Compositions comprising Anti-sortilin antibodies and uses thereof

Abstract

The present disclosure relates to multi-specific proteins comprising an antigen-binding domain linked to an anti-Sortilin antibody or antigen-binding fragment thereof. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the anti-Sortilin antibody or antigen-binding fragment thereof across the blood brain barrier (BBB).

Description

735022004240 COMPOSITIONS COMPRISING ANTI-SORTILIN ANTIBODIES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 627,654, filed January 31, 2024; U.S. Provisional Patent Application No.63 / 660,922, filed June 17, 2024; U.S. Provisional Patent Application No.63 / 660,929, filed June 17, 2024; and U.S. Provisional Patent Application No. 63 / 744,149, filed January 10, 2025; the disclosures of each of which are incorporated herein by reference in their entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (735022004240SEQLIST.xml; Size: 397,861 bytes; and Date of Creation: January 21, 2025) is herein incorporated by reference in its entirety. FIELD OF THE PRESENT DISCLOSURE

[0003] The present disclosure relates to multi-specific proteins comprising an antigen-binding domain linked to an anti-Sortilin antibody or antigen-binding fragment thereof. The antigen- binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the anti-Sortilin antibody or antigen-binding fragment thereof across the blood brain barrier (BBB). BACKGROUND

[0004] Passive transfer of substances from blood to brain is restricted by the blood brain barrier (BBB). The BBB provides precise control of central nervous system (CNS) homeostasis allowing for proper neuronal function and also protecting neural tissue from toxins and pathogens. Alterations of the BBB are an important component of pathology and progression of different neurological diseases. However, the BBB poses a problem with regard to delivering therapeutics to the CNS. While recombinant proteins and antibody therapeutics have shown much success outside the CNS, such biologics do not cross the BBB efficiently. As a result, delivery of some therapeutics to the CNS has relied on injection of the therapeutic directly into the CNS. However, such injections are invasive procedures that have efficacy but are limited byny-2872361735022004240 the rapid export of cerebral spinal fluid (CSF) containing the therapeutic from the brain to the blood. Alternatively, a therapeutic intended for the CNS may be administered systemically at a high dose to allow for sufficient penetration of the BBB by the therapeutic. However, in some cases, this approach may result in unintended effects due to the high dose in the periphery or increased manufacturing and formulation burdens to achieve the high dose.

[0005] Sortilin is a Type I transmembrane protein that acts both as a receptor of several ligands and in the sorting of select cargo from the trans-Golgi network (TGN) to late endosomes and lysosomes for degradation. For example, Sortilin binds the secreted protein Progranulin (PGRN) and targets it for lysosomal degradation, thus negatively regulating extracellular levels of PGRN (Hu, F et al. (2010) Neuron 68, 654-667). Through its various interactions with proteins, such as Progranulin, Sortilin and its multiple ligands have been shown to be involved in various diseases, disorders, and conditions, such as frontotemporal dementia, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis-frontotemporal dementia phenotypes, Alzheimer’s disease, Parkinson’s disease, depression, neuropsychiatric disorders, vascular dementia, seizures, retinal dystrophy, age related macular degeneration, glaucoma, traumatic brain injury, aging, seizures, wound healing, stroke, arthritis, and atherosclerotic vascular diseases.

[0006] Accordingly, improved products and methods for delivering anti-Sortilin therapeutics across the BBB are needed. SUMMARY OF THE PRESENT DISCLOSURE

[0007] Provided herein are multi-specific proteins comprising an antigen-binding domain linked to an anti-Sortilin antibody or antigen-binding fragment thereof, and methods of making and using the same. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the anti- Sortilin antibody or antigen-binding fragment thereof across the blood brain barrier (BBB).

[0008] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human transferrin receptor (TfR) and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin.

[0009] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-ny-2872361735022004240 binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, and wherein the multi-specific protein accumulates in a brain sample at least about 5-fold more than the antibody or antigen- binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR.

[0010] In some embodiments, the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively; SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively; SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively.ny-2872361735022004240

[0011] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 157, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 177, or 178.

[0012] In some embodiments, the VH and the VL comprise the amino acid sequences of: SEQ ID NOs: 103 and 157, respectively; SEQ ID NOs: 64 and 129, respectively; SEQ ID NOs: 65 and 130, respectively; SEQ ID NOs: 66 and 131, respectively; SEQ ID NOs: 67 and 130, respectively; SEQ ID NOs: 68 and 131, respectively; SEQ ID NOs: 69 and 130, respectively; SEQ ID NOs: 70 and 131, respectively; SEQ ID NOs: 71 and 130, respectively; SEQ ID NOs: 72 and 131, respectively; SEQ ID NOs: 73 and 130, respectively; SEQ ID NOs: 74 and 131, respectively; SEQ ID NOs: 75 and 132, respectively; SEQ ID NOs: 76 and 131, respectively; SEQ ID NOs: 77 and 132, respectively; SEQ ID NOs: 77 and 133, respectively; SEQ ID NOs: 78 and 134, respectively; SEQ ID NOs: 77 and 135, respectively; SEQ ID NOs: 77 and 136, respectively; SEQ ID NOs: 77 and 137, respectively; SEQ ID NOs: 77 and 138, respectively; SEQ ID NOs: 79 and 131, respectively; SEQ ID NOs: 77 and 139, respectively; SEQ ID NOs: 77 and 131, respectively; SEQ ID NOs: 80 and 140, respectively; SEQ ID NOs: 81 and 141, respectively; SEQ ID NOs: 82 and 131, respectively; SEQ ID NOs: 83 and 142, respectively; SEQ ID NOs: 77 and 143, respectively; SEQ ID NOs: 75 and 131, respectively; SEQ ID NOs: 75 and 144, respectively; SEQ ID NOs: 77 and 145, respectively; SEQ ID NOs: 84 and 131, respectively; SEQ ID NOs: 75 and 146, respectively; SEQ ID NOs: 85 and 131, respectively; SEQ ID NOs: 86 and 138, respectively; SEQ ID NOs: 79 and 139, respectively; SEQ ID NOs: 77 and 147, respectively; SEQ ID NOs: 75 and 148, respectively; SEQ ID NOs: 87 and 131, respectively; SEQ ID NOs: 88 and 131, respectively; SEQ ID NOs: 75 and 149, respectively; SEQ ID NOs: 89 and 150, respectively; SEQ ID NOs: 90 and 151, respectively; SEQ ID NOs: 77 and 152, respectively; SEQ ID NOs: 79 and 153, respectively; SEQ ID NOs: 91 and 131, respectively; SEQ ID NOs: 92 and 131, respectively; SEQ ID NOs: 79 and 154, respectively; SEQ ID NOs: 93 and 155, respectively; SEQ ID NOs: 80 and 131, respectively; SEQ ID NOs:ny-2872361735022004240 94 and 131, respectively; SEQ ID NOs: 95 and 131, respectively; SEQ ID NOs: 66 and 156, respectively; SEQ ID NOs: 97 and 138, respectively; SEQ ID NOs: 95 and 156, respectively; SEQ ID NOs: 98 and 157, respectively; SEQ ID NOs: 99 and 157, respectively; SEQ ID NOs: 100 and 157, respectively; SEQ ID NOs: 101 and 157, respectively; SEQ ID NOs: 102 and 158, respectively; SEQ ID NOs: 104 and 159, respectively; SEQ ID NOs: 105 and 160, respectively; SEQ ID NOs: 106 and 161, respectively; SEQ ID NOs: 107 and 162, respectively; SEQ ID NOs: 106 and 163, respectively; SEQ ID NOs: 108 and 164, respectively; SEQ ID NOs: 106 and 165, respectively; SEQ ID NOs: 108 and 166, respectively; SEQ ID NOs: 109 and 165, respectively; SEQ ID NOs: 110 and 167, respectively; SEQ ID NOs: 111 and 168, respectively; SEQ ID NOs: 112 and 160, respectively; SEQ ID NOs: 113 and 169, respectively; SEQ ID NOs: 113 and 170, respectively; SEQ ID NOs: 113 and 171, respectively; SEQ ID NOs: 114 and 169, respectively; SEQ ID NOs: 114 and 171, respectively; SEQ ID NOs: 115 and 169, respectively; SEQ ID NOs: 115 and 170, respectively; SEQ ID NOs: 115 and 171, respectively; SEQ ID NOs: 116 and 169, respectively; SEQ ID NOs: 116 and 170, respectively; SEQ ID NOs: 116 and 171, respectively; SEQ ID NOs: 117 and 170, respectively; SEQ ID NOs: 118 and 170, respectively; SEQ ID NOs: 119 and 170, respectively; SEQ ID NOs: 120 and 170, respectively; SEQ ID NOs: 121 and 170, respectively; SEQ ID NOs: 122 and 170, respectively; SEQ ID NOs: 123 and 170, respectively; SEQ ID NOs: 124 and 170, respectively; SEQ ID NOs: 125 and 170, respectively; SEQ ID NOs: 126 and 170, respectively; SEQ ID NOs: 127 and 170, respectively; SEQ ID NOs: 117 and 173, respectively; SEQ ID NOs: 117 and 174, respectively; SEQ ID NOs: 117 and 175, respectively; SEQ ID NOs: 117 and 176, respectively; SEQ ID NOs: 117 and 177, respectively; SEQ ID NOs: 117 and 178, respectively; or SEQ ID NOs: 117 and 173, respectively.

[0013] In some embodiments, the antigen-binding domain that specifically binds to human TfR is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 8, 16, and 25, respectively; SEQ ID NOs: 8, 11, and 24, respectively; SEQ ID NOs: 8, 11, and 25, respectively; SEQ ID NOs: 8, 12, and 26, respectively; SEQ ID NOs: 8, 12, and 27, respectively; SEQ ID NOs: 8, 13, and 25, respectively; SEQ ID NOs: 8, 14, and 25, respectively; SEQ ID NOs: 8, 15, and 25, respectively; SEQ ID NOs: 8, 17, and 25, respectively; SEQ ID NOs: 9, 18, and 28, respectively; SEQ ID NOs: 9, 19, and 28, respectively; SEQ ID NOs: 9, 20, and 28, respectively; SEQ ID NOs: 9, 21, and 28, respectively; SEQ ID NOs: 9, 22, and 28, respectively; SEQ ID NOs: 10, 22, and 28, respectively; SEQ IDny-2872361735022004240 NOs: 10, 22, and 30, respectively; SEQ ID NOs: 10, 22, and 31, respectively; SEQ ID NOs: 10, 22, and 32, respectively; SEQ ID NOs: 10, 22, and 33, respectively; SEQ ID NOs: 10, 22, and 34, respectively; SEQ ID NOs: 10, 22, and 35, respectively; SEQ ID NOs: 10, 22, and 36, respectively; SEQ ID NOs: 10, 22, and 37, respectively; SEQ ID NOs: 10, 22, and 38, respectively; or SEQ ID NOs: 10, 22, and 39, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127.

[0014] In some embodiments, the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen- binding domain that specifically binds to human TfR comprises a single-chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker-VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and / or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0015] In some embodiments, the antigen-binding domain that specifically binds to human TfR comprises a VH on a first polypeptide and a VL on a second polypeptide.

[0016] In some embodiments, the antigen-binding domain is a Fab. In some embodiments, the antigen-binding domain that specifically binds to human TfR is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0017] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain. In some embodiments, the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the Fc domain.

[0018] In some embodiments, the multi-specific protein is bispecific. In some embodiments, the multi-specific protein is bivalent, trivalent, or tetravalent. In some embodiments, the multi- specific protein is bivalent. In some embodiments, the multi-specific protein is trivalent,ny-2872361735022004240 optionally wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen-binding domains that each bind to Sortilin. In some embodiments, the multi-specific protein is tetravalent, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen- binding domains that each bind to Sortilin.

[0019] In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human TfR is a scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains. In some embodiments, (i) the scFv that specifically binds to human TfR comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 102, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 158; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, (i) the scFv that specifically binds to human TfR comprises the amino acid sequence of SEQ ID NO: 267; (ii) the heavy chain that is linked to the scFv comprises the amino acid sequence of SEQ ID: 299; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 300; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, (i) the scFv that specifically binds to human TfR comprises the amino acid sequence of SEQ ID NO: 267; (ii) the heavy chain that is linked to the scFv comprises the amino acid sequence of SEQ ID: 301; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 302; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

[0020] In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human TfR is an scFv linked, optionally via an amino acid linker, to the N-terminus of one of the two heavy chains.ny-2872361735022004240

[0021] In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen- binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain. In some embodiments, (i) each antigen-binding domain that specifically binds to human TfR comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 102, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 158; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second VH and a first and second VL, wherein each VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein each VL comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, (i) each antigen-binding domain that specifically binds to human TfR is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 267; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 303; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 304; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, (i) each antigen-binding domain that specifically binds to human TfR is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 267; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 305; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 306; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 258.

[0022] In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen- binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-bindingny-2872361735022004240 domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain. In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain. In some embodiments, the two antigen-binding domains that specifically bind to human TfR are two copies of the same antigen-binding domain.

[0023] In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain. In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain.

[0024] In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region. In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen- binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the C-ny-2872361735022004240 terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region. In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

[0025] In some embodiments, the Fc domain is a modified Fc domain with a modification, or modifications, listed in Table 15.

[0026] In some embodiments, the Fc region is a modified Fc region with a modification, or modifications, listed in Table 15 or Table 16.

[0027] In some embodiments, the Fc domain comprises a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0028] In some embodiments, the Fc region comprises a mutation that reduces effector function, optionally wherein the Fc region is a human IgG1 Fc region and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation.

[0029] In some embodiments, the amino acid linker is a glycine-serine linker. In some embodiments, the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217).

[0030] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / orny-2872361735022004240 P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a knob mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a hole mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0031] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the IgG antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen-binding fragment thereof or an IgG4 antibody or antigen- binding fragment thereof.

[0032] In some embodiments, the multi-specific protein is capable of binding FcRn.

[0033] In some embodiments, the multi-specific protein is linked to an imaging agent.

[0034] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252; and / or (b) a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected fromny-2872361735022004240 the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: a VH comprising the amino acid sequence of SEQ ID NO: 248 and a VL comprising the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 260.

[0035] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, any-2872361735022004240 second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258.

[0036] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, and 232, respectively; SEQ ID NOs: 230, 231, and 236, respectively; SEQ ID NOs: 237, 238, and 236, respectively; or SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252.

[0037] In some embodiments, (i) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 43, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 61; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 235. In some embodiments, (i) the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 102, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 158; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 249. In someny-2872361735022004240 embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 299, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 300, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257; and (ii) the antigen-binding domain that specifically binds to human TfR is an scFv comprising the amino acid sequence of SEQ ID NO: 267. In some embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 301, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 302, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257; and (ii) the antigen-binding domain that specifically binds to human TfR is an scFv comprising the amino acid sequence of SEQ ID NO: 267.

[0038] In some embodiments, (i) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 15, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 25, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 43, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 55, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 61; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 247. In some embodiments, (i) the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 102, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 158; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds tony-2872361735022004240 Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 303, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 304, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258; and (ii) the antigen-binding domain that specifically binds to human TfR is an scFv comprising the amino acid sequence of SEQ ID NO: 267. In some embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 305, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 306, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258; and (ii) the antigen-binding domain that specifically binds to human TfR is an scFv comprising the amino acid sequence of SEQ ID NO: 267.

[0039] In some embodiments, the multi-specific protein accumulates in a brain sample about 9.7-fold more than the antibody or antigen-binding fragment thereof that specifically binds to Sortilin when administered to a subject at a dose of about 15 mg / kg. In some embodiments, the multi-specific protein accumulates in a brain sample about 3-fold more than the antibody or antigen-binding fragment thereof that specifically binds to Sortilin when administered to a subject at a dose of about 5 mg / kg. In some embodiments, the multi-specific protein accumulates in a brain sample about 7-fold more than the antibody or antigen-binding fragment thereof that specifically binds to Sortilin when administered to a subject at a dose of about 50 mg / kg. In some embodiments, the brain sample is a vessel-depleted mouse brain sample. In some embodiments, the multi-specific protein binds to cell-surface Sortilin with a half maximal effective concentration (EC50) of about 0.5 nM to about 6 nM. In some embodiments, multi-specific protein binds to cell-surface Sortilin with an EC50 of about 2 nM to about 4.5 nM. In some embodiments, the multi-specific protein binds to cell-surface Sortilin with an EC50 of about 4.1 nM. In some embodiments, the multi-specific protein binds to cell-surface Sortilin with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR. In some embodiments, the multi-specific protein decreases cell surface levels of Sortilin with an EC50 of about 0.05 nM to about 0.5 nM. In some embodiments, the multi-specific protein decreases cell surface levels of Sortilin with an EC50 of about 0.23 nM. In some embodiments, the multi-ny-2872361735022004240 specific protein decreases cell surface levels of Sortilin with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR. In some embodiments, the multi- specific protein increases extracellular progranulin levels with an EC50 of about 0.05 nM to about 0.5 nM. In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 of about 0.22 nM. In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR. In some embodiments, cellular uptake of the multi-specific protein is at least about 1-fold, at least about 2-fold, at least about 3- fold, or at least about 4-fold greater than cellular uptake of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR.

[0040] In some aspects, provided herein is a multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv specifically binds to human TfR; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen- binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 268; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 269; and (iii) the third polypeptide and the fourthny-2872361735022004240 polypeptide each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 273; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 274; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH second polypeptide each comprise the amino acid sequence of SEQ ID NO: 248; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 249.

[0041] In some aspects, provided herein is a multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human TfR; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen- binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 275; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 276; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 277; (ii) the secondny-2872361735022004240 polypeptide comprises the amino acid sequence of SEQ ID NO: 278; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 252; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 254.

[0042] In some embodiments, the scFv that specifically binds to human TfR comprises the amino acid sequence of SEQ ID NO: 267.

[0043] In some aspects, provided herein is use of the multi-specific protein of any one of the embodiments or the pharmaceutical composition of any one of the embodiments in the method of any one of the embodiments.

[0044] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: SEQ ID NOs: 181, 185, 191, 194, 198, and 201, respectively; SEQ ID NOs: 182, 186, 191, 195, 199, and 202, respectively; SEQ ID NOs: 183, 187, 192, 196, 200, and 203, respectively; SEQ ID NOs: 9, 188, 192, 196, 200, and 203, respectively; SEQ ID NOs: 184, 189, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 190, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 284, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 285, 193, 197, 198, and 204, respectively; or SEQ ID NOs: 184, 286, 193, 197, 198, and 204, respectively.

[0045] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 287, 288, or 289. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 211, 212, 213, 214, 215, or 216. In some embodiments, the VH and the VL comprise the amino acid sequences of: SEQ ID NOs: 205 and 211, respectively; SEQny-2872361735022004240 ID NOs: 206 and 212, respectively; SEQ ID NOs: 207 and 213, respectively; SEQ ID NOs: 208 and 214, respectively; SEQ ID NOs: 209 and 215, respectively; SEQ ID NOs: 210 and 216, respectively; SEQ ID NOs: 287 and 216, respectively; SEQ ID NOs: 288 and 216, respectively; or SEQ ID NOs: 289 and 216, respectively. In some embodiments, the antigen-binding domain that specifically binds to CD98hc is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 181, 185, and 191, respectively; SEQ ID NOs: 182, 186, and 191, respectively; SEQ ID NOs: 183, 187, and 192, respectively; SEQ ID NOs: 9, 188, and 192, respectively; SEQ ID NOs: 184, 189, and 193, respectively; SEQ ID NOs: 184, 190, and 193, respectively; SEQ ID NOs: 184, 284, and 193, respectively; SEQ ID NOs: 184, 285, and 193, respectively; or SEQ ID NOs: 184, 286, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 287, 288, or 289.

[0046] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a single-chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker-VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids. In some embodiments, the linker comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0047] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a VH on a first polypeptide and a VL on a second polypeptide.

[0048] In some embodiments, the antigen-binding domain is a Fab. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0049] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the Fc domain.ny-2872361735022004240

[0050] In some embodiments, the multi-specific protein is bispecific. In some embodiments, the multi-specific protein is bivalent, trivalent, or tetravalent. In some embodiments, the multi- specific protein is bivalent. In some embodiments, the multi-specific protein is trivalent, optionally wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen-binding domains that each bind to Sortilin. In some embodiments, the multi-specific protein is tetravalent, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen- binding domains that each bind to Sortilin.

[0051] In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human CD98hc is an scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains. In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human CD98hc is an scFv linked, optionally via an amino acid linker, to the N-terminus of one of the two heavy chains.

[0052] In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hc is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain. In some embodiments, (i) each antigen- binding domain that specifically binds to human CD98hc comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 216; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second VH and a first and secondny-2872361735022004240 VL, wherein each VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein each VL comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, (i) each antigen-binding domain that specifically binds to human CD98hc is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 290; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 299; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 300; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, (i) each antigen-binding domain that specifically binds to human CD98hc is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 290; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 301; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 302; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, (i) each antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 216; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second VH and a first and second VL, wherein each VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein each VL comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, (i) each antigen-binding domain that specifically binds to human CD98hc is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 290; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 303; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 304; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, (i) each antigen-binding domain that specifically binds to human CD98hc is an scFv, wherein each scFv comprises the amino acid sequence of SEQ ID NO: 290; (ii) one of the two heavy chains comprises the amino acid sequence of SEQ ID: 305; (iii) the other heavy chain comprises the amino acid sequence of SEQ ID: 305; and (iv) the two light chains each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

[0053] In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hcny-2872361735022004240 is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain. In some embodiments, the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen- binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hc is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain. In some embodiments, the two antigen-binding domains that specifically bind to human CD98hc are two copies of the same antigen-binding domain.

[0054] In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain. In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain.

[0055] In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, 22ny-2872361735022004240 VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region. In some embodiments, the multi-specific protein is bivalent and bispecific, wherein the multi- specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region. In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

[0056] In some embodiments, the Fc domain is a modified Fc domain with a modification, or modifications, listed in Table 15.

[0057] In some embodiments, the Fc region is a modified Fc region with a modification, or modifications, listed in Table 15 or Table 16.

[0058] In some embodiments, the Fc domain comprises a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0059] In some embodiments, the Fc region comprises a mutation that reduces effector function, optionally wherein the Fc region is a human IgG1 Fc region and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation. In some embodiments, the amino acid linker is a glycine-serine linker. In some embodiments, the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217).ny-2872361735022004240

[0060] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a knob mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a hole mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0061] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the IgG antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen-binding fragment thereof or an IgG4 antibody or antigen- binding fragment thereof.

[0062] In some embodiments, the multi-specific protein is capable of binding FcRn.

[0063] In some embodiments, the multi-specific protein is linked to an imaging agent.

[0064] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252, or an amino acidny-2872361735022004240 sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252; and / or (b) a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 248 and the VL comprises the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254; the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 260.

[0065] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises:(a) a first heavy chain comprising the amino acidny-2872361735022004240 sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258.

[0066] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, and 232, respectively; SEQ ID NOs: 230, 231, and 236, respectively; SEQ ID NOs: 237, 238, and 236, respectively; or SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252. In some embodiments, (i) the antigen-binding domain that specifically binds to human CD98hc comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 184, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 190, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 193, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 197, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 198, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 204; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 235. In some embodiments, (i) the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 216; and (ii) the antibody or antigen-binding fragment thereof thatny-2872361735022004240 specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 249.

[0067] In some embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 299, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 300, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257; and (ii) the antigen-binding domain that specifically binds to human CD98hc is an scFv comprising the amino acid sequence of SEQ ID NO: 290. In some embodiments, (i) the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 301, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 302, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257; and (ii) the antigen-binding domain that specifically binds to human CD98hc is an scFv comprising the amino acid sequence of SEQ ID NO: 290.

[0068] In some embodiments, (i) the antigen-binding domain that specifically binds to human CD98hc comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 184, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 190, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 193, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 197, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 198, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 204; and (ii) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 247. In some embodiments, (i) the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 216; and (ii) the antibody or antigen-binding fragment thereof thatny-2872361735022004240 specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, (i) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 303, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 304, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258; and (ii) the antigen-binding domain that specifically binds to human CD98hc is an scFv comprising the amino acid sequence of SEQ ID NO: 290. In some embodiments, (i) the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 305, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 306, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258; and (ii) the antigen-binding domain that specifically binds to human CD98hc is an scFv comprising the amino acid sequence of SEQ ID NO: 290.

[0069] In some aspects, provided herein is a multi-specific protein comprising:(i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human CD98hc; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or SEQ ID NOs: 239,ny-2872361735022004240 240, 241, 242, 246, and 247, respectively. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 291; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 292; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 293; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 294; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 257. In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 248; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 249. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 295; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 296; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 297; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 298; and (iii) the third polypeptide and the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 258. In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 252; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 254. In some embodiments, the scFv that specifically binds to human CD98hc comprises the amino acid sequence of SEQ ID NO: 290.

[0070] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, and wherein the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region (VH)ny-2872361735022004240 comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively.

[0071] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 317, 117, 318, or 118. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 154, 319, 320, 174, 321, 322, 323, 324, or 325. In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 319, respectively; (iii) SEQ ID NOs: 102 and 320, respectively; (iv) SEQ ID NOs: 317 and 174, respectively; (v) SEQ ID NOs: 117 and 321, respectively; (vi) SEQ ID NOs: 117 and 322, respectively; (vii) SEQ ID NOs: 117 and 323, respectively; (viii) SEQ ID NOs: 117 and 324, respectively; (ix) SEQ ID NOs: 318 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 325, respectively.

[0072] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-ny-2872361735022004240 binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, and wherein the antigen-binding domain that specifically binds to human TfR is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 10, 22, and 308, respectively; or (ii) SEQ ID NOs: 10, 22, and 309, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 317 or 318.

[0073] In some embodiments, the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen- binding domain that specifically binds to human TfR comprises a single-chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker-VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and / or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0074] In some embodiments, the antigen-binding domain that specifically binds to human TfR comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a Fab.

[0075] In some embodiments, the antigen-binding domain that specifically binds to human TfR is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0076] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain. In some embodiments, the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the Fc domain.

[0077] In some embodiments, the multi-specific protein is bispecific. In some embodiments, the multi-specific protein is bivalent, trivalent, or tetravalent. In some embodiments, the multi- specific protein is bivalent. In some embodiments, the multi-specific protein is trivalent, optionally wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen-binding domains that each bind to Sortilin. In some embodiments,ny-2872361735022004240 the multi-specific protein is tetravalent, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen- binding domains that each bind to Sortilin. In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human TfR is an scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains. In some embodiments, the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

[0078] In some embodiments, the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human TfR is an scFv linked, optionally via an amino acid linker, to the N-terminus of one of the two heavy chains.

[0079] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen- binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

[0080] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen- binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-bindingny-2872361735022004240 domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain.

[0081] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen- binding domains that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

[0082] In some embodiments, the two antigen-binding domains that specifically bind to human TfR are two copies of the same antigen-binding domain.

[0083] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain.

[0084] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain.

[0085] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region.

[0086] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains,ny-2872361735022004240 wherein the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region.

[0087] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc domain is a modified Fc domain with a modification, or modifications, listed in Table 15. In some embodiments, the Fc region is a modified Fc region with a modification, or modifications, listed in Table 15 or Table 16. In some embodiments, the Fc domain comprises a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the Fc region comprises a mutation that reduces effector function, optionally wherein the Fc region is a human IgG1 Fc region and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation. In some embodiments, the antigen- binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation. In some embodiments, the amino acid linker is a glycine-serine linker. In some embodiments, the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217). In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a knobny-2872361735022004240 mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a hole mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0088] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the IgG antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen-binding fragment thereof or an IgG4 antibody or antigen- binding fragment thereof. In some embodiments, the multi-specific protein is capable of binding FcRn.

[0089] In some embodiments, the multi-specific protein is linked to an imaging agent.

[0090] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0091] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252; and / or (b) a VL comprising an amino acid sequenceny-2872361735022004240 selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 248 and a VL comprising the amino acid sequence of SEQ ID NO: 249; (ii) the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iii) the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iv) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; (v) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254; (vi) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or (vii) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 256.

[0092] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 260.ny-2872361735022004240

[0093] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258.

[0094] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, and 232, respectively; (ii) SEQ ID NOs: 230, 231, and 236, respectively; (iii) SEQ ID NOs: 237, 238, and 236, respectively; or (iv) SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252.

[0095] In some embodiments, (a) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; 37ny-2872361735022004240 (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 235.

[0096] In some embodiments, (a) the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 319, respectively; (iii) SEQ ID NOs: 102 and 320, respectively; (iv) SEQ ID NOs: 317 and 174, respectively; (v) SEQ ID NOs: 117 and 321, respectively; (vi) SEQ ID NOs: 117 and 322, respectively; (vii) SEQ ID NOs: 117 and 323, respectively; (viii) SEQ ID NOs: 117 and 324, respectively; (ix) SEQ ID NOs: 318 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 325, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 249.

[0097] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 299, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 300, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257.ny-2872361735022004240

[0098] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 299, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 300, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257.

[0099] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 301, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 302, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257.

[0100] In some embodiments, (a) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 247.ny-2872361735022004240

[0101] In some embodiments, (a) the antigen-binding domain that specifically binds to human TfR comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 319, respectively; (iii) SEQ ID NOs: 102 and 320, respectively; (iv) SEQ ID NOs: 317 and 174, respectively; (v) SEQ ID NOs: 117 and 321, respectively; (vi) SEQ ID NOs: 117 and 322, respectively; (vii) SEQ ID NOs: 117 and 323, respectively; (viii) SEQ ID NOs: 117 and 324, respectively; (ix) SEQ ID NOs: 318 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 325, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 254.

[0102] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 303, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 304, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258.

[0103] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 305, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 306, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258.

[0104] In some aspects, provided herein is a multi-specific protein comprising (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (c) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL;ny-2872361735022004240 wherein the scFv specifically binds to human TfR, wherein the scFv comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0105] In some embodiments, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively. In some embodiments, wherein: (i) the VH of the first polypeptideny-2872361735022004240 and the VH second polypeptide each comprise the amino acid sequence of SEQ ID NO: 248; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 249.

[0106] In some aspects, provided herein is a multi-specific protein comprising (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (c) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human TfR, wherein each scFv comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively;ny-2872361735022004240 (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0107] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 252; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 254.

[0108] In some embodiments, the scFv that specifically binds to human TfR comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 319, respectively; (iii) SEQ ID NOs: 102 and 320, respectively; (iv) SEQ ID NOs: 317 and 174, respectively; (v) SEQ ID NOs: 117 and 321, respectively; (vi) SEQ ID NOs: 117 and 322, respectively; (vii) SEQ ID NOs: 117 and 323, respectively; (viii) SEQ ID NOs: 117 and 324, respectively; (ix) SEQ ID NOs: 318 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 325, respectively.

[0109] In some aspects, provided herein is a composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human TfR, and the thirdny-2872361735022004240 polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin. In some aspects, provided herein is a composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a first antigen-binding domain that specifically binds to human TfR, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a second antigen-binding domain that specifically binds to human TfR, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, optionally wherein the first and second antigen-binding domains that specifically bind to human TfR comprise the same amino acid sequence.

[0110] In some embodiments, the first heavy chain comprises a knob mutation and the second heavy chain comprises a hole mutation. In some embodiments, the ratio of the first, second, and third polynucleotides is about 1:3:6. In some embodiments, the first heavy chain comprises a hole mutation and the second heavy chain comprises a knob mutation.

[0111] In some aspects, provided herein is a composition comprising a first polynucleotide and a second polynucleotide, wherein the first and second polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human TfR, and wherein the second polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

[0112] In some aspects, provided herein is a host cell comprising the composition of any one of the preceding embodiments.

[0113] In some aspects, provided herein is a polynucleotide encoding the multi-specific protein of any one of the preceding embodiments.

[0114] In some aspects, provided herein is a vector comprising the polynucleotide of any one of the preceding embodiments.

[0115] In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment.ny-2872361735022004240

[0116] In some aspects, provided herein is a method of producing a multi-specific protein comprising culturing the host of any one of the preceding embodiments so that the multi-specific protein is produced, optionally wherein the method further comprises isolating the multi-specific protein from the culture. In some aspects, provided herein is an isolated multi-specific protein thereof produced by the method of the preceding embodiment.

[0117] In some aspects, provided herein is a pharmaceutical composition comprising the multi- specific protein of any one of the preceding embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0118] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy.

[0119] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.ny-2872361735022004240

[0120] In some aspects, provided herein is a method of transporting an antibody or antigen- binding fragment thereof that specifically binds to Sortilin across the blood brain barrier (BBB) of a subject, comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject.

[0121] In some aspects, provided herein is a method of increasing the concentration of an antibody or antigen-binding fragment thereof that specifically binds to Sortilin in the cerebral spinal fluid (CSF) of a subject, comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject, wherein the concentration of the antibody or antigen-binding fragment thereof is increased in the CSF of the subject as compared to administering the antibody or antigen-binding fragment thereof alone to the subject.

[0122] In some aspects, provided herein is a method of imaging an antibody or antigen-binding fragment thereof that specifically binds to Sortilin within a subject, comprising administering to the subject the multi-specific protein of any one of the preceding embodiments and locating the imaging agent within the subject.

[0123] In some aspects, provided herein is a method of detecting Sortilin in vitro, comprising contacting an in vitro sample with the multi-specific protein of any one of the preceding embodiments and locating the imaging agent within the sample.

[0124] In some aspects, provided herein is a use of the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments in the method of any one of the preceding embodiments.

[0125] The multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments for use in the method of any one of the preceding embodiments.

[0126] The multi-specific protein of any one of the embodiments or the pharmaceutical composition of any one of the embodiments for the manufacture of a medicament for the method of any one of the embodiments.

[0127] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human CD98 heavy chain (CD98hc), wherein the antibodyny-2872361735022004240 or antigen-binding fragment thereof specifically binds to Sortilin, wherein the antigen-binding domain that specifically binds to human CD98hc comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively;ny-2872361735022004240 (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively.

[0128] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 210, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, or 385. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, or 408. In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 368 and 216, respectively; (ii) SEQ ID NOs: 369 and 216, respectively; (iii) SEQ ID NOs: 370 and 216, respectively; (iv) SEQ ID NOs: 371 and 216, respectively; (v) SEQ ID NOs: 372 and 216, respectively; (vi) SEQ ID NOs: 373 and 216, respectively; (vii) SEQ ID NOs: 374 and 216, respectively; (viii) SEQ ID NOs: 210 and 386, respectively;ny-2872361735022004240 (ix) SEQ ID NOs: 210 and 387, respectively; (x) SEQ ID NOs: 210 and 388, respectively; (xi) SEQ ID NOs: 210 and 389, respectively; (xii) SEQ ID NOs: 210 and 390, respectively; (xiii) SEQ ID NOs: 210 and 391, respectively; (xiv) SEQ ID NOs: 210 and 392, respectively; (xv) SEQ ID NOs: 370 and 388, respectively; (xvi) SEQ ID NOs: 375 and 216, respectively; (xvii) SEQ ID NOs: 376 and 216, respectively; (xviii) SEQ ID NOs: 377 and 216, respectively; (xix) SEQ ID NOs: 378 and 216, respectively; (xx) SEQ ID NOs: 379 and 216, respectively; (xxi) SEQ ID NOs: 380 and 216, respectively; (xxii) SEQ ID NOs: 381 and 216, respectively; (xxiii) SEQ ID NOs: 382 and 216, respectively; (xxiv) SEQ ID NOs: 383 and 216, respectively; (xxv) SEQ ID NOs: 384 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 393, respectively; (xxvii) SEQ ID NOs: 210 and 394, respectively; (xxviii) SEQ ID NOs: 210 and 395, respectively; (xxix) SEQ ID NOs: 210 and 396, respectively; (xxx) SEQ ID NOs: 210 and 397, respectively; (xxxi) SEQ ID NOs: 210 and 398, respectively; (xxxii) SEQ ID NOs: 210 and 399, respectively; (xxxiii) SEQ ID NOs: 210 and 400, respectively; (xxxiv) SEQ ID NOs: 210 and 401, respectively; (xxxv) SEQ ID NOs: 210 and 402, respectively; (xxxvi) SEQ ID NOs: 210 and 403, respectively; (xxxvii) SEQ ID NOs: 210 and 404, respectively; (xxxviii) SEQ ID NOs: 210 and 405, respectively; (xxxix) SEQ ID NOs: 210 and 406, respectively;ny-2872361735022004240 (xl) SEQ ID NOs: 210 and 407, respectively; (xli) SEQ ID NOs: 210 and 408, respectively; (xlii) SEQ ID NOs: 385 and 215, respectively; or (xliii) SEQ ID NOs: 385 and 408, respectively.

[0129] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human CD98 heavy chain (CD98hc), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, wherein the antigen-binding domain that specifically binds to human CD98hc is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, and 193, respectively; (ii) SEQ ID NOs: 184, 328, and 193, respectively; (iii) SEQ ID NOs: 184, 329, and 193, respectively; (iv) SEQ ID NOs: 184, 330, and 193, respectively; (v) SEQ ID NOs: 184, 331, and 193, respectively; (vi) SEQ ID NOs: 184, 332, and 193, respectively; (vii) SEQ ID NOs: 184, 333, and 193, respectively; (viii) SEQ ID NOs: 184, 334, and 193, respectively; (ix) SEQ ID NOs: 184, 190, and 335, respectively; (x) SEQ ID NOs: 184, 190, and 336, respectively; (xi) SEQ ID NOs: 184, 190, and 337, respectively; (xii) SEQ ID NOs: 184, 190, and 338, respectively; (xiii) SEQ ID NOs: 184, 190, and 339, respectively; (xiv) SEQ ID NOs: 184, 190, and 340, respectively; (xv) SEQ ID NOs: 184, 190, and 341, respectively; (xvi) SEQ ID NOs: 184, 190, and 342, respectively; (xvii) SEQ ID NOs: 184, 190, and 343, respectively; or (xviii) SEQ ID NOs: 326, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, or 385.ny-2872361735022004240

[0130] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a single-chain fragment variable (scFv). In some embodiments, the scFv is in the orientation VH-linker-VL. In some embodiments, the scFv is in the orientation VL-linker-VH. In some embodiments, the linker is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids. In some embodiments, the linker comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0131] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a Fab.

[0132] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0133] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the Fc domain.

[0134] In some embodiments, the multi-specific protein is bispecific. In some embodiments, the multi-specific protein is bivalent, trivalent, or tetravalent. In some embodiments, the multi- specific protein is bivalent.

[0135] In some embodiments, the multi-specific protein is trivalent, optionally wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen-binding domains that each bind to Sortilin.

[0136] In some embodiments, the multi-specific protein is tetravalent, wherein the multi- specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two antigen-binding domains that each bind to Sortilin.

[0137] In some embodiments, the multi-specific protein is trivalent and bi-specific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises twony-2872361735022004240 heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human CD98hc is an scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains.

[0138] In some embodiments, the multi-specific protein is trivalent and bi-specific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human CD98hc is an scFv linked, optionally via an amino acid linker, to the N-terminus of one of the two heavy chains.

[0139] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hc is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

[0140] In some embodiments, the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

[0141] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hc is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain.

[0142] In some embodiments, the multi-specific protein is tetravalent and bi-specific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hcny-2872361735022004240 is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

[0143] In some embodiments, the two antigen-binding domains that specifically bind to human CD98hc are two copies of the same antigen-binding domain.

[0144] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain.

[0145] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc domain, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain.

[0146] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region.

[0147] In some embodiments, the multi-specific protein is bivalent and bi-specific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region.ny-2872361735022004240

[0148] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc domain is a modified Fc domain with a modification, or modifications, listed in Table 15. In some embodiments, the Fc region is a modified Fc region with a modification, or modifications, listed in Table 15 or Table 16. In some embodiments, the Fc domain comprises a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the Fc region comprises a mutation that reduces effector function, optionally wherein the Fc region is a human IgG1 Fc region and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation. In some embodiments, the antigen- binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation. In some embodiments, the amino acid linker is a glycine-serine linker. In some embodiments, the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217). In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a knob mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S. In some embodiments, the antibody orny-2872361735022004240 antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain comprising a hole mutation and a mutation that reduces effector function, optionally wherein the Fc domain is a human IgG1 Fc domain and wherein the mutation that reduces effector function comprises (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

[0149] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the IgG antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen-binding fragment thereof or an IgG4 antibody or antigen- binding fragment thereof. In some embodiments, the multi-specific protein is capable of binding FcRn.

[0150] In some embodiments, the multi-specific protein is linked to an imaging agent.

[0151] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0152] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 248, 250, 251, and 252; and / or (b) a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 249, 253, 254, 255, and 256.ny-2872361735022004240

[0153] In some embodiments, wherein: (i) the VH comprises the amino acid sequence of SEQ ID NO: 248 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (ii) the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iii) the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iv) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; (v) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254; (vi) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or (vii) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 256.

[0154] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 260.

[0155] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises: (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, any-2872361735022004240 second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258.

[0156] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, and 232, respectively; (ii) SEQ ID NOs: 230, 231, and 236, respectively; (iii) SEQ ID NOs: 237, 238, and 236, respectively; or (iv) SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252.

[0157] In some embodiments, (a) the antigen-binding domain that specifically binds to human CD98hc comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively;ny-2872361735022004240 (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively; andny-2872361735022004240 (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 235.

[0158] In some embodiments, (a) the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 368 and 216, respectively; (ii) SEQ ID NOs: 369 and 216, respectively; (iii) SEQ ID NOs: 370 and 216, respectively; (iv) SEQ ID NOs: 371 and 216, respectively; (v) SEQ ID NOs: 372 and 216, respectively; (vi) SEQ ID NOs: 373 and 216, respectively; (vii) SEQ ID NOs: 374 and 216, respectively; (viii) SEQ ID NOs: 210 and 386, respectively; (ix) SEQ ID NOs: 210 and 387, respectively; (x) SEQ ID NOs: 210 and 388, respectively; (xi) SEQ ID NOs: 210 and 389, respectively; (xii) SEQ ID NOs: 210 and 390, respectively; (xiii) SEQ ID NOs: 210 and 391, respectively; (xiv) SEQ ID NOs: 210 and 392, respectively; (xv) SEQ ID NOs: 370 and 388, respectively; (xvi) SEQ ID NOs: 375 and 216, respectively; (xvii) SEQ ID NOs: 376 and 216, respectively; (xviii) SEQ ID NOs: 377 and 216, respectively; (xix) SEQ ID NOs: 378 and 216, respectively; (xx) SEQ ID NOs: 379 and 216, respectively; (xxi) SEQ ID NOs: 380 and 216, respectively; (xxii) SEQ ID NOs: 381 and 216, respectively; (xxiii) SEQ ID NOs: 382 and 216, respectively;ny-2872361735022004240 (xxiv) SEQ ID NOs: 383 and 216, respectively; (xxv) SEQ ID NOs: 384 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 393, respectively; (xxvii) SEQ ID NOs: 210 and 394, respectively; (xxviii) SEQ ID NOs: 210 and 395, respectively; (xxix) SEQ ID NOs: 210 and 396, respectively; (xxx) SEQ ID NOs: 210 and 397, respectively; (xxxi) SEQ ID NOs: 210 and 398, respectively; (xxxii) SEQ ID NOs: 210 and 399, respectively; (xxxiii) SEQ ID NOs: 210 and 400, respectively; (xxxiv) SEQ ID NOs: 210 and 401, respectively; (xxxv) SEQ ID NOs: 210 and 402, respectively; (xxxvi) SEQ ID NOs: 210 and 403, respectively; (xxxvii) SEQ ID NOs: 210 and 404, respectively; (xxxviii) SEQ ID NOs: 210 and 405, respectively; (xxxix) SEQ ID NOs: 210 and 406, respectively; (xl) SEQ ID NOs: 210 and 407, respectively; (xli) SEQ ID NOs: 210 and 408, respectively; (xlii) SEQ ID NOs: 385 and 215, respectively; or (xliii) SEQ ID NOs: 385 and 408, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 248, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 249.

[0159] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 299, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 300, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257.

[0160] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 301, theny-2872361735022004240 second heavy chain comprises the amino acid sequence of SEQ ID NO: 302, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 257.

[0161] In some embodiments, (a) the antigen-binding domain that specifically binds to human CD98hc a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively;ny-2872361735022004240 (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 247.

[0162] In some embodiments, (a) the antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 368 and 216, respectively; (ii) SEQ ID NOs: 369 and 216, respectively; (iii) SEQ ID NOs: 370 and 216, respectively; (iv) SEQ ID NOs: 371 and 216, respectively; (v) SEQ ID NOs: 372 and 216, respectively; (vi) SEQ ID NOs: 373 and 216, respectively;ny-2872361735022004240 (vii) SEQ ID NOs: 374 and 216, respectively; (viii) SEQ ID NOs: 210 and 386, respectively; (ix) SEQ ID NOs: 210 and 387, respectively; (x) SEQ ID NOs: 210 and 388, respectively; (xi) SEQ ID NOs: 210 and 389, respectively; (xii) SEQ ID NOs: 210 and 390, respectively; (xiii) SEQ ID NOs: 210 and 391, respectively; (xiv) SEQ ID NOs: 210 and 392, respectively; (xv) SEQ ID NOs: 370 and 388, respectively; (xvi) SEQ ID NOs: 375 and 216, respectively; (xvii) SEQ ID NOs: 376 and 216, respectively; (xviii) SEQ ID NOs: 377 and 216, respectively; (xix) SEQ ID NOs: 378 and 216, respectively; (xx) SEQ ID NOs: 379 and 216, respectively; (xxi) SEQ ID NOs: 380 and 216, respectively; (xxii) SEQ ID NOs: 381 and 216, respectively; (xxiii) SEQ ID NOs: 382 and 216, respectively; (xxiv) SEQ ID NOs: 383 and 216, respectively; (xxv) SEQ ID NOs: 384 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 393, respectively; (xxvii) SEQ ID NOs: 210 and 394, respectively; (xxviii) SEQ ID NOs: 210 and 395, respectively; (xxix) SEQ ID NOs: 210 and 396, respectively; (xxx) SEQ ID NOs: 210 and 397, respectively; (xxxi) SEQ ID NOs: 210 and 398, respectively; (xxxii) SEQ ID NOs: 210 and 399, respectively; (xxxiii) SEQ ID NOs: 210 and 400, respectively; (xxxiv) SEQ ID NOs: 210 and 401, respectively; (xxxv) SEQ ID NOs: 210 and 402, respectively; (xxxvi) SEQ ID NOs: 210 and 403, respectively; (xxxvii) SEQ ID NOs: 210 and 404, respectively;ny-2872361735022004240 (xxxviii) SEQ ID NOs: 210 and 405, respectively; (xxxix) SEQ ID NOs: 210 and 406, respectively; (xl) SEQ ID NOs: 210 and 407, respectively; (xli) SEQ ID NOs: 210 and 408, respectively; (xlii) SEQ ID NOs: 385 and 215, respectively; or (xliii) SEQ ID NOs: 385 and 408, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 252, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 254.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 303, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 304, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258.

[0164] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a first and second heavy chain and a first and second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 305, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 306, and the first and second light chain each comprise the amino acid sequence of SEQ ID NO: 258.

[0165] In some aspects, provided herein is a multi-specific protein comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (c) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human CD98hc, wherein each scFv comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively;ny-2872361735022004240 (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively;ny-2872361735022004240 (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen- binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0166] In some embodiments, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 248; and / or (ii) the VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 249.

[0167] In some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively. In some embodiments, (i) the VH of the first polypeptide and the VH of the second polypeptide each comprise the amino acid sequence of SEQ ID NO: 252; and / or (ii) theny-2872361735022004240 VL of the third polypeptide and the VL of the fourth polypeptide each comprise the amino acid sequence of SEQ ID NO: 254.

[0168] In some embodiments, the scFv that specifically binds to human CD98hc comprises CD98hc comprises a VH and a VL comprising the amino acid sequences of: (i) SEQ ID NOs: 368 and 216, respectively; (ii) SEQ ID NOs: 369 and 216, respectively; (iii) SEQ ID NOs: 370 and 216, respectively; (iv) SEQ ID NOs: 371 and 216, respectively; (v) SEQ ID NOs: 372 and 216, respectively; (vi) SEQ ID NOs: 373 and 216, respectively; (vii) SEQ ID NOs: 374 and 216, respectively; (viii) SEQ ID NOs: 210 and 386, respectively; (ix) SEQ ID NOs: 210 and 387, respectively; (x) SEQ ID NOs: 210 and 388, respectively; (xi) SEQ ID NOs: 210 and 389, respectively; (xii) SEQ ID NOs: 210 and 390, respectively; (xiii) SEQ ID NOs: 210 and 391, respectively; (xiv) SEQ ID NOs: 210 and 392, respectively; (xv) SEQ ID NOs: 370 and 388, respectively; (xvi) SEQ ID NOs: 375 and 216, respectively; (xvii) SEQ ID NOs: 376 and 216, respectively; (xviii) SEQ ID NOs: 377 and 216, respectively; (xix) SEQ ID NOs: 378 and 216, respectively; (xx) SEQ ID NOs: 379 and 216, respectively; (xxi) SEQ ID NOs: 380 and 216, respectively; (xxii) SEQ ID NOs: 381 and 216, respectively; (xxiii) SEQ ID NOs: 382 and 216, respectively; (xxiv) SEQ ID NOs: 383 and 216, respectively; (xxv) SEQ ID NOs: 384 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 393, respectively; (xxvii) SEQ ID NOs: 210 and 394, respectively;ny-2872361735022004240 (xxviii) SEQ ID NOs: 210 and 395, respectively; (xxix) SEQ ID NOs: 210 and 396, respectively; (xxx) SEQ ID NOs: 210 and 397, respectively; (xxxi) SEQ ID NOs: 210 and 398, respectively; (xxxii) SEQ ID NOs: 210 and 399, respectively; (xxxiii) SEQ ID NOs: 210 and 400, respectively; (xxxiv) SEQ ID NOs: 210 and 401, respectively; (xxxv) SEQ ID NOs: 210 and 402, respectively; (xxxvi) SEQ ID NOs: 210 and 403, respectively; (xxxvii) SEQ ID NOs: 210 and 404, respectively; (xxxviii) SEQ ID NOs: 210 and 405, respectively; (xxxix) SEQ ID NOs: 210 and 406, respectively; (xl) SEQ ID NOs: 210 and 407, respectively; (xli) SEQ ID NOs: 210 and 408, respectively; (xlii) SEQ ID NOs: 385 and 215, respectively; or (xliii) SEQ ID NOs: 385 and 408, respectively

[0169] In some aspects, provided herein is a composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human CD98hc, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

[0170] In some aspects, provided herein is a composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a first antigen-binding domain that specifically binds to human CD98hc, the second polynucleotide encodes a second heavy chain ofny-2872361735022004240 the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a second antigen-binding domain that specifically binds to human CD98hc, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, optionally wherein the first and second antigen-binding domains that specifically bind to human CD98hc comprise the same amino acid sequence.

[0171] In some embodiments, the first heavy chain comprises a knob mutation and the second heavy chain comprises a hole mutation.

[0172] In some embodiments, the ratio of the first, second, and third polynucleotides is about 1:3:6. In some embodiments, the first heavy chain comprises a hole mutation and the second heavy chain comprises a knob mutation.

[0173] In some aspects, provided herein is a composition comprising a first polynucleotide and a second polynucleotide, wherein the first and second polynucleotides encode the multi-specific protein of any one of the preceding embodiments, wherein the first polynucleotide encodes a heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human CD98hc, and wherein the second polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

[0174] In some aspects, provided herein is a host cell comprising the composition of any one of the preceding embodiments.

[0175] In some aspects, provided herein is a polynucleotide encoding the multi-specific protein of any one of the preceding embodiments.

[0176] In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment.

[0177] In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment.

[0178] In some aspects, provided herein is a method of producing a multi-specific protein comprising culturing the host cell of any one of the preceding embodiments so that the multi- specific protein is produced, optionally wherein the method further comprises isolating the multi- specific protein from the culture.

[0179] In some aspects, provided herein is an isolated multi-specific protein produced by the method of the preceding embodiment.ny-2872361735022004240

[0180] In some aspects, provided herein is a pharmaceutical composition comprising the multi- specific protein of any one of the preceding embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0181] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the neurological disease or disorder is selected from a neuropathy disorder, a neurodegenerative disease, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, ischemia, a behavioral disorder, and CNS inflammation. In some embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE). In some embodiments, the dementia is frontotemporal dementia (FTD). In some embodiments, the neurological disease or disorder is Alzheimer’s disease. In some embodiments, the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease. In some embodiments, the neurological disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy.

[0182] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In some embodiments, the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.

[0183] In some aspects, provided herein is a method of transporting an antibody or antigen- binding fragment thereof that specifically binds to Sortilin across the blood brain barrier (BBB) of a subject, comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject.ny-2872361735022004240

[0184] In some aspects, provided herein is a method of increasing the concentration of an antibody or antigen-binding fragment thereof that specifically binds to Sortilin in the cerebral spinal fluid (CSF) of a subject, comprising administering the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject, wherein the concentration of the antibody or antigen-binding fragment thereof is increased in the CSF of the subject as compared to administering the antibody or antigen-binding fragment thereof alone to the subject.

[0185] In some aspects, provided herein is a method of imaging an antibody or antigen-binding fragment thereof that specifically binds to Sortilin within a subject, comprising administering to the subject the multi-specific protein of any one of the preceding embodiments and locating the imaging agent within the subject. In some aspects, provided herein is a method of detecting Sortilin in vitro, comprising contacting an in vitro sample with the multi-specific protein of any one of the preceding embodiments and locating the imaging agent within the sample.

[0186] In some aspects, provided herein is a use of the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments in the method of any one of the preceding embodiments.

[0187] In some aspects, provided herein is the multi-specific protein of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments for use in the method of any one of the preceding embodiments.

[0188] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS

[0189] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0190] FIG. 1 shows an exemplary multi-specific protein with a 2+1 multi-specific protein format. Abbreviations: VL = light chain variable region; CL = light chain constant region; ScFv = single-chain variable fragment; and BBB = blood brain barrier.ny-2872361735022004240

[0191] FIG. 2 shows an exemplary multi-specific protein with a 2+2 multi-specific protein format.

[0192] FIG. 3 shows an exemplary multi-specific protein with a 2+2 multi-specific protein format.

[0193] FIGs. 4A-4C show exemplary multi-specific protein formats. Abbreviations: Fab = fragment antigen-binding domain and VHH = antigen-binding fragment of a heavy chain only antibody.

[0194] FIG. 5 shows the on-cell binding (MFI) of S-15-10-7, S-15-10-7-BBB (anti-TfR binding domain), isotype control (Iso), and isotype-BBB control (Iso-BBB) for HEK293T cells overexpressing human Sortilin as a function of antibody concentration (nM). Curves in FIG. 5 were used to calculate the half maximal effective concentration (EC50) of S-15-10-7 and S-15- 10-7-BBB. S-15-10-7 and S-15-10-7-BBB displayed similar high affinity binding to sortilin using a FACs assay on dissociated cells.

[0195] FIG. 6 shows percent sortilin downregulation as a function of antibody concentration (nM). FIG.6 shows that S-15-10-7 and S-15-10-7-BBB (anti-TfR binding domain) potently downregulated cell surface sortilin levels to a similar extent after 48 hrs incubation using a U251 astrocytoma cell line. Curves in FIG. 6 were used to calculate EC50 values of S-15-10-7 and S- 15-10-7-BBB. Isotype and isotype-BBB served as controls. The levels of cell surface sortilin were assessed using an antibody that recognizes a different epitope from S-15-10-7.

[0196] FIG. 7 shows concentration of extracellular progranulin (ng / mL) as a function of antibody concentration (nM). FIG.7 shows that upon S-15-10-7 and S-15-10-7-BBB (anti-TfR binding domain) downregulation of cell surface sortilin, extracellular levels of progranulin increase in a dose dependent manner. Curves in FIG.7 were used to calculate EC50 values of S- 15-10-7 and S-15-10-7-BBB. Isotype and isotype-BBB served as controls. The levels of extracellular progranulin were assessed by an ELISA assay in the media of the U251 cells assessed for surface sortilin levels.

[0197] FIGs. 8A-8B show the extent of cellular uptake (spot area / cell / well) in hCMEC / D3 cells of S-15-10-7 and S-15-10-7-BBB (anti-TfR binding domain) as a function of antibody concentration (nM) after 2 hrs (FIG.8A) and 24 hrs (FIG.8B) incubation. Isotype and isotype- BBB served as controls. The internalized antibodies were detected with a fluorescently labeled anti-human IgG antibody.ny-2872361735022004240

[0198] FIG. 9 shows a bar graph of S-15-10-7 and S-15-10-7-BBB (anti-TfR binding domain) concentration (ng / mg protein) in vessel depleted brain lysates of mice. FIG.9 shows that S-15- 10-7-BBB dosed at 5 mg / kg was increased by approximately 15-fold over S-15-10-7 dosed at 5 mg / kg when assessed in vessel depleted brain lysates at 24 hours.

[0199] FIG. 10 shows a bar graph of antibody concentration (ng / mg protein) in vessel depleted brain lysates of mice. FIG.10 shows that S-15-10-7-BBB (anti-TfR binding domain) dosed at 50 mg / kg was increased by approximately 6-fold over S-15-10-7 dosed at 50 mg / kg. In addition, Iso-BBB dosed at 50 mg / kg was increased approximately 8-fold over Isotype control at 50 mg / kg.

[0200] FIG. 11 shows the serum levels (huIgG ng / mL) of the dosed antibodies at all dose levels (50 mg / kg and 5 mg / kg) at 1 hr and 24 hrs. No differences were observed at 1 hr between the antibodies at the same dose levels. At 24 hrs, S-15-10-7-BBB (anti-TfR binding domain) and Iso-BBB at 50 mg / kg both showed slightly decreased levels compared to Iso and S-15-10-7 at the same dose.

[0201] FIG. 12 shows the levels of progranulin in the serum of the dosed mice at baseline (predose), 1 hr and 24 hrs post dosing (50 mg / kg and 5 mg / kg). Progranulin levels were increased at 24 hrs in all animals dosed with S-15-10-7 and are slightly increased further with S- 15-10-7-BBB (anti-TfR binding domain). Isotype and isotype-BBB served as controls.

[0202] FIG. 13 shows the effect of dosing mice with S-15-10-7 or S-15-10-7-BBB (anti-TfR scFv) on levels of circulating reticulocytes using flow cytometry. No significant differences were observed in reticulocyte percentage between the groups of mice. Shown is the percentage of circulating reticulocytes relative to that of the isotype control. Isotype-BBB served as an additional control.

[0203] FIG. 14 shows the levels of sortilin in white blood cell lysates (ng mSORT / μg protein) isolated from mice dosed with S-15-10-7 or S-15-10-7-BBB (anti-TfR binding domain). The levels of sortilin were decreased in groups dosed with S-15-10-7 (S-15-10-7; light grey bar; open circle) and reduced slightly further in groups dosed with S-15-10-7-BBB (S-15-10-7; dark grey bar; open triangle). Isotype (Iso; light grey bar; open circle) and isotype-BBB (Iso; dark grey bar; open triangle) served as controls.

[0204] FIG. 15 shows levels of sortilin in whole brain lysates (ng mSORT / μg protein) isolated from mice dosed with S-15-10-7 (S-15-10-7; light grey bar; open circle) or S-15-10-7-BBB 73ny-2872361735022004240 (anti-TfR binding domain) (S-15-10-7; dark grey bar; open triangle). No decrease in sortilin was detected in mice dosed with S-15-10-7 at all dose levels (50 mg / kg and 5 mg / kg), regardless of TfR binding. Isotype (Iso; light grey bar; open circle) and isotype-BBB (Iso; dark grey bar; open triangle) served as controls.

[0205] FIG. 16 shows the levels of sortilin in vessel depleted lysates (ng mSORT / μg protein) isolated from mice dosed with S-15-10-7 (S-15-10-7; light grey bar; open circle) or S-15-10-7- BBB (anti-TfR binding domain) (S-15-10-7; dark grey bar; open triangle). No significant decrease in sortilin was detected in mice dosed with S-15-10-7 at all dose levels (50 mg / kg and 5 mg / kg), regardless of TfR binding. Isotype (Iso; light grey bar; open circle) and isotype-BBB (Iso; dark grey bar; open triangle) served as controls.

[0206] FIG. 17 shows the levels of TfR in whole brain lysates isolated from mice dosed with S-15-10-7 (S-15-10-7; dark grey bar; closed circle) or S-15-10-7-BBB (anti-TfR binding domain) (S-15-10-7; light grey bar; closed square). No significant decrease was detected across all groups relative to Isotype control (Iso; dark grey bar; closed circle). Isotype-BBB (Iso; light grey bar; closed square) served as an additional control.

[0207] FIG. 18 shows levels of antibody brain uptake (ng huIgG / mg protein) in mice dosed with S-15-10-7 (closed circle) or S-15-10-7-TfR (open square). The mice received 2 doses of S- 15-10-7 or S-15-10-7-TfR at 5, 15, or 50 mg / kg on days 0 and 7 of the study. Isotype (Iso; closed circle) and isotype-TfR (Iso; open square) dosed at 50 mg / kg on days 0 and 7 served as controls.

[0208] FIG. 19 shows serum concentration of antibody (huIgG1 ng / mL) as a function of time in mice dosed with S-15-10-7 or S-15-10-7-TfR. The mice received 2 doses of S-15-10-7 or S- 15-10-7-TfR at 5, 15, or 50 mg / kg on days 0 and 7 (2ndDose) of the study. Isotype (Iso-control; closed circle) and isotype-TfR (Iso-TfR; closed square) dosed at 50 mg / kg on days 0 and 7 served as controls.

[0209] FIG. 20 shows serum progranulin levels (% change from predose mean) of mice dosed with S-15-10-7 or S-15-10-7-TfR. The mice received 2 doses of S-15-10-7 or S-15-10-7-TfR at 5, 15, or 50 mg / kg on days 0 and 7 of the study.

[0210] FIG. 21 shows the effect of S-15-10-7 and S-15-10-7-TfR on levels of circulating reticulocytes in mice over time (days 1, 3, and 10). Reticulocyte counts were assessed as % of total RBC and then normalized against the isotype control treated animals. The mice received 2 doses of S-15-10-7 or S-15-10-7-TfR at 5, 15, or 50 mg / kg on days 0 and 7 of the study. Isotypeny-2872361735022004240 (Iso control) and isotype-TfR (Iso-TfR) dosed at 50 mg / kg on days 0 and 7 served as controls. Each set of three columns corresponds to days 1, 3, and 10 (left to right) of the study.

[0211] FIG. 22 shows immunofluorescent detection of antibody in fixed brain sections of mice dosed with S-15-10-7 or S-15-10-7-TfR. The mice received 2 doses of S-15-10-7 or S-15-10-7- TfR at 5, 15, or 50 mg / kg on days 0 and 7 of the study. Isotype (Iso Control) and isotype-TfR (Iso TfR) dosed at 50 mg / kg on days 0 and 7 served as controls.

[0212] FIG. 23 shows levels of TfR on day 10 in vessel depleted brain lysates isolated from mice dosed with 5, 15, or 50 mg / kg (mpk) of S-15-10-7 (huIgG; square, triangle, and inverted triangle) or S-15-10-7-TfR (huIgG-TfR; square, triangle, and inverted triangle). Isotype (huIgG; circle) and isotype-TfR (huIgG-TfR; circle) dosed at 50 mg / kg served as controls.

[0213] FIG. 24 shows levels of TfR on day 10 in whole brain lysates isolated from mice dosed with 5, 15, or 50 mg / kg (mpk) of S-15-10-7 (huIgG; square, triangle, and inverted triangle) or S- 15-10-7-TfR (huIgG-TfR; square, triangle, and inverted triangle). Isotype (huIgG; circle) and isotype-TfR (huIgG-TfR; circle) dosed at 50 mg / kg served as controls.

[0214] FIG. 25 shows levels of Sortilin on day 10 in whole brain lysates isolated from mice dosed with 5, 15, or 50 mg / kg (mpk) of S-15-10-7 (huIgG; square, triangle, and inverted triangle) or S-15-10-7-TfR (huIgG-TfR; square, triangle, and inverted triangle). Isotype (huIgG; circle) and isotype-TfR (huIgG-TfR; circle) dosed at 50 mg / kg served as controls.

[0215] FIG. 26 shows levels of progranulin on day 10 in whole brain lysates isolated from mice dosed with 5, 15, or 50 mg / kg (mpk) of S-15-10-7 (huIgG; square, triangle, and inverted triangle) or S-15-10-7-TfR (huIgG-TfR; square, triangle, and inverted triangle). Isotype (huIgG; circle) and isotype-TfR (huIgG-TfR; circle) dosed at 50 mg / kg served as controls.

[0216] FIGs. 27A and 27B set forth data showing increased brain uptake of anti- CD98hc.04.048.WH1 in mice, presented as ng of antibody per mg of total protein (FIG. 27A) and fold-change compared to isotype control antibody (FIG.27B).

[0217] FIG. 28 sets forth data showing immunohistochemistry analysis of brain tissues of mice administered anti-CD98hc.04.048.WH1 compared to that of isotype control antibody.

[0218] FIG. 29 sets forth data showing no changes in red blood cell count in mice following administration of anti-CD98hc.04.048.WH1.

[0219] FIGs. 30A-30B show nonspecific binding (BVP score) of affinity-tuned anti-TfR antibodies to baculovirus particles (BVP). Shown are BVP scores for TfR.15.WH8.1.24A.42Qny-2872361735022004240 (24A_42Q), TfR.15.WH8.1.42Q.H6-4 (H6-4), TfR.15.WH8.1.42Q.L7-2 (L7-2), TfR.15.WH8.1.42Q.L10-1 (L10-1), TfR.15.WH8.1.42Q.L10-8 (L10-8), TfR.15.WH8.1.42Q.L10-16 (L10-16), TfR.15.WH8.1.42Q.H3-7 (H3-7), TfR.9.1B.39.27.L-35 (L-35), TfR.9.1B.39.38.L-21 (L-21), TfR.9.1B.39.38.L-6 (L-6), and TfR.9.1B.39.27.L-19 (L-19) antibodies. Control antibodies (isotype, negative and positive control) were tested. Parental antibodies – TfR.15.WH8.1.24A (24A), TfR.9.1B.39.38 (39.38), and TfR.15.WH8.1.42Q (42Q) – served as additional controls.

[0220] FIGs. 31A-31B show nonspecific binding (OD 450 nm) of affinity-tuned anti-TfR antibodies to dsDNA. Shown are absorbance values for 24A_42Q, H6-4, L7-2, L10-1, L10-8, L10-16, H3-7, L-35, L-21, L-6, and L-19 antibodies. Control antibodies (isotype, negative and positive control) were tested. Parental antibodies – 24A, 39.38, and 42Q – served as additional controls.

[0221] FIG. 32 shows the extent of cell uptake of affinity-tuned anti-TfR antibodies in a brain microvascular endothelial cell line (hCMEC / D3) at 2 hours. Shown is cell uptake for 24A.42Q, H6-4, L7-2, L10-1, L10-8, L10-16, H3-7, and L-35 antibodies. Isotype (Iso mvFc-Iso scFv) and parental antibodies – 24A and 42Q – served as controls. Images displayed are for human Fc detection using an anti-HuIgG fluorescent antibody.

[0222] FIGs. 33A-33B show brain uptake of antibody in huTfR KI mice dosed with 5 mg / kg of H6-4, L7-2, L10-1, L10-8, L-35, L10-16, H3-7, or 24A_42Q variant antibodies after 24 hours. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls. FIG.33A shows antibody concentration (ng / mg tissue) in vessel-depleted brain after 24 hrs. FIG. 33B shows the fold change over the matched isotype control in vessel-depleted brain.

[0223] FIG. 34 shows the ratio of antibody concentration in vessel-depleted brain to whole brain of huTfR KI mice dosed with 5 mg / kg of H6-4, L7-2, L10-1, L10-8, L-35, L10-16, H3-7, or 24A_42Q variant antibodies. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls.

[0224] FIG. 35 shows the effect of affinity-tuned anti-TfR antibodies on levels of circulating reticulocytes in mice. Mice were dosed with 5 mg / kg of H6-4, L7-2, L10-1, L10-8, L-35, L10- 16, H3-7, or 24A_42Q variant antibodies and assessed after 24 hours. Isotype (Iso) and parental antibodies – 24A and 42Q – served as controls. Levels of circulating reticulocytes are shown as absolute reticulocyte (K / ul) (left of dotted line) and percent reticulocytes (right of dotted line).ny-2872361735022004240

[0225] FIG. 36 shows the levels of TfR in whole brain lysates isolated from mice dosed with L-21, L-6, and L-35 variant antibodies. Isotype (Iso-Fab) and parental antibodies – 24A, 39.38, and 42Q – served as controls. Shown are TfR levels normalized to levels of GAPDH for each sample and the isotype control mean.

[0226] FIGs. 37A-37B set forth data showing increased brain uptake in mice of anti- CD98hc.04.048.WH1 antibody variants of the present disclosure, presented as ng of antibody per mg total protein (FIG.37A) and fold-change compared to isotype control antibody (FIG. 37B).

[0227] FIG. 38 sets forth data showing no decrease in amino acid uptake in cells treated with anti-CD98hc.04.048.WH1 antibody variants of the present disclosure.

[0228] FIGs. 39A-39B set forth data showing brain uptake of various affinity-engineered anti- CD98hc.04.048.WH1 monovalent Fab antibody variants in hCD98hc ECD+ / + KI (knock-in) mice, presented as ng of antibody per mg total protein (FIG.39A) and fold-change compared to isotype control antibody (FIG.39B).

[0229] FIG. 40A shows antibody concentration (ng / mL) over time in the serum of human CD98hc ECD+ / + KI mice dosed with 3 weekly doses of 50 mg / kg of isotype- control / CD98hc.04.048.WH1 with hIgG1 wild-type (Iso-CD98 hIgG1 WT), cis- LALAP331S / WT (Iso-CD98 hIgG1 cis-LALAPS), or LALAP331S Fc (Iso-CD98 hIgG1 LALAPS). FIG. 40B shows brain uptake of antibody in human CD98hc ECD+ / + KI mice dosed with 3 weekly doses of 50 mg / kg of isotype-control / CD98hc.04.048.WH1 with hIgG1 wild-type, cis-LALAP331S / WT, or LALAP331S Fc, presented as ng of antibody per mg total protein. Human IgG1 LALAP331S isotype antibody (Iso hIgG1 LALAPS) served as a control.

[0230] FIGs. 41A-41B show antibody concentration (ng / mL) over time in the serum of hCD98hc ECD+ / + KI mice dosed with 20 mg / kg (FIG.41A) or 3 mg / kg (FIG. 41B) of affinity- engineered anti-CD98hc.04.048.WH1 antibody variants in 2+1 format. FIGs.41C-41D set forth data showing brain uptake of antibody (ng / mg total protein) over time in hCD98hc ECD+ / + KI mice dosed with 20 mg / kg (FIG. 41C) or 3 mg / kg (FIG.41D) of affinity-engineered anti- CD98hc.04.048.WH1 antibody variants in 2+1 format. Antibodies variants in 2+1 format tested were CD98hc.04.048.WH1 (Iso-WH1 LALAPS), CD98hc.04.048.WH1.083 (Iso-WH1.083 LALAPS), and CD98hc.04.048.WH1.133 (Iso.WH1.133 LALAPS). Isotype antibody in 2+1 format (Iso-Iso LALAPS) served as a control.ny-2872361735022004240 DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

[0231] The present disclosure relates to multi-specific proteins comprising an antigen-binding domain linked to an anti-Sortilin antibody or antigen-binding fragment thereof, where the antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc). Multi-specific proteins of the present disclosure provide compositions with an increased capacity to facilitate the transport of the anti-Sortilin antibody or antigen-binding fragment thereof across the blood brain barrier, thereby meeting the need in the art for improved compositions and methods for treating patients with anti-Sortilin therapeutics.

[0232] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies such as those described in Sambrook et al. Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000). Definitions

[0233] The terms “central nervous system” or “CNS” refer to the complex of nerve tissues that control bodily function and includes the brain and spinal cord.

[0234] The terms “blood brain barrier” or “BBB” refer to a network of brain capillary endothelial cells that are closely sealed by tight junctions.

[0235] A “central nervous system antigen” or “CNS antigen” is an antigen expressed in the CNS, including the brain.

[0236] A “brain antigen” is a CNS antigen expressed in the brain.

[0237] A “neurological disorder” as used herein refers to a disease or disorder which affects the CNS and / or which has an etiology in the CNS. Exemplary CNS diseases or disorders include, but are not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease.

[0238] As used herein, an “interaction” between a Sortilin protein and a second protein encompasses, without limitation, protein-protein interaction, a physical interaction, a chemical interaction, binding, covalent binding, and ionic binding. As used herein, an antibody “inhibitsny-2872361735022004240 interaction” between two proteins when the antibody disrupts, reduces, or completely eliminates an interaction between the two proteins. An antibody of the present disclosure, or fragment thereof, “inhibits interaction” between two proteins when the antibody or fragment thereof binds to one of the two proteins.

[0239] A “blocking” antibody, an “antagonist” antibody, or an “inhibitory” antibody is an antibody, such as an anti-Sortilin antibody of the present disclosure, that inhibits or reduces one or more biological activities of the antigen it binds, such as interactions with one or more proteins. In some embodiments, blocking antibodies, antagonist antibodies, or inhibitory antibodies substantially or completely inhibit one or more biological activities or interactions of the antigen.

[0240] The terms “Transferrin receptor,” “TfR,” “TfR polypeptide,” and “TfR protein” are used interchangeably herein to refer to any native TfR from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats), unless otherwise indicated. TfR is also referred to as transferrin receptor protein 1, TR, tfR1, Trfr, T9, and p90. In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses “full-length,” unprocessed TfR, as well as any form of TfR that results from processing in the cell. Full-length transferrin receptor protein includes a short N-terminal intracellular region, a transmembrane region, and a large extracellular domain. The extracellular domain is characterized by three domains: a protease-like domain, a helical domain, and an apical domain. In some embodiments, the TfR is human TfR. As used herein, the term “human TfR” refers to a polypeptide with the following amino acid sequence: MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANVT KPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFPA ARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREFK LSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVH ANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAE LSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPS DWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAWG PGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYL SSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWASny-2872361735022004240 KVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARAA AEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARGD FFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSPKESPFRHVFWGSGS HTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF (SEQ ID NO: 1).

[0241] As used herein, the terms “CD98hc,” “CD98hc polypeptide,” and “CD98hc protein” are used interchangeably herein to refer to any native CD98hc from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos)) and rodents (e.g., mice and rats), unless otherwise indicated. CD98hc is also referred to as 4F2 cell- surface antigen heavy chain, 4F2hc, 4F2 heavy chain antigen, lymphocyte activation antigen 4F2 large subunit, solute carrier family 3 member 2, and CD98. CD98hc protein is encoded by the SLC3A2 gene and is part of the large amino acid transporter (LAT) complex. In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses “full-length,” unprocessed CD98hc, as well as any form of CD98hc that results from processing in the cell. In some embodiments, the CD98hc is human CD98hc. As used herein, the term “human CD98hc” refers to a polypeptide with the following amino acid sequence: MELQPPEASIAVVSIPRQLPGSHSEAGVQGLSAGDDSELGSHCVAQTGLELLASGDPLPS ASQNAEMIETGSDCVTQAGLQLLASSDPPALASKNAEVTGTMSQDTEVDMKEVELNEL EPEKQPMNAASGAAMSLAGAEKNGLVKIKVAEDEAEAAAAAKFTGLSKEELLKVAGSP GWVRTRWALLLLFWLGWLGMLAGAVVIIVRAPRCRELPAQKWWHTGALYRIGDLQAF QGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFD SLLQSAKKKSIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDI ENLKDASSFLAEWQNITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGST GEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLLRLYQLMLFTLPGTPVFSYGD EIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFRRLSDQ RSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLVVLNFGDVGLSAGLQASDLPASAS LPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 2).

[0242] As used herein, the terms “antibody” and “immunoglobulin” are used interchangeably and refer to an antibody molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of theny-2872361735022004240 foregoing (e.g., a glycoprotein), through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The term “antibody” encompasses monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multi-specific (e.g., bispecific) antibodies, and any other immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy-chain constant regions referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of antibodies have different and well-known subunit structures and three-dimensional configurations. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0243] The terms “anti-TfR antibody,” “antibody that binds to TfR,” and “antibody that specifically binds TfR” refer to an antibody that is capable of binding TfR with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting TfR. In some embodiments, the anti-TfR antibody is capable of transporting another diagnostic and / or therapeutic agent into the brain. In certain embodiments, an anti-TfR antibody binds to an epitope of TfR that is conserved among TfR from different species.

[0244] The terms "anti-CD98hc antibody," "antibody that binds to CD98hc," and "antibody that specifically binds CD98hc" refer to an antibody that is capable of binding CD98hc with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD98hc. In some embodiments, the anti-CD98hc antibody is capable of transporting another diagnostic and / or therapeutic agent into the brain. In certain embodiments, an anti- CD98hc antibody binds to an epitope of CD98hc that is conserved among CD98hc from different species.

[0245] The term “multi-specific protein” as used herein refers to an antigen-binding protein that comprises at least two different antigen-binding sites. Each of these antigen-binding sites is capable of binding to a different epitope, which may be present on the same antigen or different antigens. The multi-specific protein may have specificity for more than one antigen, for example two antigens, or three antigens, or four antigens.ny-2872361735022004240

[0246] An “antigen-binding domain,” “antigen-binding region,” or “antigen-binding site” refers to a monovalent portion of an antibody that binds to an antigen. An “antigen-binding domain” can comprise the antigenic determining regions of an antibody (e.g., the complementarity determining regions (CDRs)). An antibody or antigen-binding fragment thereof (including mono-specific and multi-specific (e.g., bispecific) antibodies or antigen-binding fragments thereof) can comprise an antigen-binding domain. In some embodiments, an antigen- binding domain is not present in the context of an antibody. In some aspects, provided herein is an antibody, a VHH, a Fab, a Fab’, a Fab’-SH, a F(ab’)2, a Fv, or a scFv comprising an antigen- binding domain.

[0247] The terms “anti-TfR antigen-binding domain,” “antigen-binding domain that binds to TfR,” “anti-TfR antigen-binding region,” “antigen-binding region that binds to TfR,” and “TfR binding domain” refer to an antigen-binding domain that binds to TfR with sufficient affinity such that the antigen-binding domain is useful as a diagnostic and / or therapeutic agent in targeting TfR. In one aspect, the extent of binding of an anti-TfR antigen-binding domain to an unrelated, non-TfR polypeptide is less than about 10% of the binding of the antigen-binding domain to TfR as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to TfR has a dissociation constant (KD) of about 0.01 nM to about 10,000 nM, less than about 20 μM, less than about 15 μM, less than about 12 μM, less than about 10 μM, less than about 7.5 μM, less than about 5 μM, less than about 2.5 μM, less than about 1 , less than about 100 nM, less than about 10 nM, less than about 1 nM, less than about 0.1 nM, less than about 0.01 nM, or less than about 0.001 nM (e.g., 10-8M or less, e.g. from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-TfR antigen-binding domain binds to an epitope of TfR that is conserved among TfR from different species.

[0248] The terms “anti-CD98hc antigen-binding domain,” “antigen-binding domain that binds to CD98hc,” “anti-CD98hc antigen-binding region,” “antigen-binding region that binds to CD98hc,” and “CD98hc binding domain” refer to an antigen-binding domain that binds to CD98hc with sufficient affinity such that the antigen-binding domain is useful for targeting CD98hc and / or useful as a diagnostic agent, a therapeutic agent, or for transporting a molecule or compound across the BBB. In one aspect, the extent of binding of an anti-CD98hc antigen- binding domain to an unrelated, non-CD98hc polypeptide is less than about 10% of the binding of the antigen-binding domain to CD98hc as measured, e.g., by a radioimmunoassay (RIA). Inny-2872361735022004240 certain embodiments, an antibody that binds to CD98hc has a dissociation constant (KD) of about 10 nM to about 1500 nM, about 100 nM to about 500 nM, about 500 nM to about 10 M, or less than about 20 μM, less than about 15 μM, less than about 12 μM, less than about 10 μM, less than about 7.5 μM, less than about 5 μM, less than about 2.5 μM, less than about 1 , less than about 100 nM, less than about 10 nM, less than about 1 nM, less than about 0.1 nM, less than about 0.01 nM, or less than about 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, an anti-CD98hc antigen-binding domain binds to an epitope of CD98hc that is conserved among CD98hc from different species.

[0249] The terms “full-length antibody,” “intact antibody” or “whole antibody” are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant regions can be native sequence constant regions (e.g., human native sequence constant regions) or amino acid sequence variants thereof. In some cases, the intact antibody can have one or more effector functions.

[0250] The term “native IgG antibodies” refers to heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (“L”) chains and two identical heavy (“H”) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intra-chain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.

[0251] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.

[0252] As used herein, the term “heavy chain” when used in reference to an antibody can referto any distinct type, e.g., alpha ( ), delta ( ), epsilon ( ), gamma ( ), and mu (μ), based on theamino acid sequence of the constant region, which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4.ny-2872361735022004240 Heavy chain amino acid sequences are well known in the art. In some embodiments, the heavy chain is a human heavy chain.

[0253] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.

[0254] As used herein, the term “light chain” when used in reference to an antibody can referto any distinct type, e.g., kappa ( ) or lambda ( ) based on the amino acid sequence of theconstant regions. Light chain amino acid sequences are well known in the art. In some embodiments, the light chain is a human light chain.

[0255] The terms “variable region” or “variable domain” refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen-binding sites. Generally, the variable region or variable domain is typically about the amino-terminal 110 to 120 amino acids or 110 to 125 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain.

[0256] The term “Fv” or “variable fragment” refers to the minimum antibody fragment which comprises a complete antigen-binding site and consists of a dimer of one heavy-chain variable region (VH) and one light-chain variable region (VL). From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody.

[0257] As used herein, the term “constant region” is a region of an antibody that is not the variable region of the antibody, e.g., a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to antigen, but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain. In certain embodiments, an antibody or antigen-binding fragment comprises a constant region or portion thereof that is sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).

[0258] A “constant domain” means a domain within a constant region that is capable of forming an immunoglobulin fold. Constant domains include the CH1, CH2, CH3, and CL domains.ny-2872361735022004240

[0259] The term “antibody fragment” refers to a portion of an antibody. An “antigen-binding fragment” of an antibody refers to a portion of an antibody that binds to an antigen. An antigen- binding fragment of an antibody can comprise the antigenic determining regions of an antibody (e.g., the complementarity determining regions (CDRs)). Examples of antigen-binding fragments of antibodies include, but are not limited to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single chain antibodies. An antigen-binding fragment of an antibody can be monovalent or multi-valent (e.g., bi-valent). An antigen-binding fragment of an antibody can be monospecific or multi-specific (e.g., bispecific.) An antigen-binding fragment of an antibody can be derived from any animal species, such as rodents (e.g., mouse, rat, or hamster) and humans or can be artificially produced.

[0260] The term “Fab” or “fragment antigen-binding region” refers to a region on an antibody that binds to antigens. It is composed of one constant domain, one variable domain of the heavy chain and one variable domain of the light chain. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site.

[0261] The term “F(ab')2 fragment” refers to antibody fragments that are generated by pepsin digestion of whole IgG antibodies to remove most of the Fc region while leaving intact some of the hinge region. F(ab')2 fragments have two antigen-binding F(ab) portions linked together by disulfide bonds, and therefore are divalent with a molecular weight of about 110 kDa. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group.

[0262] As used herein, a “Fc fragment,” “fragment crystallizable region,” or “Fc region” is composed of two or more polypeptides, each being an antibody heavy chain fragment and each containing at least one (e.g., two or three) heavy chain constant domains. In some embodiments, an Fc region is composed of two heavy chain fragments, each containing a CH2 domain and a CH3 domain. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region can be removed, for example, during production or purification of the antibody, or by recombinantly engineering theny-2872361735022004240 nucleic acid encoding a heavy chain of the antibody. Accordingly, an Fc region may not contain any K447 residues, may contain at least one polypeptide containing a K447 residue and at least one polypeptide that does not contain a K447 residue, or may only contain polypeptides that include a K447 residue. Suitable native-sequence Fc regions for use in the present disclosure include human IgG1, IgG2, IgG3 and IgG4. In a native antibody, an Fc region refers to the region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. However, as used herein, an Fc region can be modified to increase, decrease, or eliminate interaction with Fc receptors and / or proteins of the complement system. In native IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody’s two heavy chains. However, as used herein, the two or more polypeptides in an “Fc region” do not need to have identical sequences. In some embodiments, an “Fc region” comprises a first polypeptide comprising an Fc domain (e.g., IgG1 Fc domain) with a knob mutation and a second polypeptide comprising an Fc domain (e.g., IgG1 Fc domain) with a hole mutation. In native IgM and IgE antibody isotypes, the Fc region contains three heavy chain constant domains (CH domains 2–4) in each polypeptide chain.

[0263] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region.

[0264] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, in some embodiments, two or more amino acid substitution(s). In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and in some embodiments, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. In some embodiments, the variant Fc region possesses at least 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, at least 90% homology therewith, or at least 95% homology therewith.ny-2872361735022004240

[0265] The term “Fc domain” refers to one or more domains within an Fc region, such as a CH2 or CH3 domain in a single polypeptide. In some aspects, the Fc domain includes at least one amino acid deletion, addition, or substitution as compared to the amino acid sequence of a native Fc domain, such as by including a set of “knob-into-hole” deletions, additions, or substitutions or including amino acid deletions, additions, or substitutions to effect electrostatic steering of the Fc domain to favor attractive interactions among different polypeptide chains. In some aspects, the Fc domain is in a "knob" format. In some aspects, the Fc domain is in a "hole" format.

[0266] The term “single-chain Fv”, also abbreviated as “sFv” or “scFv”, refers to antibody fragments that comprise the VH and VL antibody domains that form a single polypeptide chain. In some embodiments, the scFv polypeptide comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding.

[0267] The term “diabodies” refers to small antibody fragments prepared by constructing scFv fragments with short linkers (about 5-10 residues) between the VHand VLdomains, such that inter-chain but not intra-chain pairing of the variable domains is achieved, thereby resulting in a bivalent fragment (i.e., a fragment having two antigen-binding sites). Bispecific diabodies are heterodimers of two “crossover” scFv fragments in which the VHand VLdomains of the two antibodies are present on different polypeptide chains.

[0268] The term “CDR” or “complementarity determining region” refers to hypervariable regions (“HVRs”) in the variable region of an immunoglobulin that determine antibody diversity and antigen specificity.

[0269] The term “Kabat numbering” and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof. In certain embodiments, CDRs can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91- 3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDRH1), amino acid positions 50 to 65 (CDRH2), and amino acid positions 95 to 102ny-2872361735022004240 (CDRH3). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDRL1), amino acid positions 50 to 56 (CDRL2), and amino acid positions 89 to 97 (CDRL3).

[0270] The term “Chothia” refers to the location of the structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927- 948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). In some embodiments, the Chothia residues are numbered as shown in the table below. In some embodiments, the CDRs may be Chothia CDRs.

[0271] The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. In some embodiments, the CDRs may be AbM CDRs.

[0272] In some embodiments, the CDRs can be “contact” CDRs. The “contact” CDRs are based on an analysis of the available complex crystal structures. In some embodiments, the CDRs may be “contact” CDRs.

[0273] The residues from each of these CDRs are noted below. Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H52-H56 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101

[0274] CDRs can comprise “extended CDRs” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94- 102, or 95-102 (H3) in the VH. The variable-domain residues are numbered according to Kabat et al., supra, for each of these extended-CDR definitions.

[0275] CDRs can also be identified according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al., (1999) Nucleic Acids Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35,ny-2872361735022004240 VH-CDR2 is at positions 51 to 57, VH-CDR3 is at positions 93 to 102, VL-CDR1 is at positions 27 to 32, VL-CDR2 is at positions 50 to 52, and VL-CDR3 is at positions 89 to 97.

[0276] The term “monoclonal” when referring to an antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term “monoclonal” antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody or antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, a “monoclonal” antibody or antigen- binding fragment thereof refers to such antibodies and antigen-binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0277] The term “chimeric” antibodies or antigen-binding fragments thereof refers to antibodies or antigen-binding fragments thereof wherein the amino acid sequence is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies or antigen-binding fragments thereof derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability, while the constant regions are homologous to the sequences in antibodies or antigen-binding fragments thereof derived from another (usually human) to avoid eliciting an immune response in that species.

[0278] The term “humanized” antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementarity determining regions (CDRs) are replaced by residues from the CDRs of a molecule originating from a non-human species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (“CDR grafted”) (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). Theny-2872361735022004240 humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and / or within the replaced non-human residues to refine and optimize the specificity, affinity, and / or capability of the antibody or antigen-binding fragment thereof. In general, the humanized antibody or antigen- binding fragment thereof will comprise VH and VL that comprise substantially all of at least one, and typically two or three, of the CDR regions that correspond to the non-human immunoglobulin, whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or Fc region, typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat.5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng.9(10):895-904 (1996). In some embodiments, a “humanized antibody” is a resurfaced antibody.

[0279] The term “human” antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin gene locus, where such antibody or antigen-binding fragment is made using any technique known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0280] “Framework” or “FR” residues are those variable-domain residues other than the CDR residues as herein defined.

[0281] An “acceptor human framework” as used herein is a framework comprising the amino acid sequence of a VLor VHframework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework can comprise the same amino acid sequence thereof, or it can comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. Where pre-existing amino acid changes are present in a VH, in some embodiments those changes occur at only three, two, or one of positions 71H, 73H and 78H; for instance, the amino acid residues at those positions can by 71A, 73T and / or 78A. In some embodiments, the VL acceptor human framework is identicalny-2872361735022004240 in sequence to the VLhuman immunoglobulin framework sequence or human consensus framework sequence.

[0282] A “human consensus framework” is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for the VL, the subgroup can be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al., supra. Additionally, for the VH, the subgroup can be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0283] An “amino-acid modification” at a specified position, e.g., of an antibody of the present disclosure, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent the specified residue. Insertion “adjacent” to a specified residue means insertion within one to two residues thereof. The insertion can be N-terminal or C- terminal to the specified residue. In some embodiments, an amino acid modification is a substitution.

[0284] 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 vary with the antibody isotype.

[0285] “Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. In some embodiments, an FcR is a native sequence human FcR. In some embodiments, an FcR isone which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc RI,Fc RII, and Fc RIII subclasses, including allelic variants and alternatively spliced forms of thesereceptors, Fc RII receptors include Fc RIIA (an “activating receptor”) and Fc RIIB (an“inhibiting receptor”), which have similar amino acid sequences that differ primarily in thecytoplasmic domains thereof. Activating receptor Fc RIIA contains an immunoreceptor tyrosine-based activation motif (“ITAM”) in its cytoplasmic domain. Inhibiting receptor Fc RIIBcontains an immunoreceptor tyrosine-based inhibition motif (“ITIM”) in its cytoplasmic domain. Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. FcRs can also increase the serum half-life of antibodies.ny-2872361735022004240

[0286] “Binding affinity” generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody or antigen-binding fragment thereof) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody or antigen-binding fragment thereof and antigen). The affinity of a molecule X for its partner Y can generally be represented by the equilibrium dissociation constant (KD). Affinity can be measured and / or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (KD), and equilibrium association constant (KA). The KDis calculated from the quotient of koff / kon, whereas KA is calculated from the quotient of kon / koff. kon refers to the association rate constant of, e.g., an antibody or antigen-binding fragment thereof to an antigen, and koff refers to the dissociation rate constant of, e.g., an antibody or antigen-binding fragment thereof from an antigen. The kon and koff can be determined by techniques known to one of ordinary skill in the art, such as BIAcore®or KinExA. Dissociation constants may also be determined through any analytical technique, including any biochemical or biophysical technique such as ELISA, surface plasmon resonance (SPR), bio-layer interferometry (see, e.g., Octet System by ForteBio), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting analyses. (See, e.g., Estep et al, (2013) MAbs 5(2):270-8.)

[0287] With regard to the binding of an antibody to a target molecule, the term “specific binding” or “specifically binds” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term “specific binding” or “specifically binds” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a KD for the target of about any of 10-4M or lower, 10-5M or lower, 10-6M or lower, 10-7M or lower, 10-8M or lower, 10-9M or lower, 10-10M or lower, 10-11M or lower, 10-12M or lower orny-2872361735022004240 a KD in the range of 10-4M to 10-6M or 10-6M to 10-10M or 10-7M to 10-9M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In some embodiments, the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0288] The term “linker” or “linked” refers to the covalent linkage between two polypeptides or two heterologous molecules. In some embodiments, a linker is a chemical linker. In some embodiments, the linker comprises a peptide bond, and the two polypeptides or two heterologous molecules are linked to each other either directly to or via one or more additional amino acids. A glycine linker is one that comprises one or more glycines, but no other amino acids, e.g., GGGG (SEQ ID NO: 3). A glycine-rich linker is one that comprises one or more glycines and can contain other amino acids as long as glycine is the predominant species in the linker e.g., GGGNGG (SEQ ID NO: 4), wherein N is any amino acid. A glycine-serine linker is one which contains both glycine and serine in any proportion, e.g., GGGS (SEQ ID NO: 5). Similarly, a proline linker is one that comprises one or more prolines but no other amino acids. A proline-rich linker is one that comprises one or more prolines and can contain other amino acids so long as proline is the predominant species in the linker.

[0289] As used herein, “percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as identical matches. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM(DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full-length of the sequences being compared. For antibody sequences, the % identity may be determined across the entire length of the candidate sequence, including the CDRs. Alternatively, the % identity may exclude one or more or all of the CDRs,ny-2872361735022004240 for example all of the CDRs are 100% identical to the subject sequence and the % identity variation is in the remaining portion of the query sequence, e.g. the framework sequence, so that the CDR sequences are fixed and intact.

[0290] A polypeptide, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature. In some embodiments, an antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure.

[0291] As used herein, “substantially pure” refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0292] The term “expression system” refers to one or more nucleic acid molecules comprising coding sequence and control sequence(s) in operable linkage, along with a host cell and / or other in vitro transcription and translation machinery, such that one or more proteins encoded by the nucleic acid molecule(s) are capable of being produced.

[0293] The term “vector,” as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid,” which refers to a circular double stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors,” or simply, “expression vectors.” In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector.ny-2872361735022004240

[0294] “Polynucleotide,” or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.

[0295] A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this disclosure. In some embodiments, the host cell is an isolated host cell.

[0296] “Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.

[0297] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully “treated”, for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated.

[0298] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that can be used to deliver a drug, e.g., an anti-human antibody or antigen- binding fragment thereof, to the desired site of biological action.

[0299] An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. An effective amount can be provided in one or more administrations. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / orny-2872361735022004240 prolonging survival. An effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result can be or is achieved.

[0300] As used herein, the terms “subject” and “patient” are used interchangeably. The subject can be a mammal such as a non-human animal (e.g., cow, pig, horse, cat, dog, rat, mouse, monkey or other primate, etc.). In some embodiments, the subject is a cynomolgus monkey. In some embodiments, the subject is a human.

[0301] As used herein, administration “in conjunction” or “in combination” with another compound or composition includes simultaneous administration and / or administration at different times. Administration in conjunction also encompasses administration as a co- formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration. In some embodiments, administration in conjunction is administration as a part of the same treatment regimen.

[0302] As used herein, the terms “about” and “approximately,” when used to modify a numeric value or numeric range, indicate that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value or range. It is understood that wherever embodiments are described herein with the language “about” or “approximately” a numeric value or range, otherwise analogous embodiments referring to the specific numeric value or range are also provided.

[0303] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly indicates otherwise. For example, reference to an “antibody” is a reference to from one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0304] It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of” and / orny-2872361735022004240 “consisting essentially of” are also provided. In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially of” are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0305] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety.

[0306] The present disclosure will be more fully understood by reference to the following Examples. They should not, however, be construed as limiting the scope of the present disclosure. All citations throughout the disclosure are hereby expressly incorporated by reference. I. Multi-Specific Proteins

[0307] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human transferrin receptor (TfR) and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin.

[0308] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human transferrin receptor (TfR), and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin. In some embodiments, the multi-specific protein accumulates in a brain sample at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 50-fold, or more than the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR.

[0309] In some embodiments, accumulation of the multi-specific protein in the brain sample is detected using an immunoassay. In some embodiments, the immunoassay uses electrochemiluminescence. In some embodiments, detection of the multi-specific protein in the brain sample is performed using an MSD (Meso Scale Discovery) method. In someny-2872361735022004240 embodiments, detection of the multi-specific protein in the brain sample is performed according to the methods as described in Example 9.

[0310] In some embodiments, the brain sample is a vessel-depleted brain sample. In some embodiments, the brain sample is a vessel-depleted mouse brain sample. In some embodiments, a vessel-depleted brain sample refers to a brain sample that has been substantially cleared of its vasculature (e.g., blood vessels), wherein, for example, the process of clearing the vasculature from the brain sample involves mincing and / or homogenizing the sample and subsequently centrifuging the sample to separate the vessel-containing fraction from the parenchyma fraction.

[0311] In some embodiments, the multi-specific protein comprises a “1+1” multi-specific protein format, wherein the multi-specific protein is bivalent and bispecific (for example, see FIG.4B). In such embodiments, the multi-specific protein comprises: (i) one antigen-binding domain that specifically binds to human TfR; and (ii) an antibody or antigen-binding fragment thereof that specifically binds to Sortilin, wherein the antibody or antigen-binding fragment thereof is a scFv, VHH, or Fab, optionally comprising an Fc domain or Fc region.

[0312] In some embodiments, the multi-specific protein comprises a “2+1” multi-specific protein format, wherein the multi-specific protein is trivalent and bispecific (for example, see FIG.4A). In some embodiments, the multi-specific protein comprises: (i) a single antigen- binding domain that specifically binds to human TfR and (ii) an antibody that specifically binds to Sortilin, wherein the antibody comprises two heavy chains and two light chains; wherein the single antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two antibody heavy chains.

[0313] In some embodiments, the multi-specific protein comprises a “1+2” multi-specific protein format, wherein the multi-specific protein is trivalent and bispecific. In some embodiments, the multi-specific protein comprises: (i) two antigen-binding domains that specifically binds to human TfR and (ii) an antibody or antigen-binding fragment thereof that specifically binds to Sortilin, wherein the antibody or antigen-binding fragment thereof is a scFv, VHH, or Fab, optionally comprising an Fc domain or Fc region.

[0314] In some embodiments, the multi-specific protein comprises a “2+2” multi-specific protein format, wherein the multi-specific protein is tetravalent and bispecific (for example, see FIG.3). In such embodiments, the multi-specific protein comprises: (i) two antigen-binding domains that specifically bind to human TfR and (ii) an antibody that specifically binds tony-2872361735022004240 Sortilin, wherein the antibody comprises two heavy chains and two light chains; wherein one antigen-binding domain that specifically binds to human TfR is linked to the C-terminus of one of the two antibody heavy chains, and the other antigen-binding domain that specifically binds to human TfR is linked to the C-terminus of the other of the two antibody heavy chains. In some embodiments, the two antigen-binding domains that bind to human TfR comprise the same amino acid sequence. In some embodiments, the two antigen-binding domains that bind to human TfR comprise different amino acid sequences.

[0315] In some aspects, the multi-specific protein comprises a “2+1” multi-specific protein format, wherein the multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv specifically binds to human TfR; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen- binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0316] In some aspects, the multi-specific protein comprises a “2+2” multi-specific protein format, wherein the multi-specific protein comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind tony-2872361735022004240 human TfR; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0317] In some aspects, provided herein is a multi-specific protein comprising an antigen- binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen- binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin.

[0318] In some embodiments, the multi-specific protein comprises a “1 +1” multi-specific protein format, wherein the multi-specific protein is bivalent and bispecific. In such embodiments, the multi-specific protein comprises: (i) one antigen-binding domain that binds specifically to human CD98hc; and (ii) an antibody or antigen-binding fragment thereof that specifically binds to Sortilin, wherein the antibody or antigen-binding fragment thereof is a scFv, VHH, or Fab, optionally comprising an Fc domain or Fc region.

[0319] In some embodiments, the multi-specific protein comprises a “2+1” multi-specific protein format, wherein the multi-specific is trivalent and bispecific. In some embodiments, the multi-specific protein comprises: (i) a single antigen-binding domain that specifically binds to human CD98hc, and (ii) an antibody that specifically binds to Sortilin, wherein the antibody comprises two heavy chains and two light chains; wherein the single antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two antibody heavy chains.

[0320] In some embodiments, the multi-specific protein comprises a “1+2” multi-specific protein format, wherein the multi-specific protein is trivalent and bispecific. In some embodiments, the multi-specific protein comprises: (i) two antigen-binding domains that specifically binds to human CD98hc and (ii) an antibody or antigen-binding fragment thereofny-2872361735022004240 that specifically binds to Sortilin, wherein the antibody or antigen-binding fragment thereof is a scFv, VHH, or Fab, optionally comprising an Fc domain or Fc region.

[0321] In some embodiments, the multi-specific protein comprises a “2+2” multi-specific protein format, wherein the multi-specific is tetravalent and bispecific. In such embodiments, the multi-specific protein comprises: (i) two antigen-binding domains that specifically bind to human CD98hc and (ii) an antibody that specifically binds to Sortilin, wherein the antibody comprises two heavy chains and two light chains; wherein one antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two antibody heavy chains, and the other antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the other of the two antibody heavy chains.

[0322] In some aspects, the multi-specific protein comprises a “2+1” multi-specific protein format, wherein the multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv specifically binds to human CD98hc; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen- binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

[0323] In some aspects, the multi-specific protein comprises a “2+2” multi-specific protein format, wherein the multi-specific protein comprises: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, any-2872361735022004240 hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human CD98hc; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen-binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively. II. Anti-Sortilin antibodies

[0324] Provided herein are multi-specific proteins comprising an antigen-binding domain linked to an anti-Sortilin antibody or antigen-binding fragment thereof. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the anti-Sortilin antibody or antigen-binding fragment thereof across the blood brain barrier (BBB). The anti-Sortilin antibody or antigen-binding fragment thereof of the multi-specific protein can inhibit one or more activities of a Sortilin protein, including, but not limited to, increasing Progranulin levels (e.g., extracellular levels of Progranulin and / or cellular levels of Progranulin), decreasing cellular levels of Sortilin (e.g., cell surface levels of Sortilin, intracellular levels of Sortilin, and / or total levels of Sortilin), inhibiting the interaction (e.g., binding) with Progranulin, and / or inhibiting interaction (e.g., binding) with one or more of pro-neurotrophins (pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro- BDNF, etc.), neurotrophins (neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), the A-beta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), and receptor associated protein (RAP), decreasing secretion of PCSK9, decreasing production of beta amyloid peptide.ny-2872361735022004240

[0325] Additionally, the anti-Sortilin antibody or antigen-binding fragment thereof of the multi-specific protein can be used to prevent, reduce risk of, or treat cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer’s disease, vascular dementia, seizures, retinal dystrophy, a traumatic brain injury, a spinal cord injury, long-term depression, atherosclerotic vascular diseases, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington’s disease, taupathy disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, Sarcoidosis, diseases of aging, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disorders, arthritis, multiple sclerosis, metabolic disorder, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, an injury, and / or one or more undesirable symptoms of normal aging.

[0326] In some embodiments, the present disclosure provides a multi-specific protein, wherein the multi-specific protein binds Sortilin, decreases cell surface levels of Sortilin, increases extracellular levels of Progranulin, or any combination thereof. In some embodiments, the multi- specific protein binds to cell-surface Sortilin with a half maximal effective concentration (EC50) of about 0.5 nM to about 6 nM. In some embodiments, the multi-specific protein binds to cell- surface Sortilin with a half maximal effective concentration (EC50) of about 2 nM to about 4.5 nM. In some embodiments, the multi-specific protein binds to cell-surface Sortilin with a half maximal effective concentration (EC50) of about 4.1 nM. In some embodiments, the multi- specific protein binds to cell-surface Sortilin with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen- binding domain that specifically binds to human TfR. In some embodiments, the EC50 is determined by FACS (see, e.g., Example 5). In some embodiments, the antibody or antigen- binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region comprisingny-2872361735022004240 the sequence of SEQ ID NO: 248 and a light chain variable region comprising the sequence of SEQ ID NO: 249.

[0327] In some embodiments, the multi-specific protein decreases cell surface levels of Sortilin with an EC50 of about 0.05 nM to about 0.5 nM. In some embodiments, the multi- specific protein decreases cell surface levels of Sortilin with an EC50 of about 0.23 nM. In some embodiments, the multi-specific protein decreases cell surface levels of Sortilin with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR. In some embodiments, the EC50 is determined by flow cytometry (see, e.g., Example 6). In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 248 and a light chain variable region comprising the sequence of SEQ ID NO: 249. In some embodiments, cell surface levels of Sortilin are decreased after cell exposure to the multi-specific protein as compared to cell surface levels of Sortilin after cell exposure to an isotype control.

[0328] In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 of about 0.05 nM to about 0.5 nM. In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 of about 0.05 nM to about 5 nM, wherein the EC50 is determined by an immunoassay. In some embodiments, the immunoassay is an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 of about 0.22 nM. In some embodiments, the multi-specific protein increases extracellular progranulin levels with an EC50 similar to the EC50 of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR. In some embodiments, the EC50 is determined by an immunoassay (see, e.g., Example 7). In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to Sortilin not linked to the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 248 and a light chain variable region comprising the sequence of SEQ ID NO: 249.

[0329] In some embodiments, the multi-specific protein comprises an anti-Sortilin antibody or antigen-binding fragment thereof as described in WO 2016164637, the content of which is hereinny-2872361735022004240 incorporated by reference in its entirety. In some embodiments, the multi-specific protein comprises an anti-Sortilin antibody or antigen-binding fragment thereof as described in WO 2020014617, the content of which is herein incorporated by reference in its entirety. A. Exemplary anti-Sortilin antibodies

[0330] In some embodiments, the multi-specific protein comprises an anti-Sortilin antibody or antigen-binding fragment thereof comprising the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of an antibody selected from the group consisting of S-15-10-7, S-15- 10, S-15-6, S-60-3, S-60-15.1 [N33T] LALAPS, S-60-15 [N33 (wt)], or S-60-16. In some embodiments, the multi-specific protein comprises an anti-Sortilin antibody or antigen-binding fragment thereof comprising the heavy chain variable region and the light chain variable region of an antibody selected from S-15-10-7, S-15-10, S-15-6, S-60-3, S-60-15.1 [N33T] LALAPS, S-60-15 [N33 (wt)], or S-60-16. In some embodiments, the multi-specific protein comprises an anti-Sortilin antibody or antigen-binding fragment thereof comprising the heavy chain and the light chain of an antibody selected from S-15-10-7, S-15-10, S-15-6, S-60-3, S-60-15.1 [N33T] LALAPS, S-60-15 [N33 (wt)], or S-60-16 (e.g., as shown in Table 1 to Table 8 ). (1) S-15-10-7

[0331] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region comprising a VH CDR1, a VH CDR2, and a VH CDR3. In some embodiments, the VH CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the VH CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 230), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR1 amino acid sequence of SEQ ID NO: 230. In some embodiments, the VH CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 231. In some embodiments, the VH CDR2 comprises an amino acid sequence containingny-2872361735022004240 substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 231), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR2 amino acid sequence of SEQ ID NO: 231. In some embodiments, the VH CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 232. In some embodiments, the VH CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 232), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR3 amino acid sequence of SEQ ID NO: 232. In some embodiments, the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 230, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 231, and the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 232.

[0332] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region comprising a VL CDR1, a VL CDR2, and a VL CDR3. In some embodiments, the VL CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 233), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR1 amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acidny-2872361735022004240 sequence of SEQ ID NO: 234), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR2 amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 235), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR3 amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 233, the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 234, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 235.

[0333] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 248; and / or the light chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 249. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 248, wherein the heavy chain variable domain comprises the VH CDR1, VH CDR2, and VH CDR3 amino acid sequences of antibody S-15-10-7. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the presentny-2872361735022004240 disclosure comprise a light chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 249, wherein the light chain variable domain comprises the VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of antibody S-15-10-7. In some embodiments, the anti-Sortilin antibody or antigen- binding fragment thereof comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 248 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-15-10-7 or the amino acid sequence of SEQ ID NO: 248. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-15-10-7 or the amino acid sequence of SEQ ID NO: 248. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VH sequence of antibody S-15-10-7 or of SEQ ID NO: 248, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) the VH CDR1 amino acid sequence of SEQ ID NO: 230, (b) the VH CDR2 amino acid sequence of SEQ ID NO: 231, and (c) the VH CDR3 amino acid sequence of SEQ ID NO: 232. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10-7 or to the amino acid sequence of SEQ ID NO: 249 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), butny-2872361735022004240 the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-10-7 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-10-7 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VL sequence of antibody S-15-10-7 or of SEQ ID NO: 249, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) the VL CDR1 amino acid sequence of SEQ ID NO: 233, (b) the VL CDR2 amino acid sequence of SEQ ID NO: 234, and (c) the VL CDR3 amino acid sequence of SEQ ID NO: 235.

[0334] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, or SEQ ID NO: 302. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 257. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 261 or SEQ ID NO: 262 and a light chain comprising the amino acid sequence of SEQ ID NO: 257. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257.ny-2872361735022004240 (2) S-15-10

[0335] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region comprising a VH CDR1, a VH CDR2, and a VH CDR3. In some embodiments, the VH CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the VH CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 230), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR1 amino acid sequence of SEQ ID NO: 230. In some embodiments, the VH CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 231. In some embodiments, the VH CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 231), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR2 amino acid sequence of SEQ ID NO: 231. In some embodiments, the VH CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 236), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR3 amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 230, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 231, and the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 236.ny-2872361735022004240

[0336] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region comprising a VL CDR1, a VL CDR2, and a VL CDR3. In some embodiments, the VL CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 233), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR1 amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 234), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR2 amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 235), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR3 amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 233, the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 234, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 235. 111ny-2872361735022004240

[0337] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 250; and / or the light chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 249. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 250, wherein the heavy chain variable domain comprises the VH CDR1, VH CDR2, and VH CDR3 amino acid sequences of antibody S-15-10. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 249, wherein the light chain variable domain comprises the VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of antibody S-15-10. In some embodiments, the anti-Sortilin antibody or antigen- binding fragment thereof comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 250 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variableny-2872361735022004240 domain amino acid sequence of antibody S-15-10 or the amino acid sequence of SEQ ID NO: 250. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-15-10 or the amino acid sequence of SEQ ID NO: 250. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VH sequence of antibody S-15-10 or of SEQ ID NO: 250, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) the VH CDR1 amino acid sequence of SEQ ID NO: 230, (b) the VH CDR2 amino acid sequence of SEQ ID NO: 231, and (c) the VH CDR3 amino acid sequence of SEQ ID NO: 236. In some embodiments, anti- Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-10 or to the amino acid sequence of SEQ ID NO: 249 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-10 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-10 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VL sequence of antibody S-15-10 or of SEQ ID NO: 249, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) the VL CDR1 amino acid sequence of SEQ ID NO: 233, (b) the VL CDR2 amino acid sequence of SEQ ID NO: 234, and (c) the VL CDR3 amino acid sequence of SEQ ID NO: 235.ny-2872361735022004240 (3) S-15-6

[0338] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region comprising a VH CDR1, a VH CDR2, and a VH CDR3. In some embodiments, the VH CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 237. In some embodiments, the VH CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 237), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR1 amino acid sequence of SEQ ID NO: 237. In some embodiments, the VH CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 238. In some embodiments, the VH CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 238), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR2 amino acid sequence of SEQ ID NO: 238. In some embodiments, the VH CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 236), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR3 amino acid sequence of SEQ ID NO: 236. In some embodiments, the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 237, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 238, and the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 236.ny-2872361735022004240

[0339] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable region comprising a VL CDR1, a VL CDR2, and a VL CDR3. In some embodiments, the VL CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 233), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR1 amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 234), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR2 amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 235), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VL CDR3 amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 233, the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 234, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 235.ny-2872361735022004240

[0340] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 251; and / or the light chain variable domain comprises an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 249. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 251, wherein the heavy chain variable domain comprises the VH CDR1, VH CDR2, and VH CDR3 amino acid sequences of antibody S-15-6. In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable domain comprising an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 249, wherein the light chain variable domain comprises the VL CDR1, VL CDR2, and VL CDR3 amino acid sequences of antibody S-15-6. In some embodiments, the anti-Sortilin antibody or antigen- binding fragment thereof comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a heavy chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 251 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variableny-2872361735022004240 domain amino acid sequence of antibody S-15-6 or the amino acid sequence of SEQ ID NO: 251. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-15-6 or the amino acid sequence of SEQ ID NO: 251. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VH sequence of antibody S-15-6 or of SEQ ID NO: 251, including post-translational modifications of that sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) the VH CDR1 amino acid sequence of SEQ ID NO: 237, (b) the VH CDR2 amino acid sequence of SEQ ID NO: 238, and (c) the VH CDR3 amino acid sequence of SEQ ID NO: 236. In some embodiments, anti- Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a light chain variable domain amino acid sequence of antibody S-15-6 or to the amino acid sequence of SEQ ID NO: 249 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-Sortilin antibody or antigen-binding fragment thereof comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-6 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody S-15-6 or the amino acid sequence of SEQ ID NO: 249. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in in the FR regions. Optionally, the anti-Sortilin antibody or antigen-binding fragment thereof comprises the VL sequence of antibody S-15-6 or of SEQ ID NO: 249, including post-translational modifications of that sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) the VL CDR1 amino acid sequence of SEQ ID NO: 233, (b) the VL CDR2 amino acid sequence of SEQ ID NO: 234, and (c) the VL CDR3 amino acid sequence of SEQ ID NO: 235.ny-2872361735022004240 (4) S-60-15.1 [N33T]

[0341] In some embodiments, anti-Sortilin antibodies or antigen-binding fragments thereof of the present disclosure comprise a heavy chain variable region comprising a VH CDR1, a VH CDR2, and a VH CDR3. In some embodiments, the VH CDR1 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 239. In some embodiments, the VH CDR1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 239), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR1 amino acid sequence of SEQ ID NO: 239. In some embodiments, the VH CDR2 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence of SEQ ID NO: 240. In some embodiments, the VH CDR2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence of SEQ ID NO: 240), but retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids been substituted, inserted, and / or deleted in the VH CDR2 amino acid sequence of SEQ ID NO: 240. In some embodiments, the VH CDR3 comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at...

Claims

735022004240 WHAT IS CLAIMED IS:

1. A multi-specific protein comprising an antigen-binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin.

2. The multi-specific protein of claim 1, wherein the multi-specific protein accumulates in a brain sample at least about 2-fold more than the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and that is not linked to the antigen-binding domain that specifically binds to human TfR.

3. The multi-specific protein of claim 1 or claim 2, wherein the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; (iv) SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; (v) SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; (vi) SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; (vii) SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; (viii) SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; (ix) SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; (x) SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; (xi) SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; (xii) SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; (xiii) SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; (xiv) SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively;ny-2872361735022004240 (xv) SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; (xvi) SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; (xvii) SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively; (xviii) SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; (xix) SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; (xx) SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; (xxi) SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; (xxii) SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; (xxiii) SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; (xxiv) SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; (xxv) SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; (xxvi) SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; (xxvii) SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; (xxviii)SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively; (xxix) SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; (xxx) SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; (xxxi) SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively; (xxxii) SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; (xxxiii)SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; (xxxiv) SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; (xxxv) SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or (xxxvi) SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively.

4. A multi-specific protein comprising an antigen-binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, wherein the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, and wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of:ny-2872361735022004240 (i) SEQ ID NOs: 8, 16, 25, 42, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 11, 24, 40, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 11, 25, 41, 55, and 61, respectively; (iv) SEQ ID NOs: 8, 12, 26, 42, 55, and 61, respectively; (v) SEQ ID NOs: 8, 12, 27, 42, 55, and 61, respectively; (vi) SEQ ID NOs: 8, 13, 25, 42, 55, and 61, respectively; (vii) SEQ ID NOs: 8, 14, 25, 42, 55, and 61, respectively; (viii) SEQ ID NOs: 8, 15, 25, 43, 55, and 61, respectively; (ix) SEQ ID NOs: 8, 17, 25, 44, 55, and 61, respectively; (x) SEQ ID NOs: 9, 18, 28, 45, 56, and 62, respectively; (xi) SEQ ID NOs: 9, 19, 28, 45, 56, and 62, respectively; (xii) SEQ ID NOs: 9, 20, 28, 46, 57, and 62, respectively; (xiii) SEQ ID NOs: 9, 20, 28, 46, 58, and 62, respectively; (xiv) SEQ ID NOs: 9, 20, 28, 47, 59, and 62, respectively; (xv) SEQ ID NOs: 9, 21, 28, 46, 57, and 62, respectively; (xvi) SEQ ID NOs: 9, 21, 28, 47, 59, and 62, respectively; (xvii) SEQ ID NOs: 9, 22, 28, 46, 57, and 62, respectively; (xviii) SEQ ID NOs: 9, 22, 28, 46, 58, and 62, respectively; (xix) SEQ ID NOs: 9, 22, 28, 47, 59, and 62, respectively; (xx) SEQ ID NOs: 10, 22, 28, 46, 58, and 62, respectively; (xxi) SEQ ID NOs: 10, 22, 30, 46, 58, and 62, respectively; (xxii) SEQ ID NOs: 10, 22, 31, 46, 58, and 62, respectively; (xxiii) SEQ ID NOs: 10, 22, 32, 46, 58, and 62, respectively; (xxiv) SEQ ID NOs: 10, 22, 33, 46, 58, and 62, respectively; (xxv) SEQ ID NOs: 10, 22, 34, 46, 58, and 62, respectively; (xxvi) SEQ ID NOs: 10, 22, 35, 46, 58, and 62, respectively; (xxvii) SEQ ID NOs: 10, 22, 36, 46, 58, and 62, respectively; (xxviii)SEQ ID NOs: 10, 22, 37, 46, 58, and 62, respectively; (xxix) SEQ ID NOs: 10, 22, 38, 46, 58, and 62, respectively; (xxx) SEQ ID NOs: 10, 22, 39, 46, 58, and 62, respectively; (xxxi) SEQ ID NOs: 10, 22, 28, 49, 58, and 62, respectively;ny-2872361735022004240 (xxxii) SEQ ID NOs: 10, 22, 28, 50, 58, and 62, respectively; (xxxiii)SEQ ID NOs: 10, 22, 28, 51, 58, and 62, respectively; (xxxiv) SEQ ID NOs: 10, 22, 28, 52, 58, and 62, respectively; (xxxv) SEQ ID NOs: 10, 22, 28, 53, 58, and 62, respectively; or (xxxvi) SEQ ID NOs: 10, 22, 28, 54, 58, and 62, respectively.

5. The multi-specific protein of claim 3 or 4, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 103 and 157, respectively; (ii) SEQ ID NOs: 64 and 129, respectively; (iii) SEQ ID NOs: 65 and 130, respectively; (iv) SEQ ID NOs: 66 and 131, respectively; (v) SEQ ID NOs: 67 and 130, respectively; (vi) SEQ ID NOs: 68 and 131, respectively; (vii) SEQ ID NOs: 69 and 130, respectively; (viii) SEQ ID NOs: 70 and 131, respectively; (ix) SEQ ID NOs: 71 and 130, respectively; (x) SEQ ID NOs: 72 and 131, respectively; (xi) SEQ ID NOs: 73 and 130, respectively; (xii) SEQ ID NOs: 74 and 131, respectively; (xiii) SEQ ID NOs: 75 and 132, respectively; (xiv) SEQ ID NOs: 76 and 131, respectively; (xv) SEQ ID NOs: 77 and 132, respectively; (xvi) SEQ ID NOs: 77 and 133, respectively; (xvii) SEQ ID NOs: 78 and 134, respectively; (xviii) SEQ ID NOs: 77 and 135, respectively; (xix) SEQ ID NOs: 77 and 136, respectively; (xx) SEQ ID NOs: 77 and 137, respectively; (xxi) SEQ ID NOs: 77 and 138, respectively; (xxii) SEQ ID NOs: 79 and 131, respectively; (xxiii) SEQ ID NOs: 77 and 139, respectively;ny-2872361735022004240 (xxiv) SEQ ID NOs: 77 and 131, respectively; (xxv) SEQ ID NOs: 80 and 140, respectively; (xxvi) SEQ ID NOs: 81 and 141, respectively; (xxvii) SEQ ID NOs: 82 and 131, respectively; (xxviii) SEQ ID NOs: 83 and 142, respectively; (xxix) SEQ ID NOs: 77 and 143, respectively; (xxx) SEQ ID NOs: 75 and 131, respectively; (xxxi) SEQ ID NOs: 75 and 144, respectively; (xxxii) SEQ ID NOs: 77 and 145, respectively; (xxxiii) SEQ ID NOs: 84 and 131, respectively; (xxxiv) SEQ ID NOs: 75 and 146, respectively; (xxxv) SEQ ID NOs: 85 and 131, respectively; (xxxvi) SEQ ID NOs: 86 and 138, respectively; (xxxvii) SEQ ID NOs: 79 and 139, respectively; (xxxviii) SEQ ID NOs: 77 and 147, respectively; (xxxix) SEQ ID NOs: 75 and 148, respectively; (xl) SEQ ID NOs: 87 and 131, respectively; (xli) SEQ ID NOs: 88 and 131, respectively; (xlii) SEQ ID NOs: 75 and 149, respectively; (xliii) SEQ ID NOs: 89 and 150, respectively; (xliv) SEQ ID NOs: 90 and 151, respectively; (xlv) SEQ ID NOs: 77 and 152, respectively; (xlvi) SEQ ID NOs: 79 and 153, respectively; (xlvii) SEQ ID NOs: 91 and 131, respectively; (xlviii) SEQ ID NOs: 92 and 131, respectively; (xlix) SEQ ID NOs: 79 and 154, respectively; (l) SEQ ID NOs: 93 and 155, respectively; (li) SEQ ID NOs: 80 and 131, respectively; (lii) SEQ ID NOs: 94 and 131, respectively; (liii) SEQ ID NOs: 95 and 131, respectively; (liv) SEQ ID NOs: 66 and 156, respectively;ny-2872361735022004240 (lv) SEQ ID NOs: 97 and 138, respectively; (lvi) SEQ ID NOs: 95 and 156, respectively; (lvii) SEQ ID NOs: 98 and 157, respectively; (lviii) SEQ ID NOs: 99 and 157, respectively; (lix) SEQ ID NOs: 100 and 157, respectively; (lx) SEQ ID NOs: 101 and 157, respectively; (lxi) SEQ ID NOs: 102 and 158, respectively; (lxii) SEQ ID NOs: 104 and 159, respectively; (lxiii) SEQ ID NOs: 105 and 160, respectively; (lxiv) SEQ ID NOs: 106 and 161, respectively; (lxv) SEQ ID NOs: 107 and 162, respectively; (lxvi) SEQ ID NOs: 106 and 163, respectively; (lxvii) SEQ ID NOs: 108 and 164, respectively; (lxviii) SEQ ID NOs: 106 and 165, respectively; (lxix) SEQ ID NOs: 108 and 166, respectively; (lxx) SEQ ID NOs: 109 and 165, respectively; (lxxi) SEQ ID NOs: 110 and 167, respectively; (lxxii) SEQ ID NOs: 111 and 168, respectively; (lxxiii) SEQ ID NOs: 112 and 160, respectively; (lxxiv) SEQ ID NOs: 113 and 169, respectively; (lxxv) SEQ ID NOs: 113 and 170, respectively; (lxxvi) SEQ ID NOs: 113 and 171, respectively; (lxxvii) SEQ ID NOs: 114 and 169, respectively; (lxxviii) SEQ ID NOs: 114 and 171, respectively; (lxxix) SEQ ID NOs: 115 and 169, respectively; (lxxx) SEQ ID NOs: 115 and 170, respectively; (lxxxi) SEQ ID NOs: 115 and 171, respectively; (lxxxii) SEQ ID NOs: 116 and 169, respectively; (lxxxiii) SEQ ID NOs: 116 and 170, respectively; (lxxxiv) SEQ ID NOs: 116 and 171, respectively; (lxxxv) SEQ ID NOs: 117 and 170, respectively;ny-2872361735022004240 (lxxxvi) SEQ ID NOs: 118 and 170, respectively; (lxxxvii) SEQ ID NOs: 119 and 170, respectively; (lxxxviii) SEQ ID NOs: 120 and 170, respectively; (lxxxix) SEQ ID NOs: 121 and 170, respectively; (xc) SEQ ID NOs: 122 and 170, respectively; (xci) SEQ ID NOs: 123 and 170, respectively; (xcii) SEQ ID NOs: 124 and 170, respectively; (xciii) SEQ ID NOs: 125 and 170, respectively; (xciv) SEQ ID NOs: 126 and 170, respectively; (xcv) SEQ ID NOs: 127 and 170, respectively; (xcvi) SEQ ID NOs: 117 and 173, respectively; (xcvii) SEQ ID NOs: 117 and 174, respectively; (xcviii) SEQ ID NOs: 117 and 175, respectively; (xcix) SEQ ID NOs: 117 and 176, respectively; (c) SEQ ID NOs: 117 and 177, respectively; or (ci) SEQ ID NOs: 117 and 178, respectively.

6. The multi-specific protein of claim 1 or claim 2, wherein the antigen-binding domain that specifically binds to human TfR is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 16, and 25, respectively; (ii) SEQ ID NOs: 8, 11, and 24, respectively; (iii) SEQ ID NOs: 8, 11, and 25, respectively; (iv) SEQ ID NOs: 8, 12, and 26, respectively; (v) SEQ ID NOs: 8, 12, and 27, respectively; (vi) SEQ ID NOs: 8, 13, and 25, respectively; (vii) SEQ ID NOs: 8, 14, and 25, respectively; (viii) SEQ ID NOs: 8, 15, and 25, respectively; (ix) SEQ ID NOs: 8, 17, and 25, respectively; (x) SEQ ID NOs: 9, 18, and 28, respectively; (xi) SEQ ID NOs: 9, 19, and 28, respectively;ny-2872361735022004240 (xii) SEQ ID NOs: 9, 20, and 28, respectively; (xiii) SEQ ID NOs: 9, 21, and 28, respectively; (xiv) SEQ ID NOs: 9, 22, and 28, respectively; (xv) SEQ ID NOs: 10, 22, and 28, respectively; (xvi) SEQ ID NOs: 10, 22, and 30, respectively; (xvii) SEQ ID NOs: 10, 22, and 31, respectively; (xviii) SEQ ID NOs: 10, 22, and 32, respectively; (xix) SEQ ID NOs: 10, 22, and 33, respectively; (xx) SEQ ID NOs: 10, 22, and 34, respectively; (xxi) SEQ ID NOs: 10, 22, and 35, respectively; (xxii) SEQ ID NOs: 10, 22, and 36, respectively; (xxiii) SEQ ID NOs: 10, 22, and 37, respectively; (xxiv) SEQ ID NOs: 10, 22, and 38, respectively; or (xxv) SEQ ID NOs: 10, 22, and 39, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 103, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, or 127.

7. A multi-specific protein comprising an antigen-binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, and wherein the antigen-binding domain that specifically binds to human TfR comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively;ny-2872361735022004240 (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively.

8. The multi-specific protein of claim 7, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 101 and 154, respectively; (ii) SEQ ID NOs: 102 and 319, respectively; (iii) SEQ ID NOs: 102 and 320, respectively; (iv) SEQ ID NOs: 317 and 174, respectively; (v) SEQ ID NOs: 117 and 321, respectively; (vi) SEQ ID NOs: 117 and 322, respectively; (vii) SEQ ID NOs: 117 and 323, respectively; (viii) SEQ ID NOs: 117 and 324, respectively; (ix) SEQ ID NOs: 318 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 325, respectively.

9. A multi-specific protein comprising an antigen-binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin, and wherein the antigen-binding domain that specifically binds to human TfR is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 10, 22, and 308, respectively; or (ii) SEQ ID NOs: 10, 22, and 309, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 317 or 318.ny-2872361735022004240 10. The multi-specific protein of any one of claims 1-5, 7, and 8, wherein the antigen-binding domain that specifically binds to human TfR comprises a single-chain fragment variable (scFv).

11. The multi-specific protein of claim 10, wherein the scFv comprises a VH and a VL linked via an amino acid linker, wherein the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acids and / or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

12. The multi-specific protein of any one of claims 1-5, 7, and 8, wherein the antigen-binding domain is a Fab.

13. The multi-specific protein of any one of claims 1-12, wherein the antigen-binding domain that specifically binds to human TfR is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

14. The multi-specific protein of claims 1-13, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain.

15. The multi-specific protein of claim 14, wherein the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the Fc domain.

16. The multi-specific protein of any one of claims 1-15, wherein the multi-specific protein is bispecific.

17. The multi-specific protein of any one of claims 1-16, wherein the multi-specific protein is bivalent, trivalent, or tetravalent.ny-2872361735022004240 18. The multi-specific protein of any one of claims 1-16, wherein the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human TfR is an scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains or to the N-terminus of one of the two heavy chains.

19. The multi-specific protein of any one of claims 1-16, wherein the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human TfR, wherein each antigen-binding domain that specifically binds to human TfR is an scFv, Fab, or VHH, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human TfR is linked, optionally (i) via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain; (ii) via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain; or (iii) via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

20. The multi-specific protein of any one of claims 15-19, wherein the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

21. The multi-specific protein of any one of claims 1-16, wherein the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein (i) the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain or (ii) the antigen-binding domain that specifically binds to human TfR is a scFv,ny-2872361735022004240 VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N- terminus of the Fc domain.

22. The multi-specific protein of any one of claims 1-16, wherein the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein (i) the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, or (ii) the antigen-binding domain that specifically binds to human TfR is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region.

23. The multi-specific protein of claim 22, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

24. The multi-specific protein of claim 21, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

25. The multi-specific protein of claim 22 or 23, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.ny-2872361735022004240 26. The multi-specific protein of any one of claims 1-20, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation.

27. The multi-specific protein of claim 26, wherein the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation.

28. The multi-specific protein of claim 26, wherein the antigen-binding domain that specifically binds to human TfR is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation.

29. The multi-specific protein of claim 27 or 28, wherein the amino acid linker is a glycine- serine linker.

30. The multi-specific protein of claim 29, wherein the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217).

31. The multi-specific protein of any one of claims 1-20 and 26-30, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a human IgG1 Fc domain comprising (a) a knob mutation and a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S; and / or (b) a hole mutation and a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.ny-2872361735022004240 32. The multi-specific protein of any one of claims 1-20 and 26-30, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen- binding fragment thereof or an IgG4 antibody or antigen-binding fragment thereof.

33. The multi-specific protein of any one of claims 1-32, wherein the multi-specific protein is linked to an imaging agent.

34. The multi-specific protein of any one of claims 1-33, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

35. The multi-specific protein of any one of claims 1-34, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 248 and a VL comprising the amino acid sequence of SEQ ID NO: 249; (ii) the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iii) the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iv) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; (v) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254;ny-2872361735022004240 (vi) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or (vii) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO:

256.

36. The multi-specific protein of any one of claims 1-34, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO:

260.

37. The multi-specific protein of any one of claims 1-33, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises: (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257;ny-2872361735022004240 (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO:

258.

38. The multi-specific protein of any one of claims 1-33, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, and 232, respectively; (ii) SEQ ID NOs: 230, 231, and 236, respectively; (iii) SEQ ID NOs: 237, 238, and 236, respectively; or (iv) SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252.

39. The multi-specific protein of any one of claims 1, 7, 8, and 10-33, wherein: (a) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively;ny-2872361735022004240 (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

235.

40. The multi-specific protein of any one of claims 1, 7, 8, and 10-33, wherein: (a) the antigen-binding domain that specifically binds to human TfR comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

247.

41. A multi-specific protein comprising:ny-2872361735022004240 (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C- terminus, a VL and a CL; wherein the scFv specifically binds to human TfR; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen- binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

42. A multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C- terminus, a VL and a CL; wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human TfR;ny-2872361735022004240 wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen- binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

43. The multi-specific protein of claim 47 or 48, wherein the scFv that specifically binds to human TfR comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 310, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 311, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 308, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 312, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 313, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 314, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 315, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 309, 50, 58, and 62, respectively; (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 316, 55, and 61, respectively.ny-2872361735022004240 44. A composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of claims 1-43, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human TfR, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

45. A composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of claims 1-43, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a first antigen-binding domain that specifically binds to human TfR, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a second antigen-binding domain that specifically binds to human TfR, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, optionally wherein the first and second antigen-binding domains that specifically bind to human TfR comprise the same amino acid sequence.

46. A composition comprising a first polynucleotide and a second polynucleotide, wherein the first and second polynucleotides encode the multi-specific protein of any one of claims 1-43, wherein the first polynucleotide encodes a heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human TfR, and wherein the second polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

47. A multi-specific protein comprising an antigen-binding domain linked to an antibody or antigen-binding fragment thereof, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antibody or antigen-binding fragment thereof specifically binds to Sortilin.ny-2872361735022004240 48. The multi-specific protein of claim 47, wherein the antigen-binding domain that specifically binds to human CD98hc comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 and a VL comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of: (i) SEQ ID NOs: 181, 185, 191, 194, 198, and 201, respectively; (ii) SEQ ID NOs: 182, 186, 191, 195, 199, and 202, respectively; (iii) SEQ ID NOs: 183, 187, 192, 196, 200, and 203, respectively; (iv) SEQ ID NOs: 9, 188, 192, 196, 200, and 203, respectively; (v) SEQ ID NOs: 184, 189, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 190, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 284, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 285, 193, 197, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 286, 193, 197, 198, and 204, respectively; (x) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively;ny-2872361735022004240 (xxvi) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxxiii) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxxiv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xl) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xlii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xliii) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xliv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xlv) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xlvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xlvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xlviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xlix) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (l) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (li) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (lii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively.

49. The multi-specific protein of claim 48, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 205 and 211, respectively;ny-2872361735022004240 (ii) SEQ ID NOs: 206 and 212, respectively; (iii) SEQ ID NOs: 207 and 213, respectively; (iv) SEQ ID NOs: 208 and 214, respectively; (v) SEQ ID NOs: 209 and 215, respectively; (vi) SEQ ID NOs: 210 and 216, respectively; (vii) SEQ ID NOs: 287 and 216, respectively; (viii) SEQ ID NOs: 288 and 216, respectively; (ix) SEQ ID NOs: 289 and 216, respectively; (x) SEQ ID NOs: 368 and 216, respectively; (xi) SEQ ID NOs: 369 and 216, respectively; (xii) SEQ ID NOs: 370 and 216, respectively; (xiii) SEQ ID NOs: 371 and 216, respectively; (xiv) SEQ ID NOs: 372 and 216, respectively; (xv) SEQ ID NOs: 373 and 216, respectively; (xvi) SEQ ID NOs: 374 and 216, respectively; (xvii) SEQ ID NOs: 210 and 386, respectively; (xviii) SEQ ID NOs: 210 and 387, respectively; (xix) SEQ ID NOs: 210 and 388, respectively; (xx) SEQ ID NOs: 210 and 389, respectively; (xxi) SEQ ID NOs: 210 and 390, respectively; (xxii) SEQ ID NOs: 210 and 391, respectively; (xxiii) SEQ ID NOs: 210 and 392, respectively; (xxiv) SEQ ID NOs: 370 and 388, respectively; (xxv) SEQ ID NOs: 375 and 216, respectively; (xxvi) SEQ ID NOs: 376 and 216, respectively; (xxvii) SEQ ID NOs: 377 and 216, respectively; (xxviii) SEQ ID NOs: 378 and 216, respectively; (xxix) SEQ ID NOs: 379 and 216, respectively; (xxx) SEQ ID NOs: 380 and 216, respectively; (xxxi) SEQ ID NOs: 381 and 216, respectively; (xxxii) SEQ ID NOs: 382 and 216, respectively;ny-2872361735022004240 (xxxiii) SEQ ID NOs: 383 and 216, respectively; (xxxiv) SEQ ID NOs: 384 and 216, respectively; (xxxv) SEQ ID NOs: 210 and 393, respectively; (xxxvi) SEQ ID NOs: 210 and 394, respectively; (xxxvii) SEQ ID NOs: 210 and 395, respectively; (xxxviii) SEQ ID NOs: 210 and 396, respectively; (xxxix) SEQ ID NOs: 210 and 397, respectively; (xl) SEQ ID NOs: 210 and 398, respectively; (xli) SEQ ID NOs: 210 and 399, respectively; (xlii) SEQ ID NOs: 210 and 400, respectively; (xliii) SEQ ID NOs: 210 and 401, respectively; (xliv) SEQ ID NOs: 210 and 402, respectively; (xlv) SEQ ID NOs: 210 and 403, respectively; (xlvi) SEQ ID NOs: 210 and 404, respectively; (xlvii) SEQ ID NOs: 210 and 405, respectively; (xlviii) SEQ ID NOs: 210 and 406, respectively; (xlix) SEQ ID NOs: 210 and 407, respectively; (l) SEQ ID NOs: 210 and 408, respectively; (li) SEQ ID NOs: 385 and 215, respectively; or (lii) SEQ ID NOs: 385 and 408, respectively.

50. The multi-specific protein of claim 47, wherein the antigen-binding domain that specifically binds to CD98hc is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 181, 185, and 191, respectively; (ii) SEQ ID NOs: 182, 186, and 191, respectively; (iii) SEQ ID NOs: 183, 187, and 192, respectively; (iv) SEQ ID NOs: 9, 188, and 192, respectively; (v) SEQ ID NOs: 184, 189, and 193, respectively; (vi) SEQ ID NOs: 184, 190, and 193, respectively; (vii) SEQ ID NOs: 184, 284, and 193, respectively;ny-2872361735022004240 (viii) SEQ ID NOs: 184, 285, and 193, respectively; (ix) SEQ ID NOs: 184, 286, and 193, respectively; (x) SEQ ID NOs: 184, 327, and 193, respectively; (xi) SEQ ID NOs: 184, 328, and 193, respectively; (xii) SEQ ID NOs: 184, 329, and 193, respectively; (xiii) SEQ ID NOs: 184, 330, and 193, respectively; (xiv) SEQ ID NOs: 184, 331, and 193, respectively; (xv) SEQ ID NOs: 184, 332, and 193, respectively; (xvi) SEQ ID NOs: 184, 333, and 193, respectively; (xvii) SEQ ID NOs: 184, 334, and 193, respectively; (xviii) SEQ ID NOs: 184, 190, and 335, respectively; (xix) SEQ ID NOs: 184, 190, and 336, respectively; (xx) SEQ ID NOs: 184, 190, and 337, respectively; (xxi) SEQ ID NOs: 184, 190, and 338, respectively; (xxii) SEQ ID NOs: 184, 190, and 339, respectively; (xxiii) SEQ ID NOs: 184, 190, and 340, respectively; (xxiv) SEQ ID NOs: 184, 190, and 341, respectively; (xxv) SEQ ID NOs: 184, 190, and 342, respectively; (xxvi) SEQ ID NOs: 184, 190, and 343, respectively; or (xxvii) SEQ ID NOs: 326, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 287, 288, 289, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, or 385.

51. The multi-specific protein of any one of claims 47-49, wherein the antigen-binding domain that specifically binds to human CD98hc comprises a single-chain fragment variable (scFv).

52. The multi-specific protein of claim 51, wherein the scFv comprises a VH and a VL linked via an amino acid linker, wherein the linker (i) is about 5 to about 25 amino acids, is about 5 to about 20 amino acids, is about 10 to about 25 amino acids, or is about 10 to about 20 amino acidsny-2872361735022004240 and / or (ii) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

53. The multi-specific protein of any one of claims 47-49, wherein the antigen-binding domain is a Fab.

54. The multi-specific protein of any one of claims 47-53, wherein the antigen-binding domain that specifically binds to human CD98hc is a murine, chimeric, humanized, or human antigen- binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

55. The multi-specific protein of claims 47-54, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises an Fc domain.

56. The multi-specific protein of claim 55, wherein the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C- terminus of the Fc domain.

57. The multi-specific protein of any one of claims 47-56, wherein the multi-specific protein is bispecific.

58. The multi-specific protein of any one of claims 47-57, wherein the multi-specific protein is bivalent, trivalent, or tetravalent.

59. The multi-specific protein of any one of claims 47-57, wherein the multi-specific protein is trivalent and bispecific, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, and wherein the antigen-binding domain that specifically binds to human CD98hc is an scFv linked, optionally via an amino acid linker, to the C-terminus of one of the two heavy chains or to the N-terminus of one of the two heavy chains.ny-2872361735022004240 60. The multi-specific protein of any one of claims 47-57, wherein the multi-specific protein is tetravalent and bispecific, wherein the multi-specific protein comprises two antigen-binding domains that specifically bind to human CD98hc, wherein each antigen-binding domain that specifically binds to human CD98hc is an scFv, Fab, or VHH, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises two heavy chains and two light chains, wherein one of the antigen-binding domains that specifically binds to human CD98hc is linked, optionally (i) via an amino acid linker, to the C-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain; (ii) via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the N-terminus of the other heavy chain; or (iii) via an amino acid linker, to the N-terminus of one of the heavy chains, and wherein the other antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the C-terminus of the other heavy chain.

61. The multi-specific protein of any one of claims 56-60, wherein the amino acid linker comprises the sequence GGSGG (SEQ ID NO: 180).

62. The multi-specific protein of any one of claims 47-57, wherein the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc domain, wherein (i) the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of the Fc domain, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain; or (ii) the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of the Fc domain, and wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N- terminus of the Fc domain.

63. The multi-specific protein of any one of claims 47-57, wherein the multi-specific protein is bivalent and bispecific, wherein the multi-specific protein further comprises an Fc region comprising two polypeptide chains, wherein (i) the antigen-binding domain that specifically bindsny-2872361735022004240 to human CD98hc is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region; or (ii) the antigen-binding domain that specifically binds to human CD98hc is a scFv, VHH, or Fab linked to the C-terminus of one of the two polypeptide chains of the Fc region, and wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is a scFv, VHH, or Fab linked to the N-terminus of one of the two polypeptide chains of the Fc region.

64. The multi-specific protein of claim 63, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

65. The multi-specific protein of claim 62, wherein the Fc domain is a human IgG1 Fc domain, wherein the human IgG1 Fc domain comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

66. The multi-specific protein of claim 63 or 64, wherein the Fc region is a human IgG1 Fc region, wherein the human IgG1 Fc region comprises a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

67. The multi-specific protein of any one of claims 47-61, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises an Fc region, wherein the Fc region comprises a first polypeptide chain comprising a knob mutation and a second polypeptide chain comprising a hole mutation.ny-2872361735022004240 68. The multi-specific protein of claim 67, wherein the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the second polypeptide chain comprising a hole mutation.

69. The multi-specific protein of claim 67, wherein the antigen-binding domain that specifically binds to human CD98hc is linked, optionally via an amino acid linker, to the first polypeptide chain comprising a knob mutation.

70. The multi-specific protein of claim 68 or 69, wherein the amino acid linker is a glycine- serine linker.

71. The multi-specific protein of claim 70, wherein the glycine-serine linker comprises the amino acid sequence (GGGGS)x3 (SEQ ID NO: 179) or the amino acid sequence (GGSGG)x3 (SEQ ID NO: 217).

72. The multi-specific protein of any one of claims 47-61 and 67-71, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a human IgG1 Fc domain comprising (a) a knob mutation and a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S; and / or (b) a hole mutation and a mutation that reduces effector function, optionally wherein the mutation that reduces effector function comprises: (i) L234A, L235A, and / or P331S; (ii) N325S and / or L328F; (iii) L234A, L235A, and / or P329G; or (iv) L234A, L235A, and / or P329S.

73. The multi-specific protein of any one of claims 47-61 and 67-71, wherein the antibody or antigen-binding fragment thereof that specifically binds to Sortilin is an IgG1 antibody or antigen- binding fragment thereof or an IgG4 antibody or antigen-binding fragment thereof.

74. The multi-specific protein of any one of claims 47-73, wherein the multi-specific protein is linked to an imaging agent.ny-2872361735022004240 75. The multi-specific protein of any one of claims 47-74, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

76. The multi-specific protein of any one of claims 47-75, wherein: (i) the VH comprises the amino acid sequence of SEQ ID NO: 248 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (ii) the VH comprises the amino acid sequence of SEQ ID NO: 250 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iii) the VH comprises the amino acid sequence of SEQ ID NO: 251 and the VL comprises the amino acid sequence of SEQ ID NO: 249; (iv) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 253; (v) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 254; (vi) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO: 255; or (vii) the VH comprises the amino acid sequence of SEQ ID NO: 252 and the VL comprises the amino acid sequence of SEQ ID NO:

256.

77. The multi-specific protein of any one of claims 47-75, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 261, and a light chain comprising the amino acid sequence of SEQ ID NO: 257;ny-2872361735022004240 (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262, and a light chain comprising the amino acid sequence of SEQ ID NO: 257; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 258; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO: 259; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 263, and a light chain comprising the amino acid sequence of SEQ ID NO: 260; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264, and a light chain comprising the amino acid sequence of SEQ ID NO:

260.

78. The multi-specific protein of any one of claims 47-74, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin comprises: (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 299, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 300, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (b) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 301, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 257; (c) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 303, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 304, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258; or (d) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 305, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 306, and a first and second light chain each comprising the amino acid sequence of SEQ ID NO: 258.ny-2872361735022004240 79. The multi-specific protein of any one of claims 47-74, wherein the antibody or antigen- binding fragment thereof that specifically binds to Sortilin is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, and 232, respectively; (ii) SEQ ID NOs: 230, 231, and 236, respectively; (iii) SEQ ID NOs: 237, 238, and 236, respectively; or (iv) SEQ ID NOs: 239, 240, and 241, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 248, 250, 251, and 252.

80. The multi-specific protein of any one of claims 47-74, wherein: (a) the antigen-binding domain that specifically binds to human CD98hc comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively;ny-2872361735022004240 (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 230, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 231, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 232, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 233, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 234, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 235.ny-2872361735022004240 81. The multi-specific protein of any one of claims 47-74, wherein: (a) the antigen-binding domain that specifically binds to human CD98hc a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively;ny-2872361735022004240 (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively; and (b) the antibody or antigen-binding fragment thereof that specifically binds to Sortilin comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 239, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 240, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 241, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 245, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:

247.

82. A multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C- terminus, a VL and a CL;ny-2872361735022004240 wherein the scFv of the first polypeptide and the scFv of the second polypeptide each specifically bind to human CD98hc; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen- binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; and wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

83. A multi-specific protein comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, a CH3, a linker, and a scFv; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; and (iii) a third polypeptide and a fourth polypeptide each comprising, from the N-terminus to the C- terminus, a VL and a CL; wherein the scFv specifically binds to human CD98hc; wherein the VH of the first polypeptide and the VL of the third polypeptide form a first antigen- binding domain that specifically binds to Sortilin; wherein the VH of the second polypeptide and the VL of the fourth polypeptide form a second antigen-binding domain that specifically binds to Sortilin; andny-2872361735022004240 wherein the first antigen-binding domain and the second antigen-binding domain each comprise a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 230, 231, 232, 233, 234, and 235, respectively; (ii) SEQ ID NOs: 230, 231, 236, 233, 234, and 235, respectively; (iii) SEQ ID NOs: 237, 238, 236, 233, 234, and 235, respectively; (iv) SEQ ID NOs: 239, 240, 241, 242, 243, and 244, respectively; (v) SEQ ID NOs: 239, 240, 241, 245, 246, and 247, respectively; (vi) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively; or (vii) SEQ ID NOs: 239, 240, 241, 242, 246, and 247, respectively.

84. The multi-specific protein of claim 82 or 83, wherein the scFv that specifically binds to human CD98hc comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 327, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 328, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 329, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 330, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 331, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 332, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 333, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 344, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 345, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 346, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 347, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 348, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 349, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 350, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 329, 193, 346, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 334, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 335, 197, 198, and 204, respectively;ny-2872361735022004240 (xviii) SEQ ID NOs: 184, 190, 336, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 337, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 338, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 339, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 340, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 341, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 342, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 343, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 351, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 352, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 353, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 354, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 355, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 356, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 357, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 358, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 359, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 360, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 361, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 362, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 363, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 364, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 365, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 366, respectively; (xlii) SEQ ID NOs: 326, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 326, 190, 193, 197, 198, and 367, respectively.

85. A composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of claims 47-84, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, the secondny-2872361735022004240 polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human CD98hc, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

86. A composition comprising a first polynucleotide, a second polynucleotide, and a third polynucleotide, wherein the first, second, and third polynucleotides encode the multi-specific protein of any one of claims 47-84, wherein the first polynucleotide encodes a first heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a first antigen-binding domain that specifically binds to human CD98hc, the second polynucleotide encodes a second heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and a second antigen-binding domain that specifically binds to human CD98hc, and the third polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin, optionally wherein the first and second antigen-binding domains that specifically bind to human CD98hc comprise the same amino acid sequence.

87. A composition comprising a first polynucleotide and a second polynucleotide, wherein the first and second polynucleotides encode the multi-specific protein of any one of claims 47-84, wherein the first polynucleotide encodes a heavy chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin and the antigen-binding domain that specifically binds to human CD98hc, and wherein the second polynucleotide encodes a light chain of the antibody or antigen-binding fragment thereof that specifically binds to Sortilin.

88. A host cell comprising the composition of any one of claims 44-46 and 85-87.

89. A polynucleotide encoding the multi-specific protein of any one of claims 1-43 and 47-84.

90. A vector comprising the polynucleotide of claim 89.

91. A host cell comprising the vector of claim 90.ny-2872361735022004240 92. A method of producing a multi-specific protein comprising culturing the host cell of claim 88 or 91 so that the multi-specific protein is produced, optionally wherein the method further comprises isolating the multi-specific protein from the culture.

93. An isolated multi-specific protein produced by the method of claim 92.

94. A pharmaceutical composition comprising the multi-specific protein of any one of claims 1-43 and 47-84.

95. The pharmaceutical composition of claim 94, further comprising a pharmaceutically acceptable carrier.

96. A method of treating a neurological disease or disorder in a subject comprising administering the multi-specific protein of any one of claims 1-43 and 47-84 or the pharmaceutical composition of claim 94 or 95 to the subject.

97. The method of claim 96, wherein the neurological disease or disorder is selected from Alzheimer's disease (AD), Huntington’s disease, dystonia, ataxia, stroke, dementia, Lewy body dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Pick's disease, encephalitis, traumatic brain injury, and limbic-predominant age-related TDP-43 encephalopathy (LATE).

98. The method of claim 96, wherein the dementia is frontotemporal dementia (FTD).

99. The method of claim 96, wherein the neurological disease or disorder is frontal temporal epilepsy.

100. A method of treating a lysosomal storage disease in a subject comprising administering the multi-specific protein of any one of claims 1-43 and 47-84 or the pharmaceutical composition of claim 94 or 95 to the subject.ny-2872361735022004240 101. A method of transporting an antibody or antigen-binding fragment thereof that specifically binds to Sortilin across the blood brain barrier (BBB) of a subject, comprising administering the multi-specific protein of any one of claims 1-43 and 47-84 or the pharmaceutical composition of claim 94 or 95 to the subject.

102. A method of increasing the concentration of an antibody or antigen-binding fragment thereof that specifically binds to Sortilin in the cerebral spinal fluid (CSF) of a subject, comprising administering the multi-specific protein of any one of claims 1-43 and 47-84 or the pharmaceutical composition of claim 94 or 95 to the subject, wherein the concentration of the antibody or antigen- binding fragment thereof is increased in the CSF of the subject as compared to administering the antibody or antigen-binding fragment thereof alone to the subject.

103. A method of imaging an antibody or antigen-binding fragment thereof that specifically binds to Sortilin within a subject, comprising administering to the subject the multi-specific protein of claim 33 or 74 and locating the imaging agent within the subject.

104. A method of detecting Sortilin in vitro, comprising contacting an in vitro sample with the multi-specific protein of claim 33 or 74 and locating the imaging agent within the sample.ny-2872361

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