Compositions comprising progranulin and uses thereof

Abstract

Provided here are complexes comprising an antigen-binding domain that binds to human transferrin receptor or human CD98 heavy chain linked to a Progranulin polypeptide. Also provided herein are isolated Progranulin mutant polypeptides. Methods of using and making such complexes and isolated polypeptides are provided herein.

Description

735022004340 COMPOSITIONS COMPRISING PROGRANULIN AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 627,682, filed January 31, 2024; U.S. Provisional Patent Application No.63 / 660,926, filed June 17, 2024; and U.S. Provisional Patent Application No.63 / 744,150, 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 (735022004340SEQLIST.xml; Size: 497,495 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 complexes comprising antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide 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 by 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 someny-2871899735022004340 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] Progranulin (PGRN) is a secreted, growth factor-like, trophic, and anti-inflammatory protein, which also plays a role as an adipokine involved in diet-induced obesity and insulin resistance (Nguyen DA et al., (2013). Trends in Endocrinology and Metabolism, 24, 597- 606). Progranulin deficiency accounts for roughly 25% of all heritable forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of- function mutations in PGRN have ~50% reduced extracellular levels of the protein and they will invariably develop FTD, making PGRN a causal gene for the disease (Baker, M et al., (2006) Nature 442, 916-919; Carecchio M et al., (2011) J Alzheimers Dis 27, 781-790; Cruts, M et al., (2008) Trends Genet 24, 186-194; Galimberti, D et al., (2010) J Alzheimers Dis 19, 171-177). In addition, PGRN mutant alleles have been identified in Alzheimer’s disease patients (Seelaar, H et al., (2011). Journal of neurology, neurosurgery, and psychiatry 82, 476-486). Importantly, PGRN acts protectively in several disease models with increased PGRN levels, accelerating behavioral recovery from ischemia (Tao, J et al., (2012) Brain Res 1436, 130-136; Egashira, Y. et al., (2013). J Neuroinflammation 10, 105), suppressing locomotor deficits in a Parkinson’s disease model (Van Kampen, J.M et al. (2014). PLoS One 9, e97032), attenuating pathology in a model of amyotrophic lateral sclerosis (Laird, A.S et al., (2010). PLoS One 5, e13368.) and arthritis (Tang, W et al., (2011). Science 332, 478-484) and preventing memory deficits in an Alzheimer’s disease model (Minami, S.S et al., (2014). Nat Med 20, 1157-1164).

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

[0007] Provided herein are complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, 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 PGRN polypeptide across the blood brain barrier (BBB).

[0008] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specificallyny-2871899735022004340 binds to human transferrin receptor (TfR), and wherein the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL.

[0009] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex.

[0010] In some embodiments, the antigen-binding domain 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, 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, 16, 25, 42, 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-2871899735022004340

[0011] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 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, 103, 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.

[0012] In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 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, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 177, or 178.

[0013] In some embodiments, the VH and the VL comprise the amino acid sequences of: 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: 94 and 131, respectively; SEQ ID NOs:ny-2871899735022004340 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: 103 and 157, 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.

[0014] In some embodiments, the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: 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, 16, 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 ID NOs: 10, 22, and 30, respectively; SEQ IDny-2871899735022004340 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: 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, 103, 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.

[0015] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain 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).

[0016] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide.

[0017] In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0018] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn.

[0019] In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn.

[0020] In some embodiments, the complex comprises: (i) a single scFv or VHH or Fab antigen-binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked tony-2871899735022004340 the N-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

[0021] In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-bindingny-2871899735022004340 domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. In some embodiments, the complex comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

[0022] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, 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. In some embodiments, the wherein the Fc domain is a single chain monovalent Fc domain. In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, 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.

[0023] In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRNny-2871899735022004340 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0024] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 320; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321.ny-2871899735022004340

[0025] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 322; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321.

[0026] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selectedny-2871899735022004340 from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide of the first polypeptide and the second polypeptide each comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321.

[0027] In some aspects, provided herein is a complex 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 PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQny-2871899735022004340 ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 332; and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 321.

[0028] In some embodiments, (i) the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and / or (ii) the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, (i) the VH comprises the amino acid sequence of SEQ ID NO: 102; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 158.

[0029] In some embodiments, the complex binds human Sortilin with a dissociation constant (KD) that ranges from about 5 nM to about 400 nM. In some embodiments, the complex binds human Sortilin with a KDthat ranges from about 50 nM to about 350 nM. In some embodiments, the complex binds human Sortilin with a KDthat ranges from about 100 nM to about 300 nM. In some embodiments, the complex increases cellular GCase activity greater than the PGRN polypeptide alone. In some embodiments, the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN polypeptide alone. In some embodiments, the complex is linked to an imaging agent.

[0030] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.ny-2871899735022004340

[0031] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the 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.

[0032] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the 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.

[0033] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject.

[0034] In some aspects, provided herein is a method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.ny-2871899735022004340

[0035] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the embodiments and locating the imaging agent within the subject. In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the embodiments and locating the imaging agent within the sample.

[0036] In some aspects, provided herein is use of the complex 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. In some aspects, provided herein is a complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments for use in the method of any one of the embodiments.

[0037] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). In some embodiments, the antigen-binding domain 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 sequences 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, 324, 193, 197, 198, and 204, respectively; SEQ ID NOs: 184, 325, 193, 197, 198, and 204, respectively; or SEQ ID NOs: 184, 326, 193, 197, 198, and 204, respectively.

[0038] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329. 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; SEQ 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: 327 and 216, respectively; SEQ ID NOs: 328 and 216, respectively; or SEQ ID NOs: 329 and 216, respectively.ny-2871899735022004340

[0039] In some embodiments, the antigen-binding domain 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, 324, and 193, respectively; SEQ ID NOs: 184, 325, and 193, respectively; or SEQ ID NOs: 184, 326, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329.

[0040] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain 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).

[0041] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide.

[0042] In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain. In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn.

[0043] In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn.

[0044] In some embodiments, the complex further comprises (i) a single scFv or VHH or Fab antigen-binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked tony-2871899735022004340 the N-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region.

[0045] In some embodiments, the complex further comprises (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains. In some embodiments, the complex further comprises (i) two scFv, Fab, or VHH antigen-binding domains that bind to human CD98hc, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C- terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

[0046] In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc,ny-2871899735022004340 (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain. In some embodiments, the complex further comprises: (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

[0047] In some embodiments, the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, 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.

[0048] In some embodiments, the Fc domain is a single chain monovalent Fc domain. In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, 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.

[0049] In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V,ny-2871899735022004340 A, I, H, K, and N; and / or (d) X4is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0050] In some embodiments, the complex is linked to an imaging agent.

[0051] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of any one of the embodiments. In some aspects, provided herein is a host cell comprising the vector of any one of the embodiments. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of any one of the embodiments so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of any one of the embodiments. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0052] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the 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 someny-2871899735022004340 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.

[0053] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the 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.

[0054] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject. In some aspects, provided herein is a method of increasing the concentration of PGRN in the CSF of a subject, comprising administering the complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject. In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the embodiments and locating the imaging agent within the subject. In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the embodiments and locating the imaging agent within the sample.

[0055] In some aspects, provided herein is use of the complex 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. In some aspects, provided herein is a complex of any one of the embodiments or the pharmaceutical composition of any one of the embodiments for use in the method of any one of the embodiments.

[0056] In some aspects, provided herein is an isolated PGRN polypeptide, wherein: (i) the isolated PGRN polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4,ny-2871899735022004340 and wherein: (a) X1is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL. In some embodiments, the isolated PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330. In some embodiments, the amino acid sequence is selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the amino acid sequence is SEQ ID NO: 231. In some embodiments, the amino acid sequence is SEQ ID NO: 232. In some embodiments, the amino acid sequence is SEQ ID NO: 233. In some embodiments, the amino acid sequence is SEQ ID NO: 234. In some embodiments, the amino acid sequence is SEQ ID NO: 235. In some embodiments, the amino acid sequence is SEQ ID NO: 236. In some embodiments, the amino acid sequence is SEQ ID NO: 237. In some embodiments, the amino acid sequence is SEQ ID NO: 238. In some embodiments, the amino acid sequence is SEQ ID NO: 239. In some embodiments, the amino acid sequence is SEQ ID NO: 240. In some embodiments, the amino acid sequence is SEQ ID NO: 241. In some embodiments, the amino acid sequence is SEQ ID NO: 242. In some embodiments, the amino acid sequence is SEQ ID NO: 243. In some embodiments, the amino acid sequence is SEQ ID NO: 244. In some embodiments, the amino acid sequence is SEQ ID NO: 245. In some embodiments, the amino acid sequence is SEQ ID NO: 246. In some embodiments, the amino acid sequence is SEQ ID NO: 248. In some embodiments, the amino acid sequence is SEQ ID NO: 249. In some embodiments, the amino acid sequence is SEQ ID NO: 250. In some embodiments, the amino acid sequence is SEQ ID NO: 251. In some embodiments, the amino acid sequence is SEQ ID NO: 252. In some embodiments, the amino acid sequence is SEQ ID NO: 253. In some embodiments, the amino acid sequence is SEQ ID NO: 254. In some embodiments, the amino acid sequence is SEQ IDny-2871899735022004340 NO: 255. In some embodiments, the amino acid sequence is SEQ ID NO: 256. In some embodiments, the amino acid sequence is SEQ ID NO: 257. In some embodiments, the amino acid sequence is SEQ ID NO: 259. In some embodiments, the amino acid sequence is SEQ ID NO: 261. In some embodiments, the amino acid sequence is SEQ ID NO: 262. In some embodiments, the amino acid sequence is SEQ ID NO: 263. In some embodiments, the amino acid sequence is SEQ ID NO: 264. In some embodiments, the amino acid sequence is SEQ ID NO: 265. In some embodiments, the amino acid sequence is SEQ ID NO: 266.

[0057] In some aspects, provided herein is an isolated nucleic acid encoding the isolated PGRN polypeptide of any one of the embodiments. In some aspects, provided herein is a vector comprising the nucleic acid of any one of the embodiments. In some aspects, provided herein is a host cell comprising the vector of any one of the embodiments. In some aspects, provided herein is a method of producing an isolated PGRN polypeptide comprising culturing the host cell of any one of the embodiments so that the isolated PGRN polypeptide is produced, optionally wherein the method further comprises isolating the isolated PGRN polypeptide from the culture. In some aspects, provided herein is an isolated PGRN polypeptide produced by the method of any one of the embodiments. In some aspects, provided herein is a pharmaceutical composition comprising the isolated PGRN polypeptide of any one of the embodiments.

[0058] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the isolated PGRN polypeptide of any one of any one of the embodiments or the pharmaceutical composition of any one of the 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.

[0059] 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 neurologicalny-2871899735022004340 disease or disorder is Parkinson’s disease. In some embodiments, the neurological disease or disorder is frontal temporal epilepsy.

[0060] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the isolated PGRN polypeptide of any one of the embodiments or the pharmaceutical composition of any one of the 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.

[0061] In some aspects, provided herein is a complex comprising (a) an antigen-binding domain that specifically binds to human transferrin receptor (TfR) and (b) a Progranulin (PGRN) polypeptide.

[0062] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 0.01 nM to 50 nM, and (b) a PGRN polypeptide.

[0063] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 51 nM to 750 nM, and (b) a PGRN polypeptide. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM.

[0064] In some aspects, provided herein is a complex comprising (a) an affinity-tuned antigen- binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 751 nM to 10,000 nM, and (b) a PGRN polypeptide.

[0065] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antigen-binding domain 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: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; 22ny-2871899735022004340 (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0066] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 154, 344, 345, 174, 346, 347, 348, 349, or 350. 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 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.

[0067] In some embodiments, a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively;ny-2871899735022004340 (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118.

[0068] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain 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).

[0069] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0070] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn.

[0071] In some embodiments, the complex comprises (i) a single scFv or VHH or Fab antigen- binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, oneny-2871899735022004340 of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C- terminus of the second polypeptide chain of the Fc region.

[0072] In some embodiments, the complex comprises (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains.

[0073] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

[0074] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region.

[0075] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain.

[0076] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and theny-2871899735022004340 PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region.

[0077] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C- terminus of the Fc domain.

[0078] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

[0079] 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 single chain monovalent Fc domain. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, 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.

[0080] In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, 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.

[0081] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO:ny-2871899735022004340 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0082] In some aspects, provided herein is a complex 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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0083] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises a VL CDR1, VL CDR2, and VL CDR3, whereinny-2871899735022004340 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0084] In some aspects, provided herein is a complex 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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 50, 58, and 62, respectively;ny-2871899735022004340 (x) SEQ ID NOs: 10, 22, 30, 50, 58, and 62, respectively; or (xi) SEQ ID NOs: 8, 14, 25, 341, 55, and 61, respectively.

[0085] In some aspects, provided herein is a complex 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 PGRN polypeptide; and (b) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0086] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a PGRN polypeptide, a linker, a CH2, and a CH3; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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;ny-2871899735022004340 (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0087] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0088] 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 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.ny-2871899735022004340

[0089] In some embodiments, the complex is linked to an imaging agent.

[0090] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the preceding embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of any one of the preceding embodiments. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0091] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex 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.

[0092] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject. In someny-2871899735022004340 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.

[0093] In some aspects, provided herein a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject.

[0094] In some aspects, provided herein is a method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex 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 PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.

[0095] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the preceding embodiments and locating the imaging agent within the subject.

[0096] In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the preceding embodiments and locating the imaging agent within the sample.

[0097] In some aspects, provided herein is a use of the complex 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.

[0098] In some aspects, provided herein is the complex 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.

[0099] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain 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 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively;ny-2871899735022004340 (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively;ny-2871899735022004340 (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively.

[0100] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, or 432. In some embodiments, the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 392 and 216, respectively; (ii) SEQ ID NOs: 393 and 216, respectively; (iii) SEQ ID NOs: 394 and 216, respectively; (iv) SEQ ID NOs: 395 and 216, respectively; (v) SEQ ID NOs: 396 and 216, respectively; (vi) SEQ ID NOs: 397 and 216, respectively; (vii) SEQ ID NOs: 398 and 216, respectively; (viii) SEQ ID NOs: 210 and 410, respectively; (ix) SEQ ID NOs: 210 and 411, respectively; (x) SEQ ID NOs: 210 and 412, respectively; (xi) SEQ ID NOs: 210 and 413, respectively; (xii) SEQ ID NOs: 210 and 414, respectively; (xiii) SEQ ID NOs: 210 and 415, respectively; (xiv) SEQ ID NOs: 210 and 416, respectively; (xv) SEQ ID NOs: 394 and 412, respectively;ny-2871899735022004340 (xvi) SEQ ID NOs: 399 and 216, respectively; (xvii) SEQ ID NOs: 400 and 216, respectively; (xviii) SEQ ID NOs: 401 and 216, respectively; (xix) SEQ ID NOs: 402 and 216, respectively; (xx) SEQ ID NOs: 403 and 216, respectively; (xxi) SEQ ID NOs: 404 and 216, respectively; (xxii) SEQ ID NOs: 405 and 216, respectively; (xxiii) SEQ ID NOs: 406 and 216, respectively; (xxiv) SEQ ID NOs: 407 and 216, respectively; (xxv) SEQ ID NOs: 408 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 417, respectively; (xxvii) SEQ ID NOs: 210 and 418, respectively; (xxviii) SEQ ID NOs: 210 and 419, respectively; (xxix) SEQ ID NOs: 210 and 420, respectively; (xxx) SEQ ID NOs: 210 and 421, respectively; (xxxi) SEQ ID NOs: 210 and 422, respectively; (xxxii) SEQ ID NOs: 210 and 423, respectively; (xxxiii) SEQ ID NOs: 210 and 424, respectively; (xxxiv) SEQ ID NOs: 210 and 425, respectively; (xxxv) SEQ ID NOs: 210 and 426, respectively; (xxxvi) SEQ ID NOs: 210 and 427, respectively; (xxxvii) SEQ ID NOs: 210 and 428, respectively; (xxxviii) SEQ ID NOs: 210 and 429, respectively; (xxxix) SEQ ID NOs: 210 and 430, respectively; (xl) SEQ ID NOs: 210 and 431, respectively; (xli) SEQ ID NOs: 210 and 432, respectively; (xlii) SEQ ID NOs: 409 and 215, respectively; or (xliii) SEQ ID NOs: 409 and 432, respectively.

[0101] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising:ny-2871899735022004340 (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409.

[0102] In some embodiments, the antigen-binding domain comprises a VH and a VL on a single polypeptide chain. In some embodiments, the antigen-binding domain 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).ny-2871899735022004340

[0103] In some embodiments, the antigen-binding domain comprises a VH on a first polypeptide and a VL on a second polypeptide. In some embodiments, the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

[0104] In some embodiments, the complex further comprises an Fc region, wherein the Fc region comprises a first and second polypeptide chain. In some embodiments, the Fc region is capable of binding FcRn. In some embodiments, the complex further comprises an Fc domain. In some embodiments, the Fc domain is capable of binding FcRn.

[0105] In some embodiments, the complex comprises (i) a single scFv or VHH or Fab antigen- binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide. In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region. In some embodiments, one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region.

[0106] In some embodiments, the complex comprises (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C- termini of one of the two antibody heavy chains.

[0107] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that bind to human CD98hc, (ii) an Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of 37ny-2871899735022004340 the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region. In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region.

[0108] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain.

[0109] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region.

[0110] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain.

[0111] In some embodiments, the complex comprises (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

[0112] 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 single chainny-2871899735022004340 monovalent Fc domain. In some embodiments, the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9. In some embodiments, 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.

[0113] In some embodiments, the Fc domain is a modified Fc domain with a modification listed in Table 8. In some embodiments, 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.

[0114] In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0115] In some embodiments, the complex is linked to an imaging agent.

[0116] In some aspects, provided herein is a polynucleotide encoding the complex of any one of the preceding embodiments. In some aspects, provided herein is a vector comprising the polynucleotide of the preceding embodiment. In some aspects, provided herein is a host cell comprising the vector of the preceding embodiment. In some aspects, provided herein is a method of producing a complex comprising culturing the host cell of the preceding embodiment so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture. In some aspects, provided herein is an isolated complex thereof produced by the method of the preceding embodiment. In some aspects, provided herein is a pharmaceutical composition comprising the complex of the preceding embodiment. In someny-2871899735022004340 embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0117] In some aspects, provided herein is a method of treating a neurological disease or disorder in a subject comprising administering the complex 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.

[0118] In some aspects, provided herein is a method of treating a lysosomal storage disease in a subject comprising administering the complex 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.

[0119] In some aspects, provided herein is a method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject.

[0120] In some aspects, provided herein is a method of increasing the concentration of PGRN in the CSF of a subject, comprising administering the complex of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to theny-2871899735022004340 subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.

[0121] In some aspects, provided herein is a method of imaging PGRN within a subject, comprising administering to the subject the complex of any one of the preceding embodiments and locating the imaging agent within the subject.

[0122] In some aspects, provided herein is a method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of any one of the preceding embodiments and locating the imaging agent within the sample.

[0123] In some aspects, provided herein is a use of the complex 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.

[0124] In some aspects, provided herein is the complex 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.

[0125] In some aspects, provided herein is a method of increasing PGRN in a subject, the method comprising administering the isolated PGRN mutant polypeptide of any one of the preceding embodiments or the pharmaceutical composition of any one of the preceding embodiments to the subject.

[0126] 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

[0127] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0128] FIGS. 1A-1J show example formats of complexes.

[0129] FIGS. 2A-2D show example formats of anti-TfR-PGRN complexes. PGRN comprises a half granulin domain, “paragranulin” (P), followed by 7 granulin domains (G-F-B-A-C-D-E).ny-2871899735022004340

[0130] FIGS. 3A-3C show representative sensor gram data using the PGRN Capture method on Carterra LSA. Shown are example sensor gram data for PGRN mutants in HEK293 and CHO cells: mvFc-PGRN_16 (QYL C-term mutation; SEQ ID NO: 462) (FIG.3A) and mvFc- PGRN_31 (“QKL” C-term mutation; SEQ ID NO: 447) (FIG. 3B). FIG. 3C shows sensor gram data for wild-type PGRN in HEK293 and CHO cells (“APLRDPALRQLL” C-term; SEQ ID NO: 451). In FIGS.3A-3C, each curve represents an Sortilin analyte concentration (4.9 nM, 14.8 nM, 44.4 nM, 133.3 nM, and 400nM Sortilin). The measured response (RU) was proportional to the analyte concentration used (e.g., highest curve = 400 nM Sortilin and lowest curve = 4.9 nM Sortilin).

[0131] FIG. 4 shows progranulin proteins containing a mouse transferrin antigen-binding domain induce greater -Glucocerebrosidase (GCase) activity in RAW 264.7 mouse macrophage cells. Legend: mTfR1 = mouse anti-TfR1 Fab domains; mvFc = monovalent Fc; Iso = isotype; Wt = wildtype; cis = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC; trans = HC1 (Fab- Fc-hole) and HC2 (Fc-knob-PGRN) and LC; and 1+2 = HC1 (mTfR1 Fab-Fc-knob-PGRN) and HC2 (Fc-hole-PGRN) and LC. N = 2 combined experiments.

[0132] FIG. 5 shows the extent of uptake of anti-TfR-PGRN complexes in a mouse brain endothelial cell line bEND.3 at 2 hours. Higher uptake is observed as compared to progranulin proteins with an isotype control domain. Images displayed are for human Fc detection using an anti-HuIgG antibody conjugated to Alexa Fluor-647. Nuclei were labeled with DAPI.

[0133] FIGS. 6A-6B show the quantification of the cell uptake experiment in FIG.5 and demonstrates that bEND.3 cells endocytose anti-TfR-PGRN complexes to a greater extent after 2 hours than those containing an isotype control domain. Shown is cellular uptake of PGRN measured by human Fc detection (FIG.6A) and human PGRN detection (FIG. 6B). Legend: mTfR1 = mouse anti-TfR1 Fab domains; mvFc = monovalent Fc; Iso = isotype; Wt = wildtype; cis = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC; trans = HC1 (Fab-Fc-hole) and HC2 (Fc-knob-PGRN) and LC; and 1+2 = HC1 (mTfR1 Fab-Fc-knob-PGRN) and HC2 (Fc- hole-PGRN) and LC.

[0134] FIGS. 7A-7B 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.42Q (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),ny-2871899735022004340 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.

[0135] FIGS. 8A-8B 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.

[0136] FIG. 9 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.

[0137] FIGS. 10A-10B 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.10A shows antibody concentration (ng / mg tissue) in vessel-depleted brain after 24 hrs. FIG. 10B shows the fold change over the matched isotype control in vessel-depleted brain.

[0138] FIG. 11 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.

[0139] FIG. 12 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).

[0140] FIG. 13 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,ny-2871899735022004340 and 42Q – served as controls. Shown are TfR levels normalized to levels of GAPDH for each sample and the isotype control mean.

[0141] FIGS. 14A-14B 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.14A) and fold-change compared to isotype control antibody (FIG. 14B).

[0142] FIG. 15 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.

[0143] FIG. 16 shows the binding curves assessed by ELISA for msTfR-msPgrn test articles used in aged Grn-KO mice for a proof-of-concept efficacy study. Both msTfR-msPgrn fusion protein affinity variants for msTfR demonstrate binding to mouse sortilin with similar EC50 values.

[0144] FIG. 17 shows the protein format for the msTfR-msPgrn fusion proteins used in an aged Grn-KO proof-of-concept efficacy study. The timeline for dosing is also shown along with mouse genotype, test article, dose level, and sample size. The affinities of 8D3v33-msPgrn and 8D3v12-msPgrn for apical mouse TfR are specified as the equilibrium dissociation constant (KD). Abbreviations: F = female; M = male.

[0145] FIG. 18 shows the serum pharmacokinetic profile of dosed msTfR-msPgrn fusion proteins in aged Grn KO mice over the course of 8 days, where mice were dosed once on Day 0 and once on Day 7 (as indicated by arrows on horizontal axis). Fusion proteins containing msTfR binders 8D3v12 and 8D3v33 display faster clearance profiles, which correlate with their affinity for msTfR.

[0146] FIG. 19 shows the levels of msTfR-msPgrn fusion proteins detected in aged Grn-KO vessel-depleted brain lysates 24 hrs post-second dose (previous dose was administered seven days prior). Animals receiving 8D3v12-msPgrn displayed the highest levels of test article, about seven-fold higher than the levels of isotype-control-msPgrn. Triangles: female mice; circles: male mice.

[0147] FIG. 20 shows the extent of reduction in the accumulation of glucosylsphingosine (GlcSph) in the brains of aged Grn-KO mice after two doses of 8D3v12-msPgrn and 8D3v33- msPgrn. The pharmacodynamic readout of GlcSph may reflect the level of lysosomal dysfunction induced by Grn deficiency and age in the mouse model.ny-2871899735022004340

[0148] FIG. 21 shows the evaluation of Gpnmb levels in aged Grn-KO whole mouse brain lysates after dosing with saline, 8D3v12-msPgrn, 8D3v33-msPgrn or isotype-control-msPgrn. Increased Gpnmb was observed in saline-dosed aged Grn-KO mouse brains, and this was partially reduced in the brains of mice dosed with 8D3v12-msPgrn. Triangles: female mice; circles: male mice. One way ANOVA with Dunnett’s multiple comparisons test. **** p < 0.0001; **: p < 0.005; ns: not significant.

[0149] FIG. 22 shows the assessment of huTfR-huPGRN variants for binding to human sortilin using an ELISA. No differences were detected in human sortilin binding for all huTfR- huPGRN variants and binding affinities are represented as EC50for all proteins.

[0150] FIG. 23 shows the evaluation of hematological parameters in huTfR-KI mice 24 hrs after administration of huTfR-huPGRN fusion proteins at various doses. Blood reticulocyte and red blood cell (RBC) counts were assessed by flow cytometry and no differences were observed between treatment groups.

[0151] FIG. 24 shows the assessment of surface huTfR levels on blood reticulocytes in huTfR- KI mice 24 hrs after dosing with huTfR-huPGRN variants or isotype-control-huPGRN. No differences were observed between treatment groups.

[0152] FIG. 25 shows the brain levels of huTfR-huPGRN or isotype-control-huPGRN detected in vessel-depleted brain lysates from huTfR-KI mice dosed once at various dose levels and collected 6 hrs or 24 hrs post-dose. A dose-dependent increase in huTfR10-16-huPGRN was observed, as expected. Similar fusion protein brain levels were observed at 6 hrs for animals dosed at 10 mg / kg huTfR10-16-huPGRN and 3 mg / kg huTfR10-8-huPGRN.

[0153] FIG. 26 shows TfR levels in whole brain lysates of mice dosed with huTfR-huPGRN fusion proteins. Tissues were collected at 6 hours or 24 hours post-dosing and analyzed by quantitative immunoblotting. No differences were observed between treatment groups, suggesting no effect on total brain TfR levels after a single dose of huTfR-huPGRN at these time points.

[0154] FIG. 27 shows the assessment of huCD98-huPGRN fusion protein variants for binding to human sortilin by ELISA. No differences were detected in binding to human sortilin for all huCD98-huPGRN variants and binding affinities are represented as EC50 for all fusion proteins.

[0155] FIG. 28 shows the brain levels of huCD98-huPGRN or isotype-control-huPGRN detected 72 hrs post-dose in vessel-depleted brain lysates from huCD98-KI mice dosed once.ny-2871899735022004340

[0156] FIG. 29 shows analytical hydrophobic interaction chromatography (aHIC) profile of indicated PGRN fusion proteins.

[0157] FIGs. 30A and 30B show levels of brain uptake of various anti-CD98hc.04.048.WH1 monovalent Fab variants of the present disclosure presented as ng binding domain / mg total protein and fold-change over control, respectively.

[0158] FIG. 31A shows serum clearance of antibodies containing an anti- CD98hc.04.048.WH1 binding domain following 3 weekly doses in mice.

[0159] FIG. 31B shows increased levels of antibodies containing an anti-CD98hc.04.048.WH1 binding domain in vessel-depleted mouse brain fractions compared to that observed with an isotype control antibody.

[0160] FIGs. 32A and 32B show serum PK measurements of various anti- CD98hc.04.048.WH1 antibody variants in mice dosed with 20 mg / kg and 3 mg / kg, respectively.

[0161] FIGs. 32C and 32D show antibody concentrations in vessel-depleted brain samples from mice following administration of various anti-CD98hc.04.048.WH1 antibody variants at 20 mg / kg and 3 mg / kg, respectively. DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

[0162] The present disclosure relates to complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, where the antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc). Complexes of the present disclosure provide compositions with an increased capacity to facilitate the transport of PGRN polypeptides across the blood brain barrier, thereby meeting the need in the art for improved compositions and methods for treating patients with diseases involving PGRN deficiency.

[0163] Certain 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).ny-2871899735022004340 Definitions

[0164] 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.

[0165] The terms “blood brain barrier” or “BBB” refer to a network of brain capillary endothelial cells that are closely sealed by tight junctions.

[0166] A “central nervous system antigen” or “CNS antigen” is an antigen expressed in the CNS, including the brain.

[0167] A “brain antigen” is a CNS antigen expressed in the brain.

[0168] 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.

[0169] A “lysosomal storage disorder” or “LSD” as used herein refers to an inherited metabolic disease characterized by the accumulation of substrates, such as undigested or partially digested macromolecules, in excess in various cells of organs, which ultimately results in cellular dysfunction and clinical abnormalities. LSDs have been defined as deficiencies in lysosomal function generally classified by the accumulated substrate and include sphingolipidoses, oligosaccharidoses, mucolipidoses, mucopolysaccharidoses, lipoprotein storage disorders, neuronal ceroid lipofuscinoses, and others. LSDs may also include other deficiencies or defects in proteins that result in accumulation of macromolecules, such as proteins necessary for normal post-translational modification of lysosomal enzymes, or proteins important for proper lysosomal trafficking. LSDs are diseases caused by defects in single genes. Enzyme defects cause nearly seventy percent of the LSDs, and the rest are defects in enzyme activator or associated proteins.

[0170] “Protein replacement therapy” or “PRT” refers to a medical treatment or therapy that supplements or replaces a protein in an individual in whom that particular protein is deficient, non-functional, or absent.

[0171] As used herein, a “mutant Progranulin polypeptide” or “Progranulin mutant polypeptide” refers to a mutated polypeptide of a wild-type Progranulin polypeptide. A Progranulin mutant polypeptide may comprise an amino acid sequence containing one or more substitutions (e.g., conservative substitutions, insertions, or deletions) relative to an amino acidny-2871899735022004340 sequence of the wild-type Progranulin polypeptide (e.g., relative to SEQ ID NO: 230). A Progranulin mutant polypeptide can have similar or substantially the same functions as those of a wild-type Progranulin polypeptide. For instance, a Progranulin mutant polypeptide may bind Sortilin or prosaposin, regulate the activity and levels of various lysosomal proteins (e.g., cathepsins), promote neurite outgrowth and neuronal survival, and / or any other function described herein.

[0172] As used herein, a “complex” refers to one or more proteins comprising connected parts. The parts can be connected e.g., via a peptide bond (e.g., in a fusion protein), a linker (e.g., a peptide linker), or via noncovalent protein-protein interactions such as disulfide bonds (e.g., in an antibody). Exemplary parts that can be included in a complex include a PGRN mutant polypeptide, an antigen-binding domain than specifically binds to CD98hc or TfR, an Fc region, and / or an Fc domain. Accordingly, non-limiting examples of a “complex” comprising an antigen-binding domain and a PGRN mutant polypeptide include (a) a fusion protein comprising an antigen-binding domain, an Fc domain, and a PGRN mutant polypeptide in a single polypeptide chain (e.g., as shown in FIG. 1A), and (b) three proteins connected via noncovalent protein-protein interactions, wherein the first protein contains a PGRN mutant polypeptide and an Fc domain, the second protein contains a heavy chain of an antigen-binding domain, and the third protein contains a light chain of an antigen-binding domain (e.g., as shown in FIG. 2B). Formats of other exemplary complexes are provided in FIGs.1 and 2.

[0173] 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:ny-2871899735022004340 MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKLAVDEEENADNNTKANVT KPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDFPA ARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQFREFK LSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVH ANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAE LSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPS DWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVGAQRDAWG PGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGATEWLEGYL SSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQFLYQDSNWAS KVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELIERIPELNKVARAA AEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEMGLSLQWLYSARGD FFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSPKESPFRHVFWGSGS HTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANALSGDVWDIDNEF (SEQ ID NO: 1).

[0174] 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 QGHGAGNLAGLKGRLDYLSSLKVKGLVLGPIHKNQKDDVAQTDLLQIDPNFGSKEDFDny-2871899735022004340 SLLQSAKKKSIRVILDLTPNYRGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDI ENLKDASSFLAEWQNITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGST GEHTKSLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLLRLYQLMLFTLPGTPVFSYGD EIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLLSLFRRLSDQ RSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLVVLNFGDVGLSAGLQASDLPASAS LPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLLRFPYAA (SEQ ID NO: 2).

[0175] 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 the 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., bi- specific) 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.

[0176] 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.

[0177] 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 transportingny-2871899735022004340 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.

[0178] An “antigen-binding domain” or “antigen-binding region” 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., bi-specific) 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.

[0179] 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 50 nM, about 51 nM to about 750 nM, about 751 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.

[0180] 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-ny-2871899735022004340 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). In certain embodiments, an antibody that binds to CD98hc has a dissociation constant (KD) of about 10 nM to about 1500 nM, about 500 nM to about 10 μM, about 100 nM to about 500 nM, less than about 0.1 , less than about 1 , less than about 10 M, 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.

[0181] 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.

[0182] 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.

[0183] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.

[0184] 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 IgMny-2871899735022004340 classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4. Heavy chain amino acid sequences are well known in the art. In some embodiments, the heavy chain is a human heavy chain.

[0185] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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).ny-2871899735022004340

[0190] 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.

[0191] 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., bi-specific.) 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.

[0192] 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.

[0193] 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 termin’s 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.

[0194] 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 aminony-2871899735022004340 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 the 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.

[0195] 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.

[0196] 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 Fcny-2871899735022004340 region of a parent polypeptide, at least 90% homology therewith, or at least 95% homology therewith.

[0197] 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.

[0198] 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 VLdomains, which enables the scFv to form the desired structure for antigen binding.

[0199] 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 VH and VL domains of the two antibodies are present on different polypeptide chains.

[0200] 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.

[0201] 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 twony-2871899735022004340 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 102 (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).

[0202] 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 are Chothia CDRs.

[0203] 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 are AbM CDRs.

[0204] 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 are “contact” CDRs.

[0205] 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

[0206] 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.

[0207] 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 Acidsny-2871899735022004340 Res 27: 209-212. According to the IMGT numbering scheme, VH-CDR1 is at positions 26 to 35, 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.

[0208] 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.

[0209] 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.

[0210] 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 etny-2871899735022004340 al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). The 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.

[0211] 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.

[0212] “Framework” or “FR” residues are those variable-domain residues other than the CDR residues as herein defined.

[0213] 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-2871899735022004340 in sequence to the VLhuman immunoglobulin framework sequence or human consensus framework sequence.

[0214] 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, 5thEd. 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.

[0215] 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.

[0216] 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.

[0217] “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-2871899735022004340

[0218] “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.)

[0219] 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-2871899735022004340 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.

[0220] 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.

[0221] 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.

[0222] A polypeptide, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in any-2871899735022004340 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] “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.ny-2871899735022004340

[0227] 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 aspects, the host cell is an isolated host cell.

[0228] “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.

[0229] 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.

[0230] 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.

[0231] 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 / or 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 ofny-2871899735022004340 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.

[0232] 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.

[0233] 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.

[0234] 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 aspects are described herein with the language “about” or “approximately” a numeric value or range, otherwise analogous aspects referring to the specific numeric value or range are also provided.

[0235] 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.

[0236] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and / or “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 aspects.ny-2871899735022004340 I. Complexes Comprising Progranulin Polypeptides

[0237] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR).

[0238] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X1X2X3X4, wherein X1is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL.

[0239] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex.

[0240] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc).

[0241] In some aspects, a “1+1 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human TfR; and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. In some aspects, a “1+1 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human CD98hc; and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. For example, see FIG. 1A-1D, 1I and 1H. In some embodiments, the Fc domain is a monovalent Fc (see FIG. 1A, 1B).

[0242] In some aspects, a “2+1 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. As used herein, a “2+1 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) an antigen-binding domain that binds to human CD98hc, (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. For example, see FIG. 1E-1F.ny-2871899735022004340

[0243] In some aspects, a “1+2 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. As used herein, a “1+2 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) two antigen-binding domains that binds to human CD98hc, (ii) a Progranulin (PGRN) polypeptide, and (iii) optionally an Fc domain or Fc region. For example, see FIG.1E-1F.

[0244] In some aspects, a “2+2 format” of a complex comprising an anti-TfR antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. In some aspects, a “2+2 format” of a complex comprising an anti-CD98hc antigen-binding domain refers to a format comprising (i) two antigen-binding domains that bind to human TfR and (ii) two Progranulin (PGRN) polypeptides, and (iii) optionally an Fc domain or Fc region. For example, see FIG.1G-1H.

[0245] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2C.

[0246] In some aspects, provided herein is a complex comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG. 2B.

[0247] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptideny-2871899735022004340 comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2D.

[0248] In some aspects, provided herein is a complex 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 PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. For example, see FIG.2A. II. Progranulin (PGRN) Polypeptides

[0249] Provided herein are complexes comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). Also provided herein are isolated PGRN polypeptides.

[0250] Progranulin is variously referred to as PGRN, proepithelin, granulin-epithelin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a 593 amino acid protein that encodes a 68.5 kD a secreted glycoprotein that has 7.5 repeats of smaller granulin (epithelin) motifs, ranging from 6-25 kDa, which can be proteolytically cleaved from the precursor PGRN. Examples of Progranulin cleavage products include, without limitation, granulin A / Epithelins 1, granulin B / Epithelins 2, granulin C, granulins D, granulin E, granulin F, granulin G and any other known peptide products derived from Progranulin.

[0251] Progranulin is widely expressed, and in non-neuronal cells has been associated with a variety of events, such as cell cycle regulation and cell motility, wound repair, inflammation, induction of growth factors such as vascular endothelial growth factor (VEGF), and tumorigenesis. Progranulin is also widely expressed in early neural development but becomes restricted in later development to defined neuronal populations, such as cortical neurons, hippocampal pyramidal neurons, and Purkinje cells. However, the role of Progranulin in neuronal cells was unclear until patients suffering from frontotemporal dementia (FTD) were shown to carry mutations in the Progranulin gene on chromosome 17. Subsequently, Progranulin has been shown to promote neuronal survival and enhance neurite outgrowth in cortical and motor neurons. Thus, although Progranulin is not a neurotrophin, or a member of theny-2871899735022004340 neurotrophin family, it has been referred to as a neurotrophic factor because of its ability to promote neuronal survival.

[0252] Further, it has been shown that haploinsufficiency of Progranulin (which include over 70 different mutations, such as loss-of-function mutations) is associated with frontotemporal dementia (FTD) with TDP-43 pathology. Furthermore, Progranulin levels in plasma are reduced with patients with FTD mutations. Progranulin mutations account for 25% of familial FTD. Additionally, low levels of Progranulin are seen in some FTD patients without Progranulin mutations, and Progranulin levels are altered in Alzheimer’s disease and ALS. Thus, it is believed that Progranulin may be generally involved in degenerative diseases.

[0253] It has also been shown that complete loss of Progranulin leads to a Neuronal Lipoid Fuscinosis (NPL) phenotype. Accordingly, it is believed that individuals with various lysosomal storage disorders may respond to increased levels of Progranulin. Progranulin is widely expressed, and in the central nervous system is produced by neurons and microglia. Progranulin is also generally thought to have an anti-inflammatory role in macrophages and microglia, and a pro-survival role in neurons.

[0254] Accordingly, the complexes and isolated PGRN mutant polypeptides provided herein that increase Progranulin levels would be beneficial for preventing, lowering the risk of, or treating conditions and / or diseases associated with decreased levels of Progranulin expression and / or activity, 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 2ny-2871899735022004340 diabetes, tissue or vascular damage, an injury, and / or one or more undesirable symptoms of normal aging.

[0255] In some embodiments, the present disclosure provides complexes and isolated PGRN mutant polypeptides that increase Progranulin levels, increase the stability of PGRN, maintain similar binding affinity to Sortilin compared to the binding affinity of wild-type PGRN, and exhibit GCase activity. In some embodiments, the complex binds human Sortilin with a dissociation constant (KD) that ranges from about 5 nM to about 400 nM, wherein the KDis determined by a capture kinetics assay (see, e.g., Example 6). In some embodiments, the capture kinetics assay is performed on Carterra LSA. In some embodiments, the complex binds human Sortilin with a KD that ranges from about 50 nM to about 350 nM. In some embodiments, the complex binds human Sortilin with a KD that ranges from about 100 nM to about 300 nM.

[0256] In some embodiments, the complex increases cellular GCase activity greater than the PGRN mutant polypeptide alone, wherein GCase activity is determined by an in-vitro GCase activity assay (see, e.g., Example 7). In some embodiments, GCase activity assay is measured by flow cytometry. In some embodiments, the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN mutant polypeptide alone. A. Complexes Comprising Progranulin Polypeptides

[0257] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide, wherein the PGRN polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1is any amino acid, and wherein X2, X3, and X4are not PIL, PFL, PPL, PYL, QRL or QHL. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A.

[0258] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide selected from PGRN (wt), PGRN_1,ny-2871899735022004340 PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_17, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_28, PGRN_29, PGRN_30, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1).

[0259] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide, wherein the PGRN polypeptide 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%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the PGRN polypeptide 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 PGRN polypeptide amino acid sequence of SEQ ID NO: 230.

[0260] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0261] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consistingny-2871899735022004340 of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A.

[0262] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide selected from PGRN (wt), PGRN_1, PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_17, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_28, PGRN_29, PGRN_30, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1).

[0263] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide, wherein the PGRN polypeptide 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%, or at least about 99% identity to an amino acid sequence of SEQ ID NO: 230. In some embodiments, the PGRN polypeptide 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 PGRN polypeptide amino acid sequence of SEQ ID NO: 230.

[0264] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc and a PGRN polypeptide, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.ny-2871899735022004340 B. Isolated PGRN Mutant Polypeptides

[0265] In some aspects, provided herein is an isolated PGRN mutant polypeptide, wherein: (i) the isolated PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, and wherein: (a) X1 is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and / or (d) X4is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4are not PIL, PFL, PPL, PYL, QRL, or QHL. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330.

[0266] In some embodiments, the isolated PGRN mutant polypeptide is an isolated PGRN mutant polypeptide selected from PGRN_1, PGRN_2, PGRN_3, PGRN_4, PGRN_5, PGRN_6, PGRN_7, PGRN_8, PGRN_9, PGRN_10, PGRN_11, PGRN_12, PGRN_13, PGRN_14, PGRN_15, PGRN_16, PGRN_18, PGRN_19, PGRN_20, PGRN_21, PGRN_22, PGRN_23, PGRN_24, PGRN_25, PGRN_26, PGRN_27, PGRN_29, PGRN_31, PGRN_32, PGRN_33, PGRN_34, PGRN_35, or PGRN_36 (e.g., as shown in Table 1).

[0267] In some embodiments, the isolated PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266.

[0268] In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 231. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 232. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 233. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 234. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 235. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 236. In some embodiments, the 73ny-2871899735022004340 isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 237. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 238. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 239. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 240. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 241. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 242. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 243. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 244. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 245. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 259. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 261. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 262. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 263. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 264. Inny-2871899735022004340 some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 265. In some embodiments, the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 266.

[0269] Table 1 shows exemplary PGRN mutant polypeptides. In Table 1, C-terminal mutations relative to wild-type (RQLL; SEQ ID NO: 230) are bold and underlined. A PGRN mutant polypeptide of a complex can comprise the amino acid sequence of SEQ ID NO: 330, wherein X is absent or any amino acid. Table 1. PGRN Mutant Polypeptide Sequencesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340III. Compositions that Bind to Blood-Brain Barrier Receptors or Proteins

[0270] Provided herein are complexes, and compositions thereof, comprising an antigen- binding domain linked to a PGRN polypeptide. The antigen-binding domain can specifically bind to human receptors or proteins of the blood-brain barrier. Such complexes are capable of crossing the blood brain barrier (BBB) and capable of transporting the PGRN polypeptide across the BBB. Exemplary human receptors or proteins of the blood-brain barrier are transferrin receptor (TfR) and CD98 heavy chain (CD98hc).ny-2871899735022004340

[0271] In some embodiments, the antigen-binding domain is a TfR antigen-binding domain. In some embodiments, the antigen-binding domain is a CD98hc antigen-binding domain. A. Antigen-Binding Domains That Bind to TfR

[0272] In some embodiments, the antigen-binding domain specifically bind to human TfR. The anti-TfR antigen-binding domain is capable of crossing the blood brain barrier (BBB) and thus transporting the PGRN polypeptide linked to the antigen-binding domain across the BBB. Accordingly, in some embodiments, provided herein are complexes comprising an antigen- binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR and is capable of being internalized in BBB epithelial cells.

[0273] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2 and Table 3 below (i.e. the three VH CDRs of the antibody listed in Table 2 and the three VL CDRs of the same antibody listed in Table 3). In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2, Table 3, or Table 4 below. In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by Kabat numbering. In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six Chothia CDRs of an antibody listed in Table 2, Table 3, or Table 4.

[0274] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human TfR can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422- 439, Springer-Verlag, Berlin (2001). In some embodiments, provided herein are antigen-binding domains that specifically bind to human TfR and comprise VH and VL CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by the method in MacCallum RM et al.

[0275] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human TfR can be determined according to the AbM numbering scheme, which refers to AbM hypervariable regions, which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.). In some embodiments, provided herein are antigen-binding domains thatny-2871899735022004340 specifically bind to human TfR and comprise VH and VL CDRs of an antibody listed in Table 2, Table 3, or Table 4 as determined by the AbM numbering scheme.

[0276] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the six IMGT CDRs of an antibody listed in listed in Table 2, Table 3, or Table 4 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, 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.

[0277] In some embodiments, an antigen-binding domain that specifically binds to human TfR provided herein is described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone. See, for example, Rader C et al., (1998) PNAS 95: 8910- 8915, which is incorporated herein by reference in its entirety, describing the humanization ofthe mouse anti- v 3 antibody by identifying a complementing light chain or heavy chain,respectively, from a human light chain or heavy chain library, resulting in humanized antibody variants having affinities as high or higher than the affinity of the original antibody. See also Clackson T et al., (1991) Nature 352: 624-628, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VL domain (or VH domain) and screening a library for the complementary variable domains. The screen produced 14 new partners for a specific VH domain and 13 new partners for a specific VL domain, which were strong binders, as determined by ELISA. See also Kim SJ & Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VH domain and screening a library (e.g., human VL library) for complementary VL domains; the selected VL domains in turn could be used to guide selection of additional complementary (e.g., human) VH domains.

[0278] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VH of an antibody listed in Table 4.

[0279] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VL of antibody listed in Table 4.ny-2871899735022004340

[0280] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the VH and the VL of an antibody listed in Table 4 (i.e., the VH of the antibody listed in Table 4 and the VL of the same antibody listed in Table 4.

[0281] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 80% identical to a VH amino acid sequence of an antibody listed in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 80% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs). In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 85% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 85% identical to the VL amino acid sequence of the same antibody in Table 4.

[0282] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 90% identical to a VH amino acid sequence of an antibody in Table 4, and (ii) a VL comprising an amino acid sequence that is at least 90% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of an antibody in listed in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0283] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 95% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 95% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0284] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 96% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequenceny-2871899735022004340 that is at least 96% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0285] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 97% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 97% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0286] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 98% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 98% identical to the VL amino acid sequence of the same antibody in Table 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0287] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises (i) a VH comprising an amino acid sequence that is at least 99% identical to a VH amino acid sequence of an antibody in Table 4 and (ii) a VL comprising an amino acid sequence that is at least 99% identical to the VL amino acid sequence of the same antibody in Tables 3 and 4. In some embodiments, the antigen-binding domain that specifically binds to human TfR also comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0288] In some embodiments, provided herein is an antigen-binding domain that competitively inhibits binding to TfR of as an antibody comprising a VH amino acid sequence of an antibody in Table 4 and a VL amino acid sequence of the same antibody in Table 4.

[0289] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises a VH and a VL on a single polypeptide chain (e.g., a VH and VL in Table 4).ny-2871899735022004340

[0290] In some embodiments, the antigen-binding domain comprises an scFv. In some embodiments, an scFv comprises a VH and a VL of an antibody listed in Table 4. The scFv can comprise a VH that is N-terminal to a VL or a VL that is N-terminal to a VH. The scFv can comprise a linker, e.g., between a VH and a VL. Accordingly, the scFv can be in the orientation VH-linker-VL or VL-linker-VH. Such a linker can be about 5 to about 25 amino acids in length. Such a linker can be about 5 to about 20 amino acids in length. Such a linker can be about 10 to about 25 amino acids in length. Such a linker can be about 10 to about 20 amino acids in length. Such a linker can be, e.g., a glycine linker, a glycine-rich linker, or a glycine-serine linker. Such a linker can comprise the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6). Such a linker can comprise the amino acid sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0291] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises a VH on a first polypeptide and a VL on a second polypeptide (e.g., a Fab). The Fab comprises one constant domain, one VH, and one VL. In some embodiments, the antigen- binding domain comprises a Fab comprising a constant domain, a VH of an antibody listed in Table 4 and a VL of the same antibody in Table 4. In some embodiments, the antigen-binding domain that comprises a Fab comprises the CDRs of the antibody in Table 2 and Table 3 (e.g., the non-identical amino acids in the VH and / or VL are outside of the CDRs).

[0292] In some embodiments, an antigen-binding domain that specifically binds to human TfR comprises the antigen-binding fragment of a heavy chain only antibody (e.g., a VHH or nanobody). In some embodiments, an antigen-binding domain comprises a VHH comprising the VH of an antibody listed in Table 4. In other embodiments, the antigen-binding domain comprises a VHH comprises the heavy chain CDRs of an antibody listed in Table 2.

[0293] In some embodiments, an antigen-binding domain that specifically binds to human TfR is a murine antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a chimeric antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a humanized antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human TfR is a human antigen-binding domain.

[0294] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR also binds to cynomolgus monkey TfR.ny-2871899735022004340

[0295] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “low” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 500 nM and 10 uM. In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 751 nM to about 10,000 nM, such as about 751 nM to about 2,500 nM, about 751 nM to about 5,000 nM, about 2,500 nM to about 5,000 nM, about 2,500 nM to about 10,000 nM, about 5,000 nM to about 10,000 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 2 μM and 5 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 1 μM and 5 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 2 μM and 8 μM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 750 nM and 2 μM.

[0296] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “medium” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 10 nM and 500 nM. In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 51 nM to about 750 nM, such as about 51 nM to about 100 nM, about 51 nM to about 250 nM, about 51 nM to about 500 nM, about 100 nM to about 250 nM, about 100 nM to about 500 nM, about 100 nM to about 750 nM, about 250 nM to about 500 nM, about 250 nM to about 750 nM, about 500 nM to about 750 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 50 nM and 500 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 100 nM and 250 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 10 nM and 100 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 250 nM and 500 nM.

[0297] In some embodiments, an antigen-binding domain provided herein binds to human TfR with “high” affinity. In some embodiments, the antigen-binding domain binds human TfR with an affinity less than 10 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.01 nM and 10 nM. In some embodiments, the antigen-binding domain provided herein specifically binds to human TfR with an affinity from about 0.01 nM to about 50 nM, such as about 0.01 nM to about 1 nM, about 0.01 nM to about 5 nM, about 0.01 nM to aboutny-2871899735022004340 25 nM, about 1 nM to about 5 nM, about 1 nM to about 25 nM, about 1 nM to about 50 nM, about 5 nM to about 25 nM, about 5 nM to about 50 nM, about 10 nM to about 25 nM, about 10 nM to about 50 nM, about 25 nM to about 50 nM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.1 nM and 10 nM. In some embodiments, the antigen-binding domain binds human TfR with an affinity between 0.01 nM and 1 nM.

[0298] In some embodiments, the antigen binding domain binds provided herein binds to human TfR with an affinity of 150 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 250 nM to 700 nM, 350 nM to 700 nM, 450 nM to 700 nM, or 550 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 575 nM to 675 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 630 nM to 650 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of about 635 nM, about 636 nM, about 637 nM, about 638 nM, about 639 nM, about 640 nM, about 641 nM, about 642 nM, about 643 nM, about 644 nM or about 645 nM. In some embodiments, the antigen- binding domain binds to human TfR with an affinity of about 639 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 639 nM.

[0299] In some embodiments, the antigen binding domain binds provided herein binds to human TfR with an affinity of 150 nM to 700 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 150 nM to 650 nM, 150 nM to 550 nM, 150 nM to 450 nM, 150 nM to 350 nM, or 150 nM to 250 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 170 nM to 190 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 175 nM to 185 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of about 175 nM, about 176 nM, about 177 nM, about 178 nM, about 179 nM, about 180 nM, about 181 nM, about 182 nM, about 183 nM, or about 184 nM. In some embodiments, the antigen- binding domain binds to human TfR with an affinity of about 182 nM. In some embodiments, the antigen-binding domain binds to human TfR with an affinity of 182 nM.ny-2871899735022004340

[0300] In some embodiments, an antigen-binding domain provided herein specifically binds to human TfR with an affinity measured using surface plasmon resonance, such as a BIACORE™ SPR system. In some embodiments, the affinity between the antigen-binding domain and TfR is measured using the Carterra LSA platform. In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR binds to human TfR as measured by, for example, radioimmunoassay (RIA), Western blot, or ELISA OD450.

[0301] In some embodiments, binding of an antigen-binding domain provided herein to human TfR is measured using surface plasmon resonance. In some embodiments, affinity measured using the Carterra LSA platform.

[0302] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR reduces cell surface expression by more than 40%, 60%, or 80% relative to cell surface expression of TfR on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0303] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR does not significantly increase cell surface expression of TfR on HCMED / D3 cells relative to cell surface expression of TfR on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0304] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR does not significantly increase cell surface expression of TfR on HCMED / D3 cells relative to cell surface expression of TfR on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0305] In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR accumulates at least 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40 or 50-fold more than an isotype control after peripheral injection. In some embodiments, an antigen-binding domain provided herein that specifically binds to human TfR at least 5-fold more than binding to an irrelevant protein and / or specifically binds to cynomolgus TfR at least 5-fold more than binding to an irrelevant protein.

[0306] Also provided herein are antigen-binding domains that bind to the same epitope of TfR as a TfR antigen-binding domain provided herein. Also provided herein are antigen-binding domains that competitively inhibit binding to TfR of a TfR antigen-binding domain provided herein.ny-2871899735022004340

[0307] As provided herein, antigen-binding domains provided herein are capable of crossing the BBB. In some embodiments, antigen-binding domains provided herein are internalized in blood-brain barrier epithelial cells greater than 5-fold, or 10-fold, as compared to internalization by an isotype control. The blood-brain barrier endothelial cells can be, e.g., HCMEC / D3 cells.

[0308] In some embodiments, antigen-binding domains provided herein do not reduce cell- surface expression of TfR on HCMEC / D3 cells by more than 20%, 40%, or 60% relative to cell- surface expression of TfR on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS. In some embodiments, antigen- binding domains provided herein do not significantly increase cell-surface expression of TfR on HCMEC / D3 cells relative to cell-surface expression of TfR on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0309] In some embodiments, antigen-binding domains provided herein accumulate at least 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold or 50-fold or more than an isotype control in vessel-depleted mouse brain. Table 2: Heavy Chain CDR Sequences of Anti-TfR Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340 Table 3: Light Chain CDR Sequences of Anti-TfR Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340Table 4: VH and VL Sequences of Anti-TfR Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340 B. Antigen-Binding Domains That Bind to CD98hc

[0310] In some embodiments, the antigen-binding domain specifically bind to human CD98hc. The anti-CD98hc antigen-binding domain is capable of crossing the blood brain barrier (BBB) and thus transporting the PGRN polypeptide linked to the antigen-binding domain across the BBB. Accordingly, in some embodiments, provided herein are complexes comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98hc and is capable of being internalized in BBB epithelial cells.

[0311] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six CDRs of an antibody listed in Table 5 and Table 6 (i.e. the three VH CDRs of the antibody listed in Table 5 and the three VL CDRs of the same antibody listed in Table 6). In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six CDRs of an antibody listed in Table 5 and Table 6 as determined by Kabat numbering. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six Chothia CDRs of an antibody listed in Table 5 and Table 6.

[0312] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human CD98hc can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422- 439, Springer-Verlag, Berlin (2001). In some embodiments, provided herein are antigen-binding domains that specifically bind to human CD98hc and comprise VH and VL CDRs of an antibody listed in Table 5 and Table 6 as determined by the method in MacCallum RM et al.

[0313] In some embodiments, the CDRs of an antigen-binding domain that specifically binds to human CD98hc can be determined according to the AbM numbering scheme (as described above). In some embodiments, provided herein are antigen-binding domains that specifically bind to human CD98hc and comprise VH and VL CDRs of an antibody listed in Table 5 and Table 6 as determined by the AbM numbering scheme.

[0314] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the six IMGT CDRs of an antibody listed in Table 5 and Table 6 according to the IMGT numbering system as described above.ny-2871899735022004340

[0315] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc provided herein is described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone.

[0316] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VH of an antibody listed in Table 7.

[0317] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VL of antibody listed in Table 7.

[0318] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the VH and the VL of an antibody listed in Table 7 (i.e., the VH of the antibody listed in Table 7 and the VL of the same antibody listed in Table 7.

[0319] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 80% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 80% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs). In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 85% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 85% identical to the VL amino acid sequence of the same antibody in Table 7.

[0320] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 90% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 90% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0321] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 95% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acidny-2871899735022004340 sequence that is at least 95% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0322] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 96% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 96% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0323] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 97% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 97% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0324] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 98% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 98% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0325] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises (i) a VH comprising an amino acid sequence that is at least 99% identical to a VH amino acid sequence of an antibody in Table 7 and (ii) a VL comprising an amino acid sequence that is at least 99% identical to the VL amino acid sequence of the same antibody in Table 7. In some embodiments, the antigen-binding domain that specifically binds to humanny-2871899735022004340 CD98hc also comprises the CDRs of the antibody in Table 5 and Table 6 (e.g., the non- identical amino acids in the VH and / or VL are outside of the CDRs).

[0326] In some embodiments, provided herein is an antigen-binding domain that competitively inhibits binding to CD98hc of as an antibody comprising a VH amino acid sequence of an antibody in Table 7 and a VL amino acid sequence of the same antibody in Table 7.

[0327] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises a VH and a VL on a single polypeptide chain (e.g., a VH and VL in Table 7). In some embodiments, the antigen-binding domain comprises an scFv. The scFv can comprise a VH that is N-terminal to a VL or a VL that is N-terminal to a VH. The scFv can comprise a linker, e.g., between a VH and a VL. Accordingly, the scFv can be in the orientation VH-linker- VL or VL-linker-VH. Such a linker can be about 5 to about 25 amino acids in length. Such a linker can be about 5 to about 20 amino acids in length. Such a linker can be about 10 to about 25 amino acids in length. Such a linker can be about 10 to about 20 amino acids in length. Such a linker can be, e.g., a glycine linker, a glycine-rich linker, or a glycine-serine linker. Such a linker can comprise the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6). Such a linker can comprise the amino acid sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

[0328] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises a VH on a first polypeptide and a VL on a second polypeptide (e.g., a Fab).

[0329] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc comprises the antigen-binding fragment of a heavy chain only antibody (e.g., a VHH or nanobody).

[0330] In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a murine antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a chimeric antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a humanized antigen-binding domain. In some embodiments, an antigen-binding domain that specifically binds to human CD98hc is a human antigen-binding domain.

[0331] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc also binds to cynomolgus monkey CD98hc.ny-2871899735022004340

[0332] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “low” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 500 nM and about 10 uM, such as about 500 nM to about 2.5 μM, about 500 nM to about 5 μM, about 1 μM to about 2.5 μM, about 1 μM to about 5 μM, about 1 μM to about 10 μM, about 2.5 μM to about 5 μM, about 2.5 μM to about 10 μM, about 5 μM to about 10 μM, and values and ranges therebetween. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 2 μM and 5 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 1 μM and 5 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 2 μM and 8 μM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 750 nM and 2 μM.

[0333] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “medium” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 100 nM and about 500 nM, such as about 100 nM to about 250 nM, about 250 nM to about 500 nM, and values and ranges therebetween. In some aspects, the antigen-binding domain binds human CD98hc with an affinity between about 200 nM and about 300 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 50 nM and 500 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 100 nM and 250 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 10 nM and 100 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 250 nM and 500 nM.

[0334] In some embodiments, an antigen-binding domain provided herein binds to human CD98hc with “high” affinity. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity less than about 100 nM, such as less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between about 0.1 nM to about 100 nM, such as about 0.1 nM to about 10 nM, about 0.1 nM to about 25 nM, about 1 nM to about 25 nM, about 1 nM to about 50 nM, about 25 nM to about 50 nM, about 25 nM to about 100 nM, about 50 nM to about 100 nM, and values and ranges therebetween. In someny-2871899735022004340 embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.01 nM and 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.1 nM and 10 nM. In some embodiments, the antigen-binding domain binds human CD98hc with an affinity between 0.01 nM and 1 nM.

[0335] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc binds to human CD98hc is measured using surface plasmon resonance. In some embodiments, affinity is measured using the Carterra LSA platform. In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc binds to human CD98hc as measured by, for example, radioimmunoassay (RIA), Western blot, or ELISA OD450.

[0336] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not reduce cell surface expression of CD98hc on HCMED / D3 cells by more than 20% relative to cell surface expression of CD98hc on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0337] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not increase cell surface expression of CD98hc on HCMED / D3 cells by more than 50% relative to cell surface expression of CD98hc on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western blot or FACS.

[0338] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc does not reduce cell surface expression of CD98hc on HCMED / D3 cells by more than 20% relative to cell surface expression of CD98hc on HCMEC / D3 cells treated with an isotype control and does not increase cell surface expression of CD98hc on HCMED / D3 cells by more than 50% relative to cell surface expression of CD98hc on HCMEC / D3 cells treated with an isotype control. Cell surface expression can be measured, e.g., using Western Blot or FACS.

[0339] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc accumulates at least 1.5-fold more than an isotype control in vessel- depleted human CD98hc knock-in mouse brain after peripheral injection. In some embodiments,ny-2871899735022004340 an antigen-binding domain provided herein that specifically binds to human CD98hc accumulates at least 1-fold more than an isotype control in vessel-depleted mouse brain.

[0340] In some embodiments, an antigen-binding domain provided herein that specifically binds to human CD98hc has at least a 5-fold increase in brain:serum concentration ratio over an isotype control 24 hours after administration to a mouse.

[0341] Also provided herein are antigen-binding domains that bind to the same epitope of CD98hc as a CD98hc antigen-binding domain provided herein. Also provided herein are antigen-binding domains that competitively inhibit binding to CD98hc of CD98hc antigen- binding domain provided herein. Table 5: Heavy Chain CDR Sequences of Anti-CD98hc Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340Table 6: Light Chain CDR Sequences of Anti-CD98hc Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340Table 7: VH and VL Sequences of Anti-CD98hc Antibodiesny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340ny-2871899735022004340IV. Antigen-Binding Domains and Compositions Comprising Antigen-Binding Domains

[0342] In some aspects, provided herein are complexes, and compositions thereof, comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB).

[0343] In some embodiments, the antigen-binding domain is an antigen-binding fragment. Antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med.9:129-134 (2003). For a review of scFvny-2871899735022004340 fragments, see, e.g., WO 93 / 16185; and U.S. Patent Nos.5,571,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No.5,869,046.

[0344] Diabodies are antibody fragments with two antigen-binding sites that can be bivalent and / or bispecific. See, for example, EP404097; WO 1993 / 01161; Hudson et al. Nat. Med.9:129- 134 (2003). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med.9:129-134 (2003). Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In some embodiments, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No.6,248,516).

[0345] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0346] In some embodiments, the antigen-binding domain is chimeric. Certain chimeric antibodies are described, e.g., in U.S. Patent No.4,816,567. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody.

[0347] In some embodiments, the antigen-binding domain is humanized. Typically, a non- human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, a humanized antibody is substantially non-immunogenic in humans. In some embodiments, a humanized antibody has substantially the same affinity for a target as an antibody from another species from which the humanized antibody is derived. See, e.g., U.S. Pat. No. 5,530,101; 5,693,761; 5,693,762; and 5,585,089. In some embodiments, amino acids of an antibody variable domain that can be modified without diminishing the native affinity of the antigen-binding domain while reducing its immunogenicity are identified. See, e.g., U.S. Pat. Nos. 5,766,886 and 5,869,619. Generally, a humanized antibody comprises one or more variable domains in which CDRs (or portions thereof) are derived from a non-human antibody, and framework regions (FRs) (or portions thereof) are derived from human antibody sequences. A humanized antibody canny-2871899735022004340 comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), for example, to restore or improve antibody specificity or affinity.

[0348] Humanized antibodies and methods of making them are reviewed, for example, in Almagro et al. Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in U.S. Patent Nos.5,821,337; 7,527,791; 6,982,321; and 7087409. Human framework regions that can be used for humanization include but are not limited to: framework regions selected using the “best- fit” method (see, e.g., Sims et al. J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA 89:4285 (1992); and Presta et al., J. Immunol.151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al. J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al. J. Biol. Chem. 271:22611-22618 (1996)).

[0349] In some embodiments, the antigen-binding domain is human. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk et al. Curr. Opin. Pharmacol.5:368-74 (2001) and Lonberg Curr. Opin. Immunol. 20:450-459 (2008).

[0350] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. One can engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci in anticipation that such mice would produce human antibodies in the absence of mouse antibodies. Large human Ig fragments can preserve the large variable gene diversity as well as the proper regulation of antibody production and expression. By exploiting the mouse machinery for antibody diversification and selection and the lack of immunological tolerance to human proteins, the reproduced human antibody repertoire in these mouse strains can yield high affinity fully human antibodies against any antigen of interest, including human antigens. Using the hybridoma technology, antigen-specific human Mabs with the desired specificity can beny-2871899735022004340 produced and selected. Certain exemplary methods are described in U.S. Pat. No.5,545,807, EP546073, and EP546073. See also, for example, U.S. Patent Nos.6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No.5,770,429 describing HUMAB® technology; U.S. Patent No.7,041,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007 / 0061900, describing VELOCIMOUSE® technology. Human variable regions from intact antibodies generated by such animals can be further modified, e.g., by combining with a different human constant region.

[0351] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001 (1984) and Boerner et al. J. Immunol. 147:86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al. Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No.7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines). Human hybridoma technology (Trioma technology) is also described in Vollmers et al. Histology and Histopathology 20(3) :927-937 (2005) and Vollmers et al. Methods and Findings in Experimental and Clinical Pharmacology 27(3):185-91 (2005). Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

[0352] In some embodiments, the antigen-binding domain is an antibody, wherein the antibody is a human antibody isolated by in vitro methods and / or screening combinatorial libraries for antibodies with the desired activity or activities. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite / Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display (Adimab), and the like. In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al. Ann. Rev. Immunol.12: 433-455 (1994). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. See alsony-2871899735022004340 Sidhu et al. J. Mol. Biol. 338(2): 299-310, 2004; Lee et al. J. Mol. Biol. 340(5): 1073-1093, 2004; Fellouse Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al. J. Immunol. Methods 284( -2):119-132 (2004). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al. EMBO J.12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers comprising random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom et al. J. Mol. Biol., 227: 381-388, 1992. Patent publications describing human antibody phage libraries include, for example: U.S. Patent No.5,750,373, and U.S. Patent Publication Nos.2007 / 0292936 and 2009 / 0002360. Antibodies isolated from human antibody libraries are considered human antibodies or human antibody fragments herein. V. Fc Domains

[0353] In some embodiments, a complex provided herein comprises an Fc domain or fragment thereof. In some embodiments, an Fc domain is of IgG class, the IgM class, or the IgA class. In some embodiments, an Fc domain or fragment thereof is an IgG Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG1 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG2 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a human IgG4 Fc domain or fragment thereof. In some embodiments, an Fc domain or fragment thereof is a monovalent Fc. In some embodiments, the Fc domain or fragment thereof is a modified Fc domain or fragment thereof comprising one or more modifications relative to the corresponding wild-type Fc domain. In some embodiments, the one or more modifications reduce effector function.

[0354] In some embodiments, the Fc domain is a modified Fc domain or fragment thereof. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG1 Fc comprising one or more modifications. For example, in some embodiments, the IgG1 modifiedny-2871899735022004340 Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc domain of the same isotype). In some embodiments, the modified Fc domain or fragment thereof is a modified IgG2 Fc domain. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG2 Fc domain comprising one or more modifications relative to a wild-type IgG2, such as one or more modifications that reduce effector function. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain relative to a wild-type IgG4. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain comprising one or more modifications relative to a wild-type IgG4, such as one or more modifications that reduce effector function. In some embodiments, the modified Fc domain or fragment thereof is a modified IgG4 Fc domain comprising one or more amino acid substitutions selected from IgG4-S228P or IgG4-S228P / L235E, wherein the amino acid position is according to the EU numbering convention. In some embodiments, the one or more amino acid substitutions are selected from N297A (Bolt S et al. (1993) Eur J Immunol 23:403-411), D265A (Shields et al. (2001) R. J. Biol. Chem.276, 6591–6604), L234A, L235A (Hutchins et al. (1995) Proc Natl Acad Sci USA, 92:11980-11984; Alegre et al., (1994) Transplantation 57:1537-1543. 31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A (Alegre et al. (1994) Transplantation 57:1537-1543.31; Xu et al. (2000) Cell Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchern et al., (2007) Blood, 109:1185-1192), P331S (Sazinsky et al., (2008) Proc Natl Acad Sci USA 2008, 105:20167-20172), K322A (Hezareh et al. (2001) J Virol. 75(24) 12161-12168), S267E, L328F, A330L, M252Y, S254T, E430G, and / or T256E, where the amino acid position is according to the EU numbering convention. In some embodiments, the Fc domain comprises the amino acid substitutions L234A, L235A, and P331S (LALAPS) according to EU numbering. In some embodiments, the Fc domain comprises N325S and L328F mutations according to EU numbering. In some embodiments, the Fc domain comprises L234A, L235A, and P329G mutations according to EU numbering. In some embodiments, the Fc domain comprises L234A, L235A, and P329S mutations according to EU numbering. In some embodiments, the Fc domain comprises K322A according to EU numbering. In some embodiments, the Fc domain comprises S228P according to EU numbering. In some embodiments, the Fc domain comprises L235E according to EU numbering. In some embodiments, the Fc domain comprises S228P and L235E according to EU numbering. In someny-2871899735022004340 embodiments, the modified Fc domain or fragment thereof is a modified IgG4 and comprises S228P and L235E according to EU numbering.

[0355] Any suitable Fc domain or fragment thereof is contemplated in the multi-specific proteins described herein, and exemplary Fc domains are provided in Table 8 below. Table 8: Exemplary Fc Domainsny-2871899735022004340ny-2871899735022004340

[0356] In some embodiments provided herein, a complex provided herein comprises one or more mutations to promote heterodimerization of Fc domains. In some embodiments, a dimerized Fc domain of a bispecific provided herein is formed by Fc domains that contain amino acid mutations, substitutions, additions, or deletions to promote heterodimerization in which different polypeptides comprising different Fc domains can dimerize to yield a heterodimer configuration. In some embodiments, a bispecific of the present disclosure comprises a first Fc sequence comprising a first CH3 region, and a second Fc sequence comprising a second CH3 region, wherein the sequences of the first and second CH3 regions are different and are such that the heterodimeric interaction between said first and second CH3 regions is stronger than each of the homodimeric interactions of said first and second CH3 regions.

[0357] Methods to promote heterodimerization of Fc domains include amino acid deletions, additions, or substitutions of the amino acid sequence of the 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 to favor attractive interactions among different polypeptide chains. Methods for promoting heterodimerization of complementary Fc polypeptides have been previously described in, for example, Ridgway et al, 1996, Protein Eng, 9:617-621; Merchant et al, 1998, Nature Biotechnol, 16:677-681; Moore et al, 2011, MAbs, 3:546-557; Von Kreudenstein et al, 2013, 5:646-654; Gunasekaran et al, 2010, J Biol Chem, 285:19637-19464; Leaver-Fay et al, 2016, Structure, 24:641-651; Ha et al, 2016, Frontiers in Immunology, 7:1; Davis et al, 2010, Protein Eng Des Sel, 23:195-202; PCT Pub. Nos. WO1996 / 027011; WO1998 / 050431; WO2006 / 028936; WO2009 / 089004; WO2011 / 143545; WO2014 / 067011; WO2012 / 058768; WO2018 / 027025; US Pub. Nos. US2014 / 0363426; US2015 / 0307628; US2018 / 0016354; US2015 / 0239991; US2017 / 0058054; U.S. Pat. Nos.5,731,168; 7,183,076; 9,701,759; 9,605,084; 9,650,446; 8,216,805; 8,765,412; and 8,258,268.

[0358] In some embodiments, complementary Fc polypeptides of an Fc heterodimer include a mutation to alter charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc domains support favorable attractive interactions, thereby promoting desired Fc heterodimer formation; whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation (Guneskaran et al, 2010, J Biol Chem, 285:19637-19646).ny-2871899735022004340 When co-expressed in a cell, association between the polypeptide chains is possible but the chains do not substantially self-associate due to charge repulsion.

[0359] “Knob-hole” or “knob-into-hole” configurations are complementary Fc polypeptides of an Fc heterodimer that promote heterodimerization of two Fc polypeptides. “Knob-into-hole” technology is described in U.S. Pat. Nos.5,731,168; 7,695,936; 8,216,805; 8,765,412; Ridgway et al., Prot Eng 9, 617-621 (1996); and Carter, J Immunol Meth 248, 7-15 (2001). Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g., by site-specific mutagenesis, or by peptide synthesis.

[0360] In some embodiments, a complex provided herein comprises an Fc dimer comprising a “knob” mutation in one Fc domain and a “hole” mutation in the other Fc domain. In some embodiments, the “knob” mutation comprises the amino acid substitution T366W according to EU numbering. In some embodiments, the “hole” mutation comprises the amino acids substitutions T366S, L368A, and Y407V according to EU numbering. In some embodiments, the “knob” mutation comprises the amino acid substitution T366W in one of the two subunits of the Fc dimer, and the “hole” mutation comprises the amino acid substitutions T366S, L368A and Y407V in the other subunit of the Fc dimer. In some embodiments, the subunit of the Fc dimer comprising the “knob” mutation additionally comprises the amino acid substitution S354C, and the subunit of the Fc dimer comprising the “hole” mutation additionally comprises the amino acid substitution Y349C. Introduction of these two cysteine residues results in the formation of a disulfide bridge between the two subunits of the Fc dimer, thus further stabilizing the dimer (Carter, J Immunol Methods 248, 7-15 (2001)). Thus, in such configurations, a first Fc polypeptide comprises amino acid modifications to form the “knob” and a second Fc polypeptide comprises amino acid modifications to form the “hole” thus forming an Fc heterodimer comprising complementary Fc polypeptides.ny-2871899735022004340

[0361] Exemplary paired amino acid modifications of complementary Fc polypeptides of an Fc heterodimeric configuration are set forth below in Table 9 (EU numbering). Table 9: Exemplary paired Fc modifications for heterodimeric Fc domainsVI. Complexes that Bind to Blood-Brain Barrier Receptors or Proteins

[0362] Provided herein are complexes, and compositions thereof, comprising an antigen- binding domain linked to a PGRN polypeptide. The antigen-binding domain can bind specifically to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc) to facilitate the transport of the PGRN polypeptide across the blood brain barrier (BBB). A. Complexes Comprising Anti-TfR Antigen-Binding Domains

[0363] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR). In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN polypeptide comprises a C- terminal amino acid sequence defined by X1X2X3X4, wherein X1is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL.ny-2871899735022004340

[0364] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR), wherein the antigen-binding domain 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: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0365] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively; (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118.

[0366] In some aspects, provided herein is a complex 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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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,ny-2871899735022004340 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0367] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0368] In some aspects, provided herein is a complex 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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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,ny-2871899735022004340 respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0369] In some aspects, provided herein is a complex 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 PGRN polypeptide; and (b) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0370] In some aspects, provided herein is a complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a PGRN polypeptide, a linker, a CH2, and a CH3; and (c) a third polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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,ny-2871899735022004340 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

[0371] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a Progranulin (PGRN) polypeptide, wherein the antigen-binding domain specifically binds to human transferrin receptor (TfR) and is not within an Fc domain of the complex.

[0372] In the complexes provided herein, the PGRN polypeptide may be any PGRN polypeptide disclosed herein.

[0373] Exemplary formats for a complex as disclosed herein are depicted in FIGs.1A-1J.

[0374] In some embodiments, the PGRN polypeptide in the complex is N-terminal to the antigen-binding domain that specifically binds to human TfR.

[0375] In some embodiments, the PGRN polypeptide in the complex is C-terminal to the antigen-binding domain that specifically binds to human TfR.

[0376] In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human TfR are directly connected via a peptide bond. In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human TfR are connected via a linker, e.g., a peptide linker. In some embodiments, the complex does not comprise an Fc portion.

[0377] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human TfR, a PGRN polypeptide, and an Fc portion. In some embodiments, the antigen-binding domain that specifically binds to human TfR and the PGRN polypeptide are linked to the N-terminus of the Fc portion of the complex.

[0378] In some embodiments, the antigen-binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the C-terminus of the Fc portion of the complex. In other embodiments, the antigen-binding domain that specifically binds to human TfR is linked to the N-terminus of the Fc portion and the PGRN polypeptide is linked to the C- terminus of the Fc portion of the complex. In other embodiments, the PGRN polypeptide isny-2871899735022004340 linked to the N-terminus of the Fc portion of the complex and the antigen-binding domain that specifically binds to human TfR is linked to the C-terminus of the Fc portion.

[0379] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, or VHH, or Fab antigen-binding domain that specifically binds to human TfR and (ii) a PGRN polypeptide, wherein the complex comprises two copies of the PGRN polypeptide. In some embodiments, the complex comprises an Fc domain. The Fc may be a heterodimeric Fc, comprising a first Fc polypeptide with a knob mutation and a second Fc polypeptide with a hole mutation (a “knob-hole” or “knob-into-hole” or “knob-hole Fc”, as described herein). In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the N-terminus of the Fc. An example of this 2+1 format is shown in FIG.1F.

[0380] In some embodiments, the single scFv, Fab or VHH antigen-binding domain that specifically binds to human TfR is linked to the N-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the C-terminus of the Fc domain. An example of this 2+1 format is shown in FIG.1E.

[0381] In FIG. 2D, an example of a “2+1” format is shown, which comprises (1) a first heavy chain comprising a Fab, an Fc domain with a knob mutation, a PGRN polypeptide linked to the C-term of the Fc domain, (2) a second heavy chain comprising an Fc domain with a hole mutation and a second PGRN polypeptide linked to the C term of the Fc domain, and (3) a light chain. The “2+1” refers to one Fab domain targeting the BBB and two PGRN polypeptides.

[0382] In some embodiments, disclosed herein is a complex comprising (i) an antibody that specifically binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of a PGRN polypeptide linked to the C-terminus of the two antibody heavy chains. An example of this 2+2 format is shown in FIG.1G.

[0383] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that specifically bind to human TfR linked to the C-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the N-terminus of the Fc domain. An example of this 2+2 format is shown in FIG.1H. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen-binding domains that specifically bind to human TfR linkedny-2871899735022004340 to the N-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the C- terminus of the Fc domain.

[0384] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the Fc domain is a single chain, engineered monovalent Fc domain. An example of this single chain 1+1 format of a complex is shown in FIG.1A, 1I, and 1J.

[0385] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide linked to C-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc. Examples of this 1+1 format of a complex are shown in FIGs.1B and 1C.

[0386] In FIG. 2A, an example “mcFv” format is shown for an anti-TfR-PGRN complex. The “mcFv” format comprises (1) a heavy chain comprising a Fab domain, a single Fc domain, and a PGRN polypeptide linked to the C terminus of the Fc domain and (2) a light chain.

[0387] In FIG. 2B, an example “trans” format is shown, which comprises (1) a first heavy chain comprising a Fab domain and an Fc with a hole mutation, (2) a second heavy chain comprising an Fc domain with a knob mutation linked to a PGRN polypeptide, and (3) a light chain. In some embodiments the first heavy chain can have an Fc with a knob mutation and the second heavy chain can have an Fc domain with a hole mutation.

[0388] In FIG. 2C, an example of a “cis” format is shown, which comprises (1) a first heavy chain comprising a Fab, Fc with a knob mutation, and a PGRN polypeptide linked to the C term of the Fc-knob, (2) a second heavy chain comprising an Fc with a hole mutation, and a (3) light chain. The “1+1” refers to one Fab domain targeting the BBB and one PGRN polypeptide.

[0389] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-ny-2871899735022004340 binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the N-terminus of the Fc domain. An example of this 1+1 format of a complex is shown in FIG.1D. In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human TfR and the PGRN polypeptide are both linked to the C-terminus of the Fc domain.

[0390] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 319; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 320; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VHny-2871899735022004340 CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and / or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and / or the VL comprises the amino acid sequence of SEQ ID NO: 158.

[0391] In some aspects, provided herein is a complex comprising: a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 322; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In someny-2871899735022004340 embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and / or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and / or the VL comprises the amino acid sequence of SEQ ID NO: 158.

[0392] In some aspects, provided herein is a complex 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 PGRN polypeptide; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide of the first polypeptide and the second polypeptide each comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the amino acid sequence of SEQ IDny-2871899735022004340 NO: 319; the second polypeptide comprises the amino acid sequence of SEQ ID NO: 323; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and / or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and / or the VL comprises the amino acid sequence of SEQ ID NO: 158.

[0393] In some aspects, provided herein is a complex 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 PGRN polypeptide; and (ii) a second polypeptide comprising, from the N- terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR. In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein: (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A. In some embodiments, the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO: 266. In some embodiments, the first polypeptide comprises the aminony-2871899735022004340 acid sequence of SEQ ID NO: 332; and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, the VH comprises a VH CDR1, VH CDR2, and VH CDR3; wherein the VH CDR1 comprises the amino acid sequence of SEQ ID NO: 8; wherein the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 15; and wherein the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 25; and / or the VL comprises a VL CDR1, VL CDR2, and VL CDR3; wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 43; wherein the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 55; and wherein the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 102; and / or the VL comprises the amino acid sequence of SEQ ID NO: 158..

[0394] In some embodiments, the complex comprises an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain is any antigen-binding domain that specifically binds to human TfR described herein, and wherein the PGRN polypeptide is any PGRN polypeptide described herein.

[0395] Table 10 to Table 12 show exemplary complex sequences. Amino acid linkers are bold and underlined. Table 10: “1+1 Cis” TfR9.1B.39.38-PGRN Complex Sequences (Format 1: 1+1 CIS = HC1 (Fab-Fc-knob-PGRN) and HC2 (Fc-hole) and LC)ny-2871899735022004340Table 11: “1+1 Trans” TfR9.1B.39.38-PGRN Complex Sequences (Format 2: 1+1 TRANS = HC1 (Fab-FcKnob) and HC2 (Fchole-PGRN) and LC)ny-2871899735022004340Table 12: “1+2” TfR9.1B.39.38-PGRN Complex Sequences (Format 3: 1+2 = HC1 (Fab- FcKnob-PGRN) and HC2 (Fc-hole-PGRN2) and LC)ny-2871899735022004340ny-2871899735022004340Table 13: “1+1” 39.38mvFc-PGRN Complex Sequencesny-2871899735022004340B. Complexes Comprising CD98hc binding domains

[0396] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc).

[0397] In some embodiments, the PGRN polypeptide is a PGRN mutant polypeptide. In some embodiments, the PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL or QHL.

[0398] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain 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 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii)ny-2871899735022004340 SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively; (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively; (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively.

[0399] In some aspects, provided herein is a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ IDny-2871899735022004340 NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409.

[0400] Exemplary formats for a complex as disclosed herein are depicted in FIGs.1A-1J.

[0401] In some embodiments, the PGRN polypeptide in the complex is N-terminal to the antigen-binding domain that specifically binds to human CD98hc.

[0402] In some embodiments, the PGRN polypeptide in the complex is C-terminal to the antigen-binding domain that specifically binds to human CD98hc.

[0403] In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human CD98hc are directly connected via a peptide bond. In some embodiments, the PGRN polypeptide and the antigen-binding domain that specifically binds to human CD98hc are connected via a linker, e.g., a peptide linker.

[0404] In some embodiments, the complex comprises an antigen-binding domain that specifically binds to human CD98hc, a PGRN polypeptide, and an Fc portion. In some embodiments, the antigen-binding domain that specifically binds to human CD98hc and the PGRN polypeptide are linked to the N-terminus of the Fc portion of the complex.

[0405] In some embodiments, the antigen-binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the C-terminus of the Fc portion of the complex. In other embodiments, the antigen-binding domain that specifically binds to human CD98hc is linked to the N-terminus of the Fc portion and the PGRN polypeptide is linked to the C-terminus of the Fc portion of the complex. In other embodiments, the PGRN polypeptide isny-2871899735022004340 linked to the N-terminus of the Fc portion of the complex and the antigen-binding domain that specifically binds to human CD98hc is linked to the C-terminus of the Fc portion.

[0406] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, or VHH, or Fab antigen-binding domain that specifically binds to human CD98hc and (ii) a PGRN polypeptide, wherein the complex comprises two copies of the PGRN polypeptide. In some embodiments, the complex comprises an Fc domain. The Fc may be a heterodimeric Fc, comprising a first Fc polypeptide with a knob mutation and a second Fc polypeptide with a hole mutation (a “knob-hole”, “knob-into-hole”, “knob-hole Fc”, as described herein). In some embodiments, the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the N-terminus of the Fc. An example of this 2+1 format is shown in FIG. 1F.

[0407] In some embodiments, the single scFv, Fab or VHH antigen-binding domain that specifically binds to human CD98hc is linked to the N-terminus of the Fc domain (i.e., to one of the two heavy chains of the Fc domain) while the two copies of the PGRN polypeptide are linked to the C-terminus of the Fc domain. An example of this 2+1 format is shown in FIG.1E.

[0408] In some embodiments, disclosed herein is a complex comprising (i) an antibody that specifically binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of a PGRN polypeptide linked to the C-terminus of the two antibody heavy chains. An example of this 2+2 format is shown in FIG. 1G.

[0409] In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen- binding domains that specifically bind to human CD98hc linked to the C-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the N-terminus of the Fc domain. An example of this format is shown in FIG.1H. In some embodiments, the complex comprises (i) two scFv, Fab, or VHH antigen-binding domains that specifically bind to human CD98hc linked to the N-terminus of the heavy chain and (ii) two copies of a PGRN polypeptide linked to the C- terminus of the Fc domain.

[0410] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fcny-2871899735022004340 domain and the PGRN polypeptide is linked to N-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc domain. An example of this single chain 1+1 format of a complex is shown in FIG. 1A, 1I, and 1J.

[0411] In some embodiments, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide linked to C-terminus of the Fc domain. In some embodiments, the Fc is a single chain, engineered monovalent Fc. An example of this 1+1 format of a complex is shown in FIG.1B and 1C.

[0412] In some aspects, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the N-terminus of the Fc domain. An example of this 1+1 format of a complex is shown in FIG. 1D.

[0413] In some aspects, disclosed herein is a complex comprising (i) a single scFv, VHH, or Fab antigen-binding domain that specifically binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen- binding domain that specifically binds to human CD98hc and the PGRN polypeptide are both linked to the C-terminus of the Fc domain.

[0414] In some embodiments, the complex comprises an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen-binding domain is any antigen-binding domain that specifically binds to human CD98hc described herein, and wherein the PGRN polypeptide is any PGRN polypeptide described herein. VII. Polynucleotides and Methods of Making the Same

[0415] In some aspects, provided herein is a nucleotide sequence encoding a complex comprising an antigen-binding domain linked to a PGRN polypeptide, wherein the antigen- binding domain specifically binds to a human BBB protein or receptor. In some embodiments, the human BBB protein or receptor is TfR. In some embodiments, the human BBB protein is CD98hc.ny-2871899735022004340

[0416] Also provided herein are polynucleotides encoding an isolated PGRN mutant polypeptide.

[0417] Provided herein are polynucleotides comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, that are optimized, e.g., by codon / RNA optimization, replacement with heterologous signal sequences, and / or elimination of mRNA instability elements. Methods to generate optimized nucleic acids for recombinant expression by introducing codon changes (e.g., a codon change that encodes the same amino acid due to the degeneracy of the genetic code) and / or eliminating inhibitory regions in the mRNA can be carried out by adapting the optimization methods described in, e.g., U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498, accordingly.

[0418] A polynucleotide comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, can be generated from nucleic acid from a suitable source (e.g., a hybridoma) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers hybridizable to the 3’ and 5’ ends of a known sequence can be performed using genomic DNA obtained from hybridoma cells producing the antibody of interest. Such PCR amplification methods can be used to obtain nucleic acids comprising, e.g., the sequence encoding the light chain and / or heavy chain of an antigen-binding domain, antibody, or antigen-binding fragment thereof. The amplified nucleic acids can be cloned into vectors for expression in host cells and for further cloning, for example, to generate a complex or isolated PGRN mutant polypeptide described herein.

[0419] Polynucleotides provided herein can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA, and DNA can be double-stranded or single-stranded. If single stranded, DNA can be the coding strand or non-coding (anti-sense) strand. In some embodiments, the polynucleotide is a cDNA or a DNA lacking one more endogenous introns. In some embodiments, a polynucleotide is a non-naturally occurring polynucleotide. In some embodiments, a polynucleotide is recombinantly produced. In some embodiments, the polynucleotides are isolated. In some embodiments, the polynucleotides are substantially pure.

[0420] In some embodiments, polynucleotides provided herein are in the form of RNA. In some embodiments, polynucleotides provided herein are in the form of RNA encoding any-2871899735022004340 complex or isolated PGRN mutant polypeptide provided herein. In some embodiments, a polynucleotide provided herein is a synthetic messenger RNA (mRNA). In some embodiments, the synthetic mRNA has at least one nucleoside modification. In some embodiments, the at least one nucleoside modification is selected from the group consisting of pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl- pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1- taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5- methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl- pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio- pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5- formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza- pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl- zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8- aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1- methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2- methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza- 8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1- methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl- 8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl- 6-thio-guanosine.ny-2871899735022004340

[0421] In certain aspects, provided herein are vectors (e.g., expression vectors) comprising polynucleotides comprising nucleotide sequences encoding the complex or isolated PGRN mutant polypeptide described herein, for recombinant expression in a host cell, e.g., in a mammalian host cell or in an E. coli cell. A vector for the production of the complex or isolated PGRN mutant polypeptide described herein, can be produced, e.g., by recombinant DNA technology using techniques well known in the art. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors comprising a nucleotide sequence encoding the complex or isolated PGRN mutant polypeptide described herein, operably linked to a promoter. Such vectors can, for example, include the nucleotide sequence encoding the constant region of an antigen- binding domain, antibody or antigen-binding fragment thereof (see, e.g., International Publication Nos. WO 86 / 05807 and WO 89 / 01036; and U.S. Patent No. 5,122,464), and variable domains of the antigen-binding domain, antibody or antigen-binding fragment thereof can be cloned into such a vector for expression of the entire heavy, the entire light chain, or both the entire heavy and light chains. In some embodiments, the vector is gene therapy vector (e.g., an AAV or lentiviral vector).

[0422] In certain aspects, provided herein are expression systems comprising polynucleotides comprising nucleotide sequences encoding the complex or isolated PGRN mutant polypeptide described herein. An expression system can be included on a vector. An expression system can also be integrated into a host cell chromosome. In some embodiments, an expression system is a cell free expression system. In some embodiments, an expressions system comprises a host cell comprising a polynucleotide and / or vector provided herein.

[0423] Accordingly, also provided herein are cells, e.g. host cells, comprising polynucleotides and / or vectors for recombinantly expressing the complex or isolated PGRN mutant polypeptide described herein. In some embodiments, for the expression of double-chained antigen-binding proteins, vectors encoding both the heavy and light chains, individually, can be co-expressed in the host cell for expression of the entire immunoglobulin. In some embodiments, a host cell contains two different vectors, a first vector comprising a polynucleotide encoding a heavy chain of an antigen-binding protein and a PGRN polypeptide described herein, and a second vector comprising a polynucleotide encoding a light chain of the antigen-binding protein. In some embodiments, a first host cell comprises a first vector comprising a polynucleotide encoding any-2871899735022004340 heavy chain and a PGRN polypeptide, and a second host cell comprises a second vector comprising a polynucleotide encoding a light chain. In some embodiments, provided herein is a population of host cells comprising such first host cell and such second host cell.

[0424] In some aspects, provided herein are methods for producing the complex or isolated PGRN mutant polypeptide described herein in a host cell.

[0425] An expression vector can be transferred to a cell (e.g., host cell) by conventional techniques, and the resulting cells can then be cultured by conventional techniques to produce the complex or isolated PGRN mutant polypeptide described herein.

[0426] A variety of host-expression vector systems can be utilized for the complex or isolated PGRN mutant polypeptide described herein (see, e.g., U.S. Patent No. 5,807,715). Such host- expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells which can, when transformed or transfected with the appropriate nucleotide coding sequences, express the compositions described herein, or a domain thereof described herein in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli and B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect ...

Claims

735022004340 WHAT IS CLAIMED IS:

1. A complex comprising (a) an antigen-binding domain that specifically binds to human transferrin receptor (TfR) and (b) a Progranulin (PGRN) polypeptide.

2. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 0.01 nM to 50 nM, and (b) a PGRN polypeptide.

3. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 51 nM to 750 nM, and (b) a PGRN polypeptide.

4. The complex of claim 3, wherein the antigen-binding domain binds to human TfR with an affinity of 600 nM to 650 nM.

5. The complex of claim 3, wherein the antigen-binding domain binds to human TfR with an affinity of 160 nM to 200 nM.

6. A complex comprising (a) an affinity-tuned antigen-binding domain that specifically binds to human TfR, wherein the antigen-binding domain binds to human TfR with an affinity of 751 nM to 10,000 nM, and (b) a PGRN polypeptide.

7. The complex of any one of claims 1-6, further comprising an Fc domain.

8. The complex of claim 7, wherein the antigen-binding domain that specifically binds to human transferrin receptor (TfR) is not within the Fc domain of the complex.

9. The complex of any one of claims 1-8, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides.

10. The complex of any one of claims 1-9, wherein the complex comprises:ny-2871899735022004340 (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 the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR.

11. The complex of claim 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3.

12. The complex of claim 10, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide.

13. The complex of claim 10, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human TfR.

14. The complex of any one of claims 1-8, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR.ny-2871899735022004340 15. The complex of any one of claims 1-8, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain.

16. The complex of any one of claims 1-8 and 15, wherein the antigen-binding domain comprises a single-chain fragment variable (scFv).

17. The complex of claim 16, wherein the scFv is in the orientation VH-linker-VL.

18. The complex of claim 16, wherein the scFv is in the orientation VL-linker-VH.

19. The complex of claim 17 or claim 18, wherein the linker (A) 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 (B) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

20. The complex of any one of claims 1-8 and 15-19, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain.

21. The complex of any one of claims 1-8 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain.

22. The complex of any one of claims 1-9 comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, andny-2871899735022004340 (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human TfR.

23. The complex of any one of claims 1-8 and 15, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain.

24. The complex of claim 23, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds TfR.

25. The complex of any one of claims 1-24, wherein the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen-binding domain is a humanized antigen-binding domain.

26. The complex of any one of claims 7-25, wherein the Fc domain is capable of binding FcRn.

27. The complex of any one of claims 1-6, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain.

28. The complex of claim 27, wherein the Fc region is capable of binding FcRn.

29. The complex of claim 27 or claim 28, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human TfR and (ii) and two copies of the PGRN polypeptide.ny-2871899735022004340 30. The complex of claim 29, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human TfR is linked to the C-terminus of one of the two copies of the PGRN polypeptide.

31. The complex of claim 29, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

32. The complex of claim 29, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region.

33. The complex of claim 29, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region.

34. The complex of claim 27 or claim 28, comprising (i) an antibody that binds to human TfR, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C-termini of one of the two antibody heavy chains.

35. The complex of claim 27 or claim 28, comprising (i) two scFv, Fab, or VHH antigen- binding domains that bind to human TfR, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human TfR is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region,ny-2871899735022004340 and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

36. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region.

37. The complex of claim 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain.

38. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region.

39. The complex of claim 7, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human TfR, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C- terminus of the Fc domain.

40. The complex of claim 27 or claim 28, comprising (i) a single scFv, VHH, or Fab antigen- binding domain that binds to human TfR, (ii) an Fc region, and (iii) a single copy of the PGRNny-2871899735022004340 polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human TfR is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

41. The complex of any one of claims 27-36, 38, and 40, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

42. The complex of any one of claims 7, 37, and 39, wherein the Fc domain is a single chain monovalent Fc domain.

43. The complex of any one of claims 27-36, 38, and 40-41, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9.

44. The complex of any one of claims 27-36, 38, 40-41, and 43, 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.

45. The complex of any one of claims 7, 37, 39, and 42, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8.

46. The complex of any one of claims 7, 37, 39, 42, and 45, 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.

47. The complex of any one of claims 1 and 7-46, wherein the antigen-binding domain comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VHny-2871899735022004340 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; (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;ny-2871899735022004340 (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.

48. The complex of claim 47, wherein 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.

49. The complex of claim 47 or claim 48, wherein 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.

50. The complex of claim 48 or claim 49, 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;ny-2871899735022004340 (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; (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;ny-2871899735022004340 (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; (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;ny-2871899735022004340 (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; (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.ny-2871899735022004340 51. The complex of any one of claims 1 and 7-46, wherein the antigen-binding domain 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; (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,ny-2871899735022004340 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.

52. The complex of any one of claims 1-46, wherein the antigen-binding domain 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: (i) SEQ ID NOs: 8, 14, 25, 41, 55, and 61, respectively; (ii) SEQ ID NOs: 8, 15, 25, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

53. The complex of claim 52, wherein the VH comprises the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118.

54. The complex of claim 52 or claim 53, wherein the VL comprises the amino acid sequence of SEQ ID NO: 154, 344, 345, 174, 346, 347, 348, 349, or 350.

55. The complex of claim 53 or claim 54, 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 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively;ny-2871899735022004340 (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.

56. The complex of any one of claims 1-46, wherein antigen-binding domain specifically binds to human TfR, and wherein the antigen-binding domain is a VHH comprising: (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 8, 14, and 25, respectively; (ii) SEQ ID NOs: 8, 15, and 25, respectively; (iv) SEQ ID NOs: 10, 22, and 333, respectively; (v) SEQ ID NOs: 10, 22, and 28, respectively; (ix) SEQ ID NOs: 10, 22, and 334, respectively; or (x) SEQ ID NOs: 10, 22, and 30, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 101, 102, 342, 117, 343, or 118.

57. The complex of any one of the preceding claims, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:

230.

58. The complex of any one of claims 1-56, wherein the PGRN polypeptide is a mutant PGRN polypeptide comprising a C-terminal amino acid sequence defined by X1X2X3X4, wherein X1 is any amino acid, and wherein X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL.

59. The complex of claim 58, wherein the PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and wherein:ny-2871899735022004340 (a) X1 is an amino acid selected from the group consisting of R, I, V, Q, T, P, and D; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is absent or is an amino acid selected from the group consisting of L, P, C, G, T, D, Y, R, S, Q, V, A, I, H, K, and N; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, E, G, P, R, D, S, H, N, V, T, I, and A.

60. The complex of any one of claims 1-56 and 58-59, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO:

266.

61. The complex of any one of claims 2-56, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 247, SEQ ID NO: 258, and SEQ ID NO:

260.

62. The complex of claim 11, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:

320.

63. The complex of claim 14, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:322;ny-2871899735022004340 (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:323; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:

321.

64. The complex of claim 12, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:319; (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:321; and (iii) the third polypeptide comprises the amino acid sequence of SEQ ID NO:

323.

65. The complex of claim 10, wherein: (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO:332, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO:

321.

66. A complex 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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively;ny-2871899735022004340 (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

67. A complex comprising: (a) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

68. A complex comprising:ny-2871899735022004340 (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 PGRN polypeptide; (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a PGRN polypeptide; and (c) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, and wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

69. A complex 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 PGRN polypeptide; and (b) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form an antigen-binding domain that specifically binds to human TfR, andny-2871899735022004340 wherein the VH comprises a VH CDR1, VH CDR2, and VH CDR3 and the VL comprises 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, 335, 55, and 61, respectively; (iii) SEQ ID NOs: 8, 15, 25, 336, 55, and 61, respectively; (iv) SEQ ID NOs: 10, 22, 333, 50, 58, and 62, respectively; (v) SEQ ID NOs: 10, 22, 28, 337, 58, and 62, respectively; (vi) SEQ ID NOs: 10, 22, 28, 338, 58, and 62, respectively; (vii) SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively; (viii) SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively; (ix) SEQ ID NOs: 10, 22, 334, 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, 341, 55, and 61, respectively.

70. The complex of any one of claims 66-69, 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 344, respectively; (iii) SEQ ID NOs: 102 and 345, respectively; (iv) SEQ ID NOs: 342 and 174, respectively; (v) SEQ ID NOs: 117 and 346, respectively; (vi) SEQ ID NOs: 117 and 347, respectively; (vii) SEQ ID NOs: 117 and 348, respectively; (viii) SEQ ID NOs: 117 and 349, respectively; (ix) SEQ ID NOs: 343 and 174, respectively; (x) SEQ ID NOs: 118 and 174, respectively; or (xi) SEQ ID NOs: 101 and 350, respectively.ny-2871899735022004340 71. The complex of any one of claims 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 340, 58, and 62, respectively.

72. The complex of claim 71, wherein the VH and the VL comprise the amino acid sequences of 117 and 349, respectively.

73. The complex of any one of claims 66-70, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOs: 10, 22, 28, 339, 58, and 62, respectively.

74. The complex of claim 73, wherein the VH and the VL comprise the amino acid sequences of 117 and 348, respectively.

75. The complex of any one of claims 66-74, wherein the PGRN polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO:

266.

76. The complex of any one of claims 1-75, wherein the complex binds human Sortilin with a dissociation constant (KD) that ranges from about 5 nM to about 400 nM.

77. The complex of any one of claims 1-76, wherein the complex binds human Sortilin with a KD that ranges from about 50 nM to about 350 nM.ny-2871899735022004340 78. The complex of any one of claims 1-77, wherein the complex binds human Sortilin with a KD that ranges from about 100 nM to about 300 nM.

79. The complex of any one of claims 1-78, wherein the complex increases cellular GCase activity greater than the PGRN polypeptide alone.

80. The complex of any one of claims 1-79, wherein the complex increases cellular GCase activity at least about 0.5-fold, at least about 1-fold, or at least about 2-fold greater than the PGRN polypeptide alone.

81. The complex of any one of claims 1-80, wherein the complex is linked to an imaging agent.

82. A polynucleotide encoding the complex of any one of claims 1-81.

83. A vector comprising the polynucleotide of claim 82.

84. A host cell comprising the vector of claim 83.

85. A method of producing a complex comprising culturing the host cell of claim 84 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture.

86. An isolated complex thereof produced by the method of claim 85.

87. A pharmaceutical composition comprising the complex of any one of claims 1-81.

88. The pharmaceutical composition of claim 87, further comprising a pharmaceutically acceptable carrier.ny-2871899735022004340 89. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject.

90. The method of claim 89, wherein 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.

91. The method of claim 90, 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).

92. The method of claim 91, wherein the dementia is frontotemporal dementia (FTD).

93. The method of claim 91, wherein the neurological disease or disorder is Alzheimer’s disease.

94. The method of claim 93, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease.

95. The method of claim 91, wherein the neurological disease or disorder is Parkinson’s disease.

96. The method of claim 91, wherein the neurological disease or disorder is frontal temporal epilepsy.ny-2871899735022004340 97. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject.

98. The method of claim 97, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.

99. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject.

100. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.

101. A method of imaging PGRN within a subject, comprising administering to the subject the complex of claim 81 and locating the imaging agent within the subject.

102. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of claim 81 and locating the imaging agent within the sample.

103. Use of the complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 in the method of any one of claims 89-102.

104. The complex of any one of claims 1-81 or the pharmaceutical composition of claim 87 or 88 for use in the method of any one of claims 89-102.

105. A complex comprising (a) an antigen-binding domain that specifically binds to human CD98 heavy chain (CD98hc) and (b) a Progranulin (PGRN) polypeptide.ny-2871899735022004340 106. The complex of claim 105, further comprising an Fc domain.

107. The complex of claim 105 or 106, wherein the antigen-binding domain comprises a VH and a VL on separate polypeptides.

108. The complex of any one of claims 105-107, wherein the complex 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 the PGRN polypeptide; and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc.

109. The complex of claim 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2 and a CH3.

110. The complex of claim 108, further comprising (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and a second PGRN polypeptide.

111. The complex of claim 108, further comprising: (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a second VH, a second CH1, a second hinge region, a second CH2, a second CH3, a second linker, and a second PGRN polypeptide; (iv) a fourth polypeptide comprising, from the N-terminus to the C-terminus, a second VL and a second CL; wherein the second VH and the second VL form a second antigen-binding domain that specifically binds to human CD98hc.

112. The complex of claim 105, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, a hinge region, a CH2, and a CH3;ny-2871899735022004340 (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a CH2, a CH3, a linker, and the PGRN polypeptide; and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc.

113. The complex of claim 105 or 106, wherein the antigen-binding domain comprises a VH and VL on a single polypeptide chain.

114. The complex of any one of claims 105, 106 and 113, wherein the antigen-binding domain comprises a single-chain fragment variable (scFv).

115. The complex of claim 114, wherein the scFv is in the orientation VH-linker-VL.

116. The complex of claim 114, wherein the scFv is in the orientation VL-linker-VH.

117. The complex of claim 115 or claim 116, wherein the linker (A) 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 (B) comprises the amino acid sequence of GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 6) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 7).

118. The complex of any one of claims 105, 106, and 113-117, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising a second Fc domain.

119. The complex of claim 105 or 106 comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second Fc domain and the antigen-binding domain.ny-2871899735022004340 120. The complex of any one of claims 105-107, comprising: (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide and a first Fc domain, (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a VH, a CH1, and a second Fc domain, and (iii) a third polypeptide comprising, from the N-terminus to the C-terminus, a VL and a CL; wherein the VH and the VL form the antigen-binding domain that specifically binds to human CD98hc.

121. The complex of any one of claims 105, 106, and 113, comprising (i) a first polypeptide comprising, from the N-terminus to the C-terminus, the PGRN polypeptide, a first Fc domain, and the antigen-binding domain and (ii) a second polypeptide comprising, from the N-terminus to the C-terminus, a second PGRN polypeptide and a second Fc domain.

122. The complex of claim 121, wherein the second polypeptide comprises, from the N- terminus to the C-terminus, the second PGRN polypeptide, the second Fc domain, and a second antigen-binding domain that specifically binds CD98hc.

123. The complex of any one of claims 105-122, wherein the antigen-binding domain is a murine, chimeric, humanized, or human antigen-binding domain, optionally wherein the antigen- binding domain is a humanized antigen-binding domain.

124. The complex of any one of claims 105-123, wherein the Fc domain is capable of binding FcRn.

125. The complex of claim 105, further comprising an Fc region, wherein the Fc region comprises a first and second polypeptide chain.

126. The complex of claim 125, wherein the Fc region is capable of binding FcRn.ny-2871899735022004340 127. The complex of claim 125 or claim 126, comprising (i) a single scFv or VHH or Fab antigen-binding domain that binds to human CD98hc and (ii) and two copies of the PGRN polypeptide.

128. The complex of claim 127, wherein the single scFv, Fab or VHH antigen-binding domain that binds to human CD98hc is linked to the C-terminus of one of the two copies of the PGRN polypeptide.

129. The complex of claim 127, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

130. The complex of claim 127, wherein the single scFv, Fab, or VHH antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region.

131. The complex of claim 127, wherein one of the two copies of the PGRN polypeptide is linked to the C-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the C-terminus of the second polypeptide chain of the Fc region.

132. The complex of claim 125 or claim 126, comprising (i) an antibody that binds to human CD98hc, wherein the antibody comprises two heavy chains and two light chains; and (ii) two copies of the PGRN polypeptide, wherein each copy of the PGRN polypeptide is linked to the C- termini of one of the two antibody heavy chains.

133. The complex of claim 125 or claim 126, comprising (i) two scFv, Fab, or VHH antigen- binding domains that bind to human CD98hc, (ii) the Fc region; and (iii) two copies of the PGRN polypeptide, wherein one of the two scFv, Fab, or VHH antigen-binding domains thatny-2871899735022004340 binds to human CD98hc is linked to the C-terminus of the first polypeptide chain of the Fc region, wherein the other scFv, Fab, or VHH antigen-binding domains that binds to human CD98hc is linked to the C-terminus of the second polypeptide chain of the Fc region, wherein one of the two copies of the PGRN polypeptide is linked to the N-terminus of the first polypeptide chain of the Fc region, and wherein the other copy of the PGRN polypeptide is linked to the N-terminus of the second polypeptide chain of the Fc region.

134. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to N-terminus of the first or second polypeptide chain of the Fc region.

135. The complex of claim 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the C-terminus of the Fc domain and the PGRN polypeptide is linked to N- terminus of the Fc domain.

136. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of the first or second polypeptide chain of the Fc region and the PGRN polypeptide is linked to the C-terminus of the first or second polypeptide chain of the Fc region.

137. The complex of claim 106, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) the Fc domain, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to humanny-2871899735022004340 CD98hc is linked to the N-terminus of the Fc domain and the PGRN polypeptide is linked to the C-terminus of the Fc domain.

138. The complex of claim 125 or claim 126, comprising (i) a single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc, (ii) an Fc region, and (iii) a single copy of the PGRN polypeptide, wherein the single scFv, VHH, or Fab antigen-binding domain that binds to human CD98hc is linked to the N-terminus of one of the two polypeptide chains of the Fc region, and wherein the PGRN polypeptide is linked to the N-terminus of the other polypeptide chain of the Fc region.

139. The complex of any one of claims 125-134, 136, and 138, wherein the Fc region is a heterodimeric Fc region, optionally comprising knob and hole mutations.

140. The complex of any one of claims 106, 135, and 137, wherein the Fc domain is a single chain monovalent Fc domain.

141. The complex of any one of claims 125-134, 136, and 138-139, wherein the Fc region is a modified Fc region with a modification listed in Table 8 or Table 9.

142. The complex of any one of claims 125-134, 136, 138-139, and 141, 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.

143. The complex of any one of claims 106, 135, 137, and 140, wherein the Fc domain is a modified Fc domain with a modification listed in Table 8.

144. The complex of any one of claims 106, 135, 137, 140, and 143, 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 functionny-2871899735022004340 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.

145. The complex of any one of claims 105-144, wherein the antigen-binding domain 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 sequences 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, 324, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 325, 193, 197, 198, and 204, respectively; or (ix) SEQ ID NOs: 184, 326, 193, 197, 198, and 204, respectively.

146. The complex of claim 145, wherein the VH comprises the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329.

147. The complex of claim 145 or 146, wherein the VL comprises the amino acid sequence of SEQ ID NO: 211, 212, 213, 214, 215, or 216.

148. The complex of claim 146 or 147, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 205 and 211, respectively; (ii) SEQ ID NOs: 206 and 212, respectively; (iii) SEQ ID NOs: 207 and 213, respectively; (iv) SEQ ID NOs: 208 and 214, respectively; (i) SEQ ID NOs: 209 and 215, respectively; (ii) SEQ ID NOs: 210 and 216, respectively;ny-2871899735022004340 (iii) SEQ ID NOs: 327 and 216, respectively; (iv) SEQ ID NOs: 328 and 216, respectively; or (v) SEQ ID NOs: 329 and 216, respectively.

149. The complex of any one of claims 105-144, wherein the antigen-binding domain 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, 324, and 193, respectively; (viii) SEQ ID NOs: 184, 325, and 193, respectively; or (ix) SEQ ID NOs: 184, 326, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 205, 206, 207, 208, 209, 210, 327, 328, or 329.

150. The complex of any one of claims 105-144, wherein the antigen-binding domain 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 sequences comprise the amino acid sequences of: (i) SEQ ID NOs: 184, 352, 193, 197, 198, and 204, respectively; (ii) SEQ ID NOs: 184, 353, 193, 197, 198, and 204, respectively; (iii) SEQ ID NOs: 184, 354, 193, 197, 198, and 204, respectively; (iv) SEQ ID NOs: 184, 355, 193, 197, 198, and 204, respectively; (v) SEQ ID NOs: 184, 356, 193, 197, 198, and 204, respectively; (vi) SEQ ID NOs: 184, 357, 193, 197, 198, and 204, respectively; (vii) SEQ ID NOs: 184, 358, 193, 197, 198, and 204, respectively; (viii) SEQ ID NOs: 184, 190, 193, 369, 198, and 204, respectively;ny-2871899735022004340 (ix) SEQ ID NOs: 184, 190, 193, 370, 198, and 204, respectively; (x) SEQ ID NOs: 184, 190, 193, 371, 198, and 204, respectively; (xi) SEQ ID NOs: 184, 190, 193, 372, 198, and 204, respectively; (xii) SEQ ID NOs: 184, 190, 193, 373, 198, and 204, respectively; (xiii) SEQ ID NOs: 184, 190, 193, 374, 198, and 204, respectively; (xiv) SEQ ID NOs: 184, 190, 193, 375, 198, and 204, respectively; (xv) SEQ ID NOs: 184, 354, 193, 371, 198, and 204, respectively; (xvi) SEQ ID NOs: 184, 359, 193, 197, 198, and 204, respectively; (xvii) SEQ ID NOs: 184, 190, 360, 197, 198, and 204, respectively; (xviii) SEQ ID NOs: 184, 190, 361, 197, 198, and 204, respectively; (xix) SEQ ID NOs: 184, 190, 362, 197, 198, and 204, respectively; (xx) SEQ ID NOs: 184, 190, 363, 197, 198, and 204, respectively; (xxi) SEQ ID NOs: 184, 190, 364, 197, 198, and 204, respectively; (xxii) SEQ ID NOs: 184, 190, 365, 197, 198, and 204, respectively; (xxiii) SEQ ID NOs: 184, 190, 366, 197, 198, and 204, respectively; (xxiv) SEQ ID NOs: 184, 190, 367, 197, 198, and 204, respectively; (xxv) SEQ ID NOs: 184, 190, 368, 197, 198, and 204, respectively; (xxvi) SEQ ID NOs: 184, 190, 193, 376, 198, and 204, respectively; (xxvii) SEQ ID NOs: 184, 190, 193, 377, 198, and 204, respectively; (xxviii) SEQ ID NOs: 184, 190, 193, 378, 198, and 204, respectively; (xxix) SEQ ID NOs: 184, 190, 193, 379, 198, and 204, respectively; (xxx) SEQ ID NOs: 184, 190, 193, 380, 198, and 204, respectively; (xxxi) SEQ ID NOs: 184, 190, 193, 381, 198, and 204, respectively; (xxxii) SEQ ID NOs: 184, 190, 193, 197, 198, and 382, respectively; (xxxiii) SEQ ID NOs: 184, 190, 193, 197, 198, and 383, respectively; (xxxiv) SEQ ID NOs: 184, 190, 193, 197, 198, and 384, respectively; (xxxv) SEQ ID NOs: 184, 190, 193, 197, 198, and 385, respectively; (xxxvi) SEQ ID NOs: 184, 190, 193, 197, 198, and 386, respectively; (xxxvii) SEQ ID NOs: 184, 190, 193, 197, 198, and 387, respectively; (xxxviii) SEQ ID NOs: 184, 190, 193, 197, 198, and 388, respectively; (xxxix) SEQ ID NOs: 184, 190, 193, 197, 198, and 389, respectively;ny-2871899735022004340 (xl) SEQ ID NOs: 184, 190, 193, 197, 198, and 390, respectively; (xli) SEQ ID NOs: 184, 190, 193, 197, 198, and 391, respectively; (xlii) SEQ ID NOs: 351, 190, 193, 197, 198, and 204, respectively; or (xliii) SEQ ID NOs: 351, 190, 193, 197, 198, and 391, respectively.

151. The complex of claim 150, wherein the VH comprises the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409.

152. The complex of claim 150 or 151, wherein the VL comprises the amino acid sequence of SEQ ID NO: 215, 216, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, or 432.

153. The complex of claim 151 or 152, wherein the VH and the VL comprise the amino acid sequences of: (i) SEQ ID NOs: 392 and 216, respectively; (ii) SEQ ID NOs: 393 and 216, respectively; (iii) SEQ ID NOs: 394 and 216, respectively; (iv) SEQ ID NOs: 395 and 216, respectively; (v) SEQ ID NOs: 396 and 216, respectively; (vi) SEQ ID NOs: 397 and 216, respectively; (vii) SEQ ID NOs: 398 and 216, respectively; (viii) SEQ ID NOs: 210 and 410, respectively; (ix) SEQ ID NOs: 210 and 411, respectively; (x) SEQ ID NOs: 210 and 412, respectively; (xi) SEQ ID NOs: 210 and 413, respectively; (xii) SEQ ID NOs: 210 and 414, respectively; (xiii) SEQ ID NOs: 210 and 415, respectively; (xiv) SEQ ID NOs: 210 and 416, respectively; (xv) SEQ ID NOs: 394 and 412, respectively; (xvi) SEQ ID NOs: 399 and 216, respectively;ny-2871899735022004340 (xvii) SEQ ID NOs: 400 and 216, respectively; (xviii) SEQ ID NOs: 401 and 216, respectively; (xix) SEQ ID NOs: 402 and 216, respectively; (xx) SEQ ID NOs: 403 and 216, respectively; (xxi) SEQ ID NOs: 404 and 216, respectively; (xxii) SEQ ID NOs: 405 and 216, respectively; (xxiii) SEQ ID NOs: 406 and 216, respectively; (xxiv) SEQ ID NOs: 407 and 216, respectively; (xxv) SEQ ID NOs: 408 and 216, respectively; (xxvi) SEQ ID NOs: 210 and 417, respectively; (xxvii) SEQ ID NOs: 210 and 418, respectively; (xxviii) SEQ ID NOs: 210 and 419, respectively; (xxix) SEQ ID NOs: 210 and 420, respectively; (xxx) SEQ ID NOs: 210 and 421, respectively; (xxxi) SEQ ID NOs: 210 and 422, respectively; (xxxii) SEQ ID NOs: 210 and 423, respectively; (xxxiii) SEQ ID NOs: 210 and 424, respectively; (xxxiv) SEQ ID NOs: 210 and 425, respectively; (xxxv) SEQ ID NOs: 210 and 426, respectively; (xxxvi) SEQ ID NOs: 210 and 427, respectively; (xxxvii) SEQ ID NOs: 210 and 428, respectively; (xxxviii) SEQ ID NOs: 210 and 429, respectively; (xxxix) SEQ ID NOs: 210 and 430, respectively; (xl) SEQ ID NOs: 210 and 431, respectively; (xli) SEQ ID NOs: 210 and 432, respectively; (xlii) SEQ ID NOs: 409 and 215, respectively; or (xliii) SEQ ID NOs: 409 and 432, respectively.

154. The complex of any one of claims 105-144, wherein the antigen-binding domain specifically binds to human CD98 heavy chain (CD98hc), and wherein the antigen-binding domain is a VHH comprising:ny-2871899735022004340 (a) a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 184, 352, and 193, respectively; (ii) SEQ ID NOs: 184, 353, and 193, respectively; (iii) SEQ ID NOs: 184, 354, and 193, respectively; (iv) SEQ ID NOs: 184, 355, and 193, respectively; (v) SEQ ID NOs: 184, 356, and 193, respectively; (vi) SEQ ID NOs: 184, 357, and 193, respectively; (vii) SEQ ID NOs: 184, 358, and 193, respectively; (viii) SEQ ID NOs: 184, 190, and 193, respectively; (ix) SEQ ID NOs: 184, 359, and 193, respectively; (x) SEQ ID NOs: 184, 190, and 360, respectively; (xi) SEQ ID NOs: 184, 190, and 361, respectively; (xii) SEQ ID NOs: 184, 190, and 362, respectively; (xiii) SEQ ID NOs: 184, 190, and 363, respectively; (xiv) SEQ ID NOs: 184, 190, and 364, respectively; (xv) SEQ ID NOs: 184, 190, and 365, respectively; (xvi) SEQ ID NOs: 184, 190, and 366, respectively; (xvii) SEQ ID NOs: 184, 190, and 367, respectively; (xviii) SEQ ID NOs: 184, 190, and 368, respectively; or (xix) SEQ ID NOs: 351, 190, and 193, respectively; or (b) a VH comprising the amino acid sequence of SEQ ID NO: 210, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, or 409.

155. The complex of any one of the preceding claims, wherein the PGRN polypeptide comprises an amino acid sequence set forth in SEQ ID NO:

230.

156. The complex of any one of claims 105-154, wherein the PGRN mutant polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 247,ny-2871899735022004340 SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO:

266.

157. The complex of any one of claims 105-156, wherein the complex is linked to an imaging agent.

158. A polynucleotide encoding the complex of any one of claims 105-157.

159. A vector comprising the polynucleotide of claim 158.

160. A host cell comprising the vector of claim 159.

161. A method of producing a complex comprising culturing the host cell of claim 160 so that the complex is produced, optionally wherein the method further comprises isolating the complex from the culture.

162. An isolated complex thereof produced by the method of claim 161.

163. A pharmaceutical composition comprising the complex of any one of claims 105-157.

164. The pharmaceutical composition of claim 163, further comprising a pharmaceutically acceptable carrier.

165. A method of treating a neurological disease or disorder in a subject comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject.

166. The method of claim 165, wherein 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.ny-2871899735022004340 167. The method of claim 166, 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).

168. The method of claim 167, wherein the dementia is frontotemporal dementia (FTD).

169. The method of claim 167, wherein the neurological disease or disorder is Alzheimer’s disease.

170. The method of claim 169, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease.

171. The method of claim 167, wherein the neurological disease or disorder is Parkinson’s disease.

172. The method of claim 165, wherein the neurological disease or disorder is frontal temporal epilepsy.

173. A method of treating a lysosomal storage disease in a subject comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject.

174. The method of claim 173, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.

175. A method of transporting a complex across the BBB of a subject, comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject.ny-2871899735022004340 176. A method of increasing the concentration of PGRN in the cerebral spinal fluid (CSF) of a subject, comprising administering the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 to the subject, wherein the concentration of PGRN is increased as compared to administering the PGRN polypeptide alone to the subject.

177. A method of imaging PGRN within a subject, comprising administering to the subject the complex of claim 157 and locating the imaging agent within the subject.

178. A method of detecting PGRN in vitro, comprising contacting an in vitro sample with the complex of claim 157 and locating the imaging agent within the sample.

179. Use of the complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 in the method of any one of claims 165-178.

180. The complex of any one of claims 105-157 or the pharmaceutical composition of claim 163 or 164 for use in the method of any one of claims 165-178.

181. An isolated PGRN mutant polypeptide, wherein: (i) the isolated PGRN mutant polypeptide comprises a C-terminal amino acid sequence defined by X1X2X3X4, and wherein: (a) X1 is an amino acid selected from the group consisting of R, D, E, I, P, or Q; (b) X2 is an amino acid selected from the group consisting of Q and P; (c) X3 is an amino acid selected from the group consisting of L, A, C, D, F, G, H, I, K, M, N, P, Q, R, S, T, V, or Y; and / or (d) X4 is absent or is an amino acid selected from the group consisting of L, R, or V; and (ii) X2, X3, and X4 are not PIL, PFL, PPL, PYL, QRL, or QHL.

182. The isolated PGRN mutant polypeptide of claim 181, wherein the isolated PGRN mutant polypeptide comprises the amino acid sequence of SEQ ID NO:

330.

183. The isolated PGRN mutant polypeptide of claim 182, wherein the amino acid sequence is selected from the group consisting of SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQny-2871899735022004340 ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO: 259, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 265, and SEQ ID NO:

266.

184. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

231.

185. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

232.

186. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

233.

187. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

234.

188. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

235.

189. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

236.

190. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

237.

191. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

238.

192. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 239.ny-2871899735022004340 193. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

240.

194. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

241.

195. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

242.

196. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

243.

197. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

244.

198. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

245.

199. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

246.

200. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

248.

201. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

249.

202. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

250.

203. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

251.

204. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 252.ny-2871899735022004340 205. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

253.

206. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

254.

207. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

255.

208. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

256.

209. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

257.

210. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

259.

211. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

261.

212. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

262.

213. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

263.

214. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

264.

215. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO: 265.ny-2871899735022004340 216. The isolated PGRN mutant polypeptide of claim 183, wherein the amino acid sequence is SEQ ID NO:

266.

217. An isolated nucleic acid encoding the isolated PGRN mutant polypeptide of any one of claims 181-216.

218. A vector comprising the nucleic acid of claim 217.

219. A host cell comprising the vector of claim 218.

220. A method of producing an isolated PGRN mutant polypeptide comprising culturing the host cell of claim 219 so that the isolated PGRN mutant polypeptide is produced, optionally wherein the method further comprises isolating the isolated PGRN mutant polypeptide from the culture.

221. An isolated PGRN mutant polypeptide produced by the method of claim 220.

222. A pharmaceutical composition comprising the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221.

223. A method of treating a neurological disease or disorder in a subject comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject.

224. The method of claim 223, wherein 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.

225. The method of claim 224, 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).ny-2871899735022004340 226. The method of claim 225, wherein the dementia is frontotemporal dementia (FTD).

227. The method of claim 225, wherein the neurological disease or disorder is Alzheimer’s disease.

228. The method of claim 227, wherein the Alzheimer's disease is early onset Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease, or late onset Alzheimer’s disease.

229. The method of claim 225, wherein the neurological disease or disorder is Parkinson’s disease.

230. The method of claim 223, wherein the neurological disease or disorder is frontal temporal epilepsy.

231. A method of treating a lysosomal storage disease in a subject comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject.

232. The method of claim 231, wherein the lysosomal storage disease is selected from Gaucher disease, Ceroid lipofuscinosis (Batten disease), Mucopolysaccharidosis (MPS) Type I, MPS Type II and MPS Type III.

233. A method of increasing PGRN in a subject, the method comprising administering the isolated PGRN mutant polypeptide of any one of claims 181-216 and 221 or the pharmaceutical composition of claim 222 to the subject.ny-2871899

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