Anti-TFR: payload fusions and methods of use thereof

Abstract

The present disclosure provides, in part, an anti-human transferrin receptor antigen binding protein, and a fusion protein comprising an anti-human transferrin receptor antigen binding protein (e.g., in the form of scFv, Fab, or an antibody) and a payload capable of fusion therewith, for delivery of the payload to a target tissue (e.g., to the brain via the blood brain barrier). The payload includes, for example, an alpha-glucosidase (GAA) polypeptide. The present disclosure provides methods of treating various diseases (e.g., glycogen storage diseases, such as Poincare disease) with such molecules and fusions.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Application No. 63 / 393,719, filed Jul. 29, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0003] Reference to a sequence listing submitted as a text file via EFS - WEB

[0004] The sequence listing written in the file 598882SEQLIST.xml is 573 kilobytes and was created on Jul. 26, 2023, and is incorporated herein by reference. Background of the invention

[0005] Delivery of iron to the brain is accomplished via binding and intracellular trafficking by the iron - binding protein transferrin (Tf). Transferrin receptor (TfR) is a target for some studies of drug delivery to the brain. For example, methods include using liposomes modified with Tf for delivery of imaging agents and DNA (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), or using iron - mimicking peptides as ligands (Staquicini et al., 2011).

[0006] The correlation between increased antibody affinity and lysosomal degradation has also been proposed (Bien-Ly et al., (2014) Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 211, 233-244), which supports the view that lower antibody affinity will help avoid intracellular degradation of the transported complex. Bien-Ly et al. found that a bispecific antibody against TfR and β-secretase (BACE1) crossed the blood-brain barrier (BBB), not only effectively reducing brain amyloid-β protein levels; but also the high-affinity binding to TfR caused a dose-dependent decrease in brain TfR levels. Similarly, Moos and Morgan (2001) compared the ability of the anti-TfR antibody OX26 and transferrin to cross the rat BBB and found that OX26 was not recycled from the brain like transferrin because the antibody exhibited a high-affinity antibody-antigen interaction with TfR, which was not easily reversed, while this interaction of Tf was easily reversed according to the pH and iron content of Tf (Restricted transport of anti-transferrin receptor antibody (OX26) through the blood-brain barrier in the rat, J Neurochem October 2001; 79(1):119-29). SUMMARY OF THE INVENTION

[0007] In one aspect, there is provided an antigen-binding protein that specifically binds to a transferrin receptor or an antigenic fragment or variant thereof. Some such antigen-binding proteins comprise: (i) an HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown 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; and / or (ii) an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown 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. Optionally, the antigen-binding protein is fused to a payload.

[0008] Some such antigen-binding proteins comprise: (1) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:2 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:7 (or a variant thereof); (2) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:12 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:17 (or a variant thereof); (3) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:22 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:27 (or a variant thereof); (4) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:32 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:37 (or a variant thereof); (5) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:42 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:47 (or a variant thereof); (6) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:52 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:57 (or a variant thereof); (7) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:62 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:67 (or a variant thereof); (8) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO:72 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO:77 (or a variant thereof);(9) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (10) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (11) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (12) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (13) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof); (14) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (15) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (16) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof);(17) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (18) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (20) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (21) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (22) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (24) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof);(25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (26) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (27) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (28) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (29) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (30) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (31) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 307 (or a variant thereof); and / or (32) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof).;

[0009] Some such antigen-binding proteins comprise: a heavy chain variable region (HCVR) containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and a light chain variable region (LCVR) containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).

[0010] Some such antigen-binding proteins comprise: a HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and a LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof).

[0011] Some such antigen-binding proteins comprise: (a) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO:3 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:4 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:5 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO:8 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:9 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:10 (or a variant thereof); (b) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO:13 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:14 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:15 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO:18 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:19 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:20 (or a variant thereof); (c) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO:23 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:24 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:25 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO:28 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:29 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:30 (or a variant thereof); (d) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO:33 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:34 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:35 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO:38 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:39 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:40 (or a variant thereof);(e) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof); (f) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof); (g) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof); (h) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 75 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof);(i) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 83 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 84 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 90 (or a variant thereof); (G) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 95 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 98 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof); (k) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof); (l) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 114 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 115 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof);(m) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 123 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 130 (or a variant thereof); (n) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof); (o) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 143 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 145 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 149 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof); (p) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 153 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 155 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof); (q) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 163 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof); (s) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 183 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 185 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 188 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 189 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof);(t)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 193 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 195 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 199 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof); (u)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 203 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 205 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof); (v)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 213 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 215 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 219 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof); (w)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof); (x) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 233 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 235 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 239 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof); (y) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof); (z) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 253 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 254 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 255 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof);(aa) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof); (ab) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof); (ac) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 283 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 285 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof); (ad) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 293 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 295 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 303 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 305 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 309 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof); and / or (at) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 313 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 315 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 320 (or a variant thereof).;

[0012] Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof). Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof).Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO:173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:175 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO:178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:180 (or a variant thereof). Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO:263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:265 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO:268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:270 (or a variant thereof). Some such antigen-binding proteins comprise: an HCVR that comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO:273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO:274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO:275 (or a variant thereof); and an LCVR that comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO:278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO:279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO:280 (or a variant thereof).

[0013] Some such antigen-binding proteins comprise: an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof).

[0014] Some such antigen-binding proteins comprise: (i) an HCVR having the amino acid sequence shown in SEQ ID NO:2 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:7 (or a variant thereof); (ii) an HCVR having the amino acid sequence shown in SEQ ID NO:12 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:17 (or a variant thereof); (iii) an HCVR having the amino acid sequence shown in SEQ ID NO:22 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:27 (or a variant thereof); (iv) an HCVR having the amino acid sequence shown in SEQ ID NO:32 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:37 (or a variant thereof); (v) an HCVR having the amino acid sequence shown in SEQ ID NO:42 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:47 (or a variant thereof); (vi) an HCVR having the amino acid sequence shown in SEQ ID NO:52 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:57 (or a variant thereof); (vii) an HCVR having the amino acid sequence shown in SEQ ID NO:62 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:67 (or a variant thereof); (viii) an HCVR having the amino acid sequence shown in SEQ ID NO:72 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:77 (or a variant thereof); (ix) an HCVR having the amino acid sequence shown in SEQ ID NO:82 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:87 (or a variant thereof); (x) an HCVR having the amino acid sequence shown in SEQ ID NO:92 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:97 (or a variant thereof); (xi) an HCVR having the amino acid sequence shown in SEQ ID NO:102 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:107 (or a variant thereof); (xii) an HCVR having the amino acid sequence shown in SEQ ID NO:112 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:117 (or a variant thereof); (xiii) an HCVR having the amino acid sequence shown in SEQ ID NO:122 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO:127 (or a variant thereof);(xiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (xv) An HCVR having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (xvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (xvii) An HCVR having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (xviii) An HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (xix) An HCVR having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (xx) An HCVR having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (xxi) An HCVR having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (xxii) An HCVR having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (xxiii) An HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (xxiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (xxv) An HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (xxvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof);and an LCVR having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (xxvii) an HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (xxix) an HCVR having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (xxx) an HCVR having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (xxxi) an HCVR having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 307 (or a variant thereof); and / or (xxxii) an HCVR having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof).;

[0015] Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof). Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).

[0016] Some such antigen-binding proteins comprise: a HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof).

[0017] In some such antigen-binding proteins, the transferrin receptor is the 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 wherein the scFv and the payload are linked by a peptide linker which is -(GGGGS) m- (SEQ ID NO: 426); where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and optionally wherein the scFv variable regions are linked by a peptide linker which is -(GGGGS) n-(SEQ ID NO: 426); wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some such antigen-binding proteins, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 429 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 433 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 442 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 438 (or a variant thereof). In some such antigen-binding proteins, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof).

[0018] Also provided is an antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and binds to one or more hTfR epitopes selected from the following: (a) an epitope having the sequence LLNE (SEQ ID NO: 525) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); (b) an epitope having the sequence DSTDFTGT (SEQ ID NO: 526) and / or an epitope having the sequence VKHPVTGQF (SEQ ID NO: 527) and / or an epitope having the sequence IERIPEL (SEQ ID NO: 528); (c) an epitope having the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529); (d) an epitope having the sequence FEDL (SEQ ID NO: 519); (e) an epitope having the sequence IVDKNGRL (SEQ ID NO: 530); (t) an epitope having the sequence IVDKNGRLVY (SEQ ID NO: 531); (g) an epitope having the sequence DQTKF (SEQ ID NO: 532); (h) an epitope having the sequence LVENPGGY (SEQ ID NO: 533) and / or an epitope having the sequence PIVNAELSF (SEQ ID NO: 534) and / or an epitope having the sequence PYLGTTMDT (SEQ ID NO: 535); (i) an epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); G) an epitope having the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or an epitope having the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or an epitope having the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (k) an epitope having the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) an epitope having the sequence GTKKDFEDL (SEQ ID NO: 512); (m) an epitope having the sequence SVIIVDKNGRL VYLVENPGGYV AYSK (SEQ ID NO: 513); (n) an epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516);(o) An epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) An epitope having the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO: 517); (q) An epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518); (r) An epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO: 520) and / or an epitope having the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521) and / or an epitope having the sequence ISRAAAEKL (SEQ ID NO: 522) and / or an epitope having the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523) and / or an epitope having 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 an epitope contained within or overlapping with the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (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 SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO: 513);(x) epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO:514) and / or epitopes contained within or overlapping with the sequence DQTKFPIVNAEL (SEQ ID NO:515) and / or epitopes contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO:516); (y) epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO:514) and / or epitopes contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO:516); (z) epitopes contained within or overlapping with the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO:517); (aa) epitopes contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO:506) and / or epitopes contained within or overlapping with the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO:518); and (ab) epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO:505) and / or epitopes contained within or overlapping with the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO:520) and / or epitopes contained within or overlapping with the sequence IYMDQTKFPIVNAELSF (SEQ ID NO:521) and / or epitopes contained within or overlapping with the sequence ISRAAAEKL (SEQ ID NO:522) and / or epitopes contained within or overlapping with the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO:523) and / or epitopes contained within or overlapping with the sequence FCEDTDYPYLGTTMDT (SEQ ID NO:524). In some such antigen-binding proteins, the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof that binds to one or more hTfR epitopes 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) Epitopes consisting of the sequence FEDL (SEQ ID NO:519); (e) Epitopes consisting of the sequence IVDKNGRL (SEQ ID NO:530); (f) Epitopes consisting of the sequence IVDKNGRLVY (SEQ ID NO:531); (g) Epitopes consisting of the sequence DQTKF (SEQ ID NO:532); (h) Epitopes consisting of the sequence LVENPGGY (SEQ ID NO:533) and / or epitopes consisting of the sequence PIVNAELSF (SEQ ID NO:534) and / or epitopes consisting of the sequence PYLGTTMDT (SEQ ID NO:535); (i) Epitopes consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO:505) and / or epitopes consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO:506) and / or epitopes consisting of the sequence TYKEL (SEQ ID NO:507); (j) Epitopes consisting of the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO:508) and / or epitopes consisting of the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO:509) and / or epitopes consisting of the sequence LIERIPELNKV ARAAAE (SEQ ID NO:510); (k) Epitopes consisting of the sequence LNENSYVPREAGSQKDENL (SEQ ID NO:511); (l) Epitopes consisting of the sequence GTKKDFEDL (SEQ ID NO:512); (m) Epitopes consisting of the sequence SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO:513); (n) Epitopes consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO:514) and / or epitopes consisting of the sequence DQTKFPIVNAEL (SEQ ID NO:515) and / or epitopes consisting of the sequence TYKELIERIPELNK (SEQ ID NO:516); (o) Epitopes consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO:514) and / or epitopes consisting of the sequence TYKELIERIPELNK (SEQ ID NO:516); (p) Epitopes consisting of the sequence SVIIVDKNGRL VYLVENPGGYVAY (SEQ ID NO:517); (q) Epitopes consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO:506) and / or epitopes 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 LVENPGGYVAYSKAATVTGKL (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).;

[0019] In some such antigen-binding proteins, the antigen-binding protein is selected from a humanized antibody or an antigen-binding fragment thereof, a human antibody or an antigen-binding fragment thereof, a murine antibody or an antigen-binding fragment thereof, a chimeric antibody or an antigen-binding fragment thereof, a monovalent Fab’, a bivalent Fab2, an F(ab)'3 fragment, a single-chain variable fragment (scFv), a bis-scFv, an (scFv)2, a diabody, a bivalent antibody, a single-arm antibody, a minibody, a nanobody, a trisbody, a tetrabody, a disulfide-stabilized Fv protein (dsFv), a single-domain antibody (sdAb), an Ig NAR, a single-chain antibody, a bispecific antibody or a binding fragment thereof, a bispecific T cell engager (BiTE), a trispecific antibody, or a chemically modified derivative thereof.

[0020] In another aspect, there is provided a fusion protein comprising any of the above antigen-binding proteins and a payload fused thereto. In another aspect, there is provided a fusion protein comprising an antigen-binding protein that specifically binds to a transferrin receptor or an antigenic fragment or variant thereof and a payload fused thereto, wherein the antigen-binding protein binds to the human transferrin receptor with a K D or stronger affinity. In some such fusion proteins, the antigen-binding protein binds to the human transferrin receptor with a K D or stronger affinity. In some such fusion proteins, the antigen-binding protein binds to the human transferrin receptor with a K D or stronger affinity. In some such fusion proteins, the antigen-binding protein binds to the human transferrin receptor with a K D or stronger affinity, or wherein the antigen-binding protein binds to the human transferrin receptor with a K of about 0.45 nM to 3 nM DBinds to human transferrin receptor. 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 human α-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 a polypeptide encoded by a human gene specified by any one of Tables C to N, or a variant thereof. In some such fusion proteins, the payload is LSD-TA, which is meglustat, erglustat, α-galactosidase A, ceramidase, β-glucosidase, sphingolipid activated protein-C activator, acid sphingomyelinase, β-galactosidase, β-hexosaminidase A and B, β-hexosaminidase A, GM2-activating protein, GM3 synthase, arylsulfatase A, sphingolipid activated factor, α-iduronidase, iduronidase-2-sulfur acid esterase, heparan N-sulfatase, N-acetyl-α-glucosaminidase, acetyl-CoA, α-glucosamide N-acetyltransferase, N-acetylglucosamine-6-sulfatase, N-acetylgalactosamine-6-sulfatase, β-galactosidase, N-acetylgalactosamine-4-sulfatase (arylsulfatase B), β-glucuronidase, hyaluronidase, α-glucosidase 2, or lysosomal acid lipase.

[0021] Some such fusion proteins are fusion proteins comprising an antigen binding protein that specifically binds to human transferrin receptor, comprising a heavy chain variable region (HCVR or V H ) and light chain variable region (LCVR or V L ), wherein the V H and V L The Fab has a K of approximately 0.65 nM D or greater affinity to bind to human transferrin receptor; and wherein, when the fusion protein is administered to mice expressing human transferrin receptor in the brain, the mice achieve a molar ratio of about 1:1 or greater in the mature GAA protein: serum GAA protein in the brain of the mice when normalized relative to the ratio in mice administered 8D3 and expressing mouse transferrin receptor.

[0022] In some such fusion proteins, the antigen binding protein is 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 has the amino acid sequence (or variant thereof) shown in SEQ ID NO:408, or has the amino acid sequence (or variant thereof) shown in SEQ ID NO:405. In some such fusion proteins, the fusion protein has the amino acid sequence (or variant thereof) shown in SEQ ID NO:408.

[0023] In some such fusion proteins, the antigen-binding protein is an antibody or an antigen-binding fragment thereof. In some such fusion proteins, the antigen-binding protein is a 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 a 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 a scFv, wherein the scFv and GAA are linked by a peptide linker. In some such fusion proteins, the scFv and GAA are linked by a peptide linker which is -(GGGGS) m- (SEQ ID NO:426); wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some such fusion proteins, the antigen-binding protein is a scFv, and the scFv variable regions are linked by a peptide linker. In some such fusion proteins, the scFv variable regions are linked by a peptide linker which is -(GGGGS) n- (SEQ ID NO:426); wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some such fusion proteins, the fusion protein binds to the human transferrin receptor with an affinity of about 1×10 -7 M K D or stronger.

[0024] Some such fusion proteins comprise: (i) an HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown 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) an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown 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.

[0025] In some such fusion proteins, the fusion protein comprises an scFv that contains a heavy chain variable region (V H ) and a light chain variable region (V L ); and an α-glucosidase polypeptide (GAA), wherein the V H , V L , and GAA are arranged as follows: (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.

[0026] Some such fusion proteins have an amino acid sequence as shown in a member of the group consisting of: SEQ ID NO: 392 - 423, SEQ ID NO: 321 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), SEQ ID NO: 322 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), SEQ ID NO: 323 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), and SEQ ID NO: 324 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence); or variants thereof.

[0027] In some such fusion proteins, when the antigen-binding protein is not fused to the GAA polypeptide, it does not block more than 50% of the binding of the C-terminal fragment of the human transferrin receptor to human holotransferrin, which occurs in the absence of such single-chain fragment variable region (scFv), antibody, or antigen-binding fragment. In some such fusion proteins, the blocking is measured in an enzyme-linked immunosorbent assay (ELISA) plate assay, where the binding of the extracellular domain of the human transferrin receptor fused to a His6-myc-myc tag is pre-bound to the scFv, antibody, or antigen-binding fragment, and then contacted with holotransferrin, which is immobilized on the plate surface by binding to an anti-holotransferrin antibody bound to the plate. In some such fusion proteins, the binding of holotransferrin and the extracellular domain of the human transferrin receptor is measured at a concentration of approximately 300 pM of the extracellular domain of the human transferrin receptor in the absence of the scFv, antibody, or antigen-binding fragment.

[0028] Some such fusion proteins or antigen-binding proteins specifically bind to the human transferrin receptor and have one or more of the following characteristics:

[0029] · An affinity (K D ) for binding to human TfR in surface plasmon resonance format at 25 °C of about 41 nM or higher;

[0030] · An affinity (K D ) for binding to monkey TfR in surface plasmon resonance format at 25 °C of about 0 nM (no detectable binding) or higher;

[0031] · The K D / K that binds to human TfR D has a ratio of 0 to 278;

[0032] · When in Fab form (IgG1), it blocks the binding of approximately 3% to 13% of hTfR to human Holo-Tf;

[0033] · When in scFv (VK-V H ) form, it blocks the binding of approximately 6% to 13% of hTfR to human Holo-Tf;

[0034] · When in scFv (V H -V L ) form, it blocks the binding of approximately 11% to 26% of hTfR to human Holo-Tf;

[0035] · When in the anti-hTfR scFv:hGAA form, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain (normalized to this ratio of the positive control 8D3:GAAscFv) of approximately 1 to 2;

[0036] · When in the anti-hTfR scFv:hGAA form, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAA scFv) of approximately 0.1 to 1.2;

[0037] · When in the anti-hTtR scFv:hGAA form, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the quadriceps femoris (normalized to this ratio of the positive control 8D3:GAA scFv) of approximately 0.67, 1.80, 1.78, or 7.74 (approximately 1 to 2);

[0038] · When in the anti-hTtR scFv:hGAA form, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAA scFv) of approximately 0.1 to 1.2;

[0039] · When in the anti-hTtR scFv:hGAA form, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it delivers mature hGAA protein to the serum, liver, brain, cerebellum, spinal cord, heart, and / or quadriceps femoris;

[0040] · When in the form of anti-hTfR scFv:hGAA, it reduces glycogen stored in the brain, cerebellum, spinal cord, heart, and / or quadriceps femoris when administered to mice expressing the human transferrin receptor (optionally lacking functional endogenous GAA).

[0041] · When containing an antigen-binding protein fused to GAA, it reduces the glycogen level in the cerebellum of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least about 90% relative to untreated mice.

[0042] · When containing an antigen-binding protein fused to GAA, it reduces the glycogen level in the quadriceps femoris of mice expressing the human transferrin receptor but lacking functional endogenous GAA by at least about 89% relative to untreated mice; and / or

[0043] · When administered to mice expressing the human transferrin receptor, it does not cause abnormal iron homeostasis.

[0044] In another aspect, there is provided a pharmaceutical composition comprising any of the above fusion proteins or antigen-binding proteins and a pharmaceutically acceptable carrier.

[0045] In another aspect, there is provided a composition or kit comprising any of the above fusion proteins or antigen-binding proteins or pharmaceutical compositions and an additional therapeutic agent in combination therewith. In some such compositions or kits, the additional therapeutic agent is selected from: alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), eliglustat, levalbuterol, antibiotics, cortisone, prednisone, bisphosphonates, and palivizumab. In some such compositions or kits, the additional therapeutic agent is selected from: β2-adrenergic agonists, steroids, bisphosphonates, infectious disease therapeutic agents, vaccines, and pneumococcal vaccines.

[0046] In another aspect, there is provided a complex comprising any of the above fusion proteins or antigen-binding proteins and a human transferrin receptor polypeptide or an antigenic fragment thereof to which it binds.

[0047] In another aspect, isolated polynucleotides encoding any of the above fusion proteins or antigen-binding proteins are provided. Some such polynucleotides contain the nucleotide sequences shown in SEQ ID NO: 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. Some such polynucleotides contain: (1) the nucleotide sequences shown in SEQ ID NO: 1 and SEQ ID NO: 6; (2) the nucleotide sequences shown in SEQ ID NO: 11 and SEQ ID NO: 16; (3) the nucleotide sequences shown in SEQ ID NO: 21 and SEQ ID NO: 26; (4) the nucleotide sequences shown in SEQ ID NO: 31 and SEQ ID NO: 36; (5) the nucleotide sequences shown in SEQ ID NO: 41 and SEQ ID NO: 46; (6) the nucleotide sequences shown in SEQ ID NO: 51 and SEQ ID NO: 56; (7) the nucleotide sequences shown in SEQ ID NO: 61 and SEQ ID NO: 66; (8) the nucleotide sequences shown in SEQ ID NO: 71 and SEQ ID NO: 76; (9) the nucleotide sequences shown in SEQ ID NO: 81 and SEQ ID NO: 86; (10) the nucleotide sequences shown in SEQ ID NO: 91 and SEQ ID NO: 96; (11) the nucleotide sequences shown in SEQ ID NO: 101 and SEQ ID NO: 106; (12) the nucleotide sequences shown in SEQ ID NO: 111 and SEQ ID NO: 116; (13) the nucleotide sequences shown in SEQ ID NO: 121 and SEQ ID NO: 126; (14) the nucleotide sequences shown in SEQ ID NO: 131 and SEQ ID NO: 136; (15) the nucleotide sequences shown in SEQ ID NO: 141 and SEQ ID NO: 146; (16) the nucleotide sequences shown in SEQ ID NO: 151 and SEQ ID NO: 156; (17) the nucleotide sequences shown in SEQ ID NO: 161 and SEQ ID NO: 166;(18) The nucleotide sequences shown in SEQ ID NO: 171 and SEQ ID NO: 176; (19) The nucleotide sequences shown in SEQ ID NO: 181 and SEQ ID NO: 186; (20) The nucleotide sequences shown in SEQ ID NO: 191 and SEQ ID NO: 196; (21) The nucleotide sequences shown in SEQ ID NO: 201 and SEQ ID NO: 206; (22) The nucleotide sequences shown in SEQ ID NO: 211 and SEQ ID NO: 216; (23) The nucleotide sequences shown in SEQ ID NO: 221 and SEQ ID NO: 226; (24) The nucleotide sequences shown in SEQ ID NO: 231 and SEQ ID NO: 236; (25) The nucleotide sequences shown in SEQ ID NO: 241 and SEQ ID NO: 246; (26) The nucleotide sequences shown in SEQ ID NO: 251 and SEQ ID NO: 256; (27) The nucleotide sequences shown in SEQ ID NO: 261 and SEQ ID NO: 266; (28) The nucleotide sequences shown in SEQ ID NO: 271 and SEQ ID NO: 276; (29) The nucleotide sequences shown in SEQ ID NO: 281 and SEQ ID NO: 286; (30) The nucleotide sequences shown in SEQ ID NO: 291 and SEQ ID NO: 296; (31) The nucleotide sequences shown in SEQ ID NO: 301 and SEQ ID NO: 306; and / or (32) The nucleotide sequences shown in SEQ ID NO: 311 and SEQ ID NO: 316.;

[0048] In another aspect, a vector comprising any of the above polynucleotides is provided.

[0049] In another aspect, a host cell comprising any of the above fusion proteins, antigen-binding proteins, polynucleotides or vectors is provided. Some such host cells are Chinese hamster ovary (CHO) cells.

[0050] In another aspect, provided are methods for preparing any of the above-described fusion proteins or antigen-binding proteins, which include culturing a host cell containing a polynucleotide encoding the fusion protein or antigen-binding protein in a culture medium under conditions conducive to the expression of the fusion protein or antigen-binding protein. Some such methods include the steps of: (a) introducing the polynucleotide into a host cell; (b) culturing the host cell under conditions conducive to the 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 the host cell; and (d) optionally, chemically conjugating the antigen-binding protein with a payload. In another aspect, provided are fusion proteins or antigen-binding proteins that are products of such methods.

[0051] In another aspect, provided are containers or injection devices containing any of the above-described fusion proteins or antigen-binding proteins.

[0052] In another aspect, provided are methods for administering any of the above-described fusion proteins or antigen-binding proteins to a subject, which include introducing the protein into the subject. In some such methods, the fusion protein or antigen-binding protein is introduced into the subject parenterally.

[0053] In another aspect, provided are methods for treating or preventing lysosomal storage diseases in a subject in need thereof, which include administering to the subject an effective amount of any of the above-described fusion proteins, wherein the payload is a lysosomal storage disease therapeutic agent (LSD-TA). In some such methods, the lysosomal storage disease is: Fabry disease, Farber lipogranulomatosis, 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 (Tay-Sachs disease), GM2-gangliosidosis (GM2-activator deficiency), GM3-gangliosidosis, metachromatic leukodystrophy, sphingolipid activator deficiency, MPS I (Hurler disease, Hurler-Scheie disease or Scheie disease), MPS II (Hunter disease), MPS IIIA (Sanfilippo syndrome type A), MPS IIIB (Sanfilippo syndrome type B), MPS IIIC (Sanfilippo syndrome type C), MPS IIID (Sanfilippo syndrome type D), MPS IVA (Morquio syndrome type A), MPS IVB (Morquio syndrome type B), MPS VI (Maroteaux-Lamy disease), 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 LSD in the subject are alleviated after administration of the fusion protein or antigen-binding protein.

[0054] In another aspect, there is provided a method for treating or preventing glycogen storage disease (GSD) in a subject in need thereof, which comprises administering to the subject an effective amount of any of the above-mentioned fusion proteins. In some such methods, the glycogen storage disease is Pompe disease. In some such methods, the Pompe disease is classical infantile-onset Pompe disease. In some such methods, the Pompe disease is non-classical infantile Pompe disease. In some such methods, the Pompe disease is late-onset Pompe disease. In some such methods, the subject has a GAA genotype selected from the group consisting of: ASP91ASN, MET318THR, GLU521LYS, GLY643ARG, ARG725TRP; IVSIAS, T-G, -13; LYS903DEL, LEU299ARG, SER529VAL, ASP645GLU, GLU689LYS, EX18DEL, PRO545LEU; I-BP DEL, 525T; ARG854TER, ALA237VAL, GLY293ARG and IVS6AS, G-C, -1.

[0055] In some such methods, the fusion protein is co-administered to the subject with an additional therapeutic agent. In some such methods, the additional therapeutic agent is selected from: alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), eliglustat, levalbuterol, antibiotics, cortisone, prednisone, bisphosphonates and palivizumab. In some such methods, the additional therapeutic agent is selected from: β2-adrenergic agonists, steroids, bisphosphonates, infectious disease therapeutic agents, vaccines and pneumococcal vaccines. In some such methods, the subject is 1 year of age or younger and exhibits symptoms selected from:

[0056] · Difficulty feeding and failure to gain weight;

[0057] · Poor head and neck control;

[0058] · Rolling over and sitting up later than expected;

[0059] · Difficulty breathing;

[0060] · Lung infections;

[0061] · Heart enlargement and thickening;

[0062] · Heart defects;

[0063] · Hepatomegaly; and

[0064] · Macroglossia.

[0065] In some such methods, the subject is an adult and exhibits symptoms selected from:

[0066] · Weakness in the legs, trunk, and / or arms;

[0067] · Shortness of breath;

[0068] · Lung infection;

[0069] · Difficulty breathing while sleeping;

[0070] · Scoliosis;

[0071] · Enlarged liver;

[0072] · Macroglossia; and

[0073] · Joint stiffness.

[0074] In some such methods, one or more signs or symptoms of GSD in the subject are alleviated after administration of the fusion protein or antigen-binding protein.

[0075] In another aspect, methods are provided for delivering a payload to a tissue or cell type in a subject, which include administering to the subject an antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and a payload fused thereto. 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 a variant thereof. In some such methods, the tissue is 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 (PBMC), small intestine, spleen, stomach, testis, peripheral nervous system, and / or bone / cartilage / joint. In some such methods, the cell type and the tissue associated with the cell type are as follows:

[0076]

[0077]

[0078]

[0079]

[0080] In some such methods, the method includes piercing the body of the subject with the needle of a syringe and then injecting into the body of the subject an antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and a payload fused thereto. In some such methods, the subject has muscular dystrophy, a metabolic disease, sarcopenia, or cachexia.

[0081] In another aspect, a method of expressing a fusion protein in a cell is provided, the fusion protein comprising an antigen-binding protein that specifically binds to a transferrin receptor or an antigenic fragment or variant thereof and a payload fused thereto, 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) integrating the isolated polynucleotide into a genomic locus of the cell; and (c) causing the cell to produce the fusion protein.

[0082] In some such methods, the method further comprises administering to the cell a nuclease reagent or one or more polynucleotides encoding a nuclease reagent, wherein the nuclease reagent cleaves a nuclease target site in the genomic locus and the isolated polynucleotide integrates into the genomic locus. In some such methods, the nuclease reagent 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 the body of a 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 comprising a 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 a pseudotyped AAV2 / 8 chimera and / or AAV that tropes to the liver. In some such methods, the genomic locus is a safe harbor locus. In some such methods, the genomic locus is at or near a locus selected from the group consisting of: the EESYR locus, the SARS locus, position 188,083,272 of human chromosome I or its non-human mammalian ortholog, position 3,046,320 of human chromosome 10 or its non-human mammalian ortholog, position 67,328,980 of human chromosome 17 or its non-human mammalian ortholog, the Adeno-Associated Virus Site 1 (AAVS1) on the chromosome, the naturally occurring AAV viral integration site on human chromosome 19 or its non-human mammalian ortholog, the Chemokine Receptor 5 (CCR5) gene, the chemokine receptor gene encoding the HIV-1 co-receptor, the mouse Rosa26 locus or its non-murine mammalian ortholog, 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.

[0083] The present disclosure provides antigen-binding proteins that can be fused to a payload and have one or more of the following characteristics: (1) an affinity (K D ) for binding to human TfR in surface plasmon resonance format at 25 °C of about 41 nM or higher; (2) an affinity (K D ) for binding to cynomolgus TfR in surface plasmon resonance format at 25 °C of about 0 nM (no detectable binding) or higher; (3) a ratio of [K D for binding to cynomolgus TfR / K D for binding to human TfR] in surface plasmon resonance format at 25 °C of 0 to 278; (4) when in Fab format (IgG1), blocks about 3% to 13% of the binding of hTtR to human Holo-Tf; (5) when in scFv (VK-V H ) format, blocks about 6% to 13% of the binding of hTfR to human Holo-Tf; (6) when in scFv (V H -V L) When in the form of [specific form], it blocks the binding of about 11% to 26% of hTfR to human Holo-Tf; (7) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows that the ratio of mature hGAA protein in the brain (normalized to this ratio of the positive control 8D3:GAAscFv) is about 1 to 2; (8) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows that the ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAA scFv) is about 0.1 to 1.2; (9) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows that the ratio of mature hGAA protein in the quadriceps femoris (normalized to this ratio of the positive control 8D3:GAA scFv) is about 0.67, 1.80, 1.78 or 7.74 (about 1 to 2); (10) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows that the ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAA scFv) is about 0.1 to 1.2; (11) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it delivers mature hGAA protein to serum, liver, brain, cerebellum, spinal cord, heart and / or quadriceps femoris; (12) When containing an antigen-binding protein fused to GAA, when in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it reduces the glycogen stored in the brain, cerebellum, spinal cord, heart and / or quadriceps femoris; (13) When containing an antigen-binding protein fused to GAA, it reduces the glycogen level in the cerebellum of mice expressing human transferrin receptor but lacking functional endogenous GAA by at least about 90% relative to untreated mice; (14) When containing an antigen-binding protein fused to GAA, it reduces the glycogen level in the quadriceps femoris of mice expressing human transferrin receptor but lacking functional endogenous GAA by at least about 89% relative to untreated mice; and / or (15) When administered to mice expressing human transferrin receptor, it does not cause abnormal iron homeostasis.

[0084] The present disclosure provides an antibody or an antigen-binding fragment thereof that specifically binds to a transferrin receptor (e.g., human transferrin receptor), comprising: (i) a heavy chain variable region containing HCDR1, HCDR2, and HCDR3, the HCVR having an amino acid sequence shown 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 light chain variable region containing LCDR1, LCDR2, and LCDR3, the LCVR having an amino acid sequence shown 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 comprises: (1) an HCVR containing HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR containing HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof); (3) an HCVR containing HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof); (4) an HCVR containing HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof);(5) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (6) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (7) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (8) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (9) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (10) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (11) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (12) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof);(13) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof); (14) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (15) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (16) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (17) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (18) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (20) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof);(21) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (22) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (24) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (26) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (27) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (28) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof);(29) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (30) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (31) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (32) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown 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 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); or (25) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises: (23) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises: (25) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof);and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment thereof comprises: (14) an HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown 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 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown 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 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown 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 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).;

[0085] In one embodiment, the antibody or antigen-binding fragment comprises: (a) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 3 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 9 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 10 (or a variant thereof); (b) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 15 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof); (c) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof); (d) an HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 35 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof);(e) An HCVR comprising an HCDR1 having the amino acid sequence shown in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof); (f) An HCVR comprising an HCDR1 having the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof); (g) An HCVR comprising an HCDR1 having the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof); (h) An HCVR comprising an HCDR1 having the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 75 (or a variant thereof); and an LCVR comprising an LCDR1 having the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof);(i) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 83 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 84 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 90 (or a variant thereof); (G) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 95 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 98 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof); (k) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof); (l) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 114 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 115 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof);(m) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 123 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 130 (or a variant thereof); (n) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof); (o) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 143 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 145 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 149 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof); (p) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 153 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 155 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof); (q) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 163 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof); (s) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 183 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 185 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 188 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 189 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof);(t)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 193 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 195 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 199 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof); (u)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 203 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 205 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof); (v)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 213 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 215 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 219 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof); (w)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof); (x) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 233 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 235 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 239 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof); (y) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof); (z) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 253 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 254 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 255 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof);(aa) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof); (ab) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof); (ac) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 283 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 285 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof); (ad) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 293 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 295 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 303 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 305 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 309 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof); and / or (af) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 313 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 315 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 320 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (w) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof);or (y) HCVR, wherein the HCVR comprises: HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and LCVR, wherein the LCVR comprises: LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (w) HCVR, wherein the HCVR comprises: HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and LCVR, wherein the LCVR comprises: LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (y) HCVR, wherein the HCVR comprises: HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and LCVR, wherein the LCVR comprises: LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (n) HCVR, wherein the HCVR comprises: HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (r) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (aa) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (ab) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof).;

[0086] In one embodiment, the antibody or antigen-binding fragment comprises: (i) a HCVR having the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof); (ii) a HCVR having the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof); (iii) a HCVR having the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof); (iv) a HCVR having the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (v) a HCVR having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (vi) a HCVR having the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (vii) a HCVR having the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (viii) a HCVR having the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (ix) a HCVR having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (x) a HCVR having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (xi) a HCVR having the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (xii) a HCVR having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and a LCVR having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (xiii) a HCVR having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof);and an LCVR having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof); (xiv) an HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (xv) an HCVR having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (xvi) an HCVR having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (xvii) an HCVR having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (xviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (xix) an HCVR having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (xx) an HCVR having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (xxi) an HCVR having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (xxii) an HCVR having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (xxiii) an HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (xxiv) an HCVR having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (xxv) an HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof);(xxvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (xxvii) An HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (xxviii) An HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (xxix) An HCVR having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (xxx) An HCVR having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (xxxi) An HCVR having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (xxxii) An HCVR having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR having the amino acid sequence shown 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 having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); or (xxv) an HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxiii) an HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxv) an HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xiv) an HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxvii) an HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the antibody or antigen-binding fragment comprises: (xxviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).

[0087] In one embodiment, the antigen-binding fragment comprises an scFv. In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof). In one embodiment, the antigen-binding fragment comprises an scFv. In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 429 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 433 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 442 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 438 (or a variant thereof).

[0088] Provided herein is an anti-hTtR:payload fusion protein that comprises a single-chain fragment variable region (scFv) that specifically binds to human transferrin receptor, an antibody (such as an IgG, such as IgG1, IgG2, IgG3, or IgG4), or an antigen-binding fragment thereof (such as, a Fab), or a container (such as, a vial) or an injection device (such as, a syringe) containing such a fusion (such as, binding to human transferrin receptor with a K -7 or stronger affinity), the fusion comprising a heavy chain variable region (V D or stronger affinity), the fusion comprising a heavy chain variable region (V H ) and a light chain variable region (V L ) fused to a payload such as an alpha-glucosidase polypeptide (GAA), wherein the Fab having said V H and V L binds to human transferrin receptor with a K Dbinds to the human transferrin receptor with an affinity of or greater than; and wherein, when the fusion protein is anti-hTtR:GAA and is administered to a mouse expressing the human transferrin receptor in the brain, the mature GAA protein:serum GAA protein molar ratio in the brain of the mouse, when normalized relative to said ratio in a mouse administered 8D3 and expressing the mouse transferrin receptor, is about 1:1 or greater. For example, when the fusion protein is an scFv, 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 ("N-" denotes the amino terminus of the polypeptide and "C-" denotes the carboxyl terminus of the polypeptide). In one embodiment, the scFv and the payload (e.g., GAA) are linked 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 linked 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.

[0089] In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO:408 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO:405 (or a variant thereof). In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO:408 (or a variant thereof). In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO:405 (or a variant thereof).

[0090] In one embodiment, the anti-hTfR:payload fusion protein comprises: (i) a heavy chain variable region containing HCDR1, HCDR2, and HCDR3, the HCVR having the amino acid sequence shown 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 light chain variable region containing LCDR1, LCDR2, and LCDR3, the LCVR having the amino acid sequence shown 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 containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof); (2) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof); (3) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof); (4) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof);(5) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (6) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (7) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (8) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (9) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (10) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (11) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (12) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof);(13) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof); (14) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (15) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (16) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (17) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (18) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (20) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof);(21) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (22) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (24) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (26) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (27) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (28) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof);(29) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (30) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (31) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (32) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof). In one embodiment, the fusion protein comprises: (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); or (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the fusion protein comprises: (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof);and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (14) an HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the fusion protein comprises: (18) an HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the fusion protein comprises: (27) an HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the fusion protein comprises: (28) an HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).;

[0091] In one embodiment, the fusion protein comprises: (a) an HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 3 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 9 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 10 (or a variant thereof); (b) an HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 15 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof); (c) an HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof); (d) an HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 35 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof);(e) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof); (f) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof); (g) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof); (h) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 75 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof);(i) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 83 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 84 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 90 (or a variant thereof); (G) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 95 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 98 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof); (k) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof); (l) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 114 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 115 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof);(m) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 123 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 130 (or a variant thereof); (n) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof); (o) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 143 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 145 (or a variant thereof); and an LCVR that contains an LCDR1 having the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 149 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof); (p) An HCVR that contains an HCDR1 having the amino acid sequence shown in SEQ ID NO: 153 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 155 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof); (q) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 163 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 170 (or a variant thereof); (r) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof); (s) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 183 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 185 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 188 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 189 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof);(t)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 193 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 195 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 199 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof); (u)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 203 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 205 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof); (v)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 213 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 215 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 219 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof); (w)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof); (x) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 233 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 235 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 239 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof); (y) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof); (z) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 253 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 254 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 255 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof);(aa) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof); (ab) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof); (ac) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 283 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 285 (or a variant thereof); and an LCVR that contains: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof); (ad) An HCVR that contains: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 293 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 295 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof); (ae) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 303 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 305 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 309 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof); and / or (af) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 313 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 315 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 320 (or a variant thereof). In one embodiment, the fusion protein comprises: (w) an HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof);or (y) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the fusion protein comprises: (w) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof). In one embodiment, the fusion protein comprises: (y) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). In one embodiment, the fusion protein comprises: (n) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof);and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof). In one embodiment, the fusion protein comprises: an (r)HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof). In one embodiment, the fusion protein comprises: an (aa)HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof). In one embodiment, the fusion protein comprises: an (ab)HCVR, the HCVR comprising: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and an LCVR, the LCVR comprising: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof).;

[0092] In one embodiment, the fusion protein comprises: (i) an HCVR having the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof); (ii) an HCVR having the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof); (iii) an HCVR having the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof); (iv) an HCVR having the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (v) an HCVR having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (vi) an HCVR having the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (vii) an HCVR having the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (viii) an HCVR having the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (ix) an HCVR having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (x) an HCVR having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (xi) an HCVR having the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (xii) an HCVR having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (xiii) an HCVR having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof);(xiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (xv) An HCVR having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (xvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (xvii) An HCVR having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (xviii) An HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (xix) An HCVR having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (xx) An HCVR having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (xxi) An HCVR having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (xxii) An HCVR having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (xxiii) An HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (xxiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (xxv) An HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (xxvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof);and an LCVR having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (xxvii) an HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (xxviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (xxix) an HCVR having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (xxx) an HCVR having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (xxxi) an HCVR having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 307 or 488 (or a variant thereof); and / or (xxxii) an HCVR having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxiii) an HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); or (xxv) an HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxiiii) an HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxv) an HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof). In one embodiment, the fusion protein comprises: (xiv) an HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof);and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof). In one embodiment, the fusion protein comprises: (xviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxvii) an HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof). In one embodiment, the fusion protein comprises: (xxviii) an HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).;

[0093] The fusion proteins provided herein are scFvs comprising a heavy chain variable region (V H ) and a light chain variable region (V L ), and a payload, such as an α-glucosidase polypeptide (GAA), wherein the V H , V L and the payload (e.g., GAA) are arranged as follows: (i) V L -V H -payload; (ii) V H -V L -payload; (iii) V L -[(GGGGS)3(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 has (i) the amino acid sequence shown in SEQ ID NO: 321 (or its mature polypeptide), (ii) the amino acid sequence shown in SEQ ID NO: 322 (or its mature polypeptide), (iii) the amino acid sequence shown in SEQ ID NO: 323 (or its mature polypeptide), (iv) the amino acid sequence shown in SEQ ID NO: 324 (or its mature polypeptide), (v) amino acids 30-1168 of SEQ ID NO: 321, (vi) amino acids 30-1171 of SEQ ID NO: 322, (vii) amino acids 30-1164 of SEQ ID NO: 323, or (viii) amino acids 30-1166 of SEQ ID NO: 324. In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 429 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 433 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 442 (or a variant thereof). In one embodiment, the scFv has the amino acid sequence shown in SEQ ID NO: 438 (or a variant thereof). In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO: 408 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 405 (or a variant thereof). In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO: 408 (or a variant thereof). In one embodiment, the fusion protein has the amino acid sequence shown in SEQ ID NO: 405 (or a variant thereof). In one embodiment, the fusion protein (e.g., the Fab of the fusion protein) has an amino acid sequence shown in a member selected from the group consisting of SEQ ID NOs: 392-423, e.g., which is fused to a payload such as a GAA polypeptide.In one embodiment, a single-chain variable fragment (scFv), antibody, or antigen-binding fragment thereof of an anti-TtR:GAA fusion protein that is not fused to a GAA polypeptide does not block more than 50% of the binding of the C-terminal fragment of the human transferrin receptor to human holotransferrin, such binding occurring in the absence of such single-chain variable fragment (scFv), antibody, or antigen-binding fragment; for example, wherein said blocking is measured in an enzyme-linked immunosorbent assay (ELISA) plate assay in which the binding of the C-terminal fragment of the human transferrin receptor fused to a His6-myc-myc tag is pre-bound to the scFv, antibody, or antigen-binding fragment and then contacted with holotransferrin, which is immobilized on the surface of the plate by binding to an anti-holotransferrin antibody bound to the plate; for example, wherein the binding of holotransferrin and the C-terminal fragment of the human transferrin receptor is measured at a concentration of about 300 pM of the C-terminal fragment of the human transferrin receptor in the absence of the scFv, antibody, or antigen-binding fragment.

[0094] Also provided is a composition comprising an anti-hTfR:GAA fusion protein provided herein; for example, a pharmaceutical composition comprising a fusion protein as disclosed herein and a pharmaceutically acceptable carrier. Also provided is a kit comprising a fusion protein as disclosed herein. Also provided are such compositions or kits that further comprise an additional therapeutic agent (e.g., alglucosidase alfa, rituximab, methotrexate, intravenous immunoglobulin (IVIG), eliglustat, levalbuterol, antibiotics, cortisone, prednisone, bisphosphonates, and palivizumab, β2-adrenergic agonists, steroids, bisphosphonates, infectious disease therapeutic agents, vaccines, and / or pneumococcal vaccines).

[0095] Also provided is a complex comprising an anti-hTfR:GAA fusion protein as disclosed herein and a human transferrin receptor polypeptide or an antigenic fragment thereof that binds thereto.

[0096] There is also provided an isolated polynucleotide encoding the anti-hTfR:GAA fusion protein disclosed herein, which, for example, comprises the nucleotide sequences shown in SEQ ID NO: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, there are provided polynucleotides comprising any one or more of the following: (1) the nucleotide sequences shown in SEQ ID NO:1 and SEQ ID NO:6; (2) the nucleotide sequences shown in SEQ ID NO:11 and SEQ ID NO:16; (3) the nucleotide sequences shown in SEQ ID NO:21 and SEQ ID NO:26; (4) the nucleotide sequences shown in SEQ ID NO:31 and SEQ ID NO:36; (5) the nucleotide sequences shown in SEQ ID NO:41 and SEQ ID NO:46; (6) the nucleotide sequences shown in SEQ ID NO:51 and SEQ ID NO:56; (7) the nucleotide sequences shown in SEQ ID NO:61 and SEQ ID NO:66; (8) the nucleotide sequences shown in SEQ ID NO:71 and SEQ ID NO:76; (9) the nucleotide sequences shown in SEQ ID NO:81 and SEQ ID NO:86; (10) the nucleotide sequences shown in SEQ ID NO:91 and SEQ ID NO:96; (11) the nucleotide sequences shown in SEQ ID NO:101 and SEQ ID NO:106; (12) the nucleotide sequences shown in SEQ ID NO:111 and SEQ ID NO:116; (13) the nucleotide sequences shown in SEQ ID NO:121 and SEQ ID NO:126; (14) the nucleotide sequences shown in SEQ ID NO:131 and SEQ ID NO:136; (15) the nucleotide sequences shown in SEQ ID NO:141 and SEQ ID NO:146; (16) the nucleotide sequences shown in SEQ ID NO:151 and SEQ ID NO:156; (17) the nucleotide sequences shown in SEQ ID NO:161 and SEQ ID NO:166;(18) The nucleotide sequences shown in SEQ ID NO: 171 and SEQ ID NO: 176; (19) The nucleotide sequences shown in SEQ ID NO: 181 and SEQ ID NO: 186; (20) The nucleotide sequences shown in SEQ ID NO: 191 and SEQ ID NO: 196; (21) The nucleotide sequences shown in SEQ ID NO: 201 and SEQ ID NO: 206; (22) The nucleotide sequences shown in SEQ ID NO: 211 and SEQ ID NO: 216; (23) The nucleotide sequences shown in SEQ ID NO: 221 and SEQ ID NO: 226; (24) The nucleotide sequences shown in SEQ ID NO: 231 and SEQ ID NO: 236; (25) The nucleotide sequences shown in SEQ ID NO: 241 and SEQ ID NO: 246; (26) The nucleotide sequences shown in SEQ ID NO: 251 and SEQ ID NO: 256; (27) The nucleotide sequences shown in SEQ ID NO: 261 and SEQ ID NO: 266; (28) The nucleotide sequences shown in SEQ ID NO: 271 and SEQ ID NO: 276; (29) The nucleotide sequences shown in SEQ ID NO: 281 and SEQ ID NO: 286; (30) The nucleotide sequences shown in SEQ ID NO: 291 and SEQ ID NO: 296; (31) The nucleotide sequences shown in SEQ ID NO: 301 and SEQ ID NO: 306; and / or (32) The nucleotide sequences shown in SEQ ID NO: 311 and SEQ ID NO: 316. A vector comprising a polynucleotide encoding a fusion protein disclosed herein, such as an expression vector, is provided. A host cell (Chinese hamster ovary (CHO) cell) comprising the fusion protein, polynucleotide, and / or vector is also provided.;

[0097] A method for preparing an anti-hTfR:GAA fusion protein as disclosed herein is also provided, which comprises the steps of: culturing a host cell (e.g., a CHO cell) comprising a polynucleotide encoding the fusion protein in a medium under conditions favorable for the expression of the fusion protein, e.g., (a) introducing the polynucleotide into the host cell; (b) culturing the host cell under conditions favorable for the expression of the fusion protein; and (c) optionally, isolating the fusion protein from the medium and / or the host cell. Such fusion proteins as products of such methods are provided.

[0098] The present invention also provides a method for administering (e.g., parenterally, such as intravenously) to a subject, optionally in combination with an additional therapeutic agent, an anti-hTfR:GAA fusion protein as disclosed herein, the subject having, for example, a GSD and / or GAA genotype selected from the group consisting of: ASP91ASN, MET318THR, GLU521LYS, GLY643ARG, ARG725TRP; IVSIAS, T-G, -13; LYS903DEL, LEU299ARG, SER529VAL, ASP645GLU, GLU689LYS, EX18DEL, PRO545LEU; I-BPDEL, 525T; ARG854TER, ALA237VAL,

[0099] GLY293ARG and IVS6AS, G-C, -1, comprising introducing the protein into the subject. The present invention also provides a method for treating or preventing glycogen storage disease (e.g., Pompe disease, such as classical infantile-onset Pompe disease, atypical infantile Pompe disease, or late-onset Pompe disease) in a subject in need thereof, the subject having, for example, a GAA genotype selected from the group consisting of: ASP91ASN, MET318THR, GLU521LYS, GLY643ARG, ARG725TRP; IVSIAS, T-G, -13; LYS903DEL, LEU299ARG, SER529VAL, ASP645GLU, GLU689LYS, EX18DEL, PRO545LEU; I-BPDEL, 525T; ARG854TER, ALA237VAL, GLY293ARG and IVS6AS, G-C, -1, comprising administering to the subject an effective amount of a fusion protein as disclosed herein, optionally in combination with an additional therapeutic agent. In one embodiment, the subject is 1 year of age or less and exhibits symptoms selected from the group consisting of: difficulty feeding and failure to gain weight, poor head and neck control, rolling over and sitting up later than expected, shortness of breath, lung infections, enlarged and thickened heart, heart defects, enlarged liver, and enlarged tongue. In one embodiment, the subject is an adult and exhibits symptoms selected from the group consisting of: weakness in the legs, trunk, and / or arms; shortness of breath, lung infections, shortness of breath during sleep, spinal curvature, enlarged liver, enlarged tongue, and joint stiffness.

[0100] The present invention also provides a method 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 tissues in a subject's body, such as cartilage, brain, cerebral cortex; cerebellum; hippocampus; caudate nucleus; parathyroid gland; adrenal gland; bronchus; lung; oral mucosa; esophagus; stomach; duodenum; small intestine; colon; rectum; liver; gallbladder; pancreas; kidney; bladder; testis; epididymis; prostate; vagina; ovary; fallopian tube; endometrium; cervix; placenta; breast; muscle, myocardium; skeletal muscle, smooth muscle, muscle endothelial vascular system; soft tissue; skin; appendix; lymph node; tonsil; 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 and a payload fused thereto. For example, the method may comprise the steps of piercing the subject's body with the needle of a syringe and then injecting the antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and the payload fused thereto into the subject's body. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 . The present invention provides V k -3 X G4S (SEQ ID NO:538)-V H amino acid sequences of various anti-human transferrin receptor scFv molecules in the form.

[0102] Figures 2A to 2C . Anti-human TFRC scFv antibody clones deliver GAA to Tfrc hum in the brains of 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 = 1 mouse. Delivered by HDD. Quantified in Table 4-1.

[0103] Figure 3 . A subset of anti-hTFRC antibodies (12798, 12850, 69323, 12841, 12843,

[0104] 12845, 12847, 12848, 12799, 69307, and 12839) deliver mature GAA in the form of scfv:GAA to the brain parenchyma (delivered by HDD). Lane E corresponds to endothelium, and lane P corresponds to parenchyma. The affinity ratio of mfffR: human TfR is shown below the image (mf refers to Macaca fascicularis). Quantified in Tables 4-2 and 4-3.

[0105] Figure 4 . Anti-hTFRC antibodies (12799, 12843, 12847, and 12839) deliver mature GAA in the form of scfv:GAA to the brain parenchyma (free AAV8 liver depot gene therapy).

[0106] Lane E corresponds to endothelium, and lane P corresponds to parenchyma. Quantified in Table 4-4.

[0107] Figure 5 . Free AAV8 liver depot anti-hTFRC scfv:GAA antibodies deliver GAA protein to Gaa - / - / Tfrc hum in the CNS (cerebellum, cerebrum, spinal cord), heart, and muscle (quadriceps) of Gaa / Tfrc mice. Quantified in Table 4-5.

[0108] Figure 6 . Free AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12839, 12843, and 12847) rescue glycogen storage - / - in Gaa / Tfrc hum mice in the central nervous system (CNS) (cerebellum, cerebrum, spinal cord), heart, and muscle (quadriceps). Quantified in Table 4-6.

[0109] Figures 7A to 7D . Free AAV8 liver depot anti-hTFRC scfv:GAA antibodies (12847, 12843, and 12799) rescue glycogen storage - / - in Gaa / Tfrc hum mice in the brain (thalamus ( Figure 7A ), cerebral cortex ( Figure 7B ), CA1 region of the hippocampus ( Figure 7C )) and muscle (quadriceps ( Figure 7D ))

[0110] Figure 8 . Albumin-inserted anti-hTFRC 12847scfv:GAA delivers mature GAA protein to the CNS and muscle of Pompe disease model mice.

[0111] Figure 9. Albumin - inserted anti - hTFRC 12847scfv:GAA rescues glycogen storage in the CNS and muscle of Pompe disease model mice. One - way ANOVA (*p < 0.01, **p < 0.001, ***p < 0.0001).

[0112] Figure 10 . Serum GAA activity after Cas9 - mediated insertion of anti - TfR1:GAA or anti - CD63:GAA into the crab - eating macaque albumin locus via AAV delivery. Only the vehicle was used as a negative control. One unit of GAA activity was 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. For vehicle, N = 1; for all others, N = 2 - 4.

[0113] Figure 11 . Albumin - inserted anti - hTFRC 12847scfv:GAA delivers mature GAA protein to the CNS and muscle of crab - eating macaques. For bar graphs, mature GAA was quantified by Western blot of tissue lysates, and error bars are SD.

[0114] Figure 12 Shows the interactions of the 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 asymmetric unit. For the Mammarenavirus machupoense GPI protein and human ferritin, only one copy in the asymmetric unit is shown for clarity to reduce the complexity of the figure.

[0115] Figure 13 Depicts that the hydrogen - deuterium exchange mass spectrometry (HDX) protection of the antibodies tested in the HDX - MS experiment can be assigned to 5 regions in TfR (PDB I SUV).

[0116] Figure 14 Displays the TfR regions protected by REGN17513, where REGN17513 is a representative antibody that causes HDX protection in the TfR apical domain, and these TfR regions overlap with the binding sites of the Mammarenavirus machupoense GPI protein, human ferritin, and Plasmodium vivax PvRBP2b protein.

[0117] Figure 15Shows the TfR regions protected by REGN17510, where REGN17510 is a representative of an HDX-protected antibody that has an HDX-protected region in the TfR apical domain that is not shared by other TfR-binding ligands shown in Figure 15 and is representative of antibodies with HDX protection that have binding sites shared with human ferritin and the Plasmodium vivax Sal-1 PvRBP2b protein in the TfR apical domain.

[0118] Figure 16 Shows the TfR regions protected by REGN17515, where REGN17515 is a representative of an HDX-protected antibody that has binding sites shared with human ferritin and the Plasmodium vivax Sal-1 PvRBP2b protein in the TfR apical domain.

[0119] Figure 17 Shows the TfR regions protected by REGN17514, where REGN17514 is a representative of an HDX-protected antibody that has binding sites shared with the Plasmodium vivax Sal-1 PvRBP2b protein in the TfR protease-like domain.

[0120] Figure 18 Shows the TfR regions protected by REGN17508, where REGN17508 is a representative of an HDX-protected antibody in the TfR protease-like domain. This region is not utilized by other TfR-interacting molecules shown in Figure 18 Detailed Description

[0121] L Review

[0122] The present disclosure provides anti-transferrin receptor antigen-binding proteins. Also provided are anti-transferrin receptor antigen-binding proteins fused to a payload. Such fusions can be used, for example, to deliver a payload to various tissues in the body, including the brain. For example, an anti-TfR:GAA fusion protein is provided that exhibits high affinity for the transferrin receptor and excellent blood-brain barrier crossing. Surprisingly, fusions that exhibit high binding affinity for TfR cross the blood-brain barrier more effectively than low-affinity binders. We have found that high-affinity antibodies in the form of anti-hTFR scfv:payload (e.g., GAA) confer optimal delivery to the CNS and muscle. This is in contrast to previous findings using monovalent and bivalent anti-TFR antibodies, where low-affinity antibodies crossed the blood-brain barrier more effectively. The fusions disclosed herein have the ability to effectively deliver GAA to the brain and are thus capable of effectively treating glycogen storage diseases, such as Pompe disease.

[0123] ​This article may employ conventional molecular biology techniques, microbiological techniques, and recombinant DNA techniques within the scope of the art. Such techniques are fully explained in the literature. See, for example, Sambrook, Fritsch, and Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (referred to herein as "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover ed., 1985); Oligonucleotide Synthesis (M.J. Gait ed., 1984); Nucleic Acid Hybridization (B.D. Hames and S.J. Higgins eds., (1985)); Transcription And Translation (B.D. Hames and S.J. Higgins eds., (1984)); Animal Cell Culture (R.I. Freshney ed., (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide To Molecular Cloning (1984); F.M. Ausubel et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0124] Polynucleotides include DNA and RNA. This article provides any polynucleotide disclosed herein that is operably linked to a promoter or other expression control sequence.

[0125] Symptoms are manifestations of a disease that are obvious to the patient himself, while signs are manifestations of a disease that are perceived by a doctor. The complete or partial alleviation of a sign or symptom can be referred to as remission of the sign or symptom.

[0126] An oligonucleotide is a polynucleotide that is up to about 30 nucleotides in length (e.g., about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides).

[0127] Transferrin receptor 1 (TfR) is a membrane receptor that is involved in controlling the iron supply to cells through the binding of transferrin, the major iron carrier protein. Transferrin receptor 1 is expressed by the TFRC gene. Transferrin receptor 1 may be referred to herein as TFRC. This receptor plays a key role in the control of cell proliferation because iron is required to maintain the activity of ribonucleotide reductase, the only enzyme that catalyzes the conversion of ribonucleotides to deoxyribonucleotides. Preferably, TfR is human TfR (hTfR). See, for example, accession numbers NP_001121620.1, BAD92491.1, and NP_001300894.1; and e! Ensembl entry: ENSG00000072274. Human transferrin receptor 1 is expressed in a number of tissues including, but not limited to: cerebral cortex; cerebellum; hippocampus; caudate nucleus; parathyroid gland; adrenal gland; bronchus; lung; oral mucosa; esophagus; stomach; duodenum; small intestine; colon; rectum; liver; gallbladder; pancreas; kidney; bladder; testis; epididymis; prostate; vagina; ovary; fallopian tube; endometrium; cervix; placenta; breast; myocardium; smooth muscle; soft tissue; skin; appendix; lymph node; tonsil; and bone marrow. See also the tissues and cell types in Table B herein. The related transferrin receptor is transferrin receptor 2 (TfR.2). Human transferrin receptor 2 has 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. March 2003; 35(3):292-6. Unless otherwise specified, transferrin receptor as used herein generally refers to transferrin receptor 1 (e.g., human transferrin receptor 1) (CD71).

[0128] Human transferrin (Tf) is a single-chain 80 kDa member of the anion-binding protein superfamily. Transferrin is a 698-amino acid precursor that is divided into a 19-amino acid signal sequence plus a 679-amino acid mature segment that usually contains 19 intramolecular disulfide bonds. The N-terminal and C-terminal flanking regions (or domains) bind ferric iron through the interaction of a specific anion (e.g., bicarbonate) and four amino acids (His, Asp, and two Tyr). Apotransferrin (or iron-free) initially binds one iron atom at the C-terminus, followed by subsequent iron binding through the N-terminus to form holotransferrin (di-iron Tf, Holo-Tf). Holotransferrin interacts with TfR on the cell surface through its C-terminal iron-binding domain, where it is internalized into acidified endosomes. Iron dissociates from the Tf molecule within these endosomes and is transported as ferrous iron into the cytosol. In addition to TfR, transferrin has also been reported to bind to cubulin, IGFBP3, microbial iron-binding proteins, and the liver-specific TfR2.

[0129] The blood-brain barrier (BBB) is located within the microvasculature of the brain and regulates the passage of molecules from the blood into 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 the following pathways: 1) leukocyte entry into cells; 2) carrier-mediated endocytosis, e.g., glucose transporter 1 (GLUT-1) endocytosis of glucose, e.g., L-type amino acid transporter 1 (LAT-1) endocytosis of amino acids, and e.g., organic anion transporting polypeptide B (OATP-B) endocytosis of small peptides; 3) paracellular channels for small hydrophobic molecules; 4) adsorptive-mediated transcytosis, e.g., transcytosis of albumin and cationic molecules; 5) passive diffusion of lipid-soluble nonpolar solutes (including CO2 and O2); and 5) receptor-mediated transcytosis, e.g., g, insulin receptor transcytosis of insulin and TfR transcytosis of Tf. Johnsen et al., Targeting the transferrin receptor for brain drug delivery, Prog Neurobiol. October 2019;181:101665.

[0130] IL anti-human transferrin receptor antigen-binding protein and fusion

[0131] Antigen-binding proteins that specifically bind to transferrin receptors, preferably human transferrin receptor 1 (anti-hTtR), such as antibodies, antigen-binding fragments thereof, such as Fab and scFv. For example, in one embodiment, the anti-hTtR is in the form of a fusion protein. The fusion protein comprises an anti-hTtR antigen-binding protein and a specific payload fused thereto (anti-hTfR:payload). The anti-hTtR disclosed herein effectively crosses the blood-brain barrier (BBB), thereby enabling delivery of the fused payload to the brain.

[0132] Antigen-binding proteins that specifically bind to transferrin receptors and their fusions (e.g., human transferrin receptor (e.g., REGN2431) or simian transferrin receptor (e.g., REGN2054)), for example, tags such as His6 and / or myc bind with an affinity of about 20 nM, for example, in surface plasmon resonance assays at about 25 °C. D or higher. Such antigen-binding proteins may be referred to as "anti-TfR". In some embodiments, the antigen-binding protein binds to the human transferrin receptor with an affinity of about 0.41 nM. D or stronger. In some embodiments, the antigen-binding protein binds to the human transferrin receptor with an affinity of about 3 nM. D or stronger. In some embodiments, the antigen-binding protein binds to the human transferrin receptor with an affinity of about 0.45 nM to 3 nM. D In some embodiments, Fab with HCVR and LCVR binds to the human transferrin receptor with an affinity of about 0.65 nM. D or stronger. In some embodiments, the fusion protein disclosed herein binds to the human transferrin receptor with an affinity of about 1×10 -7 M. D or stronger.

[0133] In one embodiment, the anti-hTfR scFv:payload or anti-TfR:payload scFv fusion protein comprises an scFv having an LCVR-HCVR or HCVR-LCVR variable region arrangement, wherein the HCVR and LCVR are optionally linked by a linker, and the scFv is optionally linked to a payload (e.g., GAA or a variant thereof) (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).

[0134] The anti-hTfR:payload optionally comprises a signal peptide linked to an antigen-binding protein that specifically binds to the transferrin receptor (TfR), preferably the human transferrin receptor (hTfR), which transferrin receptor is (optionally via a linker) fused 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).

[0135] The term "fused" or "tethered" with respect to a fusion polypeptide refers to polypeptides that are joined directly or indirectly (e.g., via a linker or other polypeptide).

[0136] In one embodiment, amino acids are assigned to each framework or CDR domain in an immunoglobulin according to the definitions in the following references: Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md., 5th ed.; NIH Publication 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, the antibodies and antigen-binding fragments provided herein include the CDRs of V H and the CDRs of V L wherein the V H and V L have the amino acid sequences as shown herein (see, e.g., the sequences in Table A, or variants thereof), wherein the CDRs are defined according to Kabat and / or Chothia.

[0137] Antibodies that specifically bind to human transferrin receptor 1 are provided herein. As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, i.e., two heavy chains (HC) and two light chains (LC). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ") (e.g., having 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, 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 "V L”) (e.g., 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, and / or 484, or variants thereof) and a light chain constant region (e.g., human κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”) (e.g., having SEQ ID NO:222 or 242, 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 “V L ”) (e.g., SEQ ID NO:227 or 247, or variants thereof) and a light chain constant region (e.g., human κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”) (e.g., having SEQ ID NO:222, 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 “V L ”) (e.g., SEQ ID NO:227, or variants thereof) and a light chain constant region (e.g., human κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”) (e.g., having SEQ ID NO:242, 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 “V L ”) (e.g., SEQ ID NO:247, or variants thereof) and a light chain constant region (e.g., human κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”) (e.g., having SEQ ID NO:132, 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 “V L ”) (e.g., SEQ ID NO:137, or variants thereof) and a light chain constant region (e.g., human κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “VH ”), e.g., having 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 κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”), e.g., having 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 κ or human λ). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “V H ”), e.g., having SEQID 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 κ or human λ). The V H region and the V L region can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), which are interspersed with more conserved regions, called framework regions (FRs). Each V 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.

[0138] The anti-TfR antigen-binding proteins provided herein can be antigen-binding fragments of antibodies capable of tethering to a payload. As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to an immunoglobulin molecule that binds an antigen but does not contain all of the sequences of a full antibody (preferably, the full 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; consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, minibodies, and small modular immunopharmaceuticals (SMIPs) are also encompassed within the expression "antigen-binding fragment" as used herein.

[0139] As mentioned, the anti-TfR antigen-binding proteins provided herein can be scFvs, which can tether to a payload. An scFv (single-chain fragment variable) has variable regions of the heavy chain (V H ) domain and the light chain (V L ) domain (in either order), which variable regions are preferably joined together by a flexible linker (e.g., a peptide linker). The length of the flexible linker used to join these two V regions can be important for the proper folding of the polypeptide chain. It has previously been estimated that the peptide linker must span between the carboxyl terminus of the variable domain and the amino terminus of the other domain without affecting the ability of these domains to fold and form a complete 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 as to separate the variable domains by about 3.5 nm.

[0140] In some embodiments, the anti-TtR antigen-binding proteins described herein include monovalent or "single-arm" antibodies. As used herein, a monovalent or "single-arm" antibody refers to an immunoglobulin comprising a single variable domain. For example, the single-arm antibody can comprise a single variable domain within a Fab, wherein the Fab is linked to at least one Fc fragment. In certain embodiments, the single-arm antibody comprises: (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) a polypeptide comprising an Fc fragment or a truncated heavy chain. In certain embodiments, the Fc fragment or truncated heavy chain comprised in a separate polypeptide is a "pseudo Fc", which refers to an Fc fragment not linked to an antigen-binding domain. The single-arm antibodies of the present disclosure can have any HCVR / LCVR pair or CDR amino acid sequences shown in Table A herein. Standard methods can be used to construct single-arm antibodies comprising a full-length heavy chain, a full-length light chain, and an additional Fc domain polypeptide (see, e.g., WO2010151792, which is incorporated herein by reference in its entirety), wherein 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 can be used to purify monovalent antibodies (see WO2010151792).

[0141] In one embodiment, the antigen-binding fragment of an antibody will comprise at least one variable domain. The variable domain can have any size or amino acid composition and will generally comprise at least one CDR that is adjacent to or in-frame with one or more framework sequences. In an antigen-binding fragment having a V L domain associated with a V H domain, the V H and V L domains can be positioned relative to each other in any suitable arrangement. For example, the variable regions can be dimeric and contain V H -V H 、V H -V L or V L -V L dimers. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0142] In certain embodiments, the antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies described herein include: (i) 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 the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly linked to each other or can be linked by a full or partial hinge region or linker region. The hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which forms a flexible or semi-flexible linker between adjacent variable and / or constant domains in a single polypeptide molecule. Additionally, antigen-binding fragments of the antibodies described herein can include homodimers or heterodimers (or other multimers) having any of the variable and constant domain configurations listed above, which non-covalently associate with each other and / or non-covalently associate with one or more monomeric V H or V L domains (e.g., via disulfide bonds). The present disclosure includes antigen-binding fragments of antigen-binding proteins (such as the antibodies shown herein).

[0143] 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 that comprise one or more variable domains from the antigen-binding proteins specifically set forth herein.

[0144] The term "specifically binds" refers to having a K D of at least about 10 -9Those antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof) with a binding affinity of M (e.g., 0.01 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, or 1.0 nM), as measured by a real-time, label-free biolayer interferometry assay, e.g., at 25 °C or 37 °C (e.g., HTX biosensor), or by surface plasmon resonance (e.g., BIACORE TM ), or by solution affinity ELISA. The present disclosure includes antigen-binding proteins that specifically bind to the TfR protein. "Anti-TfR" refers to an antigen-binding protein (or other molecule) that specifically binds to TtR, e.g., an antibody or an antigen-binding fragment thereof.

[0145] An "isolated" antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof), polypeptide, polynucleotide, and vector are at least partially free of other biomolecules from the cells or cell culture from which they are produced. Such biomolecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials such as cell debris and growth medium. An isolated antigen-binding protein may also be at least partially free of expression system components, such as biomolecules from the host cell or its growth medium. Generally, the term "isolated" is not intended to refer to the complete absence of such biomolecules (e.g., a small amount or trace amount of impurities may be retained), nor to the absence of water, buffer, or salt, nor to the absence of components included in a pharmaceutical formulation, including the antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof).

[0146] The present disclosure includes antigen-binding proteins that bind to the same epitopes as the antigen-binding proteins described herein, such as antibodies or antigen-binding fragments. In some embodiments, there is provided an antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof, which binds to one or more hTfR epitopes selected from the following: (a) an epitope having the sequence LLNE (SEQ ID NO: 525) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); (b) an epitope having the sequence DSTDFTGT (SEQ ID NO: 526) and / or an epitope having the sequence VKHPVTGQF (SEQ ID NO: 527) and / or an epitope having the sequence IERIPEL (SEQ ID NO: 528); (c) an epitope having the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529); (d) an epitope having the sequence FEDL (SEQ ID NO: 519); (e) an epitope having the sequence IVDKNGRL (SEQ ID NO: 530); (f) an epitope having the sequence IVDKNGRLVY (SEQ ID NO: 531); (g) an epitope having the sequence DQTKF (SEQ ID NO: 532); (h) an epitope having the sequence LVENPGGY (SEQ ID NO: 533) and / or an epitope having the sequence PIVNAELSF (SEQ ID NO: 534) and / or an epitope having the sequence PYLGTTMDT (SEQ ID NO: 535); (i) an epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); (j) an epitope having the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or an epitope having the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or an epitope having the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (k) an epitope having the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) an epitope having the sequence GTKKDFEDL (SEQ ID NO: 512); (m) an epitope having the sequence SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO: 513);(n) An epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516); (o) An epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) An epitope having the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO: 517); (q) An epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518); (r) An epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO: 520) and / or an epitope having the sequence TYMDQTKFPTVNAELSF (SEQ ID NO: 521) and / or an epitope having the sequence ISRAAAEKL (SEQ ID NO: 522) and / or an epitope having the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523) and / or an epitope having 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 an epitope contained within or overlapping with the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (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 SVIIVDKNGRLVYLVENPGGYVAYSK (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) An epitope contained within or overlapping with the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO:517); (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 LVENPGGYVAYSKAATVTGKL (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). In some embodiments, an antigen-binding protein is provided, wherein the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof that binds to one or more hTfR epitopes 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) Epitopes consisting of the sequence DSTDFTGT (SEQ ID NO: 526) and / or epitopes consisting of the sequence VKHPVTGQF (SEQ ID NO: 527) and / or epitopes consisting of the sequence IERIPEL (SEQ ID NO: 528); (c) Epitopes consisting of the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529); (d) Epitopes consisting of the sequence FEDL (SEQ ID NO: 519); (e) Epitopes consisting of the sequence IVDKNGRL (SEQ ID NO: 530); (f) Epitopes consisting of the sequence IVDKNGRL VY (SEQ ID NO: 531); (g) Epitopes consisting of the sequence DQTKF (SEQ ID NO: 532); (h) Epitopes consisting of the sequence LVENPGGY (SEQ ID NO: 533) and / or epitopes consisting of the sequence PIVNAELSF (SEQ ID NO: 534) and / or epitopes consisting of the sequence PYLGTTMDT (SEQ ID NO: 535); (i) Epitopes consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or epitopes consisting of the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or epitopes consisting of the sequence TYKEL (SEQ ID NO: 507); (j) Epitopes consisting of the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or epitopes consisting of the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or epitopes consisting of the sequence LIERIPELNKV ARAAAE (SEQ ID NO: 510); (k) Epitopes consisting of the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (l) Epitopes consisting of the sequence GTKKDFEDL (SEQ ID NO: 512); (m) Epitopes consisting of the sequence SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO: 513); (n) Epitopes consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitopes consisting of the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or epitopes consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516); (o) Epitopes consisting of the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitopes consisting of the sequence TYKELIERIPELNK (SEQ ID NO: 516);Epitopes consisting of the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO:517); (q) epitopes consisting of the sequence TYMDQTKFPTVNAEL (SEQ ID NO:506) and / or epitopes consisting of the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO:518); and (r) epitopes consisting of the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO:505) and / or epitopes consisting of the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO:520) and / or epitopes consisting of the sequence IYMDQTKFPIVNAELSF (SEQ ID NO:521) and / or epitopes consisting of the sequence ISRAAAEKL (SEQ ID NO:522) and / or epitopes consisting of the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO:523) and / or epitopes consisting of the sequence FCEDTDYPYLGTTMDT (SEQ ID NO:524).;

[0147] An antigen is a molecule, such as a peptide (e.g., TfR or a fragment thereof (antigenic fragment)), to which an antibody or an antigen-binding fragment thereof binds, for example. The specific region on the antigen that an antibody recognizes and binds to is called an epitope. Antigen-binding proteins (e.g., antibodies) that specifically bind to such antigens as described herein are part of the present disclosure.

[0148] The term "epitope" refers to an antigenic determinant (e.g., on TfR) that interacts with the specific antigen-binding site of an antigen-binding protein, e.g., the variable region of an antibody, called a paratope. A single antigen may have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and can have different biological effects.

[0149] The term "epitope" can also refer to the site on an antigen to which B cells and / or T cells respond, and / or the region on an antigen that is bound by an antibody. An epitope can be defined as a structural epitope or a functional epitope. A functional epitope is generally a subset of a structural epitope and has those residues that directly contribute to the affinity of the interaction. An epitope can be a linear epitope or a conformational epitope, i.e., consisting of non-linear amino acids. In certain embodiments, an epitope can include determinants that are chemical reactive surface groups of a molecule, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in certain embodiments, can have specific three-dimensional structural features and / or specific charge features. The epitopes bound by the antigen-binding proteins described herein can be included in a fragment of TfR (e.g., its extracellular domain). Antigen-binding proteins (e.g., antibodies) that bind to such epitopes as described herein are part of the present disclosure.

[0150] Methods for determining the epitopes of antigen-binding proteins (e.g., antibodies or fragments or polypeptides) include alanine-scanning mutagenesis, peptide blotting (Reineke (2004) Methods Mol. Biol. 248:443-63), peptide cleavage analysis, crystallographic studies, and NMR analysis. In addition, methods such as epitope excision, epitope extraction, and chemical modification of antigens (Tomer (2000) Prot. Sci. 9:487-496) can be employed. Another method that can be used to identify the amino acids within a polypeptide with which an antigen-binding protein (e.g., an antibody or fragment or polypeptide) interacts is to detect hydrogen / deuterium exchange by mass spectrometry. See, e.g., Ehring (1999) Analytical Biochemistry 267:252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.

[0151] The present disclosure includes antigen-binding proteins that compete with the antigen-binding proteins described herein for binding to the TfR epitopes as discussed herein. As used herein, the term "compete" means that an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) binds to an antigen (e.g., TfR) and inhibits or blocks the binding of another antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof) to the antigen. Unless otherwise specified, the term also includes competition between two antigen-binding proteins (e.g., antibodies) in two orientations, i.e., the first antibody binds to the antigen and blocks the binding of the second antibody to the antigen, or vice versa. Thus, in one embodiment, the competition occurs in one such orientation. In certain embodiments, the first antigen-binding protein (e.g., an antibody) and the second antigen-binding protein (e.g., an antibody) can bind to the same epitope. Alternatively, the first antigen-binding protein and the second antigen-binding protein (e.g., an antibody) can bind to different but, e.g., overlapping or non-overlapping epitopes, where the binding of one antigen-binding protein inhibits or blocks the binding of the second antibody, e.g., via steric hindrance. Competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art, e.g., by a real-time, label-free biolayer interferometry assay. Additionally, the binding competition between TfR-binding proteins (e.g., monoclonal antibodies (mAbs)) can be determined using a real-time, label-free biolayer interferometry assay on an Octet RED384 biosensor (Pall ForteBio Corp.).

[0152] Typically, an antibody or antigen-binding fragment modified in some way as described herein retains the ability to specifically bind to TfR. For example, when expressing its TfR-binding activity on a molar basis, it retains at least 10% of that activity (when compared to the parental antibody). Preferably, the 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 parental antibody. It is also contemplated that the antibodies or antigen-binding fragments described herein may include conservative or non-conservative amino acid substitutions that substantially do not alter their biological activity (referred to as "conservative variants" or "functionally conservative variants" of the antibody).

[0153] The anti-TfR antigen-binding proteins provided herein can be monoclonal antibodies or antigen-binding fragments of monoclonal antibodies, which can be tethered to a payload. Monoclonal anti-TfR antigen-binding proteins are provided herein, such as antibodies and their antigen-binding fragments, 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 members of a substantially homogeneous population of antibodies, i.e., the amino acid sequences of the antibody molecules making up that population of antibodies are the same, except for perhaps a few mutations that may be present naturally in small amounts. The "plurality" of such monoclonal antibodies and fragments in a composition refers to a higher concentration of the same (i.e., as discussed above, the amino acid sequences are the same, except for perhaps a few mutations that may be present naturally in small amounts) antibodies and fragments than is typically present in nature (e.g., in the blood of a host organism such as a mouse or a human).

[0154] In one embodiment, the anti-TfR antigen-binding protein, such as an antibody or antigen-binding fragment (which can be tethered to a payload), comprises a heavy-chain constant domain 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., an antibody or antigen-binding fragment) comprises a light-chain constant domain of the κ or λ type. In one embodiment, as shown herein, the V H is linked to a human heavy-chain constant domain (e.g., IgG), and as shown herein, the V L is linked to a human light-chain constant domain (e.g., κ). The present disclosure includes antigen-binding proteins containing the variable domains shown herein, which variable domains are linked to, for example, the heavy-chain constant domains and / or light-chain constant domains shown herein.

[0155] The present disclosure provides 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 human cells or transplanted into non-human cells (e.g., murine cells). See, e.g., US8502018, US6596541, or US5789215. The anti-TfR human mAbs provided herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation), such as in the CDRs, particularly in CDR3. However, as used herein, the term “human antibody” is not intended to include mAbs in which CDR sequences from the germline of another mammalian species (e.g., mouse) have been grafted onto human FR sequences. The term includes antibodies recombinantly produced in non-human mammals or cells of non-human mammals. The term is not intended to include naturally occurring antibodies isolated directly from human subjects. The present disclosure includes human antigen-binding proteins (e.g., the antibodies or antigen-binding fragments described herein).

[0156] The present disclosure provides anti-TfR chimeric antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (which can be tethered to a payload), and methods of using the same. As used herein, a “chimeric antibody” is an antibody having variable domains from a first antibody and constant domains from a second antibody, wherein the first and second antibodies are from different species. (See, e.g., US4816567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). The present disclosure includes chimeric antibodies having variable domains and non-human constant domains as shown herein.

[0157] The term “recombinant” anti-TfR antigen-binding protein such as an antibody or antigen-binding fragment thereof (which can be tethered to a payload) refers to such molecules produced, expressed, isolated, or obtained by techniques or methods known in the art such as recombinant DNA techniques (which include, e.g., DNA splicing and transgenic expression). The term includes antibodies expressed in non-human mammals (including transgenic non-human mammals, e.g., transgenic mice) or cells (e.g., CHO cells) such as cell expression systems, or antibodies isolated from recombinant combinatorial human antibody libraries. The present disclosure includes recombinant antigen-binding proteins, such as the antibodies and antigen-binding fragments described herein.

[0158] In one embodiment, an antigen-binding fragment of an antibody will comprise a structure less than that of a full antibody but will still specifically bind to an antigen, such as TtR, and will, for example, comprise at least one variable domain. The variable domain can have any size or amino acid composition and will typically comprise at least one (e.g., 3) CDRs that are adjacent to or in-frame with one or more framework sequences. In an antigen-binding fragment having a V H domain and a V L domain associated therewith, the V H domain and the V L domain can be positioned relative to each other in any suitable arrangement. For example, the variable regions can be dimeric and contain V H -V H 、V H -V L or V L -V L dimers. Alternatively, the antigen-binding fragment of an antibody can contain non-covalently associated monomeric V H and / or V L domains.

[0159] In certain embodiments, an antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies described herein include: (i) 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 the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or can be connected by a full or partial hinge region or linker region. The hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which form a flexible or semi-flexible linker between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, antigen-binding fragments of the antibodies described herein can include homodimers or heterodimers (or other multimers) having any of the variable and constant domain configurations listed above, which are non-covalently associated with each other and / or non-covalently associated with one or more monomeric V H or V L domains (e.g., via disulfide bonds). The present disclosure includes antigen-binding fragments of antigen-binding proteins such as the antibodies shown herein.

[0160] 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 that contain one or more variable domains from the antigen-binding proteins specifically described herein.

[0161] A "variant" of a polypeptide (such as an immunoglobulin chain) refers to a polypeptide whose amino acid sequence is at least about 70% to 99.9% (e.g., at least 70%, 72%, 74%, 75%, 76%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%) identical or similar to the reference amino acid sequence shown herein when compared by the BLAST algorithm, where the reference amino acid sequence is, for example, any one of the following: SEQ IDNO: 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, 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, 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 excluding the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ IDNO: 500)), 322 (optionally excluding the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 323 (optionally excluding the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 324 (optionally excluding the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500)), 328 - 423 or 427 - 458); wherein the parameters of the algorithm are selected to give the maximum match between the corresponding sequences over the entire length of the corresponding reference sequence (e.g., expected threshold: 10; word length: 3; maximum match in query range: 0; BLOSUM 62 matrix; gap penalty: existence 11, extension 1; conditional combined score matrix adjustment), and / or a polypeptide comprising the 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).

[0162] In addition, variants of the polypeptide can include polypeptides such as immunoglobulin chains, which can include the amino acid sequence of a reference polypeptide (the amino acid sequence of the reference polypeptide is specifically set forth herein), but having 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 includes a TfR-binding protein comprising: an immunoglobulin light chain (or V L ) variant having the amino acid sequence shown 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, but having one or more such mutations; and / or an immunoglobulin heavy chain (or V H)Variant, which has the amino acid sequence shown 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, but has one or more such mutations. In one embodiment, the TfR-binding protein comprises: a variant of the immunoglobulin light chain containing CDR-L1, CDR-L2 and CDR-L3, wherein one or more (e.g., 1, 2 or 3) of such CDRs have one or more such mutations (e.g., conservative substitutions); and / or a variant of the immunoglobulin heavy chain containing CDR-H1, CDR-H2 and CDR-H3, wherein one or more (e.g., 1, 2 or 3) of such CDRs have one or more such mutations (e.g., conservative substitutions).

[0163] The following references are involved: BLAST algorithms commonly used in sequence analysis: BLAST ALGORITHMS: Altschul et al., (2005) FEBS J. 272(20):5101 - 5109; Altschul, S.F. et al., (1990) J. Mol. Biol. 215:403 - 410; Gish, W. et al., (1993) Nature Genet. 3:266 - 272; Madden, T.L. et al., (1996) Meth. Enzymol. 266:131 - 141; Altschul, S.F. et al., (1997) Nucleic Acids Res. 25:3389 - 3402; Zhang, J. et al., (1997) Genome Res. 7:649 - 656; Wootton, J.C. et al., (1993) Comput. Chem. 17:149 - 163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67 - 70; alignment scoring systems: Dayhoff, M.O. et al., “A model of evolutionary change in proteins.”, Atlas of Protein Sequence and Structure, (1978) Vol. 5 Suppl. 3, M.O. Dayhoff (ed.), pp. 345 - 352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R.M., et al., “Matrices for detecting distant relationships.” Atlas of Protein Sequence and Structure, (1978) Vol. 5 Suppl. 3, M.O. Dayhoff (ed.), pp. 353 - 358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S.F., (1991) J. Mol. Biol. 219:555 - 565; States, D.J. et al., (1991) Methods 3:66 - 70; Henikoff, S. et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915 - 10919; Altschul, S.F. et al., (1993) J. Mol. 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, S.F. “Evaluating the statistical significance of multiple distinct local alignments.”, Theoretical and Computational Methods in Genome Research (S. Suhai ed.), (1997) pp. 1-14, Plenum, N.Y..

[0164] A “conservative modification variant” or “conservative substitution” (e.g., of an immunoglobulin chain as described herein) refers to a variant in which one or more amino acids in a polypeptide are replaced with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.). Such changes can be made frequently without significantly disrupting the biological activity of the antibody or fragment. Those skilled in the art recognize that, generally speaking, single amino acid substitutions in non-essential regions of a polypeptide will not substantially alter biological activity (see, e.g., Watson et al., (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th ed.)). In addition, substitutions of amino acids with similar structure or function are not likely to significantly disrupt biological activity. The present disclosure includes TfR-binding proteins containing such conservative modification variants of immunoglobulin chains.

[0165] Examples of groups of amino acids having chemically similar side chains include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxy 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 having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., (1992) Science 256:1443-45.

[0166] The antibodies and antigen-binding fragments described herein comprise immunoglobulin chains that include the amino acid sequences (and variants thereof) shown specifically herein, as well as post-translational modifications in cells and in vitro for the antibody or fragment. For example, the present disclosure includes antibodies and antigen-binding fragments thereof that specifically bind to TfR having the heavy chain amino acid sequence and / or light chain amino acid sequence shown herein, and 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 pyroglutamate (pyroE), and / or the C-terminal lysine or other amino acids are deleted.

[0167] In one embodiment, the anti-hTtR:payload or anti-hTtR:payload (e.g., in the form of a scFv, Fab, antibody, or antigen-binding fragment thereof) (e.g., where the payload is human GAA) exhibits one or more of the following characteristics:

[0168] · An affinity (K D ) for binding to human TfR in surface plasmon resonance format at 25 °C of about 41 nM or higher (e.g., about 1 nM or 0.1 nM, or about 0.18 nM to about 1.2 nM, or higher);

[0169] · An affinity (K D ) for binding to monkey TfR in surface plasmon resonance format at 25 °C of about 0 nM (no detectable binding) or higher (e.g., about 20 nM or higher);

[0170] · A ratio of K D for binding to monkey TfR / human TfR in surface plasmon resonance format at 25 °C of 0 to 278 (e.g., about 17 or 18);

[0171] · When in Fab form (IgG1), blocks about 3%, 5%, 10%, or 13% of hTfR (e.g., Hmm-hTFRC, such as REGN2431) binding to human Holo-Tf, e.g., no more than about 45% block;

[0172] · When in scFv (VK-V H ) form, blocks about 6%, 8%, 10%, or 13% of hTtR (e.g., Hmm-hTFRC, such as REGN2431) binding to human Holo-Tf, e.g., no more than about 45% block;

[0173] · When in scFv (V H -V L)When in the form of, it blocks the binding of approximately 11%, 17%, 23%, or 26% of hTfR (e.g., Hmm-hTFRC, such as REGN2431) to human Holo-Tf, for example, no more than approximately 45% blockage;

[0174] · When in the form of anti-hTfR scFv:hGAA, mice (e.g., Tfrc hum / hum knock-in mice) administered the molecule via HDD showed a ratio of mature hGAA protein in the brain (normalized to the ratio of the positive control 8D3:GAA scFv) of approximately 1 or greater, 0.67 or greater, 1.08 or greater, 0.91 or greater, 0.65 or greater, 0.55 or greater, 0.50 or greater, 0.27 or greater, 0.72 or greater, 1.05 or greater, 0.49 or greater, 0.29 or greater, 1.29 or greater, 1.72 or greater, 1.79 or greater, 3.08 or greater, 1.24 or greater, 0.59 or greater, or 0.47 or greater (or approximately 1 to 2 or greater); or delivery of mature human GAA protein to the human brain to which the scFv:hGAA molecule has been administered;

[0175] · When in the form of anti-hTfR scFv:hGAA, mice (e.g., Tfrc hum / hum knock-in mice) administered the molecule via HDD showed a ratio of mature hGAA protein in the brain parenchyma (normalized to the ratio of the positive control 8D3:GAA scFv) of approximately 0.44, 0.05, 1.13, or 0.60 (approximately 0.1 to 1.2); or delivery of mature human GAA protein to the human brain parenchyma to which the scFv:hGAA molecule has been administered;

[0176] · When in the form of anti-hTfR scFv:hGAA, mice (e.g., Tfrc hum / hum knock-in mice) administered the molecule via HDD showed a ratio of mature hGAA protein in the quadriceps (normalized to the ratio of the positive control 8D3:GAA scFv) of approximately 0.67, 1.80, 1.78, or 7.74 (approximately 1 to 2); or delivery of mature human GAA protein to the human quadriceps or other muscle tissues to which the scFv:hGAA molecule has been administered;

[0177] · When in the form of anti-hTfR scFv:hGAA, mice (e.g., Tfrc humThe knock-in mice exhibited a ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAA scFv) of approximately 0.94, 0.49, 0.61, or 1.90 (about 0.1 to 1.2); or delivering mature human GAA protein to the human brain parenchyma that has been administered the scFv:hGAA molecule by viral (e.g., AAV), hepatic depot, or parenteral delivery in the form of a scFv:hGAA fusion protein;

[0178] · When in the form of anti-hTfR scFv:hGAA, delivering mature hGAA protein to the serum, liver, brain, cerebellum, spinal cord, heart, and / or quadriceps of mice (e.g., Tfrc hum knock-in mice) that have been administered this molecule by AAV8 hepatic depot; or delivering mature human GAA protein to the human serum, liver, brain, cerebellum, spinal cord, heart, and / or quadriceps that has been administered the scFv:hGAA molecule by viral (e.g., AAV), hepatic depot, or parenteral delivery in the form of a scFv:hGAA fusion protein;

[0179] · When in the form of anti-hTfR scFv:hGAA, reducing the glycogen stored in the brain, cerebellum, spinal cord, heart, and / or quadriceps of mice (e.g., Tfrc hum knock-in mice) that have been administered this molecule by AAV8 hepatic depot; e.g., reducing by at least 75% to greater than 95% or greater than 99%; or reducing the glycogen stored in the human brain, cerebellum, spinal cord, heart, and / or quadriceps that has been administered the scFv:hGAA molecule by viral (e.g., AAV), hepatic depot, or parenteral delivery in the form of a scFv:hGAA fusion protein;

[0180] · Relative to untreated Gaa - / - / Tfrc hum mice, reducing the glycogen level in the tissues (e.g., cerebellum) of Gaa - / - / Tfrc hum mice treated with AAV8 hepatic depot anti-hTFRC scfv:hGAA (e.g., 4e11 vg / kg AAV8) by at least about 90% (e.g., about 95% or greater);

[0181] · Relative to untreated Gaa - / - / Tfrc hum mice, reducing the glycogen level in the tissues (e.g., cerebellum) of Gaa - / - / Tfrc humGlycogen levels in tissues of a mouse (e.g., quadriceps muscle) are reduced by at least about 89% (e.g., about 90% or 91% greater); or glycogen levels in human tissues (e.g., quadriceps muscle) treated with the fusion protein (e.g., by parenteral delivery of the fusion protein) are reduced;

[0182] · When administered to Tfrc (e.g., by HDD or free-form AAV8 liver depot) hum in a mouse, it does not cause abnormal iron homeostasis; e.g., wherein the mouse maintains normal serum, heart, liver, and / or spleen iron levels, normal total iron binding capacity (TIBC), and / or normal hepcidin levels); or when administered to a human (e.g., by parenteral delivery of the fusion protein), it does not cause abnormal iron homeostasis;

[0183] · When, for example, in an AAV8 vector, delivered by chromosomal insertion (e.g., into the albumin locus) or in free form to a subject (e.g., delivered to a human or a Gaa - / - / Tfrc hum / hum mouse), the DNA encoding the fusion protein causes mature human GAA expression in serum, liver, brain, and / or quadriceps muscle; and / or

[0184] · When, for example, in an AAV8 vector, delivered by chromosomal insertion (e.g., into the albumin locus) or in free form (e.g., delivered to a human or a Gaa - / - / Tfrc hum / hum mouse), the DNA encoding the fusion protein reduces glycogen levels in the brain and / or quadriceps muscle.

[0185] *Tfrc hum or Tfrc hum / hum is a homozygous knock-in mouse.

[0186] 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 anti-human transferrin receptor antigen-binding proteins of the fusions 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., scFv and Fab) fused to a payload, which antibodies and antigen-binding fragments comprise the HCVR and LCVR of the molecules in Table A; or comprise the CDRs of the molecules in Table A. In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #23 or #25 in Table A, or comprise the CDRs of #23 or #25 in Table A. In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #23 in Table A, or comprise the CDRs of #23 in Table A. In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #14 in Table A, or comprise the CDRs of #14 in Table A. In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #18 in Table A, or comprise the CDRs of #18 in Table A.

[0187] In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #27 in Table A, or comprise the CDRs of #27 in Table A. In one specific example, the anti-human transferrin receptor 1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprise the HCVR and LCVR of #28 in Table A, or comprise the CDRs of #28 in Table A.

[0188] Table A. SEQ ID NOs of domains in antibodies, antigen-binding fragments (e.g., Fab or scFv molecules), or fusion proteins (anti-hTfR: payload) H31874B

[0189]

[0190] 69323 (REGN16816 anti-hTfR

[0191] HCVR(V H ) nucleotide sequence

[0192]

[0193] HCVR(V H ) amino acid sequence

[0194]

[0195] HCDR1: GFAFSSYA (SEQ ID NO:3)

[0196] HCDR2: ISGIGGST (SEQ ID NO:4)

[0197] HCDR3: AKGGAARRMEYFQY (SEQ ID NO:5)

[0198] LCVR(V L ) nucleotide sequence

[0199]

[0200] LCVR(V L ) amino acid sequence

[0201]

[0202] LCDR1: QGISNY (SEQ ID NO:8)

[0203] LCDR2: AAS (SEQ ID NO:9)

[0204] LCDR3: QKYNSAPLT (SEQ ID NO:10)

[0205] 31863B

[0206] HCVR(V H ) nucleotide sequence

[0207]

[0208] HCVR(V H ) amino acid sequence

[0209]

[0210] HCDR1: GFTFNSYA (SEQ ID NO:13)

[0211] HCDR2: IGGSTGNT (SEQ ID NO:14)

[0212] HCDR3: AKGGAARRMEYFQH (SEQ ID NO:15)

[0213] LCVR(V L ) nucleotide sequence

[0214]

[0215] LCVR(V L ) amino acid sequence

[0216] LCDR1: QGISNY (SEQ ID NO:18)

[0217] LCDR2: AAS (SEQ ID NO:19)

[0218] LCDR3: QNHNSVPLT (SEQ ID NO:20) 69348

[0220] HCVR(V H ) nucleotide sequence

[0221]

[0222] HCVR(V H ) amino acid sequence

[0223]

[0224] HCDR1: GFTFTTYG (SEQ ID NO:23)

[0225] HCDR2: IWYDGSNK (SEQ ID NO:24)

[0226] HCDR3: TRTHGYTRSSDGFDY (SEQ ID NO:25)

[0227] LCVR(V L ) nucleotide sequence

[0228]

[0229] LCVR(V L ) amino acid sequence

[0230]

[0231] LCDR1: QSIRNV (SEQ ID NO:28)

[0232] LCDR2: AAS (SEQ ID NO:29)

[0233] LCDR3: LQHNFYPLT (SEQ ID NO:30) 69340

[0235] HCVR(V H ) nucleotide sequence

[0236]

[0237] HCVR(V H ) Amino acid sequence

[0238]

[0239] HCDR1: GFTFDDKA (SEQ ID NO:33)

[0240] HCDR2: ISWNSGTI (SEQ ID NO:34)

[0241] HCDR3: AKDGDTSGWYWYGLDV (SEQ ID NO:35)

[0242] LCVR(V L ) Nucleotide sequence

[0243]

[0244] LCVR(V L ) Amino acid sequence

[0245]

[0246] LCDR1: QSVSSY (SEQ ID NO:38)

[0247] LCDR2: DVS (SEQ ID NO:39)

[0248] LCDR3: QQRSDWPIT (SEQ ID NO:40) 69331

[0250] HCVR(V H ) Nucleotide sequence

[0251]

[0252] HCVR(V H ) Amino acid sequence

[0253]

[0254] HCDR1: GFTFSVYG (SEQ ID NO:43)

[0255] HCDR2: ISHDGNIK (SEQ ID NO:44)

[0256] HCDR3: AKDTWNSLDTFDI (SEQ ID NO:45)

[0257] LCVR(V L ) nucleotide sequence

[0258]

[0259] LCVR(V L ) amino acid sequence

[0260]

[0261] LCDR1: QGISSY (SEQ ID NO:48)

[0262] LCDR2: AAS (SEQ ID NO:49)

[0263] LCDR3: QQLNSYPLT (SEQ ID NO:50) 69332

[0265] HCVR(V H ) nucleotide sequence

[0266]

[0267] HCVR(V H ) amino acid sequence

[0268]

[0269] HCDR1: GFSLNTYGMF (SEQ ID NO:53)

[0270] HCDR2: IHWDDDK (SEQ ID NO:54)

[0271] HCDR3: ARGHNNLNYIIH (SEQ ID NO:55)

[0272] LCVR(V1) nucleotide sequence

[0273]

[0274] LCVR(V L ) amino acid sequence

[0275]

[0276] LCDR1: QGIRND (SEQ ID NO:58)

[0277] LCDR2: AAS (SEQ ID NO:59)

[0278] LCDR3: LQDYNYPFT (SEQ ID NO:60) 69326

[0280] HCVR(V H ) nucleotide sequence

[0281]

[0282] HCVR(V H ) amino acid sequence

[0283]

[0284] HCDR1: GFIFSSYE (SEQ ID NO:63)

[0285] HCDR2: ISSSGSTI (SEQ ID NO:64)

[0286] HCDR3: VSGVVLFDV (SEQ ID NO:65)

[0287] LCVR(V L ) nucleotide sequence

[0288]

[0289] LCVR(V L ) amino acid sequence

[0290]

[0291] LCDR1: QSVSSN (SEQ ID NO:68)

[0292] LCDR2: SAS (SEQ ID NO:69)

[0293] LCDR3: QQYNIWPRT (SEQ ID NO:70) 69329

[0295] HCVR(V H ) nucleotide sequence

[0296]

[0297] HCVR(V H ) amino acid sequence

[0298]

[0299] HCDR1: GFTFSNYW (SEQ ID NO:73)

[0300] HCDR2: IKEDGSEK (SEQ ID NO:74)

[0301] HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO:75)

[0302] LCVR(V L ) nucleotide sequence

[0303]

[0304] LCVR(V L ) amino acid sequence

[0305]

[0306] LCDR1: QGISSW (SEQ ID NO:78)

[0307] LCDR2: AAS (SEQ ID NO:79)

[0308] LCDR3: QKANSFPYT (SEQ ID NO:80)

[0309] scFv:hGAA) 69307 (REGN16817 anti-hTfR scFv:hGAA)

[0310] HCVR(V H ) nucleotide sequence

[0311]

[0312] HCVR(V H ) amino acid sequence

[0313]

[0314] HCDR1: GFTFDDYA (SEQ ID NO:83)

[0315] HCDR2: ISWNSGYI (SEQ ID NO:84)

[0316] HCDR3: ARGGSTLVRGVKGGYYGMDV (SEQ ID NO:85)

[0317] LCVR(V L ) nucleotide sequence

[0318]

[0319] LCVR(V L ) amino acid sequence

[0320]

[0321] LCDR1: QSISSY (SEQ ID NO:88)

[0322] LCDR2: AAS (SEQ ID NO:89)

[0323] LCDR3: QQSYSIPLT (SEQ ID NO:90) 69305

[0325] HCVR(V H ) nucleotide sequence

[0326]

[0327] HCVR(V H ) amino acid sequence

[0328]

[0329] HCDR1: GFTFSSYG (SEQ ID NO:93)

[0330] HCDR2: IWYDGSNK (SEQ ID NO:94)

[0331] HCDR3: AGQLDLFFDY (SEQ ID NO:95)

[0332] LCVR(V L ) nucleotide sequence

[0333]

[0334] LCVR(V L ) amino acid sequence

[0335] LCDR1: QSIDRY (SEQ ID NO:98)

[0336] LCDR2: TTS (SEQ ID NO:99)

[0337] LCDR3: QQSYSPPLT (SEQ ID NO:100)

[0338] 12798B (REGN17078 Fab:REGN17072 scFv:REGN16818 anti-hTfR scFv:hGAA)

[0339] HCVR(V H ) nucleotide sequence

[0340]

[0341] HCVR(V H ) Amino acid sequence

[0342]

[0343] HCDR1: GFTFSNYW (SEQ ID NO:103)

[0344] HCDR2: IKEDGSEK (SEQ ID NO:104)

[0345] HCDR3: ARDGEQLVDYYYYYVMDV (SEQ ID NO:105)

[0346] LCVR(V L ) Nucleotide sequence

[0347]

[0348] LCVR(V L ) Amino acid sequence

[0349]

[0350] LCDR1: QGISSW (SEQ ID NO:108)

[0351] LCDR2: AAS (SEQ ID NO:109)

[0352] LCDR3: QKADSLPYA (SEQ ID NO:110)

[0353] 12795B

[0354] HCVR(V H ) Nucleotide sequence

[0355]

[0356] HCVR(V H ) Amino acid sequence

[0357]

[0358] HCDR1: GFTFTSYD (SEQ ID NO:113)

[0359] HCDR2: ISGSGGNT (SEQ ID NO:114)

[0360] HCDR3: TRSHDFGAFDYFDY (SEQ ID NO:115)

[0361] LCVR(V L ) nucleotide sequence

[0362]

[0363] LCVR(V L ) amino acid sequence

[0364]

[0365] LCDR1: QGIRDH (SEQ ID NO:118)

[0366] LCDR2: AAS (SEQ ID NO:119)

[0367] LCDR3: LQYDTYPLT (SEQ ID NO:120)

[0368] 12799B (REGN17079 Fab:REGN17073 scFv:REGN16819 anti-hTfR scFv:hGAA)

[0369] HCVR(V H ) nucleotide sequence

[0370]

[0371] HCVR(V H ) amino acid sequence

[0372]

[0373] HCDR1: GFTFDDYA (SEQ ID NO:123)

[0374] HCDR2: ISWNSATR (SEQ ID NO:124)

[0375] HCDR3: AKDMDISLGYYGLDV (SEQ ID NO:125)

[0376] LCVR(V L ) nucleotide sequence

[0377]

[0378] LCVR(V L ) amino acid sequence

[0379]

[0380] LCDR1: QTVSSN (SEQ ID NO:128)

[0381] LCDR2: GSS (SEQ ID NO:129)

[0382] LCDR3: QQYNNWPPYT (SEQ ID NO:130)

[0383] 12802B (REGN16820 anti-hTfR scFv:hGAA)

[0384] HCVR(V H ) nucleotide sequence

[0385]

[0386] HCVR(V H ) amino acid sequence

[0387]

[0388] HCDR1: GFSLSTSGVG (SEQ ID NO:133)

[0389] HCDR2: IYWNDHK (SEQ ID NO:134)

[0390] HCDR3: AHYSGSYSYYYYGLDV (SEQ ID NO:135)

[0391] LCVR(V L ) nucleotide sequence

[0392]

[0393] LCVR(V L ) amino acid sequence

[0394]

[0395] LCDR1: QGIASW (SEQ ID NO:138)

[0396] LCDR2: AAS (SEQ ID NO:139)

[0397] LCDR3: QQANYFPWT (SEQ ID NO:140)

[0398] 12801B

[0399] HCVR(V H ) nucleotide sequence

[0400]

[0401] HCVR(VH ) Amino acid sequence

[0402]

[0403] HCDR1: GFTFTSYA (SEQ ID NO:143)

[0404] HCDR2: IRGSGGGT (SEQ ID NO:144)

[0405] HCDR3: ARSHDYGAFDFFDY (SEQ ID NO:145)

[0406] LCVR(V L ) Nucleotide sequence

[0407]

[0408] LCVR(V L ) Amino acid sequence

[0409]

[0410] LCDR1: QGIRTD (SEQ ID NO:148)

[0411] LCDR2: AAS (SEQ ID NO:149)

[0412] LCDR3: LQYNSYPLT (SEQ ID NO:150)

[0413] 12812B (REGN16821 anti-hTfR scFv:hGAA)

[0414] HCVR(V H ) Nucleotide sequence

[0415]

[0416] HCVR(V H ) Amino acid sequence

[0417]

[0418] HCDR1: GFTFSDYF (SEQ ID NO:153)

[0419] HCDR2: ISSTGSTI (SEQ ID NO:154)

[0420] HCDR3: TRDNWNYEY (SEQ ID NO:155)

[0421] LCVR(V LNucleotide sequence

[0422]

[0423] LCVR(V L )Amino acid sequence

[0424]

[0425] LCDR1: QSVSIN (SEQ ID NO:158)

[0426] LCDR2: VAS (SEQ ID NO:159)

[0427] LCDR3: QQYDIWPYT (SEQ ID NO:160)

[0428] 12808B

[0429] HCVR(V H )Nucleotide sequence

[0430]

[0431] HCVR(V H )Amino acid sequence

[0432]

[0433] HCDR1: GESISSNTYY (SEQ ID NO:163)

[0434] HCDR2: IDYSGTT (SEQ ID NO:164)

[0435] HCDR3: AREWGNYGYYYGMDV (SEQ ID NO:165)

[0436] LCVR(V L )Nucleotide sequence

[0437]

[0438] LCVR(V L )Amino acid sequence

[0439]

[0440] LCDR1: QGIRND (SEQ ID NO:168)

[0441] LCDR2: AAS (SEQ ID NO:169)

[0442] LCDR3: LSHNSYPWT (SEQ ID NO:170)

[0443] 12847B (REGN17083 anti-hTfR Fab:REGN17077 anti-hTfR scFv:REGN16826 anti-hTfR scFv:

[0444] HCVR(V H ) nucleotide sequence

[0445]

[0446] HCVR(V H ) amino acid sequence

[0447]

[0448] HCDR1: RGTFSSYA (SEQ ID NO:173)

[0449] HCDR2: IIPIFGTA (SEQ ID NO:174)

[0450] HCDR3: AREKGWNYFDY (SEQ ID NO:175)

[0451] LCVR(V L ) nucleotide sequence

[0452]

[0453] LCVR(V L ) amino acid sequence

[0454]

[0455] LCDR1: QGISSW (SEQ ID NO:178)

[0456] LCDR2: AAS (SEQ ID NO:179)

[0457] LCDR3: QQANSFPRT (SEQ ID NO:180)

[0458] 12816B

[0459] HCVR(V H ) nucleotide sequence

[0460]

[0461] HCVR(V H ) amino acid sequence

[0462]

[0463] HCDR1: GFTFSDYY (SEQ ID NO:183)

[0464] HCDR2: ISSSGTTI (SEQ ID NO:184)

[0465] HCDR3: AREGYGNDYYYYGIDV (SEQ ID NO:185)

[0466] LCVR(V L ) nucleotide sequence

[0467]

[0468] LCVR(V L ) amino acid sequence

[0469]

[0470] LCDR1: QSLLHGNGYNY (SEQ ID NO:188)

[0471] LCDR2: LGS (SEQ ID NO:189)

[0472] LCDR3: MQALQTPYT (SEQ ID NO:190)

[0473] 12833B

[0474] HCVR(V H ) nucleotide sequence

[0475]

[0476] HCVR(V H ) amino acid sequence

[0477]

[0478] HCDR1: GFTFSSFG (SEQ ID NO:193)

[0479] HCDR2: ISYDGSDK (SEQ ID NO:194)

[0480] HCDR3: AKENGILTDSYGMDV (SEQ ID NO:195)

[0481] LCVR(V L ) nucleotide sequence

[0482]

[0483] LCVR(V L ) Amino acid sequence

[0484]

[0485] LCDR1: QSISSY (SEQ ID NO:198)

[0486] LCDR2: AAS (SEQ ID NO:199)

[0487] LCDR3: QQSYSTPPIT (SEQ ID NO:200)

[0488] 12834B

[0489] HCVR(V H ) Nucleotide sequence

[0490]

[0491] HCVR(V H ) Amino acid sequence

[0492]

[0493] HCDR1: GYTFTSYG (SEQ ID NO:203)

[0494] HCDR2: ISVYHGNT (SEQ ID NO:204)

[0495] HCDR3: AREGYYDFWSGYYPFDY (SEQ ID NO:205)

[0496] LCVR(V L ) Nucleotide sequence

[0497]

[0498] LCVR(V L ) Amino acid sequence

[0499]

[0500] LCDR1: QSISSY (SEQ ID NO:208)

[0501] LCDR2: AAS (SEQ ID NO:209)

[0502] LCDR3: QQSYSTPPIT (SEQ ID NO:210)

[0503] 12835B

[0504] HCVR(V H ) Nucleotide sequence

[0505]

[0506] HCVR(V H ) Amino acid sequence

[0507]

[0508] HCDR1: GFTFRNYE (SEQ ID NO:213)

[0509] HCDR2: ISSSGNM K(SEQ ID NO:214)

[0510] HCDR3: ARDEFPYGMDV(SEQ ID NO:215)

[0511] LCVR(V L ) Nucleotide sequence

[0512]

[0513] LCVR(V L ) Amino acid sequence

[0514]

[0515] LCDR1: QSISSY(SEQ ID NO:218)

[0516] LCDR2: AAS(SEQ ID NO:219)

[0517] LCDR3: QQS YSTPPIT(SEQ ID NO:220)

[0518] hGAA) 12848B (REGN16827 anti-hTfR scFv:hGAA)

[0519] HCVR(V H ) Nucleotide sequence

[0520]

[0521] HCVR(V H ) Amino acid sequence

[0522]

[0523] HCDR1: GFTFDDYA(SEQ ID NO:223)

[0524] HCDR2: ISWSSGSM (SEQ ID NO:224)

[0525] HCDR3: AKAREVGDYYGMDV (SEQ ID NO:225)

[0526] LCVR(V L ) nucleotide sequence

[0527]

[0528] LCVR(V L ) amino acid sequence

[0529]

[0530] LCDR1: QSISSY (SEQ ID NO:228)

[0531] LCDR2: AAS (SEQ ID NO:229)

[0532] LCDR3: QQSYSTPPIT (SEQ ID NO:230)

[0533] 12843B (REGN17075 anti-hTfR scFv:REGN16824 anti-hTfR scFv:hGAA:REGN17081 anti-hTfR

[0534] HCVR(V H ) nucleotide sequence

[0535]

[0536] HCVR(V H ) amino acid sequence

[0537]

[0538] HCDR1: GFTFDNFG (SEQ ID NO:233)

[0539] HCDR2: LTWNSGVI (SEQ ID NO:234)

[0540] HCDR3: AKDIRNYGPFDY (SEQ ID NO:235)

[0541] LCVR(V L ) nucleotide sequence

[0542]

[0543] LCVR(V L ) amino acid sequence

[0544]

[0545] LCDR1: QSVSSSY (SEQ ID NO: 238)

[0546] LCDR2: GAS (SEQ ID NO: 239)

[0547] LCDR3: QQYGSSPWT (SEQ ID NO: 240)

[0548] Fab) 12845B (REGN17082 Fab:REGN17076 scFv:REGN16825 anti-hTfR scFv:hGAA)

[0549] HCVR(V H ) nucleotide sequence

[0550]

[0551] HCVR(V H ) amino acid sequence

[0552]

[0553] HCDR1: GFTFNIFE (SEQ ID NO: 243)

[0554] HCDR2: ISSRGTTT (SEQ ID NO: 244)

[0555] HCDR3: ARDYEATIPFDF (SEQ ID NO: 245)

[0556] LCVR(V L ) nucleotide sequence

[0557]

[0558] LCVR(V L ) amino acid sequence

[0559]

[0560] LCDR1: QSISSY (SEQ ID NO: 248)

[0561] LCDR2: AAS (SEQ ID NO: 249)

[0562] LCDR3: QQSYSTPPIT (SEQ ID NO: 250)

[0563] 12844B

[0564] HCVR(V H ) nucleotide sequence

[0565]

[0566] HCVR(V H ) Amino acid sequence

[0567]

[0568] HCDR1: GFTFDDYG (SEQ ID NO:253)

[0569] HCDR2: INWNGDRT (SEQ ID NO:254)

[0570] HCDR3: ARDQGLGVAATLDY (SEQ ID NO:255)

[0571] LCVR(V L ) Nucleotide sequence

[0572]

[0573] LCVR(V L ) Amino acid sequence

[0574]

[0575] LCDR1: QSISSY (SEQ ID NO:258)

[0576] LCDR2: AAS (SEQ ID NO:259)

[0577] LCDR3: QQSYSTPPIT (SEQ ID NO:260)

[0578] 12839B (REGN17080 Fab:REGN17074 scFv:REGN16822 anti-hTfR scFv:hGAA)

[0579] HCVR(V H ) Nucleotide sequence

[0580]

[0581] HCVR(V H ) Amino acid sequence

[0582]

[0583] HCDR1: GFTVSNYE (SEQ ID NO:263)

[0584] HCDR2: ISSSTSNI (SEQ ID NO:264)

[0585] HCDR3: VRDGIVVVPVGRGYYYYGLDV (SEQ ID NO:265)

[0586] LCVR(V L ) nucleotide sequence

[0587]

[0588] LCVR(V L ) amino acid sequence

[0589]

[0590] LCDR1: QSISSY (SEQ ID NO:268)

[0591] LCDR2: AAS (SEQ ID NO:269)

[0592] LCDR3: QQSYSTPPIT (SEQ ID NO:270)

[0593] 12841B (REGN16823 anti-hTfR scFv:hGAA)

[0594] HCVR(V H ) nucleotide sequence

[0595]

[0596] HCVR(V H ) amino acid sequence

[0597]

[0598] HCDR1: GFPFSNYV (SEQ ID NO:273)

[0599] HCDR2: IFFDGKKN (SEQ ID NO:274)

[0600] HCDR3: AKIHCPNGVCYKGYYGMDV (SEQ ID NO:275)

[0601] LCVR(V L ) nucleotide sequence

[0602]

[0603] LCVR(V L ) amino acid sequence

[0604]

[0605] LCDR1: QSISSY (SEQ ID NO:278)

[0606] LCDR2: AAS (SEQ ID NO:279)

[0607] LCDR3: QQSYSTPPIT (SEQ ID NO:280)

[0608] 12850B (REGN16828 anti-hTfR scFv:hGAA)

[0609] HCVR(V H ) nucleotide sequence

[0610]

[0611] HCVR(V H ) amino acid sequence

[0612]

[0613] HCDR1: GFTFSNYW (SEQ ID NO:283)

[0614] HCDR2: IKEDGGKK (SEQ ID NO:284)

[0615] HCDR3: AREDTTLVVDYYYYGMDV (SEQ ID NO:285)

[0616] LCVR(V L ) nucleotide sequence

[0617]

[0618] LCVR(V L ) amino acid sequence

[0619]

[0620] LCDR1: QSISSY (SEQ ID NO:288)

[0621] LCDR2: AAS (SEQ ID NO:289)

[0622] LCDR3: QQSYSTPPIT (SEQ ID NO:290)

[0623] Table B. Complete hlgG1 heavy chain sequences

[0624] HCVR(V H ) nucleotide sequence

[0625]

[0626] HCVR(V H ) Amino acid sequence

[0627]

[0628] HCDR1: GGTFNTYA (SEQ ID NO:293)

[0629] HCDR2: IIPISGIA (SEQ ID NO:294)

[0630] HCDR3: ASWNYALYYFYGMDV (SEQ ID NO:295)

[0631] LCVR(V L ) Nucleotide sequence

[0632]

[0633] LCVR(V L ) Amino acid sequence

[0634]

[0635] LCDR1: QSVSSSY (SEQ ID NO:298)

[0636] LCDR2: GAS (SEQ ID NO:299)

[0637] LCDR3: QQYGSSPWT (SEQ ID NO:300) 69261

[0639] HCVR(V H ) Nucleotide sequence

[0640]

[0641] HCVR(V H ) Amino acid sequence

[0642]

[0643] HCDR1: GFTFSVYY (SEQ ID NO:303)

[0644] HCDR2: ISSSGSTI (SEQ ID NO:304)

[0645] HCDR3: GREGYSGTYSYYGMDV (SEQ ID NO:305)

[0646] LCVR(V L ) nucleotide sequence

[0647]

[0648] LCVR(V L ) amino acid sequence

[0649]

[0650] LCDR1: QSLLHSNGYNY (SEQ ID NO:308)

[0651] LCDR2: LGS (SEQ ID NO:309)

[0652] LCDR3: MQALQTPYT (SEQ ID NO:310) 69263

[0654] HCVR(V H ) nucleotide sequence

[0655]

[0656] HCVR(VH) amino acid sequence

[0657]

[0658] HCDR1: GFTFDDYA (SEQ ID NO:313)

[0659] HCDR2: ISWNSGTR (SEQ ID NO:314)

[0660] HCDR3: VKDITISPNYYGMDV (SEQ ID NO:315)

[0661] LCVR(V L ) nucleotide sequence

[0662]

[0663] LCVR(V L ) amino acid sequence

[0664]

[0665] LCDR1: QDISHY (SEQ ID NO:318)

[0666] LCDR2: AAS (SEQ ID NO:319)

[0667] LCDR3: QKYNSVPLT (SEQ ID NO:320)

[0668] As discussed, the anti-hTfR: payload scFv fusion proteins (e.g., 31874B, 31863B, 69348, 69340, 69331, 69332, 69326, 69329, 69323, 69305, 69307, 12795B, 12798B, 12799B, 12801B, 12802B, 12808B, 12812B, 12816B, 12833B, 12834B, 12835B, 12847B, 12848B, 12843B, 12844B, 12845B, 12839B, 12841B, 12850B, 69261 or 69263) contain an optional signal peptide that is linked to the scFv (e.g., including V optionally linked by a linker L and V H ), the scFv is linked to an optional linker, and the optional linker is linked to a payload such as GAA or a variant thereof, where, for example:

[0669] (I) The optional signal peptide is, for example, the signal peptide from Mus musculus Ror1 (e.g., consisting of the amino acids MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO:500));

[0670] (II) The scFv contains:

[0671] (i) A heavy chain variable region containing HCDR1, HCDR2, and HCDR3, the HCVR having the amino acid sequence shown 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

[0672] (ii) a light chain variable region containing LCDR1, LCDR2, and LCDR3, the LCVR having the amino acid sequence shown 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;

[0673] or the scFv comprises:

[0674] (1) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 2 or 462 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof);

[0675] (2) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 12 or 463 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof);

[0676] (3) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 22 or 464 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof);

[0677] (4) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 37 or 465 (or a variant thereof);

[0678] (5) an HCVR containing HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR containing LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 47 or 466 (or a variant thereof);

[0679] (6) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 52 or 467; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 57 or 468;

[0680] (7) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 62 or 492; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 67 or 469;

[0681] (8) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 72 or 470; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 77 or 471;

[0682] (9) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 82; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 87;

[0683] (10) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 92 or 472; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 97;

[0684] (11) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 102; and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence (or a variant thereof) shown in SEQ ID NO: 107;

[0685] (12) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 112 or 473 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 117 or 474 (or a variant thereof);

[0686] (13) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof);

[0687] (14) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof);

[0688] (15) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 142 or 475 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 147 or 476 (or a variant thereof);

[0689] (16) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof);

[0690] (17) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having an amino acid sequence shown in SEQ ID NO: 162 or 477 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having an amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof);

[0691] (18) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof);

[0692] (19) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 182 or 478 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 187 or 479 (or a variant thereof);

[0693] (20) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 192 or 480 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof);

[0694] (21) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 202 or 481 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof);

[0695] (22) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof);

[0696] (23) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof);

[0697] (24) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof);

[0698] (25) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof);

[0699] (26) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 252 or 482 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof);

[0700] (27) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof);

[0701] (28) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof);

[0702] (29) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof);

[0703] (30) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof);

[0704] (31) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 302 or 483 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 307 or 488 (or a variant thereof);

[0705] (32) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 317 or 484 (or a variant thereof);

[0706] Or the scFv comprises:

[0707] (a) An HCVR that contains:

[0708] HCDR1 having the amino acid sequence shown in SEQ ID NO: 3 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof), and

[0709] HCDR3 having the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); and

[0710] An LCVR that contains:

[0711] LCDR1 having the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof), LCDR2 having the amino acid sequence shown in SEQ ID NO: 9 (or a variant thereof), and

[0712] LCDR3 having the amino acid sequence shown in SEQ ID NO: 10 (or a variant thereof);

[0713] (b) An HCVR that contains:

[0714] HCDR1 having the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof),

[0715] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), and

[0716] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 15 (or a variant thereof); and

[0717] An LCVR, the LCVR comprising:

[0718] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof),

[0719] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 19 (or a variant thereof), and

[0720] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof);

[0721] (c) An HCVR, the HCVR comprising:

[0722] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof),

[0723] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof), and

[0724] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof); and

[0725] An LCVR, the LCVR comprising:

[0726] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof),

[0727] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof), and

[0728] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof);

[0729] (d) An HCVR, the HCVR comprising:

[0730] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof),

[0731] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 34 (or a variant thereof), and

[0732] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 35 (or a variant thereof); and

[0733] An LCVR, the LCVR comprising:

[0734] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof),

[0735] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 39 (or a variant thereof), and

[0736] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof);

[0737] (e) An HCVR, the HCVR comprising:

[0738] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 43 (or a variant thereof),

[0739] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), and

[0740] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); and

[0741] An LCVR, the LCVR comprising:

[0742] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof),

[0743] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and

[0744] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof);

[0745] (f) An HCVR, the HCVR comprising:

[0746] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof),

[0747] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and

[0748] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof); and

[0749] An LCVR, the LCVR comprising:

[0750] LCDR1 having the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof),

[0751] LCDR2 having the amino acid sequence shown in SEQ ID NO: 59 (or a variant thereof), and

[0752] LCDR3 having the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof);

[0753] (g) HCVR, which HCVR comprises:

[0754] HCDR1 having the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof),

[0755] HCDR2 having the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof), and

[0756] HCDR3 having the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof); and

[0757] LCVR, which LCVR comprises:

[0758] LCDR1 having the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof),

[0759] LCDR2 having the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and

[0760] LCDR3 having the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof);

[0761] (h) HCVR, which HCVR comprises:

[0762] HCDR1 having the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof),

[0763] HCDR2 having the amino acid sequence shown in SEQ ID NO: 74 (or a variant thereof), and

[0764] HCDR3 having the amino acid sequence shown in SEQ ID NO: 75 (or a variant thereof); and

[0765] LCVR, which LCVR comprises:

[0766] LCDR1 having the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof),

[0767] LCDR2 having the amino acid sequence shown in SEQ ID NO:79 (or a variant thereof), and

[0768] LCDR3 having the amino acid sequence shown in SEQ ID NO:80 (or a variant thereof);

[0769] (i) HCVR, which HCVR contains:

[0770] HCDR1 having the amino acid sequence shown in SEQ ID NO:83 (or a variant thereof),

[0771] HCDR2 having the amino acid sequence shown in SEQ ID NO:84 (or a variant thereof), and

[0772] HCDR3 having the amino acid sequence shown in SEQ ID NO:85 (or a variant thereof); and

[0773] LCVR, which LCVR contains:

[0774] LCDR1 having the amino acid sequence shown in SEQ ID NO:88 (or a variant thereof),

[0775] LCDR2 having the amino acid sequence shown in SEQ ID NO:89 (or a variant thereof), and

[0776] LCDR3 having the amino acid sequence shown in SEQ ID NO:90 (or a variant thereof);

[0777] (j) HCVR, which HCVR contains:

[0778] HCDR1 having the amino acid sequence shown in SEQ ID NO:93 (or a variant thereof),

[0779] HCDR2 having the amino acid sequence shown in SEQ ID NO:94 (or a variant thereof), and

[0780] HCDR3 having the amino acid sequence shown in SEQ ID NO:95 (or a variant thereof); and

[0781] LCVR, which LCVR contains:

[0782] LCDR1 having the amino acid sequence shown in SEQ ID NO:98 (or a variant thereof),

[0783] LCDR2 having the amino acid sequence shown in SEQ ID NO:99 (or a variant thereof), and

[0784] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof);

[0785] (k) An HCVR that contains:

[0786] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof),

[0787] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and

[0788] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof); and

[0789] An LCVR that contains:

[0790] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof),

[0791] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), and

[0792] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof);

[0793] (1) An HCVR that contains:

[0794] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof),

[0795] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 114 (or a variant thereof), and

[0796] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 115 (or a variant thereof); and

[0797] An LCVR that contains:

[0798] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof),

[0799] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 119 (or a variant thereof), and

[0800] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof);

[0801] (m)HCVR, the HCVR contains:

[0802] HCDR1 having the amino acid sequence shown in SEQ ID NO: 123 (or a variant thereof),

[0803] HCDR2 having the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), and

[0804] HCDR3 having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); and

[0805] LCVR, the LCVR contains:

[0806] LCDR1 having the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof),

[0807] LCDR2 having the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and

[0808] LCDR3 having the amino acid sequence shown in SEQ ID NO: 130 (or a variant thereof);

[0809] (n)HCVR, the HCVR contains:

[0810] HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof),

[0811] HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and

[0812] HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and

[0813] LCVR, the LCVR contains:

[0814] LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof),

[0815] LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and

[0816] LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof);

[0817] (o)HCVR, the HCVR contains:

[0818] HCDR1 having the amino acid sequence shown in SEQ ID NO: 143 (or a variant thereof),

[0819] HCDR2 having the amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and

[0820] HCDR3 having the amino acid sequence shown in SEQ ID NO: 145 (or a variant thereof); and

[0821] LCVR, the LCVR comprising:

[0822] LCDR1 having the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof),

[0823] LCDR2 having the amino acid sequence shown in SEQ ID NO: 149 (or a variant thereof), and

[0824] LCDR3 having the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof);

[0825] (p)HCVR, the HCVR comprising:

[0826] HCDR1 having the amino acid sequence shown in SEQ ID NO: 153 (or a variant thereof),

[0827] HCDR2 having the amino acid sequence shown in SEQ ID NO: 154 (or a variant thereof), and

[0828] HCDR3 having the amino acid sequence shown in SEQ ID NO: 155 (or a variant thereof); and

[0829] LCVR, the LCVR comprising:

[0830] LCDR1 having the amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof),

[0831] LCDR2 having the amino acid sequence shown in SEQ ID NO: 159 (or a variant thereof), and

[0832] LCDR3 having the amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof);

[0833] (q)HCVR, the HCVR comprising:

[0834] HCDR1 having the amino acid sequence shown in SEQ ID NO: 163 (or a variant thereof),

[0835] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), and

[0836] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof); and

[0837] An LCVR, the LCVR comprising:

[0838] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof),

[0839] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 169 (or a variant thereof), and

[0840] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 170 (or a variant thereof);

[0841] (r)HCVR, the HCVR comprising:

[0842] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof),

[0843] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and

[0844] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and

[0845] An LCVR, the LCVR comprising:

[0846] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof),

[0847] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and

[0848] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof);

[0849] (s)HCVR, the HCVR comprising:

[0850] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 183 (or a variant thereof),

[0851] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof), and

[0852] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 185 (or a variant thereof); and

[0853] An LCVR, the LCVR comprising:

[0854] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 188 (or a variant thereof),

[0855] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 189 (or a variant thereof), and

[0856] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof);

[0857] (t)An HCVR, the HCVR comprising:

[0858] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 193 (or a variant thereof),

[0859] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof), and

[0860] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 195 (or a variant thereof); and

[0861] An LCVR, the LCVR comprising:

[0862] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof),

[0863] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 199 (or a variant thereof), and

[0864] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof);

[0865] (u)An HCVR, the HCVR comprising:

[0866] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 203 (or a variant thereof),

[0867] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), and

[0868] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 205 (or a variant thereof); and

[0869] An LCVR, the LCVR comprising:

[0870] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof),

[0871] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 209 (or a variant thereof), and

[0872] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof);

[0873] (v) An HCVR, the HCVR comprising:

[0874] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 213 (or a variant thereof),

[0875] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and

[0876] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 215 (or a variant thereof); and

[0877] An LCVR, the LCVR comprising:

[0878] An LCDR1 having the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof),

[0879] An LCDR2 having the amino acid sequence shown in SEQ ID NO: 219 (or a variant thereof), and

[0880] An LCDR3 having the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof);

[0881] (w) An HCVR, the HCVR comprising:

[0882] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof),

[0883] An HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and

[0884] An HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and

[0885] An LCVR, the LCVR comprising:

[0886] LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof),

[0887] LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and

[0888] LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof);

[0889] (x) HCVR, which HCVR comprises:

[0890] HCDR1 having the amino acid sequence shown in SEQ ID NO: 233 (or a variant thereof),

[0891] HCDR2 having the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and

[0892] HCDR3 having the amino acid sequence shown in SEQ ID NO: 235 (or a variant thereof); and

[0893] LCVR, which LCVR comprises:

[0894] LCDR1 having the amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof),

[0895] LCDR2 having the amino acid sequence shown in SEQ ID NO: 239 (or a variant thereof), and

[0896] LCDR3 having the amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof);

[0897] (y) HCVR, which HCVR comprises:

[0898] HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof),

[0899] HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and

[0900] HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and

[0901] LCVR, which LCVR comprises:

[0902] LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof),

[0903] LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and

[0904] LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof);

[0905] (z)HCVR, which HCVR comprises:

[0906] HCDR1 having the amino acid sequence shown in SEQ ID NO: 253 (or a variant thereof),

[0907] HCDR2 having the amino acid sequence shown in SEQ ID NO: 254 (or a variant thereof), and

[0908] HCDR3 having the amino acid sequence shown in SEQ ID NO: 255 (or a variant thereof); and

[0909] LCVR, which LCVR comprises:

[0910] LCDR1 having the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof),

[0911] LCDR2 having the amino acid sequence shown in SEQ ID NO: 259 (or a variant thereof), and

[0912] LCDR3 having the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof);

[0913] (aa)HCVR, which HCVR comprises:

[0914] HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof),

[0915] HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and

[0916] HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and

[0917] LCVR, which LCVR comprises:

[0918] LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof),

[0919] LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and

[0920] LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof);

[0921] (ab)HCVR, the HCVR comprising:

[0922] HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof),

[0923] HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and

[0924] HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and

[0925] LCVR, the LCVR comprising:

[0926] LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof),

[0927] LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and

[0928] LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof);

[0929] (ac)HCVR, the HCVR comprising:

[0930] HCDR1 having the amino acid sequence shown in SEQ ID NO: 283 (or a variant thereof),

[0931] HCDR2 having the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), and

[0932] HCDR3 having the amino acid sequence shown in SEQ ID NO: 285 (or a variant thereof); and

[0933] LCVR, the LCVR comprising:

[0934] LCDR1 having the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof),

[0935] LCDR2 having the amino acid sequence shown in SEQ ID NO: 289 (or a variant thereof), and

[0936] LCDR3 having the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof);

[0937] (ad)HCVR, the HCVR contains:

[0938] HCDR1 having the amino acid sequence shown in SEQ ID NO: 293 (or a variant thereof),

[0939] HCDR2 having the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), and

[0940] HCDR3 having the amino acid sequence shown in SEQ ID NO: 295 (or a variant thereof); and

[0941] LCVR, the LCVR contains:

[0942] LCDR1 having the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof),

[0943] LCDR2 having the amino acid sequence shown in SEQ ID NO: 299 (or a variant thereof), and

[0944] LCDR3 having the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof);

[0945] (ae)HCVR, the HCVR contains:

[0946] HCDR1 having the amino acid sequence shown in SEQ ID NO: 303 (or a variant thereof),

[0947] HCDR2 having the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof), and

[0948] HCDR3 having the amino acid sequence shown in SEQ ID NO: 305 (or a variant thereof); and

[0949] LCVR, the LCVR contains:

[0950] LCDR1 having the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof),

[0951] LCDR2 having the amino acid sequence shown in SEQ ID NO: 309 (or a variant thereof), and

[0952] LCDR3 having the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof);

[0953] And / or (af)HCVR, the HCVR contains:

[0954] An HCDR1 having the amino acid sequence shown in SEQ ID NO: 313 (or a variant thereof),

[0955] an HCDR2 having the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof), and

[0956] an HCDR3 having the amino acid sequence shown in SEQ ID NO: 315 (or a variant thereof); and

[0957] an LCVR, the LCVR comprising:

[0958] an LCDR1 having the amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof),

[0959] an LCDR2 having the amino acid sequence shown in SEQ ID NO: 319 ...

Claims

1. An antigen-binding protein that specifically binds to a transferrin receptor or an antigenic fragment or variant thereof, comprising: (i) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown 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; and / or (ii) An LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown 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; Optionally, it is fused with a payload.

2. The antigen-binding protein according to claim 1, comprising: (1) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 2, and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 7; (2) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 12, and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 17; (3) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 22, and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 27; (4) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 32, and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has an amino acid sequence (or a variant thereof) shown in SEQ ID NO: 37; (5) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (6) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (7) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (8) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (9) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (10) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (11) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO∶102 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (12) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (13) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 127 (or a variant thereof); (14) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (15) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (16) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (17) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof); (18) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO∶182 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (20) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO∶192 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (21) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (22) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (23) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (24) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (25) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (26) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (27) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (28) An HCVR comprising HCDR1, HCDR2, and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2, and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (29) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (30) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (31) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 307 (or a variant thereof); and / or (32) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof).

3. The antigen-binding protein according to claim 1 or 2, comprising: (1) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (2) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (3) An HCVR comprising HCDR1, HCDR2 and HCDR3 and having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising LCDR1, LCDR2 and LCDR3 and having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (4) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (5) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); and / or (6) An HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).

4. The antigen-binding protein according to any one of claims 1 to 3, which comprises: an HCVR that contains HCDR1, HCDR2, and HCDR3 and has the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR that contains LCDR1, LCDR2, and LCDR3 and has the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof).

5. The antigen-binding protein according to any one of claims 1 to 4, which comprises: (a) An HCVR, wherein the HCVR contains: HCDR1 having the amino acid sequence shown in SEQ ID NO: 3 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); and An LCVR, wherein the LCVR contains: LCDR1 having the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof), LCDR2 having the amino acid sequence shown in SEQ ID NO: 9 (or a variant thereof), and LCDR3 having the amino acid sequence shown in SEQ ID NO: 10 (or a variant thereof); (b) An HCVR, wherein the HCVR contains: HCDR1 having the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof), HCDR2 having the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), and HCDR3 having the amino acid sequence shown in SEQ ID NO: 15 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 19 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof); (c) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof); (d) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 34 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 35 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof); (e) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 43 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof); (f) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 59 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof); (g) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof); (h) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 74 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 75 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof); (i) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 83 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 84 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 90 (or a variant thereof); (i) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 94 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 95 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 98 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 99 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof); (k) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof); (1) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 114 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 115 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof); (m) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 123 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 130 (or a variant thereof); (n)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof); (o)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 143 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 145 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 149 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof); (p)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 153 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 154 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 155 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 159 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof); (q)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 163 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 169 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 170 (or a variant thereof); (r) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 175 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof); (s) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 183 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 185 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 188 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 189 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof); (t) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 193 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 195 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 199 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof); (u)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 203 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 205 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 209 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof); (v)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 213 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 215 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 219 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof); (w)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof); (x)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 233 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 235 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 239 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof); (y) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof); (z) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 253 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 254 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 255 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 259 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof); (aa) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof); (ab)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof); (ac)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 283 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 285 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 289 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof); (ad)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 293 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 295 (or a variant thereof); and LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 299 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof); (ae)HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 303 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 305 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 309 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof); and / or (af) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 313 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 315 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 319 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 320 (or a variant thereof).

6. The antigen-binding protein according to any one of claims 1 to 5, comprising: (a) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof); (b) An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 243 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 245 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 249 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof). (c) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 135 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 139 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof); (d) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 173 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO∶175 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 179 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof); (e) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 263 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 265 (or a variant thereof); and an LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 269 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof); and / or (f) HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 273 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 275 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 279 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof).

7. The antigen-binding protein according to any one of claims 1 to 6, comprising: An HCVR, wherein the HCVR comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 223 (or a variant thereof), an HCDR2 having the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and an HCDR3 having the amino acid sequence shown in SEQ ID NO: 225 (or a variant thereof); and An LCVR, wherein the LCVR comprises: an LCDR1 having the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), an LCDR2 having the amino acid sequence shown in SEQ ID NO: 229 (or a variant thereof), and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof).

8. The antigen-binding protein according to any one of claims 1 to 7, comprising: (i) an HCVR having the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof); (ii) an HCVR having the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 17 (or a variant thereof); (iii) an HCVR having the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 27 (or a variant thereof); (iv) an HCVR having the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (v) an HCVR having the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof); (vi) an HCVR having the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof); (vii) an HCVR having the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 67 (or a variant thereof); (viii) An HCVR having the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (ix) An HCVR having the amino acid sequence shown in SEQ ID NO: 82 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof); (x) An HCVR having the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof); (xi) An HCVR having the amino acid sequence shown in SEQ ID NO∶102 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 107 (or a variant thereof); (xii) An HCVR having the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (xiii) An HCVR having the amino acid sequence shown in SEQ ID NO: 122 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ IDNO: 127 (or a variant thereof); (xiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (xv) An HCVR having the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 147 (or a variant thereof); (xvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 157 (or a variant thereof); (xvii) An HCVR having the amino acid sequence shown in SEQ ID NO: 162 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ IDNO: 167 (or a variant thereof); (xviii) An HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ IDNO: 177 (or a variant thereof); (xix) An HCVR having the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 187 (or a variant thereof); (xx) An HCVR having the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 197 (or a variant thereof); (xxi) An HCVR having the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 207 (or a variant thereof); (xxii) An HCVR having the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 217 (or a variant thereof); (xxiii) An HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (xxiv) An HCVR having the amino acid sequence shown in SEQ ID NO: 232 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 237 (or a variant thereof); (XXV) An HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (xxvi) An HCVR having the amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 257 (or a variant thereof); (xxvii) An HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); (xxviii) An HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof); (xxix) An HCVR having the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 287 (or a variant thereof); (XXX) An HCVR having the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 297 (or a variant thereof); (xxxi) An HCVR having the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 307 (or a variant thereof); and / or (xxxii) An HCVR having the amino acid sequence shown in SEQ ID NO: 312 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 317 (or a variant thereof).

9. The antigen-binding protein according to any one of claims 1 to 8, comprising: (i) An HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof); (ii) An HCVR having the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 247 (or a variant thereof); (iii) An HCVR having the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); (iv) An HCVR having the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 177 (or a variant thereof); (v) An HCVR having the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 267 (or a variant thereof); and / or (vi) An HCVR having the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 277 (or a variant thereof).

10. The antigen-binding protein according to any one of claims 1 to 9, comprising: an HCVR having the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof); and an LCVR having the amino acid sequence shown in SEQ ID NO: 227 (or a variant thereof).

11. The antigen-binding protein according to any one of claims 1 to 10, wherein the transferrin receptor is a human transferrin receptor or a variant thereof.

12. The antigen-binding protein according to any one of claims 1 to 11, which is an antibody or an antigen-binding fragment thereof.

13. The antigen-binding protein according to any one of claims 1 to 12, which is a Fab.

14. The antigen-binding protein according to any one of claims 1 to 12, which is a scFv; Optionally, wherein the scFv and the payload are linked by a peptide linker, the peptide linker being -(GGGGS) m -(SEQ ID NO: 426); where m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and Optionally, wherein said scFv variable regions are linked by a peptide linker, said peptide linker being -(GGGGS) n -(SEQ ID NO: 426); wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

15. The antigen-binding protein according to claim 14, wherein the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 440 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 429 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 433 (or a variant thereof), has the amino acid sequence shown in SEQ ID NO: 442 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 438 (or a variant thereof).

16. The antigen-binding protein according to claim 14 or 15, wherein the scFv has the amino acid sequence shown in SEQ ID NO: 443 (or a variant thereof).

17. An antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof, which binds to one or more hTfR epitopes selected from the following: (a) an epitope having the sequence LLNE (SEQ ID NO: 525) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); (b) an epitope having the sequence DSTDFTGT (SEQ ID NO: 526) and / or an epitope having the sequence VKHPVTGQF (SEQ ID NO: 527) and / or an epitope having the sequence IERIPEL (SEQ ID NO: 528); (c) an epitope having the sequence LNENSYVPREAGSQKDEN (SEQ ID NO: 529); (d) an epitope having the sequence FEDL (SEQ ID NO: 519); (e) an epitope having the sequence IVDKNGRL (SEQ ID NO: 530); (f) an epitope having the sequence IVDKNGRLVY (SEQ ID NO: 531); (g) an epitope having the sequence DQTKF (SEQ ID NO: 532); (h) an epitope having the sequence LVENPGGY (SEQ ID NO: 533) and / or an epitope having the sequence PIVNAELSF (SEQ ID NO: 534) and / or an epitope having the sequence PYLGTTMDT (SEQ ID NO: 535); (i) an epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence TYKEL (SEQ ID NO: 507); (j) An epitope having the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or an epitope having the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or an epitope having the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (k) An epitope having the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (1) An epitope having the sequence GTKKDFEDL (SEQ ID NO: 512); (m) An epitope having the sequence SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO: 513); (n) An epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516); (o) An epitope having the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or an epitope having the sequence TYKELIERIPELNK (SEQ ID NO: 516); (p) An epitope having the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO: 517); (q) An epitope having the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or an epitope having the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518); (r) An epitope having the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or an epitope having the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO: 520) and / or an epitope having the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521) and / or an epitope having the sequence ISRAAAEKL (SEQ ID NO: 522) and / or an epitope having the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523) and / or an epitope having 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) epitopes contained within or overlapping with the sequence KRKLSEKLDSTDFTGTIKL (SEQ ID NO: 508) and / or epitopes contained within or overlapping with the sequence YTLIEKTMQNVKHPVTGQFL (SEQ ID NO: 509) and / or epitopes contained within or overlapping with the sequence LIERIPELNKVARAAAE (SEQ ID NO: 510); (u) epitopes contained within or overlapping with the sequence LNENSYVPREAGSQKDENL (SEQ ID NO: 511); (v) epitopes contained within or overlapping with the sequence GTKKDFEDL (SEQ ID NO: 512); (w) epitopes contained within or overlapping with the sequence SVIIVDKNGRLVYLVENPGGYVAYSK (SEQ ID NO: 513); (x) epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitopes contained within or overlapping with the sequence DQTKFPIVNAEL (SEQ ID NO: 515) and / or epitopes contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (y) epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDEN (SEQ ID NO: 514) and / or epitopes contained within or overlapping with the sequence TYKELIERIPELNK (SEQ ID NO: 516); (z) epitopes contained within or overlapping with the sequence SVIIVDKNGRLVYLVENPGGYVAY (SEQ ID NO: 517); (aa) epitopes contained within or overlapping with the sequence IYMDQTKFPIVNAEL (SEQ ID NO: 506) and / or epitopes contained within or overlapping with the sequence FGNMEGDCPSDWKTDSTCRM (SEQ ID NO: 518); and (bb) Epitopes contained within or overlapping with the sequence LLNENSYVPREAGSQKDENLAL (SEQ ID NO: 505) and / or epitopes contained within or overlapping with the sequence LVENPGGYVAYSKAATVTGKL (SEQ ID NO: 520) and / or epitopes contained within or overlapping with the sequence IYMDQTKFPIVNAELSF (SEQ ID NO: 521) and / or epitopes contained within or overlapping with the sequence ISRAAAEKL (SEQ ID NO: 522) and / or epitopes contained within or overlapping with the sequence VTSESKNVKLTVSNVLKE (SEQ ID NO: 523) and / or epitopes contained within or overlapping with the sequence FCEDTDYPYLGTTMDT (SEQ ID NO: 524).

18. The antigen-binding protein according to claim 17, wherein the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof that binds to one or more hTfR epitopes selected from the following: (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 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); (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 LIERIPELNKVARAAAE (SEQ ID NO: 510); (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 SVIIVDKNGRLVYLVENPGGYVAYSK (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 SVIIVDKNGRLVYLVENPGGYVAY (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 LVENPGGYVAYSKAATVTGKL (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).

19. The antigen-binding protein according to claim 17 or 18, wherein the antigen-binding protein is selected from a humanized antibody or an antigen-binding fragment thereof, a human antibody or an antigen-binding fragment thereof, a murine antibody or an antigen-binding fragment thereof, a chimeric antibody or an antigen-binding fragment thereof, a monovalent Fab', a bivalent Fab2, an F(ab')3 fragment, a single-chain variable fragment (scFv), a bis-scFv, (scFv)2, a diabody, a bivalent antibody, a single-arm antibody, a minibody, a nanobody, a trisbody, a tetrabody, a disulfide-stabilized Fv protein (dsFv), a single-domain antibody (sdAb), an Ig NAR, a single-chain antibody, a bispecific antibody or a binding fragment thereof, a bispecific T cell engager (BiTE), a trispecific antibody, or a chemically modified derivative thereof.

20. A fusion protein comprising the antigen-binding protein according to any one of claims 1 to 19 and a payload fused thereto.

21. A fusion protein comprising an antigen-binding protein that specifically binds to a transferrin receptor or an antigenic fragment or variant thereof, and a payload fused thereto, wherein the antigen-binding protein binds to the human transferrin receptor with an affinity of about 41 nM D or stronger.

22. The fusion protein according to claim 20 or 21, wherein the antigen-binding protein binds to human transferrin receptor with a K of about 3 nM D or stronger affinity, or wherein the antigen-binding protein binds to human transferrin receptor with a K of about 0.45 nM to 3 nM D and binds to human transferrin receptor.

23. The fusion protein according to any one of claims 20 to 22, wherein 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.

24. The fusion protein according to any one of claims 20 to 23, wherein the payload is a lysosomal storage disease therapeutic agent (LSD-TA), optionally wherein the payload is an LSD-TA which is miglustat, eliglustat, alpha-galactosidase A, ceramidase, beta-glucosidase, sphingolipid activator protein-C activator, acid sphingomyelinase, beta-galactosidase, beta-hexosaminidase A and B, beta-hexosaminidase A, GM2-activator protein, GM3 synthase, arylsulfatase A, sphingolipid activator factor, alpha-L-iduronidase, iduronate-2-sulfatase, heparan N-sulfatase, N-acetyl-alpha-glucosaminidase, acetyl-CoA, alpha-glucosamine N-acetyltransferase, N-acetylglucosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate sulfatase, beta-galactosidase, N-acetylgalactosamine-4-sulfatase (arylsulfatase B), beta-glucuronidase, hyaluronidase, alpha-glucosidase 2, or lysosomal acid lipase; or a polypeptide or a polypeptide encoded by a human gene designated by any one of Tables C to N, or a variant thereof.

25. A fusion protein comprising an antigen-binding protein that specifically binds to the human transferrin receptor, which comprises a heavy chain variable region (HCVR or V H ) and a light chain variable region (LCVR or V L ), and the fusion protein is fused with an α-glucosidase polypeptide (GAA), Among them, those having said V H and V L The Fab binds to the human transferrin receptor with an affinity of about 0.65 nM D or greater; and Among them, 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:serum GAA protein of about 1:1 or greater when normalized to the ratio in a mouse administered 8D3 and expressing the mouse transferrin receptor.

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

27. The fusion protein according to claim 26, wherein the fusion protein has the amino acid sequence shown in SEQ ID NO: 408 (or a variant thereof), or has the amino acid sequence shown in SEQ ID NO: 405 (or a variant thereof).

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

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

30. The fusion protein according to any one of claims 20 to 28, wherein the antigen-binding protein is a scFv comprising domains arranged in the following orientation: N-heavy chain variable region - light chain variable region - GAA protein - C.

31. The fusion protein according to any one of claims 20 to 28, wherein the antigen-binding protein is a scFv comprising domains arranged in the following orientation: N-light chain variable region - heavy chain variable region - GAA protein - C.

32. The fusion protein according to any one of claims 24 to 31, wherein the antigen-binding protein is a scFv, and the scFv and GAA are linked by a peptide linker.

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

34. The fusion protein according to any one of claims 24 to 33, wherein the antigen-binding protein is a scFv, and the scFv variable regions are linked by a peptide linker.

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

36. The fusion protein according to any one of claims 24 to 35, wherein the fusion protein binds to the human transferrin receptor with an affinity of about 1×10 7 M K D or stronger.

37. The fusion protein according to any one of claims 24 to 36, comprising: (i) HCVR, the HCVR containing HCDR1, HCDR2 and HCDR3, and having the amino acid sequence shown 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) An LCVR, said LCVR contains LCDR1, LCDR2 and LCDR3, and has an amino acid sequence (or its variant) shown 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.

38. The fusion protein according to any one of claims 24 to 37, which is a scFv comprising a heavy chain variable region (V H ) and a light chain variable region (V L ), and an α-glucosidase polypeptide (GAA), wherein the V H , V L and GAA are arranged as follows: (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.

39. The fusion protein according to any one of claims 24 to 38, which has an amino acid sequence shown in a member selected from the group consisting of: SEQ ID NO: 392-423, SEQ ID NO: 321 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), SEQ ID NO: 322 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence), SEQ ID NO: 323 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence) and SEQ ID NO: 324 (optionally lacking the N-terminal MHRPRRRGTRPPPLALLAALLLAARGADA (SEQ ID NO: 500) signal sequence); or its variant.

40. The fusion protein according to any one of claims 24 to 39, wherein when the antigen-binding protein is not fused with the GAA polypeptide, it does not block more than 50% of the binding of the C-terminal fragment of the human transferrin receptor to human holotransferrin, and the binding occurs in the absence of such 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, wherein the binding of the extracellular domain of the human transferrin receptor fused with His6-myc-myc tag is pre-bound to the scFv, antibody or antigen-binding fragment, and then contacted with holotransferrin, and the holotransferrin is immobilized on the surface of the plate by binding to the anti-holotransferrin antibody bound to the plate.

42. The fusion protein according to claim 40 or 41, wherein the binding of the holotransferrin and the extracellular domain of the human transferrin receptor is measured at a concentration of about 300 pM of the extracellular domain of the human transferrin receptor in the absence of the scFv, antibody or antigen-binding fragment.

43. A fusion protein or antigen-binding protein that specifically binds to human transferrin receptor, having one or more of the following characteristics: · The affinity (K D ) for binding to human TfR in the surface plasmon resonance form at 25 °C is about 41 nM or higher; · The affinity (K D ) for binding to monkey TfR in the surface plasmon resonance format at 25 °C is about 0 nM (no detectable binding) or higher; · The ratio of [K for binding to monkey TfR D / K for binding to human TfR D in the surface plasmon resonance form at 25 °C is from 0 to 278; · When in Fab form (IgG1), it blocks about 3% to 13% of the binding of hTfR to human Holo-Tf; · When in the form of scFv(V K -V H ), it blocks the binding of approximately 6% to 13% of hTfR to human Holo-Tf; · When in the form of scFv(V H -V L ), it blocks the binding of about 11% to 26% of hTfR to human Holo-Tf; · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain (normalized to this ratio of the positive control 8D3:GAA scFv) of about 1 to 2; · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAAscFv) of about 0.1 to 1.2; · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the quadriceps (normalized to this ratio of the positive control 8D3∶GAAscFv) of about 0.67, 1.80, 1.78 or 7.74 (about 1 to 2); · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it shows a ratio of mature hGAA protein in the brain parenchyma (normalized to this ratio of the positive control 8D3:GAAscFv) of about 0.1 to 1.2; · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it delivers mature hGAA protein to serum, liver, brain, cerebellum, spinal cord, heart and / or quadriceps; · When in the form of anti-hTfR scFv:hGAA, when administered to mice expressing human transferrin receptor (optionally lacking functional endogenous GAA), it reduces glycogen stored in the brain, cerebellum, spinal cord, heart and / or quadriceps; · When containing an antigen-binding protein fused with GAA, it reduces the glycogen level in the cerebellum of mice expressing human transferrin receptor but lacking functional endogenous GAA by at least about 90% relative to untreated mice; · When containing an antigen-binding protein fused with GAA, it reduces the glycogen level in the quadriceps of mice expressing human transferrin receptor but lacking functional endogenous GAA by at least about 89% relative to untreated mice; and / or · When administered to mice expressing human transferrin receptor, it does not cause abnormal iron homeostasis.

44. A pharmaceutical composition comprising the fusion protein according to any one of claims 20 to 43 or the antigen-binding protein according to any one of claims 1 to 19 and 43 and a pharmaceutically acceptable carrier.

45. A composition or a kit, which comprises the fusion protein as described in any one of claims 20 to 43, or the antigen-binding protein as described in any one of claims 1 to 19 and 43, or their pharmaceutical composition, and an additional therapeutic agent in combination therewith.

46. The composition or the kit according to claim 45, wherein the additional therapeutic agent is selected from: agalsidase alpha, rituximab, methotrexate, intravenous immunoglobulin (IVIG), eliglustat, levalbuterol, antibiotics, cortisone, prednisone, bisphosphonates, and palivizumab.

47. The composition or the kit according to claim 45, wherein the additional therapeutic agent is selected from: beta2-adrenergic agonists, steroids, bisphosphonates, therapeutic agents for infectious diseases, vaccines, and pneumococcal vaccines.

48. A complex, which comprises the fusion protein as described in any one of claims 20 to 43, or the antigen-binding protein as described in any one of claims 1 to 19 and 43, and a human transferrin receptor polypeptide or an antigenic fragment thereof bound thereto.

49. An isolated polynucleotide, which encodes the fusion protein as described in any one of claims 20 to 43, or the antigen-binding protein as described in any one of claims 1 to 19 and 43.

50. The polynucleotide according to claim 49, which comprises the nucleotide sequence shown in SEQ ID NO: 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.

51. The polynucleotide according to claim 49 or 50, which comprises: (1) The nucleotide sequences shown in SEQ ID NO: 1 and SEQ ID NO: 6; (2) The nucleotide sequences shown in SEQ ID NO: 11 and SEQ ID NO: 16; (3) The nucleotide sequences shown in SEQ ID NO: 21 and SEQ ID NO: 26; (4) The nucleotide sequences shown in SEQ ID NO: 31 and SEQ ID NO: 36; (5) The nucleotide sequences shown in SEQ ID NO: 41 and SEQ ID NO: 46; (6) The nucleotide sequences shown in SEQ ID NO: 51 and SEQ ID NO: 56; (7) The nucleotide sequences shown in SEQ ID NO: 61 and SEQ ID NO: 66; (8) The nucleotide sequences shown in SEQ ID NO: 71 and SEQ ID NO: 76; (9) The nucleotide sequences shown in SEQ ID NO: 81 and SEQ ID NO: 86; (10) The nucleotide sequences shown in SEQ ID NO: 91 and SEQ ID NO: 96; (11) The nucleotide sequences shown in SEQ ID NO: 101 and SEQ ID NO: 106; (12) The nucleotide sequences shown in SEQ ID NO: 111 and SEQ ID NO: 116; (13) The nucleotide sequences shown in SEQ ID NO: 121 and SEQ ID NO: 126; (14) The nucleotide sequences shown in SEQ ID NO: 131 and SEQ ID NO: 136; (15) The nucleotide sequences shown in SEQ ID NO: 141 and SEQ ID NO: 146; (16) The nucleotide sequences shown in SEQ ID NO: 151 and SEQ ID NO: 156; (17) The nucleotide sequences shown in SEQ ID NO: 161 and SEQ ID NO: 166; (18) The nucleotide sequences shown in SEQ ID NO: 171 and SEQ ID NO: 176; (19) The nucleotide sequences shown in SEQ ID NO: 181 and SEQ ID NO: 186; (20) The nucleotide sequences shown in SEQ ID NO: 191 and SEQ ID NO: 196; (21) The nucleotide sequences shown in SEQ ID NO: 201 and SEQ ID NO: 206; (22) The nucleotide sequences shown in SEQ ID NO: 211 and SEQ ID NO: 216; (23) The nucleotide sequences shown in SEQ ID NO: 221 and SEQ ID NO: 226; (24) The nucleotide sequences shown in SEQ ID NO: 231 and SEQ ID NO: 236; (25) The nucleotide sequences shown in SEQ ID NO: 241 and SEQ ID NO: 246; (26) The nucleotide sequences shown in SEQ ID NO: 251 and SEQ ID NO: 256; (27) The nucleotide sequences shown in SEQ ID NO: 261 and SEQ ID NO: 266; (28) The nucleotide sequences shown in SEQ ID NO: 271 and SEQ ID NO: 276; (29) The nucleotide sequences shown in SEQ ID NO: 281 and SEQ ID NO: 286; (30) The nucleotide sequences shown in SEQ ID NO: 291 and SEQ ID NO: 296; (31) The nucleotide sequences shown in SEQ ID NO: 301 and SEQ ID NO: 306; and / or (32) The nucleotide sequences shown in SEQ ID NO: 311 and SEQ ID NO:

316.

52. A vector comprising the polynucleotide according to any one of claims 49 to 51.

53. A host cell comprising the fusion protein according to any one of claims 20 to 43, the antigen-binding protein according to any one of claims 1 to 19 and 43, the polynucleotide according to any one of claims 49 to 51, or the vector according to claim 52.

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

55. A method for producing the fusion protein according to any one of claims 20 to 43 or the antigen-binding protein according to any one of claims 1 to 19 and 43, which comprises culturing a host cell comprising a polynucleotide encoding the fusion protein or the antigen-binding protein in a medium under conditions favorable for the expression of the fusion protein or the antigen-binding protein.

56. The method according to claim 55, which comprises the following steps: (a) introducing the polynucleotide into a host cell; (b) culturing the host cell under conditions favorable for the expression of the fusion protein or the antigen-binding protein; and (c) optionally, isolating the fusion protein or the antigen-binding protein from the medium and / or the host cell; and (d) optionally, chemically conjugating the antigen-binding protein with a payload.

57. A fusion protein or an antigen-binding protein, which is a product of the method according to claim 55 or 56.

58. A container or an injection device comprising the fusion protein according to any one of claims 20 to 43 and 57 or the antigen-binding protein according to any one of claims 1 to 19, 43 and 57.

59. A method for administering to a subject the fusion protein according to any one of claims 20 to 43 and 57 or the antigen-binding protein according to any one of claims 1 to 19, 43 and 57, which comprises introducing the protein into the body of the subject.

60. The method according to claim 59, wherein the fusion protein or the antigen-binding protein is introduced into the body of the subject parenterally.

61. A method for treating or preventing lysosomal storage disease in a subject in need thereof, which comprises administering to the subject an effective amount of the fusion protein according to any one of claims 20 to 43 and 57, wherein the payload is a lysosomal storage disease therapeutic agent (LSD-TA).

62. The method according to claim 61, wherein the lysosomal storage disease is: Fabry disease, Farber lipogranulomatosis, 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 (Tay-Sachs disease), GM2-gangliosidosis (GM2-activator deficiency), GM3-gangliosidosis, metachromatic leukodystrophy, sphingolipid activator deficiency, MPS I (Scheie disease, Hurler-Scheie disease or Hurler disease), MPS II (Hunter disease), MPS IIIA (Sanfilippo syndrome type A), MPS IIIB (Sanfilippo syndrome type B), MPS IIIC (Sanfilippo syndrome type C), MPS IIID (Sanfilippo syndrome type D), MPS IVA (Morquio syndrome type A), MPS IVB (Morquio syndrome type B), MPS VI (Maroteaux-Lamy disease), MPS VII (Sly disease), MPS IX, Pompe disease (glycogen storage disease type II), or lysosomal acid lipase deficiency (LAL-D; Wolman disease).

63. The method according to claim 61 or 62, wherein one or more signs or symptoms of the LSD in the subject are alleviated after administering the fusion protein or antigen-binding protein.

64. A method for treating or preventing glycogen storage disease (GSD) in a subject in need thereof, comprising administering to the subject an effective amount of the fusion protein according to any one of claims 20 to 43 and 57.

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

66. The method according to claim 65, wherein the Pompe disease is the classical infantile-onset form of Pompe disease.

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

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

69. The method according to any one of claims 64 to 68, wherein the subject has a GAA genotype selected from the group consisting of: ASP91ASN, MET318THR, GLU521LYS, GLY643ARG, ARG725TRP; IVS1AS, T-G, -13; LYS903DEL, LEU299ARG, SER529VAL, ASP645GLU, GLU689LYS, EX1 8DEL, PRO545LEU; I-BPDEL, 525T; ARG854TER, ALA237VAL, GLY293ARG and IVS6AS, G-C, -1.

70. The method according to any one of claims 64 to 69, wherein the fusion protein is co-administered to the subject with an additional therapeutic agent.

71. The method according to claim 70, wherein the additional therapeutic agent is selected from: agalsidase alpha, rituximab, methotrexate, intravenous immunoglobulin (IVIG), alglucosidase alfa, levalbuterol, antibiotics, cortisone, prednisone, bisphosphonates, and palivizumab.

72. The method according to claim 70, wherein the additional therapeutic agent is selected from: β2 - adrenergic agonists, steroids, bisphosphonates, infectious disease therapeutic agents, vaccines, and pneumococcal vaccines.

73. The method according to any one of claims 64 to 72, wherein the subject is 1 year old or younger and exhibits symptoms selected from: · Difficulty feeding and failure to gain weight; · Poor head and neck control; · Rolling over and sitting up later than expected; · Difficulty breathing; · Lung infections; · Enlarged and thickened heart; · Heart defects; · Enlarged liver; and · Enlarged tongue.

74. The method according to any one of claims 64 to 73, wherein the subject is an adult and exhibits symptoms selected from: · Weakness in the legs, trunk, and / or arms; · Shortness of breath; · Lung infections; · Difficulty breathing during sleep; · Scoliosis; · Enlarged liver; · Enlarged tongue; and · Joint stiffness.

75. The method according to any one of claims 64 to 74, wherein after administering the fusion protein or antigen - binding protein, one or more signs or symptoms of GSD in the subject are alleviated.

76. A method for delivering a payload to a tissue or cell type in 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 and a payload fused thereto.

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

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

79. The method according to any one of claims 76 to 78, wherein the tissue is 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 (PBMC), small intestine, spleen, stomach, testis, peripheral nervous system, and / or bone / cartilage / joint.

80. The method according to any one of claims 76 to 79, wherein the cell type and the tissue associated with the cell type are as follows: (1) Brain / spinal cord / CNS tissue Endothelial cells Neurons (all types) Oligodendrocytes (and / or precursors) Pericytes Meningeal / leptomeningeal cells Arachnoid barrier cells Peripheral glia Astrocytes Glia Schwann cells Ependymal cells Microglia; (2) Eye tissue Rod photoreceptor cells Müller glial cells bipolar cells Cone photoreceptor cells Endothelial cells Cornea Sclera Optic nerve Pupillary sphincter; (3) Skeletal muscle tissue Skeletal muscle cells Fibroblasts Endothelial cells Macrophages Satellite cells; (4) Adipose tissue Adipocytes Fibroblasts T cells Macrophages B cells Dendritic cells; (5) Blood / bone marrow tissue T cells B cells Macrophages Erythroid cells Granulocytes Dendritic cells; (6) Mammary gland tissue Glandular cells T cells Fibroblasts Macrophages Endothelial cells Myoepithelial cells Adipocytes; (7) Lung / bronchus tissue Basal respiratory cells Respiratory ciliated cells Club cells Smooth muscle cells Ionocytes Macrophages Alveolar cells (type 1 and / or type 2) T cells Endothelial cells; (8) Colon tissue Distal intestinal epithelial cells Intestinal goblet cells Undifferentiated cells T cells Paneth cells B cells Enteroendocrine cells; (9) Uterus tissue Glandular and luminal cells Endometrial stromal cells Endothelial cells Smooth muscle cells T cells Macrophages; (10) Esophagus tissue Fibroblasts Squamous epithelial cells Endothelial cells Smooth muscle cells Macrophages Plasma cells T cells; (11) Heart tissue Cardiomyocytes Endothelial cells Fibroblasts Macrophages T cells B cells Dendritic cells; (12) Kidney tissue Proximal tubule cells T cells Macrophages Collecting duct cells B cells Glomeruli Fibroblasts; (13) Liver tissue Hepatocytes B cells Erythroid cells; (14) Lymph node tissue B cells T cells; (15) Ovary tissue Granulosa cells Fibroblasts Smooth muscle cells Macrophages T cells Follicular cells Fibroblasts; (16) Pancreas tissue Duct cells Pancreatic endocrine cells Smooth muscle cells Endothelial cells Macrophages Exocrine gland cells Monocytes; (17) Placenta tissue Cytotrophoblast Extravillous trophoblast cells Fibroblasts Hofbauer cells Endothelial cells; (18) Prostate tissue Prostate basal cells Prostate glandular cells Urothelial cells Endothelial cells Fibroblasts Smooth muscle cells Macrophages T cells; (19) Rectum tissue Undifferentiated cells Intestinal goblet cells Paneth cells Distal intestinal epithelial cells Enteroendocrine cells; (20) Skin tissue Langerhans cells Fibroblasts Endothelial cells Basal keratinocytes Suprabasal keratinocytes T cells Smooth muscle cells Melanocytes; (21) PBMC tissue Monocytes T cells NK cells Dendritic cells; (22) Small intestine tissue Proximal intestinal epithelial cells Undifferentiated cells Intestinal goblet cells Paneth cells; (23) Spleen tissue B cells T cells Plasma cells Macrophages; (24) Stomach tissue B cells T cells Gastric mucus-secreting cells Plasma cells Fibroblasts Macrophages; (25) Testis tissue Leydig cells Late spermatids Spermatogonia Early spermatids Macrophages Spermatocytes Peritubular cells Sertoli cells Endothelial cells; (26) Peripheral nervous system tissue Motor neurons Sensory neurons Schwann cells Dorsal root ganglia; (27) Bone / cartilage / joint tissue Chondrocytes Chondroblasts Mesenchymal cells Osteoblasts Osteoclasts.

81. The method according to any one of claims 76 to 80, which comprises piercing the body of the subject with the needle of a syringe and then injecting into the body of the subject the antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and the payload fused thereto.

82. The method according to any one of claims 76 to 81, wherein the subject has muscular dystrophy, a metabolic disease, sarcopenia or cachexia.

83. A method of expressing a fusion protein in a cell, the fusion protein comprising an antigen-binding protein that specifically binds to the transferrin receptor or an antigenic fragment or variant thereof and a payload fused thereto, the method comprising: (a) administering to the cell a gene therapy vector comprising the isolated polynucleotide according to any one of claims 49 to 51, wherein the isolated polynucleotide encodes the fusion protein; (b) integrating the isolated polynucleotide into a genomic locus of the cell; and (c) causing the cell to produce the fusion protein.

84. The method according to claim 83, which further comprises administering to the cell a nuclease reagent or one or more polynucleotides encoding the nuclease reagent, wherein the nuclease reagent cleaves a nuclease target site in the genomic locus and the isolated polynucleotide integrates into the genomic locus.

85. The method according to claim 84, wherein the nuclease reagent 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).

86. The method according to any one of claims 83 to 85, wherein the cell is in a subject.

87. The method according to any one of claims 83 to 85, wherein the cell is an isolated cell.

88. The method according to any one of claims 83 to 87, wherein the gene therapy vector is a viral vector, a naked polynucleotide or a polynucleotide complex, optionally wherein the polynucleotide complex is a lipid nanoparticle comprising the polynucleotide.

89. The method according to any one of claims 83 to 88, wherein 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.

90. The method according to any one of claims 83 to 89, wherein the gene therapy vector is an adeno-associated virus (AAV) vector, optionally wherein the gene therapy vector is a pseudotyped AAV2 / 8 chimera and / or AAV tropic to the liver.

91. The method according to any one of claims 83 to 90, wherein the genomic locus is a safe harbor locus.

92. The method 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, position 188,083,272 of human chromosome 1 or its non-human mammalian ortholog, position 3,046,320 of human chromosome 10 or its non-human mammalian ortholog, position 67,328,980 of human chromosome 17 or its non-human mammalian ortholog, the adeno-associated virus site 1 (AAVS1) on the chromosome, the naturally occurring AAV viral integration site on human chromosome 19 or its non-human mammalian ortholog, the chemokine receptor 5 (CCR5) gene, the chemokine receptor gene encoding an HIV-1 co-receptor, the mouse Rosa26 locus or its non-murine mammalian ortholog, and the albumin (alb) locus.

93. The method according to any one of claims 83 to 92, wherein the cell is a human cell.

94. The method according to any one of claims 83 to 93, wherein the cell is a hepatocyte.

Images