ALA237VAL;GLY293ARG; and IVS6AS,G-C,-1.

70. The composition according to claim 64, characterized in that the subject is administered the fusion protein in a state associated with a further therapeutic agent.

71. The composition according to claim 70, wherein the further therapeutic agent is selected from alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), avalglucosidase alfa, revalbuterol, antibacterial agents, cortisone, prednisone, bisphosphonates, and palivizumab.

72. The composition according to claim 70, wherein the further therapeutic agent is selected from beta-2-adrenergic agonists, steroids, bisphosphonates, infectious disease treatments, vaccines, and pneumococcal vaccines.

73. The subject is under one year old, - Difficulty eating and not gaining weight, - Insufficient control of the head and neck, - Rolling over and sitting up later than expected, ・Difficulty breathing, ・Lung infection, - Enlarged and thickened heart Heart defect, - Enlarged liver, and The composition according to claim 64, which is used to describe symptoms selected from an enlarged tongue.

74. The subject is an adult, - Weakness of the legs, torso, and / or arms, ·shortness of breath, ・Lung infection, ・Difficulty breathing during sleep, ・Spinal curvature, - Enlarged liver, - Enlarged tongue, and The composition according to claim 64, which is used to describe symptoms selected from joint stiffness.

75. The composition according to claim 64, wherein one or more signs or symptoms of GSD in the subject are alleviated after administration of the fusion protein or anti-TfR antigen-binding protein.

76. A composition for use in a method for delivering a payload to a target tissue or cell type in the body, wherein the composition comprises an anti-TfR antigen-binding protein fused to the payload.

77. The composition according to claim 76, wherein the payload is one or more antibodies or antigen-binding fragments thereof, proteins, enzymes, or viral vectors, each containing one or more polynucleotides or oligonucleotides.

78. The composition according to claim 76 or 77, wherein the payload is a human GAA protein or a variant thereof.

79. The composition according to claim 76 or 77, wherein the tissue is the brain / spinal cord / CNS, eye, skeletal muscle, adipose tissue, blood / bone marrow, breast, lung / bronchus, colon, uterus, esophagus, heart, kidney, liver, lymph node, ovary, pancreas, placenta, prostate, rectum, skin, peripheral blood mononuclear cells (PBMCs), small intestine, spleen, stomach, testis, peripheral nervous system, and / or bone / cartilage / joint.

80. The cell type and the tissue associated with the cell type are Table 299-1 Table 299-2 Table 299-3 Table 299-4 The composition according to claim 76 or 77.

81. The composition according to claim 76 or 77, wherein the method comprises puncturing the body of the subject with the needle of a syringe and injecting the anti-TfR antigen-binding protein fused to the payload into the body of the subject.

82. The composition according to claim 76 or 77, wherein the subject is suffering from a muscle atrophy, metabolic disease, sarcopenia, or cachexia.

83. A composition for use in a method for expressing a fusion protein in cells, the fusion protein comprising an anti-TfR antigen-binding protein fused to a payload, wherein the method is (a) Administering to the cells a gene therapy vector comprising an isolated polynucleotide according to claim 49, wherein the isolated polynucleotide encodes the fusion protein, (b) To enable the integration of the isolated polynucleotide into the genomic locus of the cell, (c) A composition comprising enabling the cells to produce the fusion protein.

84. The composition according to claim 83, wherein the method further comprises administering a nuclease agent, or one or more polynucleotides encoding the nuclease agent, to the cells, wherein the nuclease agent cleaves a nuclease target site in the genomic locus, and the isolated polynucleotide is incorporated into the genomic locus.

85. The composition according to claim 84, wherein the nuclease agent comprises a clustered regular interval short palindromic repeat (CRISPR) / CRISPR-related (Cas) system, a zinc finger nuclease (ZFN), or a transcription activator-like effector nuclease (TALEN).

86. The composition according to claim 83, wherein the cells are present in the target in vivo.

87. The composition according to claim 83, wherein the cells are present in ex vivo.

88. The composition according to claim 83, wherein the gene therapy vector is a viral vector, a naked polynucleotide, or a polynucleotide complex, and optionally the polynucleotide complex is a lipid nanoparticle containing the polynucleotide.

89. The composition according to claim 83, wherein the gene therapy vector is a viral vector selected from the group consisting of retroviruses, adenoviruses, herpes simplex viruses, poxviruses, vaccinia viruses, lentiviruses, or adeno-associated viruses.

90. The composition according to claim 83, wherein the gene therapy vector is an adeno-associated virus (AAV) vector, and optionally the gene therapy vector is an AAV2 / 8 chimera and / or a pseudo-AAV for liver.

91. The composition according to claim 83, wherein the genomic locus is a safe harbor locus.

92. The composition according to claim 91, wherein the genomic locus is located at or near a locus selected from the group consisting of the EESYR locus, the SARS locus, positions 188,083,272 on human chromosome 1 or its non-human mammalian ortholog, positions 3,046,320 on human chromosome 10 or its non-human mammalian ortholog, positions 67,328,980 on human chromosome 17 or its non-human mammalian ortholog, adeno-associated virus site 1 (AAVS1) on a chromosome, a naturally occurring integration site of the AAV virus on human chromosome 19 or its non-human mammalian ortholog, the chemokine receptor 5 (CCR5) gene, the chemokine receptor gene encoding the HIV-1 coreceptor, the mouse Rosa26 locus or its non-mouse mammalian ortholog, and the albumin (alb) locus.

93. The composition according to claim 83, wherein the cells are human cells.

94. The composition according to claim 83, wherein the cells are liver cells.

95. An anti-transferrin receptor (TfR) antigen-binding protein comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 222, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or variant thereof) described in SEQ ID NO: 227, An antigen-binding protein that is optionally fused to the payload.

96. An HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 223, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 224, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 225, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 228, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 230, The anti-TfR antigen-binding protein according to claim 95, comprising:

97. The anti-TfR antigen-binding protein according to claim 95, comprising HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 222, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

227.

98. An anti-transferrin receptor (TfR) antigen-binding protein comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 262, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 267, An antigen-binding protein that is optionally fused to the payload.

99. An HCVR comprising HCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 263, HCDR2 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 264, and HCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 265, LCVR includes LCDR1 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 268, LCDR2 containing the amino acid sequence AAS (or variant thereof), and LCDR3 containing the amino acid sequence (or variant thereof) described in SEQ ID NO: 270, The anti-TfR antigen-binding protein according to claim 98, comprising:

100. The anti-TfR antigen-binding protein according to claim 98, comprising HCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO: 262, and LCVR containing the amino acid sequence (or a variant thereof) described in SEQ ID NO:

267.

101. The anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 95 to 100, wherein the anti-TfR antigen-binding protein comprises a bivalent antibody.

102. The anti-TfR antigen-binding protein according to any one of claims 1 to 19 and 95 to 100, wherein the anti-TfR antigen-binding protein comprises a one-arm antibody.

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