Brain-targeted amyloid beta binding proteins

Abstract

Bispecific protein constructs capable of binding to amyloid beta peptides or protofibrils and to human transferrin receptor 1, compositions thereof, and methods using such bispecific protein constructs.

Description

Attorney Docket No.: PGY-08025BRAIN-TARGETED AMYLOID BETA BINDING PROTEINS CROSS-RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 776,918 filed March 24, 2025, and U.S. Provisional Application Serial No 63 / 776,932, filed March 24, 2025. The entire contents of which are incorporated herein by this reference.BACKGROUND

[0002] Alzheimer’s disease (AD) is characterized by the presence of extracellular plaques and intracellular neurofibrillary tangles (NFTs) in the brain. The major protein component of these plaques is amyloid-beta (AP) peptide, a 40- to 43- amino-acid peptide cleaved from amyloid precursor protein by secretase (BACE) and a putative (gamma) secretase. Ap within these extracellular deposits are fibrillar in their character with a P-pleated sheet structure. Two forms of Ap peptides, AP40 and Ap42, are the dominant species in AD neuritic plaques, while AP40 is the prominent species in cerebrovascular amyloid associated with AD.

[0003] Therapeutic antibodies have been developed to target Ap, and some of these slow the progression of Alzheimer's disease (AD). However, the risk-benefit profile of existing Ap antibodies could be improved.

[0004] There remains a need for treatments for brain diseases characterized by amyloid beta plaques, such as Alzheimer’s.SUMMARY

[0005] The present disclosure addresses this need with bispecific protein constructs which are capable of binding to Ap and to a transferrin receptor, e.g., human transferrin receptor 1 (hTfRl), related compositions, and related methods.

[0006] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an amyloid beta (AP) binding region comprising:an immunoglobulin heavy chain variable domain (VH) (anti-AP-Vu) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, andan immunoglobulin light chain variable domain (VL) (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) a human transferrin receptor (hTfRl) binding region comprising:Attorney Docket No.: PGY-08025a VH (anti-hTfRl-Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, anda VL (anti-hTfRl-Vr) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ IDNOs: 130, 131, 132, 133, 134, and 135, respectively; b. SEQ IDNOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ IDNOs: 149, 150, 151, 152, 144, and 145, respectively; d. SEQ IDNOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ IDNOs: 159, 160, 161, 162, 163, and 164, respectively; f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively; g. SEQ IDNOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ IDNOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively; j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively; k. SEQ IDNOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively; m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ IDNOs: 191, 192, 193, 194, 195, and 196, respectively; o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ IDNOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively; s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively; t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ IDNOs: 140, 141, 264, 143, 144, and 145, respectively, and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.

[0007] In some embodiments of any or some of the foregoing or related aspects, the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

[0008] In some aspects, the disclosure provides a bispecific protein construct comprising:Attorney Docket No.: PGY-08025(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, anda VL (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ ID NOs: 130, 131, 132, 133, 134, and 135, respectively; b. SEQ ID NOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ ID NOs: 149, 150, 151, 152, 144, and 145, respectively; d. SEQ ID NOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ ID NOs: 159, 160, 161, 162, 163, and 164, respectively; f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively; g. SEQ ID NOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ ID NOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively; j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively; k. SEQ ID NOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively; m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ ID NOs: 191, 192, 193, 194, 195, and 196, respectively; o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ ID NOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively; s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively; t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ ID NOs: 140, 141, 264, 143, 144, and 145, respectively; andAttorney Docket No.: PGY-08025(c) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

[0009] In some embodiments or any or some of the foregoing or related aspects, the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region.

[0010] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, anda VL (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ ID NOs: 130, 131, 132, 133, 134, and 135, respectively; b. SEQ ID NOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ ID NOs: 149, 150, 151, 152, 144, and 145, respectively; d. SEQ ID NOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ ID NOs: 159, 160, 161, 162, 163, and 164, respectively; f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively; g. SEQ ID NOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ ID NOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively; j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively; k. SEQ ID NOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively; m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ ID NOs: 191, 192, 193, 194, 195, and 196, respectively;Attorney Docket No.: PGY-08025o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ ID NOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively; s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively; t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ ID NOs: 140, 141, 264, 143, 144, and 145, respectively; and(c) a human IgGl Fc region(i) having an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 1 or 112; and(ii) comprising a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0011] In some embodiments or any or some of the foregoing or related aspects, the amino acid mutation or set of amino acid mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0012] In some embodiments or any or some of the foregoing or related aspects, the Fc region is an IgGl, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is an IgGl Fc region. In some embodiments, the IgGl Fc region is a human or humanized IgGl Fc region.

[0013] In some embodiments or any or some of the foregoing or related aspects, the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences having at least 85% identity to that of:(a) SEQ ID NOs: 128 and 129, respectively,(b) SEQ ID NOs: 138 and 139, respectively,(c) SEQ ID NOs: 138 and 146, respectively,(d) SEQ ID NOs: 147 and 148, respectively,(e) SEQ ID NOs: 234 and 235, respectively,(f) SEQ ID NOs: 236 and 237, respectively,(g) SEQ ID NOs: 238 and 239, respectively,(h) SEQ ID NOs: 241 and 242, respectively,Attorney Docket No.: PGY-08025(i) SEQ ID NOs: 243 and 244, respectively,(j) SEQ ID NOs: 245 and 246, respectively,(k) SEQ ID NOs: 247 and 248, respectively,(l) SEQ ID NOs: 249 and 250, respectively,(m) SEQ ID NOs: 251 and 252, respectively,(n) SEQ ID NOs: 253 and 254, respectively,(o) SEQ ID NOs: 255 and 256, respectively,(p) SEQ ID NOs: 197 and 198, respectively,(q) SEQ ID NOs: 197 and 202, respectively,(r) SEQ ID NOs: 206 and 207, respectively,(s) SEQ ID NOs: 257 and 258, respectively,(t) SEQ ID NOs: 259 and 260, respectively,(u) SEQ ID NOs: 221 and 222, respectively,(v) SEQ ID NOs: 262 and 263, respectively, or(w) SEQ ID NOs: 138 and 265, respectively.

[0014] In some embodiments or any or some of the foregoing or related aspects, the anti-hTfRl-Vn and anti-hTfRl-Vr comprise amino acid sequences of:(a) SEQ ID NOs: 128 and 129, respectively,(b) SEQ ID NOs: 138 and 139, respectively,(c) SEQ ID NOs: 138 and 146, respectively,(d) SEQ ID NOs: 147 and 148, respectively,(e) SEQ ID NOs: 234 and 235, respectively,(f) SEQ ID NOs: 236 and 237, respectively,(g) SEQ ID NOs: 238 and 239, respectively,(h) SEQ ID NOs: 241 and 242, respectively,(i) SEQ ID NOs: 243 and 244, respectively,(j) SEQ ID NOs: 245 and 246, respectively,(k) SEQ ID NOs: 247 and 248, respectively,(l) SEQ ID NOs: 249 and 250, respectively,(m) SEQ ID NOs: 251 and 252, respectively,(n) SEQ ID NOs: 253 and 254, respectively,(o) SEQ ID NOs: 255 and 256, respectively,(p) SEQ ID NOs: 197 and 198, respectively,(q) SEQ ID NOs: 197 and 202, respectively,Attorney Docket No.: PGY-08025(r) SEQ ID NOs: 206 and 207, respectively,(s) SEQ ID NOs: 257 and 258, respectively,(t) SEQ ID NOs: 259 and 260, respectively,(u) SEQ ID NOs: 221 and 222, respectively,(v) SEQ ID NOs: 262 and 263, respectively, or(w) SEQ ID NOs: 138 and 265, respectively.

[0015] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vu) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, anda VL (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively; and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.

[0016] In some embodiments or any or some of the foregoing or related aspects, the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

[0017] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-AP-Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, anda VL (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) an hTfRl binding region comprising:Attorney Docket No.: PGY-08025a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively; andc) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

[0018] In some embodiments or any or some of the foregoing or related aspects, the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region.

[0019] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, anda VL (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively; and(c) a human IgGl Fc region(i) having an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 1 or 112; and(ii) comprising a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0020] In some embodiments or any or some of the foregoing or related aspects, the amino acid mutation or set of amino acid mutations is selected from the group consisting ofAttorney Docket No.: PGY-08025M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0021] In some embodiments or any or some of the foregoing or related aspects, the Fc region is an IgGl, IgG2, or IgG4 Fc region. In some embodiments, the Fc region is an IgGl Fc region. In some embodiments, the IgGl Fc region is a human or humanized IgGl Fc region.

[0022] In some embodiments or any or some of the foregoing or related aspects, the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences having at least 85% identity to that of SEQ ID NOs: 128 and 129, respectively. In some embodiments, the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences of SEQ ID NOs: 128 and 129, respectively.

[0023] In some embodiments or any or some of the foregoing or related aspects, the anti-AP-VH and anti-AP-VL comprise amino acid sequences having at least 85% identity to that of SEQ ID NOs: 271 and 272, respectively. In some embodiments, the anti-AP-Vu and anti-AP-VL comprise amino acid sequences of SEQ ID NOs: 271 and 272, respectively.

[0024] In some embodiments or any or some of the foregoing or related aspects, the Ap binding region comprises an antibody fragment. In some embodiments, the Ap binding region comprises a human or humanized antibody fragment.

[0025] In some embodiments or any or some of the foregoing or related aspects, the hTfRl binding region comprises an antibody fragment. In some embodiments, the hTfRl binding region comprises a human or humanized antibody fragment.

[0026] In some embodiments or any or some of the foregoing or related aspects, two Ap binding regions and one hTfRl binding region.

[0027] In some embodiments or any or some of the foregoing or related aspects, the hTfRl binding region comprises an scFv, a Fab, or a CrossFab.

[0028] In some embodiments or any or some of the foregoing or related aspects, the hTfRl binding region comprises a CrossFab comprising (1) a first hTfRl-binding polypeptide comprising the anti -hTfR-Vu and an immunoglobulin Ckappa domain; and (2) a second hTfRl-binding polypeptide comprising the anti -hTfR-VL and an immunoglobulin CH domain.Attorney Docket No.: PGY-08025

[0029] In some embodiments or any or some of the foregoing or related aspects, the Fc region comprises a first Fc polypeptide and a second Fc polypeptide. In some embodiments, the first and second Fc polypeptides have non-identical amino acid sequences.

[0030] In some embodiments or any or some of the foregoing or related aspects, the first and second Fc polypeptides comprise complementary Fc heterodimerization variations.

[0031] In some embodiments or any or some of the foregoing or related aspects, the hTfRl binding region is connected to the C-terminus of the first or second Fc polypeptide.

[0032] In some embodiments or any or some of the foregoing or related aspects, the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, the bispecific protein construct comprising(a) a first polypeptide comprising the anti-AP-VL,(b) a second polypeptide comprising the anti-Ap-Vu and the first Fc polypeptide, (c) a third polypeptide comprising the anti-Ap-Vu, the second Fc polypeptide, and the anti-hTfRl-Vu,(d) a fourth polypeptide comprising the anti-AP-VL, and(e) a fifth polypeptide comprising the anti-hTfRl-VL.

[0033] In some embodiments or any or some of the foregoing or related aspects, the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, the bispecific protein construct comprising(a) a first polypeptide comprising the anti-AP-VL,(b) a second polypeptide comprising the anti-Ap-Vu and the first Fc polypeptide, (c) a third polypeptide comprising the anti-Ap-Vu, the second Fc polypeptide, and an scFv comprising the anti-hTfRl-Vu and the anti-hTfRl-VL, and(d) a fourth polypeptide comprising the anti-AP-VL.

[0034] In some aspects, the disclosure provides bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-AP-Vu) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 271, anda VL (anti-Ap -VL) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 272;(b) an hTfRl binding region comprisingAttorney Docket No.: PGY-08025a VH (anti -hTfRl -VH) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 128, anda VL (anti -hTfRl -VL) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 129; and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.

[0035] In some embodiments or any or some of the foregoing or related aspects, the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

[0036] In some aspects, the disclosure provides a bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vu) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 271, anda VL (anti-Ap -VL) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 272;(b) an hTfRl binding region comprisinga VH (anti -hTfRl -VH) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 128, anda VL (anti -hTfRl -VL) having an amino acid sequence comprising the amino acid sequence of SEQ IDNO: 129; and(c) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

[0037] In some embodiments or any or some of the foregoing or related aspects, the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region. In some embodiments, the amino acid mutation or set of amino acid mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0038] In some embodiments or any or some of the foregoing or related aspects, the hTfRl binding region comprises (1) a first hTfRl-binding polypeptide comprising the antiAttorney Docket No.: PGY-08025hTfRl-Vnand an immunoglobulin Ckappa domain; and (2) a second hTfRl-binding polypeptide comprising the anti-hTfRl-VLand an immunoglobulin CH domain.

[0039] In some embodiments or any or some of the foregoing or related aspects, wherein the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, and the bispecific protein construct comprises:(a) a first polypeptide comprising the anti-Ap-Vi.,(b) a second polypeptide comprising the anti-Ap-Vu and the first Fc polypeptide, (c) a third polypeptide comprising the anti-Ap-Vu, the second Fc polypeptide, and the anti-hTfRl-Vu,(d) a fourth polypeptide comprising the anti-Ap-Vi., and(e) a fifth polypeptide comprising the anti-hTfRl-VL.

[0040] In some aspects, the disclosure provides a bispecific protein construct comprising (a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 275;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 277;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

[0041] In some aspects, the disclosure provides a bispecific protein construct comprising (a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 278;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 279;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

[0042] In some aspects, the disclosure provides a bispecific protein construct comprising (a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 283;Attorney Docket No.: PGY-08025(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 284;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

[0043] In some aspects, the disclosure provides a bispecific protein construct comprising (a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 287;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 288;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

[0044] In some aspects, the disclosure provides a bispecific protein construct, comprising (a) a first polypeptide comprising a first anti-Ap-Vi.,(b) a second polypeptide comprising a first anti-AP-Vu and a first IgGl Fc polypeptide,(c) a third polypeptide comprising a second anti-AP-Vu, a second IgGl Fc polypeptide, and an anti-hTfRl-Vu,(d) a fourth polypeptide comprising a second anti-Ap-Vi., and(e) a fifth polypeptide comprising an anti-hTfRl-VLand a constant heavy domain; whereinthe first and second anti A -VH each have an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 271,the first and second anti A -VL each have an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 272,the anti-hTfRl-Vu has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 128,the anti-hTfRl-VLhas an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 129,Attorney Docket No.: PGY-08025the first IgGl Fc polypeptide has an amino sequence comprising the amino acid sequence at least 85% identical to that of SEQ ID NO: 1; a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS); and one or more knob-in-hole mutations; the second IgGl Fc polypeptide has an amino acid sequence comprising the amino acid sequence at least 85% identical to that of SEQ ID NO: 1; a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS); and one or more knob-in-hole mutations complementary to the one or more knob-in-hole mutations on the first IgGl Fc polypeptide.

[0045] In some aspects, the disclosure provides an isolated nucleic acid encoding a polypeptide of the bispecific protein construct of any or some of the foregoing or related aspects.

[0046] In some aspects, the disclosure provides a set of isolated nucleic acids collectively encoding the bispecific protein construct of any or some of the foregoing or related aspects.

[0047] In some aspects, the disclosure provides an expression vector comprising the isolated nucleic acid of any or some of the foregoing or related aspects.

[0048] In some aspects, the disclosure provides a set of expression vectors which collectively comprise the set of isolated nucleic acids of any or some of the foregoing or related aspects.

[0049] In some aspects, the disclosure provides a host cell comprising the isolated nucleic acid, the set of nucleic acids, the expression vector, or set of expression vectors of any or some of the foregoing or related aspects.

[0050] In some embodiments or any or some of the foregoing or related aspects, the host cell is a mammalian host cell.

[0051] In some aspects, the disclosure provides a pharmaceutical composition comprising the bispecific protein construct of any or some of the foregoing or related aspects and a pharmaceutically acceptable carrier.

[0052] In some aspects, the disclosure provides a method comprising a step of administering to a subject in need thereof an effective amount of the bispecific proteinAttorney Docket No.: PGY-08025construct or the pharmaceutical composition of any or some of the foregoing or related aspects.

[0053] In some embodiments or any or some of the foregoing or related aspects, the subject has or is at risk of having amyloid beta plaques in the brain. In some embodiments, the subject has or is at risk of having Alzheimer’s disease.

[0054] In some embodiments or any or some of the foregoing or related aspects, the step of administering comprises systemic administration of the bispecific protein construct or composition. In some embodiments, the systemic administration comprises intravenous administration.BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1A depicts a schematic of an example Fab format (left) and an example CrossFab format. Image reproduced with permission from the web site whose address is “https: / / ” followed immediately by “creativecommons. org / licenses / by / 4.0 / .”

[0056] FIG. IB depicts a schematic of an example bispecific format, a “2+1” format in which one binding region takes the form of a CrossFab attached to the C-terminus of an Fc polypeptide, and two copies of other binding regions are present as Fabs. In this example of a 2+1 format, two Fc polypeptides heterodimerize via “knob-in-hole” complementary variations.

[0057] FIG. 1C depicts a schematic of an example bispecific format, a “2+1” format in which one binding region takes the form of an scFv attached to the C-terminus of an Fc polypeptide, and two copies of other binding regions are present as Fabs. In this example of a 2+1 format, two Fc polypeptides heterodimerize via “knob-in-hole” complementary variations.

[0058] FIG. 2 is an image of an SDS-PAGE gel of reduced (R) and non-reduced (NR) forms of a bispecific Ap / hTfRl antibody (Reference Antibody 2b). “M” denotes protein markers. Four micrograms were loaded per sample. The red arrow denotes the expected 175 kDa band. See Example 1.

[0059] FIG. 3 provides a graph showing surface plasma resonance (SPR) binding as a calculated dissociation constant (KD). Cyno neonatal Fc receptor FcRn (pH 5.8 & pH 7.4), human CD32aH, human CD32aR, human CD32b, human CD16aV, human CD16aF, and human CD 16b were analyzed for Reference Antibody 1, Reference Antibody 2, Reference Antibody 2b, bispecific antibody B2.1, bispecific antibody B2.1b, bispecific antibody B2.1La, and IgGl LS control.Attorney Docket No.: PGY-08025

[0060] FIG. 4 provides a graph showing serum concentration of bispecific antibody B2. lb or control antibodies Reference Antibody 1, Reference Antibody 2, and Reference Antibody 2b over time after administration at in cynomolgus monkey via intravenous injection.Animals were administered on Day 0 and serum was measured through Day 14.

[0061] FIG. 5 provides a graph showing serum concentration of bispecific antibody B2. lb or control antibodies Reference Antibody 1 and Reference Antibody 2 in cynomolgus monkey by intravenous injection as shown in in Table 12. Reference Antibody 1 treated animals were euthanized at 72 hours and Reference Antibody 2 and bispecific antibody B2.1b animals were euthanized at 168 hours with serum concentration of antibody being measured at 1, 8, 24, 72, 96, 120, and 168 hours.

[0062] FIG. 6 provides a graph showing concentration of antibody in whole brain of cynomolgus monkeys at 24, 72, and 168 hours post administration of bispecific antibody B2.1b or control antibodies Reference Antibody 1 and Reference Antibody 2.

[0063] FIG. 7 provides a graph showing concentration of antibody in serum versus whole brain of cynomolgus monkeys at 24, 72, and 168 hours post administration of bispecific antibody B2.1b or control antibodies Reference Antibody 1 and Reference Antibody 2.

[0064] FIG. 8 provides a graph showing maximum concentration (Cmax) in the brain of cynomolgus monkeys administered bispecific antibody B2.1b or control antibodies Reference Antibody 1 and Reference Antibody 2 as set forth in Table 12.

[0065] FIGs. 9 and 10 provide graphs showing maximum concentration (Cmax) in different regions of the brain of cynomolgus monkeys administered bispecific antibody B2.1b or control antibodies Reference Antibody 1 and Reference Antibody 2 as set forth in Table 12. FIG. 9 includes Choroid Plexus measurements and FIG. 10 excludes Choroid Plexus measurements.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0066] Provided herein are bi specific protein constructs which are capable of binding to Ap and to a transferrin receptor, e.g., human transferrin receptor 1 (hTfRl), related compositions, and related methods. TfR-binding (e.g., hTfRl-binding) may facilitate transport of the bispecific protein constructs across the blood brain barrier. Provided bispecific protein constructs may, in some embodiments, include a means for half-life extension, as explained further below.Attorney Docket No.: PGY-08025Definitions

[0067] As used herein, the terms “about,” “approximately,” and “comparable to,” when used herein in reference to a value, refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by "about," “approximately,” and “comparable to” in that context. For example, in some embodiments, the terms "about," “approximately,” and “comparable to” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0068] As used herein, the terms “antagonistic,” “neutralizing” or “blocking,” when used in reference to an antibody or antigen-binding fragment thereof, is intended to refer to an antibody or fragment thereof whose binding to its target results in inhibition of at least some of the biological activity of the target.

[0069] As used herein, “antibody” refers to a polypeptide whose amino acid sequence includes immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof. Antibodies in accordance with the present invention may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., IgAl, IgA2, IgGl, IgG2, IgG3, or IgG4). Those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include amino acids found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof). Moreover, those of ordinary skill in the art will appreciate that a characteristic sequence or portion of an antibody may include one or more polypeptide chains, and may include sequence elements found in the same polypeptide chain or in different polypeptide chains.

[0070] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g. Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such asAttorney Docket No.: PGY-08025that described in U.S. Pat. No. 5,500,362 or 5,821,337 may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0071] An “antigen-binding fragment” of an antibody, or “antibody fragment" comprises a portion of an intact antibody, which portion is still capable of antigen binding. In some embodiments, the antibody has a function in addition to that of antigen-binding, and an antigenbinding fragment retains that function. Typically, an antigen-binding fragment comprises the variable region of the antibody. Papain digestion of antibodies produce two identical antigenbinding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CHI). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and that is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain, including one or more cysteines from the antibody hinge region. Fab '-SH designates an Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0072] As used herein, the term “chimeric antibody” refers to an antibody that has a portion of its heavy and / or light chain identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass.

[0073] As used herein, the terms “co-administer,” “administer in combination,” “combined administration,” and like terms means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient. Thus, two or more agents that are administered in combination need not be administered together. In some embodiments, they are administered within 90 days (e.g., withinAttorney Docket No.: PGY-0802580, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day(s)), within 28 days (e.g., with 14, 7, 6, 5, 4, 3, 2, or 1 day(s), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour(s), or within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial effect is achieved.

[0074] A “complementarity determining region” (abbreviated “CDR”) is a region of hypervariability interspersed within regions that are more conserved, termed “framework regions” (abbreviated “FR”). In some embodiments, the sequences of the framework regions are identical to the framework regions in human germline sequences. In some embodiments, the sequences of the framework regions are modified with respect to the human germline sequence.

[0075] As used herein, the phrase “complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to antibodies (of the appropriate subclass) which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.

[0076] As used herein, the expression “control sequences” refers to DNA sequences necessary or advantageous for the expression of an operably linked coding sequence in a particular host organism. Control sequences that are typically suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0077] As used herein, antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and which typically vary with the antibody isotype. Examples of antibody effector functions include, but are not limited to, Clq binding and complement dependent cytotoxicity, Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis, down regulation of cell surface receptors (e.g. B cell receptor), and B cell activation.

[0078] As used herein, the term “epitope” is an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, known as the paratope, and which is comprised of the six complementary-determining regions of the antibody. A single antigen may have more than one epitope. Epitopes may be conformational or linear. A conformational epitope is comprised of spatially juxtaposed amino acids fromAttorney Docket No.: PGY-08025different segments of a linear polypeptide chain. A linear epitope is comprised of adjacent amino acid residues in a polypeptide chain.

[0079] An Fc fragment comprises the carboxy -terminal portions of both heavy chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.

[0080] As used herein, the term “humanized,” when used in reference to an antibody, refers to a form of a non-human (e.g., murine) antibody in which the antigen-binding complementarity-determining regions (CDRs) are grafted onto a human antibody framework, resulting in an antibody that is predominantly human in sequence but retains antigen specificity. A “humanized antibody” contains minimal sequences derived from non-human immunoglobulin. Typically, humanized antibodies are human immunoglobulins (recipient or acceptor antibody) in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having a desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance such as binding affinity. Generally, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence although the framework regions may include one or more amino acid substitutions that improve binding affinity. In some embodiments, no more than six amino acid substitutions in the heavy chain and no more than three amino acid substitutions are used in the light chain in the framework region. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0081] As used herein, an “isolated” nucleic acid molecule is a nucleic acid molecule that is identified and separated from at least one contaminant molecule with which it is ordinarily associated in the natural source of the antibody nucleic acid. An isolated nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from the nucleic acid molecule as they exist in natural cells.Attorney Docket No.: PGY-08025

[0082] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies may be made by a hybridoma method, such as that first described by Kohler et al., Nature 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). “Monoclonal antibodies” may also be isolated from phage antibody libraries, e.g., using techniques described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991).

[0083] As used herein, a nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is “operably linked” to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is “operably linked” to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is “operably linked” to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking may be accomplished, e.g., by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers may be used in accordance with conventional practice.

[0084] As used herein, “polypeptide,” which may be used interchangeably with “protein,” refers to a string of at least two amino acids attached to one another by a peptide bond. In some embodiments, a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides can include one or more “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain. In some embodiments, a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moi eties. In some embodiments, a single “polypeptide” (e.g., an antibodyAttorney Docket No.: PGY-08025polypeptide) may comprise two or more individual polypeptide chains, which may in some cases be linked to one another, for example by one or more disulfide bonds or other means.

[0085] As used herein, the phrase “reference level” generally refers to a level considered “normal” for comparison purposes, e.g., a level of an appropriate control. For example, in the context of half-life (e.g. serum half-life) of a protein (e.g., a binding protein) a reference level may refer to the half-life of a “reference binding protein” which may be, e.g., an immunoglobulin of the same class (e.g., IgGl, IgG2, or IgG4) having a wild-type Fc region or an Fc region lacking a half-life extending mutation. In some embodiments, the reference binding protein comprises the same complementarity-determining regions as those of the binding protein of interest (e.g., a bispecific protein construct as described herein). In some embodiments, the reference binding protein comprises the same variable regions (e.g., heavy chain and / or light chain variable region) as those of the binding protein of interest (e.g., a bispecific protein construct as described herein.)

[0086] As used herein, the phrases “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the type of disease (e.g., disease state, age, sex, and / or weight of the individual, and the ability of an antibody (or pharmaceutical composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of the antibody or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.

[0087] As used herein, to “treat” a condition or “treatment” of the condition (e.g., the conditions described herein) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.Bispecific binding proteinsAttorney Docket No.: PGY-08025

[0088] In one aspect, provided are bispecific protein constructs that are capable of binding to human amyloid beta (AP) and to a transferrin receptor, e.g., human transferrin receptor 1 (hTfRl). In some embodiments, provided bispecific protein constructs are capable of binding to an epitope of an amyloidogenic form of a human Ap peptide, e.g., Ap42. In some embodiments, provided bispecific protein constructs are capable of binding to an epitope of a protofibril of an a human Ap peptide, e.g., an Ap42 protofibril. In some embodiments, provided bispecific protein constructs are capable of binding to the N-terminus of Ap. In some embodiments, provided bispecific protein constructs are capable neutralizing toxic effects of Ap peptides or plaques.

[0089] Provided bispecific protein constructs generally comprise (1) one or more Ap binding regions, e.g., as described herein; (2) one or more TfR binding regions (e.g., one or more hTfRl binding regions), e.g., as described herein, and (3) an Fc region, e.g., as described herein.

[0090] In some embodiments, the Ap binding regions and / or the TfR binding regions (e.g., hTfRl binding regions) within bispecific protein constructs are antigen-binding antibody fragments. In some embodiments, the antigen-binding antibody fragments are fragments of monoclonal antibodies. In some embodiments, the antigen-binding antibody fragments are fragments of chimeric antibodies. In some embodiments, the antigen-binding antibody fragments are fragments of humanized or human antibodies.

[0091] Antigen-binding fragments may be, e.g., an scFv, a Fab, an scFab (single-chain Fab), or a CrossFab fragment. As used herein, the term “scFv” is used in accordance with its common usage in the art to refer to a single chain in which the VH domain and the VL domain from an antibody are joined, typically via a linker. As used herein, the term “Fab fragment” is used in accordance with its common usage in the art. Fab fragments typically comprise an entire light chain (VL and CLI domains), the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CHI). In a typical Fab format, the VH region of a binding region and a CHI domain are connected with each other on a first polypeptide chain and pair with the VL region of the same binding region and a CL (e.g., Ckappa) domain on a second polypeptide chain. In an example CrossFab format, a Vuof a binding region and a CL (e.g., Ckappa) domain are connected with each other on a first polypeptide chain and pair with the VL region of the same binding region and CHI domain, which are connected with each other on a second polypeptide chain. (See FIG. 1A.)Amyloid beta (A0) binding regionsAttorney Docket No.: PGY-08025

[0092] In some embodiments, the present disclosure provides antibodies and antigen binding fragments (also referred to herein as a binding region) that specifically bind to amyloidbeta (AP).

[0093] In some embodiments, the Ap binding region comprises a fragment crystallizable region (Fc region). In some embodiments, the Ap binding region comprises an Fc region associated to one antigen binding fragment (Fab) region ( / .< ., one Fab arm). In some embodiments, the Ap binding region comprises an Fc region associated to two Fab regions (i.e., two Fab arms).Variable Regions

[0094] In some embodiments, the Ap binding region comprises a light chain variable region (VL) and a heavy chain variable region (VH). In some embodiments, the VL comprises a VL complementarity determining region (CDR) 1 (CDR-L1), a CDR 2 (CDR-L2), and a CDR 3 (CDR-L3), and the VH comprises a VH CDR 1 (CDR-H1), a VH CDR 2 (CDR-H2), and a VH CDR 3 (CDR-H3).

[0095] The positions of the CDRs and framework regions of the antibody or antigen binding fragment thereof (or the binding region referred to herein) can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT) (on the worldwide web at imgt.cines.fr / ), and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997)). In some embodiments, VH and VL sequences identified as described herein were compared to known human germline sequences from human VH genes and human VLkappa genes (IMGT® the international ImMunoGeneTics information system® www.imgt.org). In various embodiments, the positions of the CDRs and framework regions of the antibody or antigen binding fragment thereof (or the binding region referred to herein) are determined using Kabat numbering convention.

[0096] In some embodiments, the Ap binding region comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in Table 1. In some embodiments, the Ap binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 266, CDR-H2 as set forth in SEQ ID NO: 267, and CDR-H3 as set forth in SEQ ID NO: 268. In some embodiments, the Ap binding region further comprises a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 withAttorney Docket No.: PGY-08025sequences as shown in Table 1. In some embodiments, the Ap binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 269, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 270.

[0097] In some embodiments, the Ap binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 266, CDR-H2 as set forth in SEQ ID NO: 267, and CDR-H3 as set forth in SEQ ID NO: 268, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 269, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 270.

[0098] In some embodiments, the Ap binding region comprises a heavy chain variable domain with heavy chain variable sequences as shown in Table 1. In some embodiments, the Ap binding region comprises a heavy chain variable domain which comprises a variant of a heavy chain variable sequence shown in Table 1, in that the heavy chain variable domain has (1) CDR-H1, CDR-H2, and CDR-H3 with sequences as shown for the same table of Table 1 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the heavy chain variable domain sequence shown in Table 1.

[0099] In some embodiments, the Ap binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 271, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 266, 267, and 268, respectively.

[0100] In some embodiments, the Ap binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 272, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 269, 163, and 270, respectively.

[0101] In some embodiments, the Ap binding region comprises a heavy chain variable domain as shown in Table 1 and further comprise a light chain variable region which has (1) CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in Table 1 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the light chain variable domain sequence shown in Table 1Attorney Docket No.: PGY-08025

[0102] In some embodiments, the Ap binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 271, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 266, 267, and 268, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 272, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 269, 163, and 270, respectively.

[0103] In some embodiments, the Ap binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 271.

[0104] In some embodiments, the Ap binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 272.

[0105] In some embodiments, the Ap binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 271, and a VL comprising the sequence set forth in SEQ ID NO: 272.

[0106] In some embodiments, the Ap binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 271.

[0107] In some embodiments, the Ap binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 272.

[0108] In some embodiments, the Ap binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 271; and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 272.

[0109] In some embodiments , the Ap binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (VL / ) having the amino acid of SEQ ID NO: 271 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 272.Attorney Docket No.: PGY-08025

[0110] In some embodiments, the Ap binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 271 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 272, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 266, a CDR-H2 as set forth in SEQ ID NO: 267, and a CDR-H3 as set forth in SEQ ID NO: 268, and a light chain variable domain comprising a CDR-L1 as set forth in SEQ ID NO: 269, a CDR-L2 as set forth in SEQ ID NO: 163, and a CDR-L3 as set forth in SEQ ID NO: 270.Full Chains[OHl] In some embodiments, the Ap binding region comprises (1) a full heavy chain (including constant domain) with an amino acid sequence shown for a binding protein as shown in Table 1 and (2) a full light chain (including constant domain) with an amino acid sequence as shown in Table 1. In some embodiments, the Ap binding region comprises (1) a full heavy chain (including constant domain) with an amino acid sequence having at least 85%, at least 90%, at least 92.5%, at least 95%, or at least 97.5% sequence identity to the full heavy chain sequence shown for a binding protein as shown in Table 1 and (2) a full light chain (including constant domain) with an amino acid sequence having at least 85% at least 90%, at least 92.5%, at least 95%, or at least 97.5% sequence identity to the full light chain sequence shown for in Table 1, wherein the Ap binding region comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences as shown in Table 1.

[0112] In some embodiments, the Ap binding region comprises a full heavy chain (HC) comprising the sequence set forth in SEQ ID NO: 273.

[0113] In some embodiments, the Ap binding region comprises a full heavy chain (HC) comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 273.

[0114] In some embodiments, the Ap binding region comprises a full light chain (LC) comprising the sequence set forth in SEQ ID NO: 274.

[0115] In some embodiments, the Ap binding region comprises a full light chain (LC) comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:Attorney Docket No.: PGY-08025

[0116] In some embodiments, the Ap binding region comprises a full heavy chain (HC) comprising the sequence set forth in SEQ ID NO: 273, and a full light chain (LC) comprising the sequence set forth in SEQ ID NO: 274.

[0117] In some embodiments, the Ap binding region comprises a full heavy chain (HC) comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 273; and a full light chain (LC) comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 274.Table 1. Exemplary sequences of human amyloid beta (A|J) binding regions Descript HC LC VH VL Kabation CDR- CDR CDR CDR CDR CDR- H1 -H2 -H3 -LI -L2 L3 AP 273 274 271 272 266 267 268 269 163 270 bindingregionSEQ IDNOsNote: numerical values refer to SEQ ID NOs. For instance, “274” refers to SEQ ID NO: 274.Transferrin receptor binding regions

[0118] In some embodiments, the present disclosure provides antibodies and antigen binding fragments (also referred to herein as a binding region) that specifically bind transferrin receptor (TfR). In some embodiments, the transferrin receptor is transferrin receptor 1. In some embodiments, the transferrin receptor is human transferrin receptor 1 (hTfRl). In some embodiments, the TfR binding region is capable of binding to hTfRl as set forth in SEQ ID NO: 118. In some embodiments, the hTfRl is associated with UniProt accession no. P02786.

[0119] In some embodiments, the hTfRl binding region comprises a fragment crystallizable region (Fc region). In some embodiments, the hTfRl binding region comprises an Fc region associated to one antigen binding fragment (Fab) region (i.e., one Fab arm). In some embodiments, the hTfRlbinding region comprises an Fc region associated to two Fab regions (i.e., two Fab arms).Variable RegionsAttorney Docket No.: PGY-08025

[0120] In some embodiments, the hTfRl binding region comprises a light chain variable region (VL) and a heavy chain variable region (VH). In some embodiments, the VL comprises a VL complementary determining region (CDR) 1 (CDR-L1), a CDR 2 (CDR-L2), and a CDR 3 (CDR-L3), and the VH comprises a VH CDR 1 (CDR-H1), a VH CDR 2 (CDR-H2), and a VH CDR 3 (CDR-H3).

[0121] The positions of the CDRs and framework regions of the antibody or antigen binding fragment thereof (or the binding region referred to herein) can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT) (on the worldwide web at imgt.cines.fr / ), and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997)). In some embodiments, VH and VL sequences identified as described herein were compared to known human germline sequences from human VH genes and human VLkappa genes (IMGT® the international ImMunoGeneTics information system® www.imgt.org). In various embodiments, the positions of the CDRs and framework regions of the antibody or antigen binding fragment thereof (or the binding region referred to herein) are determined using Kabat numbering convention.

[0122] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of:(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;Attorney Docket No.: PGY-08025(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively.

[0123] In some embodiments, the transferrin receptor (TfR) binding region comprises a heavy chain variable domain comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in Table 2.

[0124] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ IDAttorney Docket No.: PGY-08025NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231. In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264.

[0125] In some embodiments, the TfR binding region comprises a heavy chain variable domain with heavy chain variable sequences as shown in Table 2. In some embodiments, TfR binding regions comprise a heavy chain variable domain which comprises a variant of a heavy chain variable sequence shown in Table 2, in that the heavy chain variable domain has (1) CDR-H1, CDR-H2, and CDR-H3 with sequences as shown in Table 2 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%Attorney Docket No.: PGY-08025identical to the amino acid sequence of the heavy chain variable domain sequence shown in Table 2

[0126] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 130, 131, and 132, respectively.

[0127] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 140, 141, and 142, respectively.

[0128] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 147, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 149, 150, and 151, respectively.

[0129] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 234, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 153, 154, and 155, respectively.

[0130] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 236, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 159, 160, and 161, respectively.

[0131] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 238, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 165, 166, and 167, respectively.

[0132] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%,Attorney Docket No.: PGY-0802586%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 241, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 171, 172, and 173, respectively.

[0133] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 243, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 176, 177, and 178, respectively.

[0134] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 245, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 182, and 178, respectively.

[0135] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 247, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 183, and 178, respectively.

[0136] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 249, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 184, and 178, respectively.

[0137] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 251, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 185, and 178, respectively.

[0138] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 253, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 186, 187, and 188, respectively.Attorney Docket No.: PGY-08025

[0139] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 255, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 191, 192, and 193, respectively.

[0140] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 199, 200, and 201, respectively.

[0141] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 208, 209, and 210, respectively.

[0142] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 257, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 214, 215, and 216, respectively.

[0143] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 259, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 214, 215, and 216, respectively.

[0144] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 221, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 223, 224, and 225, respectively.

[0145] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical toAttorney Docket No.: PGY-08025SEQ ID NO: 262, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 229, 230, and 231, respectively.

[0146] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 140, 141, and 264, respectively.

[0147] In some embodiments, the TfR binding region further comprises a light chain variable domain comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in Table 2.

[0148] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively.

[0149] In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ IDAttorney Docket No.: PGY-08025NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 228. In some embodiments, the TfR binding regionAttorney Docket No.: PGY-08025comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 261. In some embodiments, the TfR binding region comprises a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0150] In some embodiments, the TfR binding region comprises a heavy chain variable domain as shown in Table 2 and further comprises a light chain variable domain which has (1) CDR-L1, CDR-L2, and CDR-L3 with sequences as shown in Table 2 and (2) an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of the light chain variable domain sequence shown in Table 2

[0151] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 129, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 133, 134, and 135, respectively.

[0152] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 139, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0153] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0154] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 148, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 152, 144, and 145, respectively.

[0155] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%,Attorney Docket No.: PGY-0802586%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 235, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 156, 157, and 158, respectively.

[0156] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 237, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 162, 163, and 164, respectively.

[0157] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 239, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 168, 169, and 170, respectively.

[0158] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 242, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 174, 240, and 175, respectively.

[0159] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 244, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0160] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 246, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0161] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 248, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.Attorney Docket No.: PGY-08025

[0162] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 250, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0163] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 252, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0164] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 254, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 189, 190, and 181, respectively.

[0165] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 256, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 194, 195, and 196, respectively.

[0166] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 198, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 203, 204, and 205, respectively.

[0167] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 203, 204, and 205, respectively.

[0168] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical toAttorney Docket No.: PGY-08025SEQ ID NO: 207, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 211, 212, and 213, respectively.

[0169] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 258, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 217, 218, and 219, respectively.

[0170] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 260, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 220, 218, and 219, respectively.

[0171] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 226, 227, and 228, respectively.

[0172] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 263, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 232, 233, and 261, respectively.

[0173] In some embodiments, the TfR binding region comprises a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 265, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0174] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135.

[0175] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ IDAttorney Docket No.: PGY-08025NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0176] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0177] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158.

[0178] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164.

[0179] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170.

[0180] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175.

[0181] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.Attorney Docket No.: PGY-08025

[0182] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0183] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0184] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0185] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0186] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181.

[0187] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196.

[0188] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domainAttorney Docket No.: PGY-08025comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205.

[0189] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213.

[0190] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219.

[0191] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219.

[0192] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 228.

[0193] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 261.

[0194] In some embodiments, the TfR binding region comprises a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0195] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%,Attorney Docket No.: PGY-0802586%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 130, 131, and 132, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 129, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 133, 134, and 135, respectively.

[0196] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 140, 141, and 142, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 139, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0197] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 140, 141, and 142, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0198] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 147, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%,Attorney Docket No.: PGY-0802581%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 148, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 152, 144, and 145, respectively.

[0199] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 234, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 153, 154, and 155, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 235, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 156, 157, and 158, respectively.

[0200] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 236, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 159, 160, and 161, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 237, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 162, 163, and 164, respectively.

[0201] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 238, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 165, 166, and 167, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 239, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 168, 169, and 170, respectively.Attorney Docket No.: PGY-08025

[0202] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 241, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 171, 172, and 173, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 242, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 174, 240, and 175, respectively.

[0203] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 243, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 177, and 178, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 244, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0204] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 245, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 182, and 178, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 246, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0205] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 247, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-Attorney Docket No.: PGY-08025H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 183, and 178, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 248, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0206] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 249, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 176, 184, and 178, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 250, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0207] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 251, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 176, 185, and 178, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 252, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 179, 180, and 181, respectively.

[0208] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 253, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 186, 187, and 188, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 254, and (ii) complementarity-determining regionsAttorney Docket No.: PGY-08025CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 189, 190, and 181, respectively.

[0209] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 255, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 191, 192, and 193, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 256, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 194, 195, and 196, respectively.

[0210] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 199, 200, and 201, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 198, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 203, 204, and 205, respectively.

[0211] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 199, 200, and 201, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 203, 204, and 205, respectively.

[0212] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%,Attorney Docket No.: PGY-0802586%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 208, 209, and 210, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 207, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 211, 212, and 213, respectively.

[0213] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 257, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 214, 215, and 216, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 258, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 217, 218, and 219, respectively.

[0214] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 259, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 214, 215, and 216, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 260, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 220, 218, and 219, respectively.

[0215] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 221, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 223, 224, and 225, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%,Attorney Docket No.: PGY-0802581%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 226, 227, and 228, respectively.

[0216] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 262, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CORED comprising the amino acid sequences of: SEQ ID NOs: 229, 230, and 231, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 263, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 232, 233, and 261, respectively.

[0217] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and (ii) complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of: SEQ ID NOs: 140, 141, and 264, respectively; and a light chain variable domain (VL) comprising (i) an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 265, and (ii) complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of: SEQ ID NOs: 143, 144, and 145, respectively.

[0218] In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in any one of SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 128. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 138. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 147. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 234. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 236. In some embodiments, the TfR binding region comprises a VH comprising the sequence setAttorney Docket No.: PGY-08025forth in SEQ ID NO: 238. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 241. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 243. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 245. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 247. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 249. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 251. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 253. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 255. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 197. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 206. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 257. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 259. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 221. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 262.

[0219] In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in any one of SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 129. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 139. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 146. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 148. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 235. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 237. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 239. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 242. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 244. In some embodiments, the TfR binding regionAttorney Docket No.: PGY-08025comprises a VL comprising the sequence set forth in SEQ ID NO: 246. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 248. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 250. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 252. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 254. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 256. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 198. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 202. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 207. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 258. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 260. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 222. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 263. In some embodiments, the TfR binding region comprises a VL comprising the sequence set forth in SEQ ID NO: 265.

[0220] In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in any one of SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, and a VL comprising the sequence set forth in any one of SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 128, and a VL comprising the sequence set forth in SEQ ID NO: 129. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 138, and a VL comprising the sequence set forth in SEQ ID NO: 139. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 138, and a VL comprising the sequence set forth in SEQ ID NO: 146. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 147, and a VL comprising the sequence set forth in SEQ ID NO: 148. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 234, and a VL comprising the sequence set forth in SEQ ID NO: 235. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 236, and aAttorney Docket No.: PGY-08025VL comprising the sequence set forth in SEQ ID NO: 237. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 238, and a VL comprising the sequence set forth in SEQ ID NO: 239. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 241, and a VL comprising the sequence set forth in SEQ ID NO: 242. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 243, and a VL comprising the sequence set forth in SEQ ID NO: 244. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 245, and a VL comprising the sequence set forth in SEQ ID NO: 246. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 247, and a VL comprising the sequence set forth in SEQ ID NO: 248. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 249, and a VL comprising the sequence set forth in SEQ ID NO: 250. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 251, and a VL comprising the sequence set forth in SEQ ID NO: 252. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 253, and a VL comprising the sequence set forth in SEQ ID NO: 254. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 255, and a VL comprising the sequence set forth in SEQ ID NO: 256. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 197, and a VL comprising the sequence set forth in SEQ ID NO: 198. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 197, and a VL comprising the sequence set forth in SEQ ID NO: 202. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 206, and a VL comprising the sequence set forth in SEQ ID NO: 207. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 257, and a VL comprising the sequence set forth in SEQ ID NO: 258. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 259, and a VL comprising the sequence set forth in SEQ ID NO: 260. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 221, and a VL comprising the sequence set forth in SEQ ID NO: 222. In some embodiments, the TfR binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 262, and a VL comprising the sequence set forth in SEQ ID NO: 263. In some embodiments, the TfRAttorney Docket No.: PGY-08025binding region comprises a VH comprising the sequence set forth in SEQ ID NO: 138, and a VL comprising the sequence set forth in SEQ ID NO: 265.

[0221] In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 147. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 234. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 236. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 238. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 241. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 243. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 245. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 247. In some embodiments, the TfR binding region comprisesAttorney Docket No.: PGY-08025a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 249. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 251. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 253. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 255. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 257. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 259. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 221. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 262. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138.

[0222] In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222,Attorney Docket No.: PGY-08025263, and 265. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 129. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 139. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 148. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 235. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 237. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 239. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 242. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 244. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 246. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 248. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 250. In some embodiments, the TfR binding region comprises a VL comprising an aminoAttorney Docket No.: PGY-08025acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 252. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 254. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 256. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 198. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 207. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 258. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 260. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 263. In some embodiments, the TfR binding region comprises a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 265.

[0223] In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138,Attorney Docket No.: PGY-08025and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 129. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 139. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 147, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 148. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 234, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 235. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 236, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 237. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence atAttorney Docket No.: PGY-08025least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 238, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 239. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 241, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 242. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 243, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 244. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 245, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 246. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 247, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 248. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 249, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 250. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 251, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 252. In someAttorney Docket No.: PGY-08025embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 253, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 254. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 255, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 256. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 198. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 197, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 202. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 206, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 207. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 257, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 258. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 259, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,Attorney Docket No.: PGY-0802592%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 260. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 221, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 222. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 262, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 263. In some embodiments, the TfR binding region comprises a VH comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 138, and a VL comprising an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 265.

[0224] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 128 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 129, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135.

[0225] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 138 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 139, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0226] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 138Attorney Docket No.: PGY-08025and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 146, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0227] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 147 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 148, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0228] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 234 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 235, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158.

[0229] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 236 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 237, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164.

[0230] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 238 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 239, wherein the VH and VL comprise a heavy chain variable domainAttorney Docket No.: PGY-08025comprising a CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170.

[0231] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 241 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 242, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175.

[0232] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 243 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 244, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0233] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 245 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 246, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0234] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 247 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 248, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domainAttorney Docket No.: PGY-08025comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0235] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 249 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 250, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0236] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 251 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 252, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181.

[0237] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 253 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 254, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181.

[0238] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 255 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 256, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196.Attorney Docket No.: PGY-08025

[0239] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 197 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 198, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205.

[0240] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 197 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 202, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205.

[0241] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 206 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 207, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213.

[0242] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 257 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 258, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219.

[0243] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 259Attorney Docket No.: PGY-08025and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 260, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219.

[0244] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 221 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 222, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 228.

[0245] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 262 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 263, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 261.

[0246] In some embodiments, the TfR binding region comprises a heavy chain variable domain (VH) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 138 and a light chain variable domain (VL) having an amino acid sequence at least 85% identical to that of SEQ ID NO: 265, wherein the VH and VL comprise a heavy chain variable domain comprising a CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0247] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (VJ7) having the amino acid of SEQ ID NO: 128 and three light chainAttorney Docket No.: PGY-08025complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 129.

[0248] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 138 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 139.

[0249] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 147 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 148.

[0250] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 234 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 235.

[0251] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 236 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 237.

[0252] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 238 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 239.

[0253] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 241 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 242.

[0254] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chainAttorney Docket No.: PGY-08025variable domain (V77) having the amino acid of SEQ ID NO: 243 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 244.

[0255] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 245 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 246.

[0256] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 247 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 248.

[0257] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 249 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 250.

[0258] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 251 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 252.

[0259] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 253 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 254.

[0260] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 255 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 256.Attorney Docket No.: PGY-08025

[0261] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 197 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 198.

[0262] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 197 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 202.

[0263] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 206 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 207.

[0264] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 257 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 258.

[0265] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 259 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 260.

[0266] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 221 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 222.

[0267] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (V77) having the amino acid of SEQ ID NO: 262 and three light chainAttorney Docket No.: PGY-08025complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 263.

[0268] In some embodiments , the TfR binding protein comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, and CDR-H3) of a heavy chain variable domain (VL / ) having the amino acid of SEQ ID NO: 138 and three light chain complementarity determining regions (CDR-L1, CDR-L2, and CDR-L3) of a light chain variable domain (VL) having the amino acid of SEQ ID NO: 165.

[0269] In some embodiments, the TfR binding region comprises a CrossFab format, a VH of a binding region and a CL (e.g., Ckappa) domain are connected with each other on a first polypeptide chain and pair with the VL region of the same binding region and CHI domain, which are connected with each other on a second polypeptide chain. (See FIG. 1A). In some embodiments, the CrossFab comprises the VH-CKappa set forth in SEQ ID NO: 136. In some embodiments, the CrossFab comprises the VL-CH set forth in SEQ ID NO: 137.

[0270] Non-limiting examples of TfR binding regions including binding regions whose characteristic sequences are shown in Table 2.Table 2. Exemplary sequences of TfR binding regionsDescription VH VL KabatSEQ SEQ Heavy Chain CDR Light Chain CDR SEQ ID ID SEQ ID NO ID NO NO NO 1 2 3 1 2 3 hTfRl binding 128 129 130 131 132 133 134 135 region 1hTfRl binding 138 139 140 141 142 143 144 145 region 2Variant 1hTfRl binding 138 146 140 141 142 143 144 145 region 2Variant 2hTfRl binding 147 148 149 150 151 152 144 145 region 2Variant 3hTfRl binding 234 235 153 154 155 156 157 158 region 3hTfRl binding 236 237 159 160 161 162 163 164 region 4hTfRl binding 238 239 165 166 167 168 169 170 region 5hTfRl binding 241 242 171 172 173 174 240 175region 6Attorney Docket No.: PGY-08025hTfRl binding 243 244 176 177 178 179 180 181 region 7Variant 1hTfRl binding 245 246 176 182 178 179 180 181 region 7Variant 2hTfRl binding 247 248 176 183 178 179 180 181 region 7Variant 3hTfRl binding 249 250 176 184 178 179 180 181 region 7Variant 4hTfRl binding 251 252 176 185 178 179 180 181 region 7Variant 5hTfRl binding 253 254 186 187 188 189 190 181 region 8hTfRl binding 255 256 191 192 193 194 195 196 region 9hTfRl binding 197 198 199 200 201 203 204 205 region 10Variant 1hTfRl binding 197 202 199 200 201 203 204 205 region 10Variant 2hTfRl binding 206 207 208 209 210 211 212 213 region 10Variant 3hTfRl binding 257 258 214 215 216 217 218 219 region 11Variant 1hTfRl binding 259 260 214 215 216 220 218 219 region 11Variant 2hTfRl binding 221 222 223 224 225 226 227 228 region 12hTfRl binding 262 263 229 230 231 232 233 261 region 13hTfRl binding 138 265 140 141 264 143 144 145region 14Note: numerical values refer to SEQ ID NOs. For instance, “138” refers to SEQ ID NO: 138.Additional non-limiting examples of TfR binding regions and Ap binding regions are provided, e.g., in W02014033074A1; US20150322149A1; US20170051071A1; WO2018210898 Al; US20210292440 Al; US20210301030A1; US20230174669A1; US20230174646A1; WO2023170291 Al; WO2023170295 Al; US11124567B2;Attorney Docket No.: PGY-08025US11912778B2; WO2024206161A1; US11498974B2; WO2022258841A1; W02024200271A1; WO2024026471A1; WO2024026472A2; US20230256112A1; WO2023283531A2; US11583591B2; WO2015098989A1; EP3473270A1; Boado, R.J., etal., Biotechnol Bioeng. 2009 Mar 1; 102(4): 1251-8; WO2016179257A2; W01993010819A1; US20220411527A1; US11795233B2; WO2020144233; Hultqvist, G., etal., Theranostics 7.2 (2017): 308; US4364934A; Schneider, C., et al, Journal of biological Chemistry 257.14 (1982): 8516-8522; US9994641B2; Gatter, K.C., et al, Journal of clinical pathology 36.5 (1983): 539-545; WO2016081643 Al; US9708406B2; Lee, H.J., et al. The Journal of pharmacology and experimental therapeutics 292.3 (2000): 1048-1052; US20100077498A1; Haobam, B., et al., Cellular Microbiology 16.12 (2014): 1806-1821; US20110311544A1; Ortiz-Zapater, E., etal., The Plant Journal 48.5 (2006): 757-770; US7572895B2; Trowbridge, I.S., and Domingo, D.L., Nature 294.5837 (1981): 171-173, US11440953B2, and US11802149B2, the relevant disclosures of each of which are herein incorporated by reference in their entirety.Fc DomainsFc regions

[0271] In some embodiments, provided bispecific binding constructs comprise an Fc region, which typically comprises one or more Fc polypeptides, such as a first Fc polypeptide and a second Fc polypeptide). An IgG Fc polypeptide typically contains two constant heavy domains (CH2 and CH3) and a hinge region connected to the CH2 domain. Typical Fc regions comprise two Fc polypeptides which dimerize with one another; however, an Fc region may have a single Fc polypeptides or more than two Fc polypeptides, e.g., as may be present in some antibody formats.

[0272] In some embodiments, provided bispecific binding constructs comprise an IgGl Fc region (e.g., human IgGl Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgGl Fc. In some embodiments, the wild type IgGl Fc is a human IgGl Fc, in which each Fc polypeptide has an amino acid sequence of SEQ ID NO: 1. In some embodiments, provided bispecific binding constructs comprise an Fc region, each Fc polypeptide of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc polypeptide within a wildtype IgGl Fc.Attorney Docket No.: PGY-08025

[0273] In some embodiments, provided bispecific binding constructs comprise an IgG2 Fc region (e.g., human IgG2 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG2 Fc. In some embodiments, the wild type IgG2 Fc is a human IgG2 Fc, in which each Fc polypeptide has an amino acid sequence of SEQ ID NO: 2. In some embodiments, provided bispecific binding constructs comprise an Fc region, each Fc polypeptide of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc polypeptide within a wildtype IgG2 Fc.

[0274] In some embodiments, provided bispecific binding constructs comprise an IgG4 Fc region (e.g., human IgG4 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG4 Fc. In some embodiments, the wild type IgG4 Fc is a human IgG4 Fc, in which each Fc polypeptide has an amino acid sequence of SEQ ID NO: 3. In some embodiments, provided bispecific binding constructs comprise an Fc region, each Fc polypeptide of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to that of an Fc polypeptide within a wildtype IgG4 Fc.

[0275] In some embodiments, the Fc region comprises a means for extending the half-life of the bispecific protein construct. Examples of such means include Fc modifications (such as amino acid mutations or sets of amino acid mutations), including certain Fc modifications discussed herein.Fc modifications

[0276] In certain embodiments, Fc regions are modified (e.g., substituted) at one more amino acid residues.

[0277] In some embodiments, the Fc region comprises one or more modifications which modify binding to Fc-gamma receptors, e.g., by promoting selective binding, reducing binding, or enhancing binding thereto.

[0278] In certain embodiments, modifications to Fc regions alter the half-life of a molecule (e.g., bispecific protein construct) which comprises the Fc region by altering (e.g., enhancing) binding to an Fc receptor such as the neonatal Fc receptor (FcRn.) For example, in someAttorney Docket No.: PGY-08025embodiments, the Fc region is modified to enhance the half-life of the molecule (e.g., bispecific protein construct) which comprises the Fc region. Non-limiting examples of half-life-enhancing mutations or sets of mutations include, e.g., M252Y / S254T / T256E (YTE), M428L / N434S (LS), H433K / N434F (KF), and L309D / Q311H / N434S (DHS). In some embedments, the half-life-enhancing mutations or sets of mutations include, e.g., M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

[0279] In some embodiments, modifications to Fc regions prevent Fab arm (e.g., IgG4 Fab arm) exchange. An example of such a modification in the context of an IgG4 Fc region is the S228P mutation.

[0280] In some embodiments, modifications to Fc regions reduce or abrogate effector functions, e.g., Fey receptor-mediated effector functions. Non-limiting examples of effectorreducing mutations or sets of mutations include, e.g., aglycosylation mutations (e.g., N297A orN297Q orN297G), L234A / L235A (for IgGl Fcregions), H268Q / V309L / A330S / P331S (for IgG2 Fc regions), and V234A / G237A / P238S / H268A / V309L / A330S / P331S (for IgG2 Fc regions).

[0281] In some embodiments, modifications to Fc regions enhance Fey receptor-mediated effector functions. Non -limiting examples of FcyRIIIa effector-enhancing mutations or sets of mutations include, e.g., F243L / R292P / Y300L / V305I / P396L, S298A / E333A / K334A, S239D / I332E, S239D / I332E / A330L, and L234Y / L235Q / G236W / S239M / H268D / D270E / S298A in one Fc polypeptide and D270E / K326D / A330M / K334E in another Fc polypeptide.

[0282] In some embodiments, modifications to Fc regions enhance antibody-dependent cellular phagocytosis (ADCP). A non-limiting example of an ADCP-enhancing set of mutations is G236A / S239D / I332E.

[0283] In some embodiments, modifications to Fc regions enhance complement-dependent cytotoxicity (CDC) and / or binding to complement protein Clq. Non-limiting examples of an CDC-enhancing and / or Cl q-binding-enhancing sets of mutations include, e.g., K326WZE333S, S267E / H268F / S324T, and E345R / E430G / S440Y.In some embodiments, modifications to Fc regions enhance co-engagement with antigens and Fey receptors. Non-limiting examples of co-engagement-enhancing sets of mutations include, e.g., S267E / L328F and N325S / L328F.

[0284] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, asAttorney Docket No.: PGY-08025described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0285] Amino acid sequences of exemplary Fc sequences are provided in the Sequence Listing Table.

[0286] In some embodiments, the bispecific protein construct comprises an Fc region comprising one or more modifications in SEQ ID NO: 1 (hlgGl). In some embodiments, the bispecific protein construct comprises an Fc region comprising one or more modifications in SEQ ID NO: 2 (hIgG2). In some embodiments, the bispecific protein construct comprises an Fc region comprising one or more modifications in SEQ ID NO: 3 (hIgG4). In some embodiments, the Fc region comprises an Fc polypeptide whose amino acid sequence has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 1-3. In some embodiments, the Fc region comprises an amino acid sequence according to any one of SEQ ID NOs: 1-3.

[0287] In certain embodiments, the bispecific protein construct comprises an Fc region (“modified Fc region”) with at least one amino acid modification relative to a wild type Fc region. Bispecific protein constructs with a modified Fc region may comprise mutations in one Fc polypeptide, or in multiple Fc polypeptide (e.g., when two or more Fc polypeptide are present). Within a bispecific protein construct with modifications in multiple Fc polypeptide, the modifications on each Fc polypeptide may be the same or different. In some embodiments the modified Fc region comprises a half-life extending mutation or set of mutations, e.g., M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0288] In some embodiments, the modified Fc region comprises a modification selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, S267D, and combinations thereof. In some embodiments, the modified Fc region comprises a modification selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, N434W, and combinations thereof.

[0289] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A; V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S;Attorney Docket No.: PGY-08025C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; L234A / L235A / P329G; and combinations thereof.

[0290] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA); M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G (LALAPG); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE; LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAG A / D W; LALAGA / DW; LALAPG / DW; N297A / YD; D265A / YD; LALA / YD; LAGA / YD; LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV; LALAPG / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L; SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L; LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L; LALAPG / Q311R / M428L; and combinations thereof. In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS) and M252Y / S254T / T256E (YTE). In some embodiments, the modified Fc region comprises M428L / N434S (LS) (e.g., SEQ ID NO: 19, SEQ ID NO: 36, SEQ ID NO: 43) modifications. In some embodiments, the modified Fc region comprises M252Y / S254T / T256E (YTE) (e.g., SEQ ID NO: 12, SEQ ID NO: 33, SEQ ID NO: 42) modifications.

[0291] In some embodiments, bispecific protein constructs include modifications to improve their ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc region towards an activatingAttorney Docket No.: PGY-08025receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).

[0292] In some aspects, an antibody provided herein comprises an Fc region (e.g., an IgGl Fc region) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc region. Such Fc regions are known to confer improved ADCC activity to the binding proteins which comprise them. In some aspects, such binding proteins do not comprise any fucose at position Asn 297.

[0293] In some embodiments, the bispecific protein construct comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of an Fc polypeptide. In some embodiments, a bispecific protein construct provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0294] In some embodiments, the Fc region comprises an Fc polypeptide whose amino acid sequence has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 1-117.

[0295] In some embodiments, the bispecific protein construct comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0296] In some embodiments, the bispecific protein construct comprises one or more alterations that improve or diminish Clq binding and / or CDC.

[0297] In certain embodiments, the bispecific protein construct comprises an Fc region with one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with a comparable bispecific protein construct whose Fc region lacks the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased binding protein half-life at pH 6.0 compared to binding protein comprising a wildtype Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region.Attorney Docket No.: PGY-08025

[0298] In certain embodiments, the bispecific protein construct comprises an Fc region which comprise one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared to a comparable bispecific protein construct whose Fc region lacks the one or more substitutions.

[0299] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0300] In some embodiments, the bispecific protein construct has an extended half-life (i.e., serum half-life) relative to the half-life of a reference binding protein. In some embodiments, the bispecific protein construct has a half-life of at least about 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks. In some embodiments, the bispecific protein construct has a half-life of mor than 52 weeks. In some embodiments, the bispecific protein construct has a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 days. In some embodiments, the bispecific protein construct has a half-life in a range of about 14 weeks to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, of about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the bispecific protein construct has a half-life in a range of about 42 days to about 56 days. Methods of measuring half-life are known in the art. In some embodiments, the half-life is measured in a non-human primate. In some embodiments, the half-life is measured in a human. In some embodiments, the half-life is measured following intravenous administration. In some embodiments, the half-life is measured following subcutaneous administration.

[0301] In some embodiments, the bispecific protein construct has a half-life that is at least 20% longer than a reference binding protein. In some embodiments, the half-life of the bispecific protein construct is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than the half-life of the reference binding protein. In some embodiments, the half-life of the bispecific protein construct comprises is longer than the half-life of the reference binding protein by at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, or at least 10 fold.Attorney Docket No.: PGY-08025Fc dimerization

[0302] In certain embodiments, the first Fc polypeptide and the second Fc polypeptide are do not have identical amino acid sequences. In some embodiments, the first and second Fc polypeptides comprise one or more features, e.g. , in their respective CH3 domains, that promote formation of a heterodimer (e.g., of the first and second Fc polypeptide) over a homodimer (e.g., of two first Fc polypeptides or two second Fc polypeptides). Heterodimerization of nonidentical Fc polypeptides can be achieved using any of a variety of methods known in the art, e.g., as described in Ha et al. “Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins.” FRONT IMMUNOL. 2016 Oct 6;7:394.

[0303] Generally, heterodimerization strategies involve having a feature (such as a mutation or set of mutations) on one CH3 chain and a non-identical feature (such as another a mutation or set of mutations) on the other CH3 chain, which features complement each other and favor heterodimerization (“complementary Fc heterodimerization variations” as used herein.”

[0304] Many of these heterodimerization methods fall into one of four general strategies: i) symmetric-to-asymmetric steric complementarity design (e.g., knob-in-hole (KiH), HA-TF, and ZW1), (ii) charge-to-charge swap (e.g., DD-KK) (25), (iii) charge-to-steric complementarity swap plus additional long-range electrostatic interactions (e.g., EW-RVT) (26), and (iv) isotype strand swap (e.g., strand-exchange engineered domain (SEED), as further explained below and in Table 3. Non-limiting examples of complementary Fc heterodimerization variations include those depicted in Table 3. (Unless otherwise specified, amino acid numbering of residues is according to the EU index of Kabat.)Table 3: Designs and strategies for heterodimeric Fc variants.Design Paired mutations Type of Reference(s) CH3 chain “A” CH3 chain “B” heterodimericfavoringinteractionsKnob- T366W T366S / L368A / Y4 Hydrophobic / steric Merchant et al. in-hole 07V complementarity 1998(KiH)KiHs-s T366W / S354C T366S / L368A / KiH + inter-CH3 Merchant et al.Y407V / Y349C domain S-S bond 1998;Attorney Docket No.: PGY-08025Schaefer et al.2011HA-TF S364H / F405A Y349T / T394F Hydrophobic / steric Moore et al.complementarity 2011ZW1 T350V / L351Y / T350V / T366L / Hydrophobic / steric von F405A / Y407V K392L / T394W complementarity Kreudenstein et al. 2013 7.8.60 K360D / D399M E345R / Q347R / Hydrophobic / steric Leaver-Fay et / Y407A T366V / K409V complementarity + al. 2016 electrostaticcomplementarityDD-KK K409D / K392D D399K / E356K Electrostatic Gunasekaran K.complementarity et al. 2010 EW- K360E / K409W Q347R / D399V / Hydrophobic / steric Choi et al. 2013, RVT F405T complementarity plus Choi et al. 2015 long-range (MOL electrostatic IMMUNOL) interactionEW- K360E / K409W / Q347R / D399V / EW-RVT + inter- Choi et al. 2015 RVTs-s Y349C F405T / S354C CH3 domain S-S (MOLbond IMMUNOL) SEED IgA-derived 45 IgGl -derived 57 Hydrophobic / steric Davis et al.residues on residues on IgA complementarity 2010 IgGl CH3 CH3 (strand exchangebetween IgG and IgA)A107 K370E / K409W E357N / D399V / Hydrophobic / steric Choi et al. 2015F405T complementarity + (PLoS ONE) hydrogen bonding complementarity(directed evolutionusing yeast surfacedisplay)Attorney Docket No.: PGY-08025References for Table 3

[0305] Choi HJ et al. “A heterodimeric Fc-based bispecific antibody simultaneously targeting VEGFR-2 and Met exhibits potent antitumor activity.” MOL CANCER Ther (2013) 12(12):2748-59.

[0306] Choi HJ et al. “Crystal structures of immunoglobulin Fc heterodimers reveal the molecular basis for heterodimer formation.” MOL IMMUNOL (2015) 65(2):377-83.

[0307] Choi HJ et al. “Engineering of immunoglobulin Fc heterodimers using yeast surface-displayed combinatorial Fc library screening.” PLoS ONE (2015) 10(12)

[0308] Davis JH et al. “SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies.” PROTEIN ENG DES SEL (2010) 23(4): 195-202.

[0309] Gunasekaran K et al. “Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG.” J BIOL CHEM (2010) 285(25): 19637-46.

[0310] Leaver-Fay et al." Computationally designed bispecific antibodies using negative state repertoires.” STRUCTURE (2016) 24(4):641-51.

[0311] Merchant, A.M. et al. “An efficient route to human bispecific IgG.” NAT. BIOTECHNOL. 16 (1998) 677-681.

[0312] Moore GL et al. “A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens.” MABS (2011) 3(6):546-57.

[0313] Schaefer W et al. “Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies.” PROC NATL ACAD SCI US A (2011) 108(27): 11187— 92.

[0314] Von Kreudenstein TS et al. “Improving biophysical properties of a bispecific antibody scaffold to aid developability: quality by molecular design.” MABS (2013) 5(5):646-54.

[0315] For example, the first and second Fc polypeptides can be devised using a strandexchange engineered domains (SEED)-based CH3 platform, as described, e.g., in U.S. Patent Nos. 8,871,912 and 9,505,848. In this platform, each SEED-CH3 domain comprises alternating segments of human IgA and IgG sequences. The “AG SEED” refers to a CH3 domain that has an IgAl sequence segment on the N-terminal end, while the “GA seed” refers to a CH3 that has an IgGl sequence segment on the N-terminal end. When the SEED platform is used, the first and second Fc polypeptides collectively comprise an AG SEED paired with a GA SEED, e.g., 1) the first Fc polypeptide comprises an AG SEED and the second Fc polypeptide comprises aAttorney Docket No.: PGY-08025GA SEED, or 2) the second Fc polypeptide comprises an AG SEED and the first Fc polypeptide comprises a GA SEED.

[0316] In some embodiments, the first and second Fc polypeptides comprise complementary Fc heterodimerization mutations. For example, the first and second Fc polypeptides may have complementary knob-in-hole mutations, as described, e.g., in International PCT Publication W01996 / 027011; Ridgway, J.B., et al., PROTEIN ENG. 9 (1996) 617-621; Merchant, A.M. et al., “An efficient route to human bispecific IgG.” NAT BIOTECHNOL 16 (1998) 677-681; and in International PCT Publication WO1998 / 050431. In knob-in-hole (KiH) methods, the interaction surfaces of the CH3 domains from the two Fc polypeptides intended to be heterodimerized (e.g., the first and second Fc polypeptides) are altered such one or more protuberances (“knobs”) on one Fc polypeptide fit one or more cavities (“holes”) on the other Fc polypeptide. “Knobs” can be generated by replacing a small amino acid residue with a larger one; conversely, “holes” can be generated by replacing a large amino acid residue with a smaller one.Formats

[0317] In some embodiments, bispecific protein constructs comprise two Ap binding regions, one hTfRl binding region, and one Fc region comprising two Fc polypeptides per construct. For example, bispecific protein constructs may be provided in a “2+1” format in which the hTfRl binding region is an scFv, a Fab, or CrossFab which is connected to the C-terminus of an Fc polypeptide. (See FIG. IB.) In some embodiments, bispecific protein constructs comprise two Ap binding regions, one TfR binding region, and one Fc region comprising two Fc polypeptides per construct. As discussed further herein, the two Fc polypeptides may be non-identical and may be capable of heterodimerizing via, e.g., knob-in-hole complementary Fc variations.

[0318] The term “CrossFab” refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged. In some embodiments, the variable regions of the Fab heavy and light chain are exchanged, i.e. the CrossFab molecule comprises a peptide chain composed of the light chain variable (VL) domain and the heavy chain constant domain (CHI), and a peptide chain composed of the heavy chain variable domain (VH) and the light chain constant domain (CL). In some embodiments, when the constant regions of the Fab heavy and light chain are exchanged, the crossover Fab molecule comprises a peptide chain composed of the heavy chain variable domain (VH) and the light chain constant domain (CL), and a peptide chain composed of the light chain variable domainAttorney Docket No.: PGY-08025(VL) and the heavy chain constant domain. In some embodiments, the TfR binding region comprises a CrossFab comprising (1) a VH and an immunoglobulin Ckappa domain; and (2) a VL and an immunoglobulin heavy constant domain.

[0319] In some embodiments, a multispecific antibody has a multispecific antibody format described herein. For example, the format of a multispecific antibody can be selected from the group consisting of (a) Single chain Fv (scFv), (b) tandem scFv format of bispecific T cell engager (BiTE), (c) disulfide-linked diabody format of dual affinity retargeting (DART) bsAb, (d) tandem diabody (TandAb), (e) conventional immunoglobulin G (IgG), (f) IgGs with additional binding units such as scFv, (g) dual variable domain immunoglobulin (DVD-Ig), (h) quadromab bsAb, (i) knobs-into-holes (KiH) bsAb with a common light chain, (j) KiH-CrossMabCHl-CL or any known CrossMab, (k) DuoBody ®, and (1) bsAb by controlled Fab arm exchange (cFAE). (see Shim et al. (2020) Biomolecules 26;10(3):360.) In some embodiments, the format of the multispecific antibody is selected from the group consisting of IgG-scFv, CrossMab, and DuoBody ®. In some embodiments, the format of the multispecific antibody is IgG-scFv. In some embodiments, the format of the multispecific antibody is CrossMab. In some embodiments, the format of the multispecific antibody is DuoBody ®.

[0320] In some embodiments, the multispecific antibody is in a DuoBody® format. A DuoBody® is created using the naturally-occurring process of Fab-arm exchange. A DuoBody® is a heterodimeric construct with two different Fabs binding to a first and second target, fused to an Fc which is stabilized by specific mutations that mediate controlled Fab arm exchange.Antibody fragments

[0321] In certain embodiments, provided bispecific protein constructs may comprises antibody fragments, rather than whole antibodies.

[0322] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the production of large amounts of these fragments. Antibody fragments can be isolated from, e.g., antibody phage libraries. Alternatively or additionally, Fab'-SH fragments can be directly recovered from E. coli and chemically coupledAttorney Docket No.: PGY-08025to form F(ab')2 fragments (Carter et al., Bio / Technology 10:163-167 (1992)). According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab')2 fragment with increased in vivo half-life comprising a salvage receptor binding epitope residues are described, e.g., in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner.

[0323] In some embodiments, the antigen-binding fragment is a single chain Fv fragment (scFv). See, e.g., WO 93 / 16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458. Fv and scFv are species with intact combining sites that are devoid of constant regions; thus, these fragments may be suitable for reduced nonspecific binding during in vivo use. scFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an scFv. See, e.g., Antibody Engineering, ed. Borrebaeck. An antigenbinding antibody fragment may also be a “linear antibody”, e.g., as described in U.S. Pat. No.5,641,870.Linkers

[0324] In some embodiments, the TfR binding domain or region is operably linked to the C-terminal amino acid residue of an Fc region described herein. In some embodiments, the linker is a flexible, stable linker. Glycine-serine-rich linkers of 2 to 80 amino acids or 6 to 30 ammo acids are used in certain instances because the short side chain provides conformational flexibility and minimal immunogenicity and because serine improves solubility. Any suitable linker known in the art or described herein can be used, such as a (GS)n linker (SEQ ID NO: 119), a (GGS)n ((G2S)n) linker (SEQ ID NO: 120), a (GGGS)n ((G3S)n) linker (SEQ ID NO: 121), a (GGGGS)n ((G4S)n) linker (SEQ ID NO: 122), and a (GGGGGS)n ((G5S)n) linker (SEQ ID NO: 123), wherein n is 1 , 2, 3, 4, 5, or 6. In some embodiments, the linker is a G4S3linker (GGGGSGGGGSGGGGS; SEQ ID NO: 124). In some embodiments, the linker is a G4Si linker (GGGGS; SEQ ID NO: 125). In some embodiments, the linker comprises the amino acid sequence of GTEGKSSGSGSESKST (SEQ ID NO: 126). In some embodiments, the linker comprises the amino acid sequence of GGGSGGSGGCPPCGGSGG (SEQ ID NO: 127). In some embodiments, the linker comprises a linker sequence as described in US2023 / 0174646, the contents of which are incorporated herein by reference. In some embodiments, the linker comprises a linker sequence as described in WO2023 / 170291.Exemplary bispecific binding protein constructsAttorney Docket No.: PGY-08025

[0325] In some embodiments, the bispecific binding protein described herein comprises an Ap binding protein described herein, a TfR binding protein described herein, and a half-life extending Fc region. In some embodiments, the bispecific binding protein described herein comprises an Ap binding protein set forth in Table 1, a TfR binding protein set forth in Table 2, and a half-life extending Fc region.

[0326] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0327] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0328] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of:(1) SEQ ID NOs: 130, 131, and 132, respectively;Attorney Docket No.: PGY-08025(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;Attorney Docket No.: PGY-08025(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0329] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprising1) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,4) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,5) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,Attorney Docket No.: PGY-080257) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,14) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,17) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,18) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 26121) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0330] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andAttorney Docket No.: PGY-08025ii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;Attorney Docket No.: PGY-08025(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0331] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprising1) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,Attorney Docket No.: PGY-080254) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,5) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,7) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,14) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,17) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,18) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 261Attorney Docket No.: PGY-0802521) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145.

[0332] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises the amino acid sequence set forth in SEQ ID NO: 271, and ii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises the amino acid sequence set forth in SEQ ID NO: 272, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0333] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0334] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:Attorney Docket No.: PGY-08025(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0335] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises the amino acid sequence set forth in SEQ ID NO: 271, and ii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises the amino acid sequence set forth in SEQ ID NO: 272, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andAttorney Docket No.: PGY-08025ii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0336] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,b) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;Attorney Docket No.: PGY-08025(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0337] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprising a full heavy chain (HC) having the amino acid sequence set forth in SEQ ID NO: 273 and a full light chain (LC) comprising the amino acid sequence set forth in SEQ ID NO: 274, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;Attorney Docket No.: PGY-08025(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region.

[0338] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0339] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of:(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;Attorney Docket No.: PGY-08025(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0340] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingAttorney Docket No.: PGY-08025i) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprising1) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,4) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,5) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,7) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,14) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,Attorney Docket No.: PGY-0802517) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,18) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 26121) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145, wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0341] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of:Attorney Docket No.: PGY-08025(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;Attorney Docket No.: PGY-08025(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0342] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprising1) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,4) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,Attorney Docket No.: PGY-080255) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,7) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,14) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,17) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,18) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 26121) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,Attorney Docket No.: PGY-08025wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0343] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0344] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;Attorney Docket No.: PGY-08025(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0345] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises the amino acid sequence set forth in SEQ ID NO: 271, and ii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises the amino acid sequence set forth in SEQ ID NO: 272, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0346] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andAttorney Docket No.: PGY-08025ii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,b) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0347] In some embodiments, the bispecific binding protein described herein comprises:Attorney Docket No.: PGY-08025a) an amyloid beta (AP) binding region comprising a full heavy chain (HC) having the amino acid sequence set forth in SEQ ID NO: 273 and a full light chain (LC) comprising the amino acid sequence set forth in SEQ ID NO: 274, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M428L / N434S (LS).

[0348] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingAttorney Docket No.: PGY-08025i) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0349] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of:(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;Attorney Docket No.: PGY-08025(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0350] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingAttorney Docket No.: PGY-080251) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,4) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,5) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,7) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,14) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,17) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,Attorney Docket No.: PGY-0802518) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 26121) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145, wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0351] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, wherein the second VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 selected from the amino acid sequences of:(1) SEQ ID NOs: 130, 131, and 132, respectively;(2) SEQ ID NOs: 140, 141, and 142, respectively;(3) SEQ ID NOs: 149, 150, and 151, respectively;Attorney Docket No.: PGY-08025(4) SEQ ID NOs: 153, 154, and 155, respectively;(5) SEQ ID NOs: 159, 160, and 161, respectively;(6) SEQ ID NOs: 165, 166, and 167, respectively;(7) SEQ ID NOs: 171, 172, and 173, respectively;(8) SEQ ID NOs: 176, 177, and 178, respectively;(9) SEQ ID NOs: 176, 182, and 178, respectively;(10) SEQ ID NOs: 176, 183, and 178, respectively;(11) SEQ ID NOs: 176, 184, and 178, respectively;(12) SEQ ID NOs: 176, 185, and 178, respectively;(13) SEQ ID NOs: 186, 187, and 188, respectively;(14) SEQ ID NOs: 191, 192, and 193, respectively;(15) SEQ ID NOs: 199, 200, and 201, respectively;(16) SEQ ID NOs: 208, 209, and 210, respectively;(17) SEQ ID NOs: 214, 215, and 216, respectively;(18) SEQ ID NOs: 223, 224, and 225, respectively;(19) SEQ ID NOs: 229, 230, and 231, respectively; or(20) SEQ ID NOs: 140, 141, and 264, respectively, andii) a second VL, wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 selected from the amino acid sequences of:(1) SEQ ID NOs: 133, 134, and 135, respectively;(2) SEQ ID NOs: 143, 144, and 145, respectively;(3) SEQ ID NOs: 152, 144, and 145, respectively;(4) SEQ ID NOs: 156, 157, and 158, respectively;(5) SEQ ID NOs: 162, 163, and 164, respectively;(6) SEQ ID NOs: 168, 169, and 170, respectively;(7) SEQ ID NOs: 174, 240, and 175, respectively;(8) SEQ ID NOs: 179, 180, and 181, respectively;(9) SEQ ID NOs: 189, 190, and 181, respectively;(10) SEQ ID NOs: 194, 195, and 196, respectively;(11) SEQ ID NOs: 203, 204, and 205, respectively;(12) SEQ ID NOs: 211, 212, and 213, respectively;(13) SEQ ID NOs: 217, 218, and 219, respectively;(14) SEQ ID NOs: 220, 218, and 219, respectively;(15) SEQ ID NOs: 226, 227, and 228, respectively;Attorney Docket No.: PGY-08025(16) SEQ ID NOs: 232, 233, and 261, respectively; or(17) SEQ ID NOs: 143, 144, and 145, respectively,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0352] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in the amino acid sequences of SEQ ID NOs: 266, 267, and 268, respectively, andii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in the amino acid sequences of SEQ ID NOs: 269, 163, and 270, respectively, andb) a transferrin receptor (TfR) binding region comprising1) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 130, CDR-H2 as set forth in SEQ ID NO: 131, and CDR-H3 as set forth in SEQ ID NO: 132, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 133, CDR-L2 as set forth in SEQ ID NO: 134, and CDR-L3 as set forth in SEQ ID NO: 135,2) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 142, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,3) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 149, CDR-H2 as set forth in SEQ ID NO: 150, and CDR-H3 as set forth in SEQ ID NO: 151, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 152, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,4) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 153, CDR-H2 as set forth in SEQ ID NO: 154, and CDR-H3 as set forth in SEQ ID NO: 155, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 156, CDR-L2 as set forth in SEQ ID NO: 157, and CDR-L3 as set forth in SEQ ID NO: 158,5) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 159, CDR-H2 as set forth in SEQ ID NO: 160, and CDR-H3 as set forth in SEQ ID NO: 161,Attorney Docket No.: PGY-08025and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 162, CDR-L2 as set forth in SEQ ID NO: 163, and CDR-L3 as set forth in SEQ ID NO: 164,6) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 165, CDR-H2 as set forth in SEQ ID NO: 166, and CDR-H3 as set forth in SEQ ID NO: 167, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 168, CDR-L2 as set forth in SEQ ID NO: 169, and CDR-L3 as set forth in SEQ ID NO: 170,7) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 240, and CDR-L3 as set forth in SEQ ID NO: 175,8) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 177, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,9) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 182, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,10) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 183, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,11) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 184, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,12) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 176, CDR-H2 as set forth in SEQ ID NO: 185, and CDR-H3 as set forth in SEQ ID NO: 178, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 179, CDR-L2 as set forth in SEQ ID NO: 180, and CDR-L3 as set forth in SEQ ID NO: 181,13) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 186, CDR-H2 as set forth in SEQ ID NO: 187, and CDR-H3 as set forth in SEQ ID NO: 188, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 189, CDR-L2 as set forth in SEQ ID NO: 190, and CDR-L3 as set forth in SEQ ID NO: 181,Attorney Docket No.: PGY-0802514) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, and CDR-H3 as set forth in SEQ ID NO: 193, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196,15) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 199, CDR-H2 as set forth in SEQ ID NO: 200, and CDR-H3 as set forth in SEQ ID NO: 201, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 203, CDR-L2 as set forth in SEQ ID NO: 204, and CDR-L3 as set forth in SEQ ID NO: 205,16) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 208, CDR-H2 as set forth in SEQ ID NO: 209, and CDR-H3 as set forth in SEQ ID NO: 210, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 211, CDR-L2 as set forth in SEQ ID NO: 212, and CDR-L3 as set forth in SEQ ID NO: 213,17) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 217, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,18) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 214, CDR-H2 as set forth in SEQ ID NO: 215, and CDR-H3 as set forth in SEQ ID NO: 216, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 220, CDR-L2 as set forth in SEQ ID NO: 218, and CDR-L3 as set forth in SEQ ID NO: 219,19) heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 223, CDR-H2 as set forth in SEQ ID NO: 224, and CDR-H3 as set forth in SEQ ID NO: 225, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 226, CDR-L2 as set forth in SEQ ID NO: 227, and CDR-L3 as set forth in SEQ ID NO: 22820) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 229, CDR-H2 as set forth in SEQ ID NO: 230, and CDR-H3 as set forth in SEQ ID NO: 231, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 232, CDR-L2 as set forth in SEQ ID NO: 233, and CDR-L3 as set forth in SEQ ID NO: 26121) a heavy chain variable domain comprising CDR-H1 as set forth in SEQ ID NO: 140, CDR-H2 as set forth in SEQ ID NO: 141, and CDR-H3 as set forth in SEQ ID NO: 264, and a light chain variable domain comprising CDR-L1 as set forth in SEQ ID NO: 143, CDR-L2 as set forth in SEQ ID NO: 144, and CDR-L3 as set forth in SEQ ID NO: 145,Attorney Docket No.: PGY-08025wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0353] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0354] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, and ii) a light chain comprising a first variable light chain (VL), andb) a transferrin receptor (TfR) binding region comprisingi) a second VH, andii) a second VL, wherein the second VH and second VL are selected from the amino acid sequences of:(1) SEQ ID NOs: 128 and 129, respectively;(2) SEQ ID NOs: 138 and 139, respectively;(3) SEQ ID NOs: 138 and 146, respectively;(4) SEQ ID NOs: 147 and 148, respectively;(5) SEQ ID NOs: 234 and 235, respectively;(6) SEQ ID NOs: 236 and 237, respectively;(7) SEQ ID NOs: 238 and 239, respectively;(8) SEQ ID NOs: 241 and 242, respectively;(9) SEQ ID NOs: 243 and 244, respectively;Attorney Docket No.: PGY-08025(10) SEQ ID NOs: 245 and 246, respectively;(11) SEQ ID NOs: 247 and 248, respectively;(12) SEQ ID NOs: 249 and 250, respectively;(13) SEQ ID NOs: 251 and 252, respectively;(14) SEQ ID NOs: 253 and 254, respectively;(15) SEQ ID NOs: 255 and 256, respectively;(16) SEQ ID NOs: 197 and 198, respectively;(17) SEQ ID NOs: 197 and 202, respectively;(18) SEQ ID NOs: 206 and 207, respectively;(19) SEQ ID NOs: 257 and 258, respectively;(20) SEQ ID NOs: 259 and 260, respectively;(21) SEQ ID NOs: 221 and 222, respectively;(22) SEQ ID NOs: 262 and 263, respectively; or(23) SEQ ID NOs: 138 and 265, respectively; andwherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0355] In some embodiments, the bispecific binding protein described herein comprises: a) an amyloid beta (AP) binding region comprisingi) a heavy chain comprising a first variable heavy chain (VH) and an Fc region, wherein the first VH comprises the amino acid sequence set forth in SEQ ID NO: 271, and ii) a light chain comprising a first variable light chain (VL), wherein the first VL comprises the amino acid sequence set forth in SEQ ID NO: 272, andb) a transferrin receptor (TfR) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,wherein the TfR binding region is operably linked to the Fc region of the Ap binding region, wherein the Fc region comprises the amino acid modifications of M252Y / S254T / T256E (YTE).

[0356] In some embodiments, the bispecific binding protein described herein comprises:Attorney Docket No.: PGY-08025a) an amyloid beta (AP) binding region comprisingi) a second VH wherein the second VH comprises an amino acid sequence selected from SEQ ID NOs: 128, 147, 234, 236, 238, 241, 243, 245, 247, 249, 251, 253, 255, 197, 206, 257, 259, 221, 262, and 138, andii) a second VL wherein the second VL comprises an amino acid sequence selected from SEQ ID NOs: 129, 139, 146, 148, 235, 237, 239, 242, 244, 246, 248, 250, 252, 254, 256, 198, 202, 207, 258, 260, 222, 263, and 265,b) a transferrin receptor (TfR) binding region comprisingi) a second ...

Claims

1. Attorney Docket No.: PGY-08025CLAIMS1. A bispecific protein construct comprising:(a) an amyloid beta (AP) binding region comprising:an immunoglobulin heavy chain variable domain (VH) (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, andan immunoglobulin light chain variable domain (VL) (anti-Ap -VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively;(b) a human transferrin receptor (hTfRl) binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3 anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ ID NOs: 130, 131, 132, 133, 134, and 135, respectively; b. SEQ ID NOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ ID NOs: 149, 150, 151, 152, 144, and 145, respectively; d. SEQ ID NOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ ID NOs: 159, 160, 161, 162, 163, and 164, respectively; f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively; g. SEQ ID NOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ ID NOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively;j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively;k. SEQ ID NOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively;m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ ID NOs: 191, 192, 193, 194, 195, and 196, respectively; o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ ID NOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively; s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively;Attorney Docket No.: PGY-08025t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ ID NOs: 140, 141, 264, 143, 144, and 145, respectively; and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.

2. The bispecific protein construct of claim 1, wherein the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

3. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, and a VL (anti-Ap -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively; (b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ ID NOs: 130, 131, 132, 133, 134, and 135, respectively;b. SEQ ID NOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ ID NOs: 149, 150, 151, 152, 144, and 145, respectively;d. SEQ ID NOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ ID NOs: 159, 160, 161, 162, 163, and 164, respectively;f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively;g. SEQ ID NOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ ID NOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively;j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively;k. SEQ ID NOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively;m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ ID NOs: 191, 192, 193, 194, 195, and 196, respectively;Attorney Docket No.: PGY-08025o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ ID NOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively;s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively;t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ ID NOs: 140, 141, 264, 143, 144, and 145, respectively; and(c) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

4. The bispecific protein construct of claim 3, wherein the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region.

5. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, and a VL (anti-Ap -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively; (b) a hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences set forth in;a. SEQ ID NOs: 130, 131, 132, 133, 134, and 135, respectively;b. SEQ ID NOs: 140, 141, 142, 143, 144, and 145, respectively; c. SEQ ID NOs: 149, 150, 151, 152, 144, and 145, respectively;d. SEQ ID NOs: 153, 154, 155, 156, 157, and 158, respectively; e. SEQ ID NOs: 159, 160, 161, 162, 163, and 164, respectively;f. SEQ ID NOs: 165, 166, 167, 168, 169, and 170, respectively;g. SEQ ID NOs: 171, 172, 173, 174, 240, and 175, respectively; h. SEQ ID NOs: 176, 177, 178, 179, 180, and 181, respectively; i. SEQ ID NOs: 176, 182, 178, 179, 180, and 181, respectively;Attorney Docket No.: PGY-08025j. SEQ ID NOs: 176, 183, 178, 179, 180, and 181, respectively;k. SEQ IDNOs: 176, 184, 178, 179, 180, and 181, respectively; l. SEQ ID NOs: 176, 185, 178, 179, 180, and 181, respectively;m. SEQ ID NOs: 186, 187, 188, 189, 190, and 181, respectively; n. SEQ IDNOs: 191, 192, 193, 194, 195, and 196, respectively; o. SEQ ID NOs: 199, 200, 201, 203, 204, and 205, respectively; p. SEQ IDNOs: 208, 209, 210, 211, 212, and 213, respectively; q. SEQ ID NOs: 214, 215, 216, 217, 218, and 219, respectively; r. SEQ ID NOs: 214, 215, 216, 220, 218, and 219, respectively;s. SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively;t. SEQ ID NOs: 229, 230, 231, 232, 233, and 261, respectively; or u. SEQ IDNOs: 140, 141, 264, 143, 144, and 145, respectively; and(c) a human IgGl Fc region(i) having an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 1 or 112; and(ii) comprising a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

6. The bispecific protein construct of any one of claims 2 or 4 wherein the amino acid mutation or set of amino acid mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

7. The bispecific protein construct of any one of claims 1-4, or 6, wherein the Fc region is an IgGl, IgG2, or IgG4 Fc region.

8. The bispecific protein construct of claim 7, wherein the Fc region is an IgGl Fc region.

9. The bispecific binding protein of claim 8, wherein the IgGl Fc region is a human or humanized IgGl Fc region.Attorney Docket No.: PGY-0802510. The bispecific protein construct of any of claims 1-9, wherein the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences having at least 85% identity to that of:(a) SEQ IDNOs: 128 and 129, respectively,(b) SEQ ID NOs: 138 and 139, respectively,(c) SEQ IDNOs: 138 and 146, respectively,(d) SEQ ID NOs: 147 and 148, respectively,(e) SEQ ID NOs: 234 and 235, respectively,(f) SEQ ID NOs: 236 and 237, respectively,(g) SEQ ID NOs: 238 and 239, respectively,(h) SEQ ID NOs: 241 and 242, respectively,(i) SEQ ID NOs: 243 and 244, respectively,(j) SEQ ID NOs: 245 and 246, respectively,(k) SEQ ID NOs: 247 and 248, respectively,(l) SEQ ID NOs: 249 and 250, respectively,(m) SEQ ID NOs: 251 and 252, respectively,(n) SEQ ID NOs: 253 and 254, respectively,(o) SEQ ID NOs: 255 and 256, respectively,(p) SEQ ID NOs: 197 and 198, respectively,(q) SEQ ID NOs: 197 and 202, respectively,(r) SEQ ID NOs: 206 and 207, respectively,(s) SEQ ID NOs: 257 and 258, respectively,(t) SEQ ID NOs: 259 and 260, respectively,(u) SEQ ID NOs: 221 and 222, respectively,(v) SEQ ID NOs: 262 and 263, respectively, or(w) SEQ ID NOs: 138 and 265, respectively.

11. The bispecific protein construct of any of claims 1-9, wherein the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences of:(a) SEQ IDNOs: 128 and 129, respectively,(b) SEQ ID NOs: 138 and 139, respectively,(c) SEQ IDNOs: 138 and 146, respectively,(d) SEQ ID NOs: 147 and 148, respectively,(e) SEQ ID NOs: 234 and 235, respectively,(f) SEQ ID NOs: 236 and 237, respectively,Attorney Docket No.: PGY-08025(g) SEQ ID NOs: 238 and 239, respectively,(h) SEQ ID NOs: 241 and 242, respectively,(i) SEQ ID NOs: 243 and 244, respectively,(j) SEQ ID NOs: 245 and 246, respectively,(k) SEQ ID NOs: 247 and 248, respectively,(l) SEQ ID NOs: 249 and 250, respectively,(m) SEQ ID NOs: 251 and 252, respectively,(n) SEQ ID NOs: 253 and 254, respectively,(o) SEQ ID NOs: 255 and 256, respectively,(p) SEQ ID NOs: 197 and 198, respectively,(q) SEQ ID NOs: 197 and 202, respectively,(r) SEQ ID NOs: 206 and 207, respectively,(s) SEQ ID NOs: 257 and 258, respectively,(t) SEQ ID NOs: 259 and 260, respectively,(u) SEQ ID NOs: 221 and 222, respectively,(v) SEQ ID NOs: 262 and 263, respectively, or(w) SEQ ID NOs: 138 and 265, respectively.

12. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, and a VL (anti-Ap -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively; (b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively; and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.Attorney Docket No.: PGY-0802513. The bispecific protein construct of claim 12, wherein the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

14. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, and a VL (anti-Ap -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively; (b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively; andc) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

15. The bispecific protein construct of claim 14, wherein the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region.

16. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-AP-Vn) comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 266, 267, and 268, respectively, and a VL (anti-Ap -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 269, 163, and 270, respectively; (b) an hTfRl binding region comprising:a VH (anti -hTfRl -VH) comprising complementarity determining regions CDR- Hl, CDR-H2, and CDR-H3 set forth in SEQ ID NOs: 130, 131, and 132, respectively, anda VL (anti -hTfRl -VL) comprising complementarity-determining regions CDR- Ll, CDR-L2, and CDR-L3 set forth in SEQ ID NOs: 133, 134, and 135, respectively;Attorney Docket No.: PGY-08025and(c) a human IgGl Fc region(i) having an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 1 or 112; and(ii) comprising a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

17. The bispecific protein construct of any one of claims 13 or 15 wherein the amino acid mutation or set of amino acid mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

18. The bispecific protein construct of any one of claims 12-15, or 17, wherein the Fc region is an IgGl, IgG2, or IgG4 Fc region.

19. The bispecific protein construct of claim 18, wherein the Fc region is an IgGl Fc region.

20. The bispecific binding protein of claim 19, wherein the IgGl Fc region is a human or humanized IgGl Fc region.

21. The bispecific protein construct of any one of claims 12-20, wherein the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences having at least 85% identity to that of SEQ IDNOs: 128 and 129, respectively.

22. The bispecific protein construct of any one of claims 12-20, wherein the anti-hTfRl-Vu and anti-hTfRl-VL comprise amino acid sequences of SEQ ID NOs: 128 and 129, respectively.

23. The bispecific protein construct of any one of claims 1-22, wherein the anti-AP-Vu and anti-AP-VL comprise amino acid sequences having at least 85% identity to that of SEQ ID NOs: 271 and 272, respectively.Attorney Docket No.: PGY-0802524. The bispecific protein construct of any one of claims 1-22, wherein the anti-AP-Vu and anti-AP-V comprise amino acid sequences of SEQ ID NOs: 271 and 272, respectively.

25. The bispecific protein construct of any one of claims 1-22, wherein the Ap binding region comprises an antibody fragment.

26. The bispecific protein construct of claim 25, wherein the Ap binding region comprises a human or humanized antibody fragment.

27. The bispecific protein construct of any one of claims 1-26, wherein the hTfRl binding region comprises an antibody fragment.

28. The bispecific protein construct of claim 27, wherein the hTfRl binding region comprises a human or humanized antibody fragment.

29. The bispecific protein construct of any one of claims 1-28, comprising two Ap binding regions and one hTfRl binding region.

30. The bispecific protein construct of claim 29, wherein the hTfRl binding region comprises an scFv, a Fab, or a CrossFab.

31. The bispecific protein construct of claim 30, wherein the hTfRl binding region comprises a CrossFab comprising (1) a first hTfRl-binding polypeptide comprising the anti-hTfR-Vu and an immunoglobulin Ckappa domain; and (2) a second hTfRl-binding polypeptide comprising the anti -hTfR-VL and an immunoglobulin CH domain.

32. The bispecific protein construct of any one of claims 1-31, wherein the Fc region comprises a first Fc polypeptide and a second Fc polypeptide.

33. The bispecific protein construct of claim 32, wherein the first and second Fc polypeptides have non-identical amino acid sequences.

34. The bispecific protein construct of claim 33, wherein the first and second Fc polypeptides comprise complementary Fc heterodimerization variations.Attorney Docket No.: PGY-0802535. The bispecific protein construct of any one of claims 32-34, wherein the hTfRl binding region is connected to the C-terminus of the first or second Fc polypeptide.

36. The bispecific protein construct of claim 31, wherein the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, the bispecific protein construct comprising(a) a first polypeptide comprising the anti-Ap-Vu,(b) a second polypeptide comprising the anti-Ap-Vu and the first Fc polypeptide, (c) a third polypeptide comprising the anti-Ap-Vu, the second Fc polypeptide, and the anti-hTfRl-Vu,(d) a fourth polypeptide comprising the anti-Ap-Vi., and(e) a fifth polypeptide comprising the anti-hTfRl-VL.

37. The bispecific protein construct of claim 30, wherein the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, the bispecific protein construct comprising(a) a first polypeptide comprising the anti-Ap-Vi.,(b) a second polypeptide comprising the anti-Ap-Vn and the first Fc polypeptide, (c) a third polypeptide comprising the anti-Ap-Vn. the second Fc polypeptide, and an scFv comprising the anti-hTfRl-Vu and the anti-hTfRl-VL, and(d) a fourth polypeptide comprising the anti-Ap-Vi..

38. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-AP-Vu) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 271, anda VL (anti-Ap -VL) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 272;(b) an hTfRl binding region comprisinga VH (anti-hTfRl-Vu) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 128, anda VL (anti-hTfRl-VL) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 129; and(c) an Fc region comprising a means for extending the half-life of the bispecific protein construct.Attorney Docket No.: PGY-0802539. The bispecific protein construct of claim 38, wherein the means for extending the half-life comprises an amino acid mutation or set of amino acid mutations in the Fc region.

40. A bispecific protein construct comprising:(a) an Ap binding region comprising:a VH (anti-A -Vn) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 271, anda VL (anti-Ap -VL) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 272;(b) an hTfRl binding region comprisinga VH (anti -hTfRl -VH) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 128, anda VL (anti -hTfRl -VL) having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 129; and(c) an Fc region comprising an Fc modification which extends the half-life of the bispecific protein construct.

41. The bispecific protein construct of claim 40, wherein the Fc modification comprises an amino acid mutation or set of amino acid mutations in the Fc region.

42. The bispecific protein construct of claim 39 or 41, wherein the amino acid mutation or set of amino acid mutations is selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS).

43. The bispecific protein construct of any one of claims 38-42, wherein the hTfRl binding region comprises (1) a first hTfRl-binding polypeptide comprising the anti-hTfRl-Vu and an immunoglobulin Ckappa domain; and (2) a second hTfRl-binding polypeptide comprising the anti-hTfRl-VLand an immunoglobulin CH domain.

44. The bispecific protein construct of claim 43, wherein the Fc region comprises a first Fc polypeptide and a second Fc polypeptide, and the bispecific protein construct comprises:(a) a first polypeptide comprising the anti-AP-VL,Attorney Docket No.: PGY-08025(b) a second polypeptide comprising the anti-AP-Vn and the first Fc polypeptide, (c) a third polypeptide comprising the anti-AP-Vn, the second Fc polypeptide, and the anti-hTfRl-Vn,(d) a fourth polypeptide comprising the anti-Ap-Vi., and(e) a fifth polypeptide comprising the anti-hTfRl -VL.

45. A bispecific protein construct comprising(a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 275;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 277;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

46. A bispecific protein construct comprising(a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 278;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 279;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

47. A bispecific protein construct comprising(a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 283;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 284;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acidAttorney Docket No.: PGY-08025sequence of SEQ ID NO: 137.

48. A bispecific protein construct comprising(a) a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 287;(b) a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 288;(c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 276; and(d) a fourth polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 137.

49. A bispecific protein construct, comprising(a) a first polypeptide comprising a first anti-AP-VL,(b) a second polypeptide comprising a first anti-AP-Vu and a first IgGl Fc polypeptide,(c) a third polypeptide comprising a second anti-AP-Vu, a second IgGl Fc polypeptide, and an anti-hTfRl-Vu,(d) a fourth polypeptide comprising a second anti-AP-VL, and(e) a fifth polypeptide comprising an anti-hTfRl-VLand a constant heavy domain; whereinthe first and second anti AP-VH each have an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 271,the first and second anti AP-VL each have an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 272,the anti-hTfRl-Vu has an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 128,the anti-hTfRl-VLhas an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 129,the first IgGl Fc polypeptide has an amino sequence comprising the amino acid sequence at least 85% identical to that of SEQ ID NO: 1; a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), and L309D / Q311H / N434S (DHS); and one or more knob-in-hole mutations;Attorney Docket No.: PGY-08025the second IgGl Fc polypeptide has an amino acid sequence comprising the amino acid sequence at least 85% identical to that of SEQ ID NO: 1; a set of amino acid mutations selected from the group consisting of M252Y / S254T / T256E (YTE), M428L / N434S (LS), M428L / N434A (LA), H433K / N434F (KF), andL309D / Q311H / N434S (DHS); and one or more knob-in-hole mutations complementary to the one or more knob-in-hole mutations on the first IgGl Fc polypeptide.

50. An isolated nucleic acid encoding a polypeptide of the bispecific protein construct of any one of claims 1-49.

51. A set of isolated nucleic acids collectively encoding the bispecific protein construct of any one of claims 1-49.

52. An expression vector comprising the isolated nucleic acid of claim 50.

53. A set of expression vectors which collectively comprise the set of isolated nucleic acids of claim 51.

54. A host cell comprising the isolated nucleic acid of claim 50, the set of nucleic acids of claim 53, the expression vector of claim 52, or set of expression vectors of claim 53.

55. The host cell of claim 54, wherein the host cell is a mammalian host cell.

56. A pharmaceutical composition comprising the bispecific protein construct of any one of claims 1-49 and a pharmaceutically acceptable carrier.

57. A method comprising a step of administering to a subject in need thereof an effective amount of the bispecific protein construct of any one of claims 1-49 or the pharmaceutical composition of claim 56.

58. The method of claim 57, wherein the subject has or is at risk of having amyloid beta plaques in the brain.Attorney Docket No.: PGY-0802559. The method of claim 58, wherein the subject has or is at risk of having Alzheimer’s disease.

60. The method of any one of claims 57-59, wherein the step of administering comprises systemic administration of the bispecific protein construct or composition.

61. The method of claim 60, wherein the systemic administration comprises intravenous administration.

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