Compositions comprising a progranulin domain for the prevention and treatment of neurodegenerative diseases

Abstract

A compound comprising a progranulin domain, a TfR1 binding domain, and optionally an albumin binding domain when administered to a patient, such as a human, can: (1) modulate tau in the patient, (2) lead to the reduction of tau in a patient previously having elevated tau, (3) lead to the prevention of tau tangles in a patient without elevated tau or in a patient having elevated tau, and / or (4) prevent the accumulation of tau in a patient without elevated tau and / or prevent a patient's tau levels from becoming elevated. Treatment and prevention of a neurodegenerative disease through the administration of the compound.

Description

COMPOSITIONS COMPRISING A PROGRANULIN DOMAIN FOR THE PREVENTION AND TREATMENT OF NEURODEGENERATIVE DISEASESREFERENCE TO A SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “31172” created 26 September 2024 and is 80 kilobytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to methods of treating and / or preventing neurodegenerative diseases relating to elevated levels of tau, the method comprising administering a compound comprising a transferrin receptor 1 (TfRl) binding domain, a progranulin domain, and optionally an albumin binding domain to a patient in need of treatment. The present invention also relates to methods of modulating tau, the method comprising administering to the patient a compound comprising a transferrin receptor 1 (TfRl) binding domain, a progranulin domain, and optionally an albumin binding domain.BACKGROUND OF THE INVENTION

[0003] Progranulin, a 593 amino acid protein, is a precursor protein that in humans is encoded by the GRN gene. Individual granulin proteins are cleaved from progranulin. Naturally occurring progranulin includes the pro-protein, represented by para granulin (p), attached to a 7 granulin protein structure, G-F-B-A-C-D-E, where each of the granulin proteins are represented by a capital letter. In total, naturally occurring progranulin has the structure of p-G-F-B-A-C- D-E.

[0004] Various neurodegenerative disease states, have been associated with the deficiency of progranulin in the brain or cerebrospinal fluid (CSF). Progranulin deficiency accounts for roughly 25 percent of all heritable forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Progranulin acts protectively in several disease models with increased progranulin 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, el3368.) 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).

[0005] Additionally, it has been reported that patients showing reduced progranulin is associated with increased levels of tubulin associated unit (tau) proteins in the CSF in AD patients (Fardo et al. CSF Protein Changes Associated with Hippocampal sclerosis risk gene variants highlight impact of GRN / PGRN, Exp Gerontol (2017) Apr:90:83-89 ). Tau proteins have been found to be accumulated in patients with FTD, AD, and PD. Excess amounts of tau proteins, such as in insoluble tau tangles, are known to lead to toxic effects in cells that can accelerate cognitive decline in certain patients.

[0006] While compounds designed to deliver progranulin variants across the BBB are known, such as in US Patent Application NO: 2022 / 0213155, these compounds include a progranulin variant, not a naturally occurring sequence.

[0007] Accordingly, there is a need to develop therapies that can treat and prevent neurodegenerative diseases by providing a naturally occurring sequence of progranulin, which can modulate tau.SUMMARY OF THE INVENTION

[0008] It has been surprisingly found that a compound comprising a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain when administered to a patient, can: (1) modulate tau in the patient, (2) lead to the reduction of tau in a patient previously having elevated tau, (3) lead to the prevention of tau tangles in a patient without elevated tau or in a patient having elevated tau, and / or (4) prevent the accumulation of tau in a patient without elevated tau and / or prevent a patient’s tau levels from becoming elevated.

[0009] Also disclosed herein are methods of preventing, delaying onset of, or reducing the risk of developing a neurogenerative disease in a patient, the methods comprising administering to the patient a compound, the compound comprising: (a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and (b) a transferrin receptor 1 (TfRl) binding domain.

[0010] Also disclosed herein are methods of treating a tauopathy in a patient in need of treatment, the methods comprising administering to the patient a compound, the compound comprising: (a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 orSEQ ID NO: 2; and (b) a transferrin receptor 1 (TfRl) binding domain, wherein the tauopathy is selected from the group consisting of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt- Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age- related tauopathy (PART), Neurodegeneration with brain iron accumulation, and globular glial tauopathies (GGT).

[0011] Also disclosed herein is a use of a compound to prevent a neurodegenerative disease, the compound comprising: (a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and (b) a transferrin receptor 1 (TfRl) binding domain.

[0012] Also disclosed herein is a use of a compound to treat a tauopathy, the compound comprising: (a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and (b) a transferrin receptor 1 (TfRl) binding domain, wherein the tauopathy is selected from the group consisting of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple systemtauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt- Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age- related tauopathy (PART), Neurodegeneration with brain iron accumulation, and globular glial tauopathies (GGT).

[0013] Also disclosed herein are methods for the modulation of tau in a patient, the method comprising administering a compound a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0014] Also disclosed herein are methods for the reduction of tau in a patient having elevated tau, the method comprising administering a compound a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0015] Also disclosed herein, are methods for the prevention of tau levels from becoming elevated in a patient not having elevated levels of tau, the method comprising administering a compound a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0016] Also disclosed herein are methods for the prevention of the formation of tau tangles in a patient, the method comprising administering a compound a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows impact of two BBB-PGRN molecules on total Tau levels in PBS fraction (FIG. 1 A) and RIPA fraction (FIG. IB) of wild type FVB mice.

[0018] FIG. 2 shows impact of BBB-PGRN on soluble AT8+ tau in rTg4510 mice. Data are normalized based on wet weight (W.W., FIG.2A) or ratio with total tau (FIG. 2B).

[0019] FIG. 3 shows impact of BBB-PGRN on brain volume change measured by longitudinal volumetric MRI (vMRI) (FIG. 3 A and FIG. 3B) and correlation with soluble AT8 tau levels (FIG. 3C).DETAILED DESCRIPTION OF THE INVENTION

[0020] Modulation of Tau

[0021] Disclosed herein are methods for the modulation of tau in a patient, the method comprising administering a compound of the present disclosure, such as a compound comprising a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0022] The modulation of tau can occur in the central nervous system, the brain, the cerebral spinal fluid, the peripheral nervous system, or any other location in a human where TfRl is expressed, including but not limited to organ systems, such as the lungs.

[0023] As used herein, the term “modulate” or “modulation” means that the disclosed compounds can influence and / or exert a modifying or controlling influence on tau or levels of tau in a patient, such as a human. Modulation of tau can also include modifying tau levels in a patient through an indirect or a direct interaction with at least a portion of the disclosed compounds, such as, for example, the progranulin domain of the disclosed compounds.

[0024] The modulation of tau in a patient can result in a reduction of tau levels in a patient, the prevention of tau tangles in a patient, the prevention of tau from becoming elevated in a patient, and / or the treatment or prevention of a disease at least partially due to an abnormal level of tau, such as a tauopathy and / or a neurodegenerative disease.

[0025] Reduction of Tau

[0026] Also disclosed herein are methods for the reduction of tau in a patient having elevated tau levels. The method for the reduction of tau in a patient can comprise administering a compound of the present disclosure, such as a compound comprising a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0027] It has been surprisingly found that administration of a disclosed compound to a patient having elevated tau led to the reduction of tau levels in the patient. It is believed that the reduction of tau observed is due to the modulation of tau by a compound disclosed herein when administered to a patient with elevated level of tau.

[0028] It is understood that a person of ordinary skill in the art, such as a physician, can identify the total levels of tau in a patient that is being evaluated for potential treatment. The total amount of tau in a particular patient can vary based on the location and type of assessment, the disease state the patient is experiencing, and / or the patient’s specific genotype as described in Bos et al. 2019), Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum. Alzheimer's & Dementia, 15: 644-654.

[0029] The tau level of a human subject can be determined by techniques and methods familiar to the diagnosing physician or a person of ordinary skill in the art. In some embodiments, such methods can also be used to prescreen, screen, diagnose, evaluate increase or reduction in brain tau burden, and / or to assess the progress achieved in the treatment or prevention of the diseases described herein. In some embodiments, the methods can also be used to stratify subjects into groups and / or to identify which group of subjects is responsive to treatment / prevention of a disease (as described herein) using the antibodies, the dosing regimen, or the methods described herein. In some embodiments, the methods or techniques used to determine / detect tau level of a patient can be used for prescreening or screening subjects and determining which subjects are responsive to treatment / prevention of a disease (as described herein) using the antibodies, the dosing regimen, or the methods described herein.

[0030] In some embodiments, the tau level of a patient can be determined using techniques or methods that, e.g., detect or quantitate i) brain tau deposition, ii) tau in plasma, or iii) tau in cerebrospinal fluid. In some embodiments, brain tau burden, tau in plasma, or tau in cerebrospinal fluid can be used to stratify subjects into groups and to identify which group of patients is responsive to treatment / prevention of diseases (described herein) using the compounds described herein.

[0031] Tau levels in the brain of human subject can be determined using methods, such as, tau imaging with radiolabeled PET compounds (Leuzy et al., “Diagnostic Performance of RO948 F18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders,” JAMA Neurology 77.8:955-965 (2020); Ossenkoppele et al., “Discriminative Accuracy of F18-flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders,” JAMA 320, 1151-1162, doi: 10.1001 / jama.2018.12917 (2018), which are hereby incorporated by reference in their entireties.

[0032] An elevated level of tau can include a level of tau that is 10% or greater, 15% or greater, or 20% or greater level of tau in cerebrospinal fluid (CSF) than predicted based on the human patient’s anticipated level of tau.

[0033] A reduction of tau can include decreasing the level of tau in CSF by at least 5%, at least 10%, at least 15%, at least 20%, or at least 30% relative to the levels of tau prior to administration of one of the disclosed compounds. For example, if the patient previously had a level of tau in CSF of 80 pg / mL, a reduction of tau to a level of 68 pg / mL would correspond to a 15 % reduction in the levels of tau in the CSF.

[0034] Prevention of Tau from Becoming Elevated.

[0035] Also disclosed herein are methods for the prevention of tau levels from becoming elevated in a patient not having elevated levels of tau. The method for the prevention of tau from becoming elevated in a patient can comprise administering a compound of the present disclosure, such as a compound comprising a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain to the patient.

[0036] Human patients that are particularly susceptible to experiencing traumatic brain injury and / or developing chronic traumatic encephalopathy (CTE) may also benefit from a preventive treatment comprising administering a compound of the present disclosure in advance of a clinical diagnosis of elevated tau levels. Suitable patients under this category can include individuals participating in combat sports, such as mixed martial arts, boxing, wrestling, or the like, individuals participating in contact sports, such as American football, soccer, rugby, basketball, or the like, individuals operating heavy machinery, such as motor vehicles, farm equipment, or any other equipment, soldiers, construction workers, first responders,

[0037] Additionally, individuals that recently experienced a traumatic brain injury may benefit from a preventative treatment with one of the disclosed compounds. It is believed that treatment with one of the disclosed compounds can prevent tau levels from rising in patients that have recently experience a traumatic brain injury, such as patients recently experiencing a motor vehicle accident, individuals experiencing a fall, or any individual experiencing a blow to the head.

[0038] Prevention of Tau Tangles

[0039] Tau tangles or neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are associated with neurodegenerative diseases, such asAlzheimer's disease. Tau tangles are also associated with a variety of tauopathies. Tau tangles are known to form when tau levels are elevated in the brain and / or central nervous system. As described above, disclosed herein are methods for the reduction of tau in patients with elevated levels of tau and disclosed herein are methods for the prevention of tau from becoming elevated in patients with normal levels of tau.

[0040] Accordingly, also disclosed herein are methods for the prevention of the formation of tau tangles. While not wishing to be bound by theory, it is believed that the prevention of tau tangles is due to the reduction in the levels of elevated tau and / or the prevention of tau from becoming elevated through the administration of a compound disclosed herein to a patient.

[0041] Methods of Treatment

[0042] Disclosed herein are methods for the treatment of a tauopathy, which are diseases related to abnormal levels of tau. Treatment includes administration of a compound of the present disclosure for the treatment of a tauopathy.

[0043] The tauopathy can be treated by administering a patient in need of treatment a compound of the present disclosure. The patient can be treated of the tauopathy as the disclosed compound can modulate tau, reduce tau levels, prevent tau tangles, and / or prevent tau levels from becoming elevated, as described herein, when administered to the patient.

[0044] Provided herein are methods of treating a tauopathy in a patient in need thereof, and such the method comprises administering to the patient an effective amount of the disclosed compounds or a pharmaceutical composition described herein. In some embodiments, the tauopathy can be Alzheimer’s disease, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Parkinson’s disease, Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy,Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), nonGuamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC 9 A6 -related mental retardation, subacute sclerosingpan encephalitis, Tangle-only dementia, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, or globular glial tauopathies (GGT).

[0045] The tauopathy can also be selected from the group consisting of some embodiments, the tauopathy is selected from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt- Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, Tangle-only dementia, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, or globular glial tauopathies (GGT).

[0046] In a further aspect, provided herein are methods of treating a neurodegenerative synucleinopathy in a patient in need thereof, and such the method comprises administering to the patient an effective amount of the disclosed compounds or a pharmaceutical composition described herein. In some embodiments, the neurodegenerative synucleinopathy is selected from Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, or Lewy body dementia.

[0047] Methods of Prevention of, Delaying Onset of, or Reducing the Risk of Developing a Neurodegenerative Disease

[0048] Disclosed herein are methods for the prevention of, delaying onset of, or reducing the risk of developing a neurodegenerative disease, such as a neurodegenerative synucleinopathy or a tauopathy. Treatment includes administration of a compound of the present disclosure for the prevention of the neurodegenerative disease.

[0049] The neurodegenerative disease can be prevented, delayed, or risk of developing the neurodegenerative disease can be accomplished by administering a patient in need of treatment a compound of the present disclosure. Neurodegenerative diseases can be prevented, delayed, or the risk of developing the neurodegenerative diseases can be accomplished in a patient as the disclosed compound can modulate tau, reduce tau levels, prevent tau tangles, and / or prevent tau levels from becoming elevated, as described herein, when administered to the patient.

[0050] The tauopathy can be Alzheimer’s disease, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Parkinson’s disease, Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt- Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease,meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, Tangle-only dementia, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, or globular glial tauopathies (GGT).

[0051] The tauopathy can also be selected from the group consisting of some embodiments, the tauopathy is selected from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt- Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, Tangle-only dementia, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, or globular glial tauopathies (GGT).

[0052] The neurodegenerative synucleinopathy can be Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, or Lewy body dementia.

[0053] Compounds for the Modulation of Tau, Reduction of Tau Levels, Prevention of Tau from Becoming Elevated, Prevention of Tau Tangles, Treatment of a Tauopathy, and Prevention of a Neurodegenerative Disease.

[0054] The disclosed compounds can modulate tau in a patient. The disclosed compounds can be used to modulate tau in any region of the body where tau can be found. In particular, the disclosed compounds can be used to modulate tau found in the brain. Additionally, the disclosed compounds can also deliver progranulin, a fragment of progranulin, and / or at least one granulin protein across the BBB with a long enough half-life to persist in the brain and / or CSF. The disclosed compounds comprise a progranulin domain, a TfRl binding domain, and optionally an albumin binding domain. The disclosed compounds can also comprise a progranulin domain, X; a TfRl binding domain, Y, linked to X with a first linker, Li; and an albumin domain, Z, linked to X or Y with a second linker, L2, such as shown in Formula I or II.Y-LrX-L2-ZFormula I.

[0055] In some embodiments, the compounds can be represented by Formula I. The TfRl binding domain, Y, can be linked to the progranulin domain, X, with a first linker, Li. The TfRl binding domain can be attached to the progranulin domain at the N-terminus or the C- terminus of the progranulin domain. The albumin binding domain, Z, can be linked to the progranulin domain with a second linker L2 at the N-terminus or the C-terminus of the progranulin domain. The TfRl binding domain and the albumin binding domain can be linked at opposite ends of the progranulin domain. For example, the TfRl binding domain can be linked at or within 5 amino acids of the N-terminus of the progranulin domain while the albumin binding domain can be linked at or within 5 amino acids of the C-terminus of the progranulin domain, or the TfRl binding domain can be linked at or within 5 amino acids of the C-terminus of the progranulin domain while the albumin binding domain can be linked at or within 5 amino acids of the N-terminus of the progranulin domain.Z-L2-Y-LrXFormula II. Compound

[0056] In some embodiments, the compounds can be represented by Formula II. The progranulin domain, X, can be linked to the TfRl binding domain, with a first linker, Li. The progranulin domain can be attached to the TfRl binding domain at the N-terminus or the C-terminus of the TfRl binding domain. The albumin binding domain, Z, can be linked to the TfRl binding domain with a second linker L2 at the N-terminus or the C-terminus of the progranulin domain. The progranulin domain and the albumin binding domain can be linked at opposite ends of the TfRl binding domain. For example, the progranulin domain can be linked at or within 5 amino acids of the N-terminus of the TfRl binding domain while the albumin binding domain can be linked at or within 5 amino acids of the C-terminus of the TfRl binding domain, or the progranulin domain can be linked at or within 5 amino acids of the C-terminus of the TfRl binding domain while the albumin binding domain can be linked at or within 5 amino acids of the N-terminus of the TfRl binding domain.

[0057] In some embodiments, the progranulin domain and the albumin binding domain can be linked at either the same end or opposite ends of the TfRl binding domain.

[0058] In some embodiments, the progranulin domain, X, can be linked to the TfRl binding domain, with a first linker, Li. The progranulin domain can be attached to the TfRl binding domain at the N-terminus or the C-terminus of the TfRl binding domain. The albumin binding domain, Z, can be linked to the TfRl binding domain with a second linker L2 at the N-terminus or the C-terminus of the progranulin domain. The progranulin domain and the albumin binding domain can be linked at the same end of the TfRl binding domain. For example, the progranulin domain and the albumin binding domain can be linked at or within 5 amino acids of the N-terminus or the C-terminus of the TfRl binding domain.

[0059] In some embodiments, the progranulin domain can be linked to the heavy chain or the light chain of the TfRl binding domain.

[0060] In some embodiments, the compounds are made from one or more polypeptide and / or protein sequences. Thus, in some embodiments, the compound can also be a fusion protein. In some embodiments, the compound is a polypeptide, a protein, and / or a fusion protein.

[0061] In some embodiments, any two of the progranulin domain, the TfRl binding domain, and / or albumin binding domain do not form a dimer. For example, in some embodiments, even when the TfRl binding domain and the albumin binding domain are at the same end of the progranulin domain, they do not interact to form a TfRl binding domain-albumin binding domain dimer. The dimer can be a heterodimer, such as an Fc heterodimer.

[0062] In some embodiments, the compound comprises a heavy chain comprising SEQ ID NO: 25, SEQ ID NO: 26, and / or SEQ ID NO: 29. In some embodiments, the compound comprises light chain comprising SEQ ID NO: 19, SEQ ID NO: 32, and / or SEQ ID NO: 33.

[0063] In some embodiments, the compound comprises a heavy chain comprising SEQ ID NO:25. In some embodiments, the compound comprises a light chain comprising SEQ ID NO: 19.

[0064] In some embodiments, the compound comprises a heavy chain comprising SEQ ID NO:26. In some embodiments, the compound comprises a light chain comprising SEQ ID NO: 19.

[0065] In some embodiments, the compound comprises a heavy chain comprising SEQ ID NO: 29. In some embodiments, the compound comprises a light chain comprising SEQ ID NO: 32.

[0066] In some embodiments, the compound comprises a heavy chain comprising SEQ ID NO: 29. In some embodiments, the compound comprises a light chain comprising SEQ ID NO: 33.

[0067] In some embodiments, the compound comprises a heavy chain with an amino acid sequence having at least 90%, 95%, and / or 99% sequence identity to the amino acid sequence given by SEQ ID NO: 25, SEQ ID NO: 26, and / or SEQ ID NO: 29.

[0068] In some embodiments, the compound comprises a light chain with an amino acid sequence having at least 90%, 95%, and / or 99% sequence identity to the amino acid sequence given by SEQ ID NO: 19, SEQ ID NO: 32, and / or SEQ ID NO: 33.

[0069] Progranulin Domain

[0070] The disclosed compounds include a progranulin domain. The progranulin domain is the portion of the disclosed compounds that include the amino acid sequence representing at least one unmodified, naturally occurring, and / or wildtype granulin protein. Progranulin is a precursor protein for granulin proteins, which are cleaved from the full-length progranulin precursor. Progranulin includes a pro-protein (p) followed by 7 granulin protein sequences: G- F-B-A-C-D-E.

[0071] The progranulin domain can include at least one, at least two, at least three, at least four, at least 5, at least 6, or all 7 unmodified granulin protein(s).

[0072] The progranulin domain can include the full-length unmodified progranulin sequence including the pro-protein and all 7 granulin proteins: p-G-F-B-A-C-D-E, which is described in SEQ. ID NO: 1.

[0073] The progranulin domain can include fragments of the full-length sequence of progranulin. For example, the progranulin domain can include the progranulin fragment known as B-A-C-D-E, or PGRNApGF, which is described in SEQ. ID NO: 2. The progranulin domain can also include other fragments of progranulin, such as, for example, p-G-F, G-F-B-A-C-D-E, among others.

[0074] The progranulin domain can include an unmodified, wild-type, and / or naturally occurring progranulin sequence or a fragment thereof. In some embodiments, the progranulin domain does not include and / or is free of modified granulin protein sequences that do not naturally exist.

[0075] It has been unexpectedly found that when the progranulin domain included a fragment of progranulin, i.e. a progranulin fragment or PGRNApGF, which is described in SEQ. ID NO: 2, the compound remained stable longer than when the progranulin domain included a full length progranulin sequence. While not wishing to being bound by theory, it is believed that the fragment of full length progranulin, PGRNApGF, had a longer stability due to a decrease in clipping present in a smaller progranulin domain.

[0076] The progranulin fragment can have a length of less than 550 residues, less than 500 residues, from 100 residues to 500 residues, from 350 residues to 450 residues, from 400 residues to 425 residues, or 414 residues.

[0077] TfRl Binding Domain

[0078] The disclosed compounds can also include a transferrin receptor 1 (TfRl) binding domain. The TfRl binding domain is a portion of the compound that specifically binds to a TfRl receptor and / or a patient TfRl receptor. TfRl receptors are found in neurons and glial cells, thus, while not wishing to being bound by theory, it is believed that attaching a TfRl binding domain with high binding affinity to TfRl receptors to a progranulin domain, the penetration across the blood brain barrier (BBB) is enhanced relative to a progranulin sequence that is not attached to a TfRl binding domain. It is further believed that if delivery of the progranulin domain across the BBB is enhanced, it can allow for peripheral dosing to a patient deficient in progranulin.

[0079] The TfRl binding domain can be a peptide, a protein, an antibody, a fragment of an antibody, a Fc region, a Fab region, a single domain antibody, or combinations thereof. The TfRl binding domain can include a Fab region. The TfRl binding domain can also not include and / or be free of an Fc region.

[0080] The TfRl binding domain can also be described by its affinity to a TfRl receptor. The TfRl binding domain can have an affinity to a patient TfRl receptor of from about 1 nM to about 100 nM, from about 1 nM to about 50 nM, less than 100 nM, greater than 1 nM to less than 20 nM, from about 5 nM to less than 20 nM, from about 5 nM to about 20 nM, about 10 nM, or 10 nM. Preferably, the affinity of the TfRl binding domain can be about 10 nM or 10nM. Normally, it would be expected that the transport across the BBB would be maximized as the affinity concentration of the TfRl binding domain decreases. Unexpectedly, it has been found that transport across the BBB is maximized when the affinity is less than 20 nM, but greater than 1 nM or about 10 nM.

[0081] In some embodiments, the TfRl binding domain can have a heavy chain comprising SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, and / or SEQ ID NO: 18. In some embodiments, the TfRl binding domain can have a light chain comprising SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and / or SEQ ID NO: 22.

[0082] In some embodiments, the TfRl binding domain has a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 19.

[0083] In some embodiments, the TfRl binding domain has a heavy chain comprising SEQ ID NO: 16 and a light chain comprising SEQ ID NO: 20.

[0084] In some embodiments, the TfRl binding domain has a heavy chain comprising SEQ ID NO: 17 and a light chain comprising SEQ ID NO: 21.

[0085] In some embodiments, the TfRl binding domain has a heavy chain comprising SEQ ID NO: 18 and a light chain comprising SEQ ID NO: 22.

[0086] In some embodiments, the TfRl binding domain can include an amino acid sequence having at least 90%, 95%, and / or 99% sequence identity to the amino acid sequence given by SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and / or SEQ ID NO: 22.

[0087] In some embodiments, a suitable TfRl binding domain can be defined by its complementary determining regions (CDRs), which are the regions of the domain that are believed to interact with the TfRl receptor. Suitable CDRs for the heavy chain of the TfRl binding domain can comprise SEQ ID NO: 45, SEQ ID NO: 46, and / or SEQ ID NO: 47. Suitable CDRs for the light chain of the TfRl binding domain can comprise SEQ ID NO: 48, SEQ ID NO: 49, and / or SEQ ID NO: 50.

[0088] In some embodiments, the TfRl binding domain comprises one or more of SEQ ID NO: 45-50.

[0089] In some embodiments, the TfRl binding domain comprises SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49 and SEQ ID NO: 50.

[0090] some embodiments, a suitable TfRl binding domain can comprise the CDRs described in TABLE A.TABLE A. Example Sequences of CDRs that Bind TfRlCDRs of TABLE A are defined as described in North, with the exception of HCDR2 which is defined as described in Kabat. (Kabat, et al., Ann. NY Acad. Set. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication NO: 91-3242 (1991)), and North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)).

[0091] TABLE A-l. Example Sequences of CDRs that Bind TfRlThe CDRs of TABLE A-l are defined according to methods well known to a person of ordinary skill in the art including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901- 917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0092] Albumin Binding Domain

[0093] The disclosed compounds can also include an albumin binding domain. The albumin binding domain is a portion of the compound that specifically binds albumin and / or human serum albumin. In some embodiments, the albumin binding domain binds human serum albumin, but also binds to serum albumins of other species, such as, but not limited to, mouse, rat, and cynomolgus monkey.

[0094] It has been expectedly found that by attaching the albumin binding domain to the C- terminus of the progranulin domain, that the half-life of the progranulin domain with be improved and / or the transport of the progranulin domain across the BBB will be improved. While not wishing to being bound by theory, it is believed that the half-life of the progranulin domain is improved because the albumin binding domain attachment at the C-terminus of the progranulin domain will prevent C-terminus clipping of the progranulin domain and / or allow for the progranulin to be recycled through the albumin turnover process.

[0095] In some embodiments, the albumin binding domain is attached to the C-terminus of the progranulin domain through a linker, such as Li or L2.

[0096] The albumin binding domain can be a peptide, a protein, an antibody, a fragment of an antibody, a Fc region, a Fab region, a single domain antibody, or combinations thereof. Preferably, the albumin binding domain can be a single domain antibody, such as a VHH.

[0097] In some embodiments, the albumin binding domain can be represented by SEQ ID NO: 23 or SEQ ID NO: 24.

[0098] In some embodiments, the albumin binding domain can include an amino acid sequence having at least 90%, 95%, and / or 99% sequence identity to the amino acid sequence given by SEQ ID NO: 23 or SEQ ID NO: 24.

[0099] In some embodiments, a suitable albumin binding domain can be defined by its complementary determining regions (CDRs), which are the regions of the domain that are believed to interact with albumin. Suitable CDRs for the albumin binding domain can comprise SEQ ID NO: 51, SEQ ID NO: 52, and / or SEQ ID NO: 53.

[0100] In some embodiments, the TfRl binding domain comprises SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

[0101] In some embodiments, a suitable albumin binding domain can comprise the CDRs described in TABLE B.

[0102] TABLE B. Example Sequences of CDRs that Bind AlbuminCDRs are defined as described in North, with the exception of CDR2 which is defined as described in Kabat. (Kabat, et al., ^4««. NY Acad. Set. 190:382-93 (1971); Kabat et al., Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH PublicationNO: 91-3242 (1991)), and North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)).

[0103] Linker

[0104] The disclosed compounds include one or more linkers, Li, L2, L3, etc. The linkers are used to connect the progranulin domain, the TfRl binding domain, and the albumin binding domain to one another. In some embodiments, the disclosed compounds have one linker, two linkers, three linkers, or from one to three linkers.

[0105] In some embodiments, a first linker, Li, connects the TfRl binding domain, Y, to the progranulin domain, X. In some embodiments, a second linker, L2, connects the albumin binding domain, Z, to the progranulin domain, X, or the TfRl binding domain, Y. In some embodiments, Li and L2 are identical. In some embodiments, Li and L2 are not identical.

[0106] The linker(s) can independently comprise a covalent bond, a peptide linker, a PEG linker, a disulfide bond, a thioacetal linkage, or a thioester linkage. The linker(s) can be independently selected from covalent bond, a peptide linker, a PEG linker, a disulfide bond, a thioacetal linkage, and a thioester linkage.

[0107] In some embodiments, the linker(s) is a peptide linker. Suitable peptide linkers include peptides of from 2 to 50 amino acids in length. Other suitable peptide linkers include (G4U)n, wherein U is any suitable amino acid and n is a whole digit integer from 1 to 10. Suitable amino acids that can be represented by U include glutamine (Q), serine (S), asparagine (N), alanine (A), among others. Preferably, the linker(s) is (G4Q)nor (G4S)nwherein n is from 3 to 5.

[0108] In some embodiments, the linker(s) can be represented by one or more of SEQ ID NO: 5-14.

[0109] In some embodiments the first linker and the second linker can be represented by SEQ ID NO: 7.

[0110] In some embodiments, the linker(s) is a PEG linker. Suitable PEG linkers include those represented by Formula III, wherein n is a whole number integer from 1 to 10.Formula III. PEG Linker

[0111] Other suitable peptide linkers include DKT(G4U)n, wherein U is any suitable amino acid and n is a whole digit integer from 1 to 10. Suitable amino acids that can be represented by Uinclude glutamine (Q), serine (S), asparagine (N), alanine (A), among others. In some embodiments, the linker(s) is DKT(G4Q)nor DKT(G4S)nwherein n is from 3 to 5.

[0112] Compositions and Routes of Administration

[0113] The compounds of the present invention can be used as medicaments in human medicine, administered by a variety of routes. Most preferably, such compositions are for parenteral administration. Such pharmaceutical compositions can be prepared by methods well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, 19th ed. (1995), A. Gennaro et al., Mack Publishing Co.) and comprise the compounds as disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0114] Definitions

[0115] The term “antibody,” as used herein, refers to an immunoglobulin molecule that binds an antigen. Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, bispecific or multispecific antibody, or conjugated antibody. The antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4).

[0116] An exemplary antibody of the present disclosure is an immunoglobulin G (IgG) type antibody comprised of four polypeptide chains: two heavy chains (HC) and two light chains (LC) that are cross-linked via inter-chain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region. The IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).

[0117] The VH and VL regions can be further subdivided into regions of hyper-variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxylterminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the threeCDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specific interactions with the antigen. Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0118] Embodiments of the present disclosure also include antibody fragments or antigenbinding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, scFab, disulfide-linked Fvs (sdFv), a Fd fragment.

[0119] The terms “bind” and “binds” as used herein are intended to mean, unless indicated otherwise, the ability of a binding domain of a compound to form a chemical bond or attractive interaction with another protein or molecule, which results in proximity of the two proteins or molecules as determined by common methods known in the art.

[0120] The term “progranulin domain” refers to a portion of a compound, or polypeptide sequence, of the present disclosure that includes the amino acid sequence representing at least one unmodified, or wildtype granulin protein. In some embodiments, the progranulin domain can include the amino acid sequence representing up to all seven granulin proteins and the proprotein naturally contained in progranulin. In some embodiments, the progranulin domain can include the amino acid sequence representing more than one, but less than the seven granulin proteins and the pro-protein naturally contained in progranulin, i.e. a progranulin fragment. In one non-limiting example, the progranulin domain is represented by the amino acid sequence corresponding to SEQ ID NO: 1, SEQ ID NO: 2 and / or SEQ ID NO: 3. In another non-limited example, the progranulin domain excludes SEQ ID NO: 4.

[0121] The term “TfRl binding domain” refers to an antibody, a portion of an antibody, a portion of a compound, or a polypeptide sequence, that binds a transferrin receptor, i.e. TfRl.

[0122] The term “albumin binding domain” refers to an antibody, a portion of an antibody, a portion of a compound, or a polypeptide sequence, that binds albumin. In one non-limiting example, albumin binding domain refers to a portion of a compound of the present disclosure that binds to human serum albumin.

[0123] As used interchangeably herein, the term “patient,” “subject,” and “individual,” refers to an animal, such as a human. In certain embodiments, the patient is further characterized with a CNS disease, disorder, or condition (for example, a CNS neurodegenerative disorder). In some embodiments, the patient may be further characterized as being at risk of developing a CNS disorder, disease, or condition.

[0124] As used herein, a “Fab” means a fragment antigen-binding region of an antibody. Additionally, as used herein, the Fab region includes a heavy chain, which is linked to another portion of the disclosed compound, such as a linker, progranulin domain, TfRl binding domain, and / or albumin binding domain. The Fab region also includes a light chain, which is covalently bonded to the heavy chain.

[0125] As used herein, a “single-domain antibody” is an antibody fragment consisting of a single monomeric variable antibody chain. The single-domain antibody includes an antigenbinding region.

[0126] As used herein, a “VHH fragment” is a single-domain antibody that is engineered from heavy-chain antibodies found in camelids.

[0127] As used herein, the term “peptide” or “peptide chain”, refers to a polymer comprising two (2) or more amino acids and / or amino acid derivatives which, in general, are linked via peptide bonds. Embodiments of peptides may include modifications or amino acid derivatives, including post-translational modifications such as, phosphorylation, hydroxylation, sulfonation, palmitoylation, glycosylation and disulfide formation.

[0128] The term, “linked to” or “linked with”, as used herein, refers to a first nucleotide (or polynucleotide) or peptide being associated, attached, connected or otherwise joined to a second nucleotide (or polynucleotide) or peptide. For example, a first polynucleotide can be linked to a second polynucleotide sequence such that they form a fusion peptide or protein when the sequence is translated. Likewise, a first peptide sequence can be linked to a second peptide sequence via covalent or non-covalent interactions to form a multimeric peptide. Alternatively, “linked to” or “linked with” refers to a nucleotide (or polynucleotide sequence) or peptide that is associated, connected or joined to a non-nucleotide or non-peptide moiety. For example, a peptide may be linked to a fatty acid moiety (i.e., acylated) to form a conjugated peptide.

[0129] The term “conjugate group,” as used herein, refers to a group that is attached or linked to a peptide. Conjugate groups can include a conjugate moiety and a conjugate linker for attaching or linking the conjugate moiety to the peptide.

[0130] The term “conjugate linker,” as used herein, refers to an atom, group of atoms, molecule or compound (such as an amino acid or group of amino acids) comprising at least one bond that attaches or links a conjugate moiety to a peptide herein.

[0131] The term “conjugate moiety,” as used herein, means a molecule or compound, especially a non-peptide molecule or compound, that is attached or linked to a peptide herein either directly or via a conjugate linker.

[0132] The terms “treatment,” “treating” or “to treat” and the like include restraining, slowing, or stopping the progression or severity of an existing symptom, condition, disease, or disorder in a patient.

[0133] The term “prevention” means prophylactic administration of the compound of the present disclosure to an asymptomatic subject or a subject with a pre-clinical neurodegenerative disease or tauopathy to prevent onset or progression of the disease.EXAMPLES

[0134] EXAMPLE 1 - Expression of Disclosed Compounds

[0135] The compounds of TABLE I and 2 can be expressed essentially as follows. An appropriate host cell, such as HEK 293 or CHO, can be either transiently or stably transfected with an expression system for secreting antibodies using an optimal predetermined HC:LC vector ratio (such as 1 :3, 1 :2, 1 : 1) or a single vector system encoding both the HC and the LC.

[0136] Purification of kappa designs

[0137] To assess the purification properties of the CI pool, IL of sCHO supernatant containing the CI were purified using a 3-column process. Supernatant was applied to a ~60 mL prepacked CaptoL resin column preequilibrated with 20 mM Tris (pH 7.0). Column with loaded supernatant was subsequently washed with 5 column volumes of 20 mM Tris (pH 7.0). mAh was eluted from CaptoL resin by applying 5 column volumes of a mixed acid elution buffer (20 mM Acetic acid, 5 mM Citric acid). CaptoL elution pool was neutralized to pH 5 with 0.5 M Tris base, centrifuged and applied to a 0.22-micron sterile filter. This CaptoL purified material was further purified by PrismA resin affinity purification. CaptoL pool was adjusted to pH~7 using IM Tris pH7.5 and was applied to a 58 mL PrismA prepacked column preequilibrated in 50 mM Tris (pH8.0), washed with 5 column volumes of equilibration buffer, and eluted with 5 column volumes of a mixed acid elution buffer (20 mM Acetic acid, 5 mM Citric acid). PrismA pool was neutralized to pH~5 using 0.5M Tris base. Pool was further purified using Cation Exchange chromatography (CEX). CaptoL pool was loaded onto a 70 mL prepacked Poros HS50 CEX column equilibrated in 20mM Acetate, pH5, and eluted with same buffer supplemented with IM NaCl with a 5-60% linear gradient over 15 column volumes. Subsequently, eluted fractions containing monomer were pooled, sterile filtered and dialyzed into PBS overnight at 4 C. Following dialysis, protein was sterile filtered and protein concentration / yield was determined at A280 using the calculated extinction coefficient. This sCHO material was used to all developability and HCP protein analysis.

[0138] TABLE 1. Kappa Designs Expressed and Purified

[0139] Purification of sandwich designs

[0140] To assess the purification properties of the CI pool, 3L of sCHO supernatant containing the CI were purified using a 3-column process. Supernatant was applied to a -138 mL prepacked PrismA resin column preequilibrated with 50 mM Tris (pH 8.0). Column with loaded supernatant was subsequently washed with 5 column volumes of 50 mM Tris (pH 8.0). mAb was eluted from PrismA resin by applying 5 column volumes of a mixed acid elution buffer (20 mM Acetic acid, 5 mM Citric acid). PrismA elution pool was neutralized to pH 5 with 0.5 M Tris base, centrifuged and applied to a 0.22-micron sterile filter. This PrismA purified material was further purified by CaptoL resin affinity purification. PrismA pool was adjusted to pH~7 using IM Tris pH7.5 and was applied to a 120 mL CaptoL prepacked column preequilibrated in 20 mM Tris pH7, washed with 5 column volumes of equilibration buffer, and eluted with 5 column volumes of a mixed acid elution buffer (20 mM Acetic acid, 5 mM Citric acid). CaptoL pool was neutralized to pH~5 using 0.5M Tris base. Pool was further purifiedusing Cation Exchange chromatography (CEX). CaptoL pool was loaded onto a 70 mL prepacked Poros HS50 CEX column equilibrated in 20mM Acetate, pH5, and eluted with same buffer supplemented with IM NaCl with a 5-60% linear gradient over 15 column volumes. Subsequently, eluted fractions containing monomer were pooled, sterile filtered and dialyzed into PBS overnight at 4 C. Following dialysis, protein was sterile filtered and protein concentration / yield was determined at A280 using the calculated extinction coefficient. This sCHO material was used to all developability and HCP protein analysis.

[0141] TABLE 2. Sandwich Designs Expressed and Purifiedlinker used for Connection Between TfRl Binding Domain / / Progranulin Domain and Progranulin Domain / / Albumin Binding Domain

[0142] Expression and Purification of Fc Examples. tCHO or HEK293 supernatants were applied to a PrismA resin column preequilibrated with 50 mM Tris (pH 8.0). Column with loaded supernatant was subsequently washed with 5 column volumes of 50 mM Tris (pH 8.0). mAb was eluted from PrismA resin by applying 5 column volumes of a mixed acid elution buffer (20 mM Acetic acid, 5 mM Citric acid) and the arginine-succinate buffer (1 M arginine, 685 mM succinic acid pH 5.0) was added to adjust the pH. Protein aggregates were removed using size exclusion chromatography (SEC) on Superdex 200 increase 26 / 60 GL column using arginine-succinate pH 5.0 buffer.

[0143] TABLE 3. Examples

[0144] Example 2 - Impact of PGRN compound treatment on Tau protein levels in wildtype mice

[0145] To investigate the effect of PGRN supplementation on Tau protein homeostasis under normal condition, wildtype FVB mice were treated with PGRN comparative Ex. 1 or Kappa ex.5 compound weekly at a concentration of 5mg per kg. Brain hemispheres were harvested 7 days after the second dose. Total tau concentration was determined in both phosphate-buffered saline (PBS) buffer soluble fraction and RIP A (a buffer used to lyse membrane structures) soluble fractions by ELISA.

[0146] Table 4 shows total tau concentration (in ng per g of wet weight) in PBS soluble fraction and RIPA soluble fraction of brain hemispheres of FVB mice after treatment.

[0147] Table 4.

[0148] Table 4 shows that the mice treated with Fc Ex. 1 and / or Kappa Ex. 5, which both contain a progranulin domain, had an about 15% reduction in the total tau concentration relative to the untreated Vehicle leg. Thus, the treatment of mice with a compound comprising a progranulin domain led to an up to 15% reduction in total tau concentration in wildtype mice.

[0149] Example 3 - PGRN treatment reduced pathological Tau in Tau transgenic mice rTg4510 mice.

[0150] 6-month old rTg4510 mice were treated with Kappa Ex. 6 every other week at 5mg per kg body weight. Prior to the treatment, rTg4510 mice were treated with anti-CD4 antibody GK1.5 at lOmg per kg body weight to reduce the induction of anti-drug antibody. A subgroup of mice was taken down at the beginning of the study as Time 0 group to assess baseline pathology. Doxycycline (Dox) administration led to the reduction of human MAPT transgene overexpression and was used as positive control. Volume matric MRI (vMRI) was measured at week 0, week 6, week 12 and week 17 after initial treatment. Mice were taken down at week 18 to assess accumulation of pathological tau in the brain.

[0151] To assess accumulation of pathological tau, cortical tissues were homogenized in H buffer (a high salt buffer) and soluble and insoluble fraction of protein homogenates were collected and analyzed for AT8+ and total tau by ELISA (Table 5). Soluble tau oligomers are more closely associated with neuronal loss, impact of compound comprising progranulin on brain atrophy as the downstream effect of tau toxicity was examined by vMRI. Brain volume changes were normalized to baseline and summarized in Table 6.

[0152] Table 5

[0153] Table 5 shows that transgenic mice without treatment had a level of elevated tau concentration of 518533 ng / g while transgenic mice that had been treated with a positive control had a total level of tau of 171974 ng / g. Transgenic mice that had been treated with Kapp Ex. 6 had a reduced level of tau of 330274 ng / g, which corresponded to a reduction of tau of 36.3% relative to the Normal Feed. As such, treatment with compounds comprising a progranulin domain and a TfRl binding domain can lead to a reduction in the total levels of tau by at least 15 %, at least 25 %, at least 30%, or at least 35% relative to the original levels of tau found in a patient having elevated tau.

[0154] Table 6SEQUENCE LISTINGProgranulin SequencesSEQ ID NO: 1 - Human ProgranulinTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSAGHSCIF TVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECP DFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHPLAKKL PAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQ DTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGC CPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEI VAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQ HCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRD NRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQL LSEQ ID NO: 2 - Human Progranulin APGFTPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNA TCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYT CCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHL SLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQ LPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWD APLRDPALRQLLSEQ ID NO: 3 - PGRNdesQLLTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSAGHSCIF TVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECP DFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHPLAKKL PAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLQDPALRSEQ ID NO: 4 - Human Progranulin with QLL altered to PIL at amino acid residue number 574-576TRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRPILPeptide LinkersSEQ ID NO: 5 - (G4Q)iGGGGQSEQ ID NO: 6 - (G4Q)2GGGGQGGGGQSEQ ID NO: 7 - (G4Q)3GGGGQGGGGQGGGGQSEQ ID NO: 8 - (G4Q)4GGGGQGGGGQGGGGQGGGGQSEQ ID NO: 9 - (G4Q)5GGGGQGGGGQGGGGQGGGGQGGGGQSEQ ID NO: 10 - (G4S)iGGGGSSEQ ID NO: 11 - (G4S)2GGGGSGGGGSSEQ ID NO: 12 - (G4S)3GGGGSGGGGSGGGGSSEQ ID NO: 13 - (G4S)4GGGGSGGGGSGGGGSGGGGSSEQ ID NO: 14 - (G4S)5GGGGSGGGGSGGGGSGGGGSGGGGSHeavy Chains of Fab as TfRl Binding DomainSEQ ID NO: 15 - H09 Fab Heavy ChainEVQLVESGGGL VKPGGSLRLSC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDNWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTSEQ ID NO: 16 - H3.03 Fab Heavy ChainEVQLVESGGGL VKPGGSLRLSC VASGFTFS S YSMNWVRQ APGKGLEWVS SISRS S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIHGYSNSDAFDKWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGL YSLS S VVT VP S S SLGTQT YICNVNHKP SNTKVDKKVEPKSCDKTHTSEQ ID NO: 17 - 8d3 Fab Heavy ChainEVQLVESGGGL VQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSK MNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVS VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS SWT VP S S SLGTQT YICNVNHKP SNTKVDKKVEPKSCDKTHTSEQ ID NO: 18 - 10E10 Fab Heavy ChainQSLEESGGDLVKPEGSLTLTCTASGFSFSGSYWICWVRQAPGKGLEWIGCIYSTSGGRT YYASWVKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGDDSISDAYFDLWGPGTLV TVSSASTKGPCVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS S VVT VP S S SLGTKT YTCNVDHKP SNTKVDKRVESK YGPPLight Chains of Fab as TfRl Binding DomainSEQ ID NO: 19 -H09 Fab Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 20 -8D3 Fab Light ChainDIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVP SRFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 21 - H3.03 Fab Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISNYLAWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 22 -10E10 Fab Light ChainALDMTQTASPVSAAVGGTVTINCQSSQSVYNNNRLAWYQQKPGQPPKLLIYDASTLAS GVPSRFKGSGSGTQFTLTISGVQSDDSATYYCQGTYFSSGWSWAFGGGTEVVVKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSK DSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECVHH as Albumin Binding DomainSEQ ID NO: 23 - C90.43 VHHEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDIT YYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCGARPGRPLITSKVADLYPYW GQGTLVTVSSPPSEQ ID NO: 24 - C80.43 VHHEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDIT YYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCAARPGRPLITSKVADLYPYW GQGTLVTVSSPPSandwich PGRN PayloadSEQ ID NO: 25 - Heavy Chain of H09 Fab - PGRN - C90.43E VQLVESGGGL VKPGGSLRLSC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDNWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTGGG GQGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQ VDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNS VGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTR CITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPN ATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGY TCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAH LSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQ LPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWD APLRDPALRQLLGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYID ETAVAWFRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCGARPGRPLITSKVADLYPYWGQGTLVTVSSPPSEQ ID NO: 26 - H09 Fab - PGRNApGF - C90.43 Heavy ChainE VQLVESGGGL VKPGGSLRLSC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDNWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTGGGGQ GGGGQGGGGQTPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSG KYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKC DMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQ VPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSD HQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCC PSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHV GVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARG TKCLRREAPRWDAPLRDPALRQLLGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGS LRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNS KNTLYLQMNSLRPEDTAVYYCGARPGRPLITSKVADLYPYWGQGTLVTVSSPPSEQ ID NO: 27 - 8D3-PGRN-C90.43 Heavy ChainEVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSK MNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVS VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGL YSLS S VVT VP S S SLGTQT YICNVNHKP SNTKVDKKVEPKSCDKTHTGGGG QGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQV DAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSV GAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCI TPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNA TCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYT CCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHL SLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQ LPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGH FCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWD APLRDPALRQLLGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCGARPGRPLITSKVADLYPYWGQGTLVTVSSPPSEQ ID NO: 28 - H3.03-PGRN-C90.43 Heavy ChainEVQLVESGGGLVKPGGSLRLSC VASGFTFS S YSMNWVRQAPGKGLEWVS SISRS S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIHGYSNSDAFDKWGQGTL VTVSSASTKGPCVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ S SGL YSLS SWT VP S S SLGTQT YICNVNHKP SNTKVDKKVEPKSCDKTHTGGGG QGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQV DAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSV GAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCI TPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNA TCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYT CCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHL SLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGH FCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWD APLRDPALRQLLGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYID ETAVAWFRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCGARPGRPLITSKVADLYPYWGQGTLVTVSSPPKappa PGRN PayloadSEQ ID NO: 29 -H09-C90.43 Heavy ChainE VQLVESGGGL VKPGGSLRLSC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDNWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTGGGGQ GGGGQGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAW FRQAPGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCGARPGRPLITSKVADLYPYWGQGTLVTVSSPPSEQ ID NO: 30 - H09 PGRNdesQLL Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGQGGGGQGGGGQGGGGQ GGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSA GHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPD SQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHP LAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHL HCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSG AWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQA LKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQ RGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCC EDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLQDPA LRSEQ ID NO: 31 - H09 PGRNApGF desQLL Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGQGGGGQGGGGQGGGGQ GGGGQTPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCC PMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSC PDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEK APAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQ GYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSW ACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVEC GEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREA PRWDAPLRDPALRSEQ ID NO: 32 - H09 PGRN Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGQGGGGQGGGGQGGGGQ GGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSA GHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPD SQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHP LAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHL HCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSG AWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQA LKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQ RGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCC EDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLQDPA LRQLLSEQ ID NO: 33 - H09 PGRNApGF Light ChainDIQMTQSPSAMSASVGDRVTITCRASQGISHYLVWFQQKPGKVPKRLIYAASSLQSGVP SRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGQGGGGQGGGGQGGGGQ GGGGQTPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCC PMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSC PDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEK APAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQ GYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSW ACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVEC GEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREA PRWDAPLRDPALRQLLSEQ ID NO: 34 - 10E10-C80.43 Heavy ChainQSLEESGGDLVKPEGSLTLTCTASGFSFSGSYWICWVRQAPGKGLEWIGCIYSTSGGRT YYASWVKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGDDSISDAYFDLWGPGTLV TVSSASTKGPCVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQ S SGL YSLS S VVT VP S S SLGTKT YTCNVDHKP SNTKVDKRVESK YGPPGGGGQGGG GQGGGGQGGGGQGGGGQEVQLLESGGGLVQPGGSLRLSCAASGRYIDETAVAWFRQ APGKGREFVAGIGGGVDITYYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCA ARPGRPLITSKVADLYPYWGQGTLVTVSSPPSEQ ID NO: 35 - 10E10 PGRN Light ChainALDMTQTASPVSAAVGGTVTINCQSSQSVYNNNRLAWYQQKPGQPPKLLIYDASTLAS GVPSRFKGSGSGTQFTLTISGVQSDDSATYYCQGTYFSSGWSWAFGGGTEVVVKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGQGGGGQGG GGQGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPC QVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHT RCITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMP NATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDG YTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPA HLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYT CVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEG HFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRW DAPLRDPALRQLLSEQ ID NO: 36 - 10E10 PGRNApGF Light ChainALDMTQTASPVSAAVGGTVTINCQSSQSVYNNNRLAWYQQKPGQPPKLLIYDASTLAS GVPSRFKGSGSGTQFTLTISGVQSDDSATYYCQGTYFSSGWSWAFGGGTEVVVKRAD AAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSK DSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECGGGGQGGGGQGGG GQGGGGQGGGGQTPTGTHPLAKKLP AQRTNRAVALS S S VMCPD ARSRCPDGSTCCEL PSGKYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDV KCDMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGP HQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCC SDHQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQT CCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSP HVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAA RGTKCLRREAPRWDAPLRDPALRQLLSEQ ID NO: 37 - 10E10 R32W (300nM) PGRN Light ChainALDMTQTASPVSAAVGGTVTINCQSSQSVYNNNWLAWYQQKPGQPPKLLIYDASTLA SGVPSRFKGSGSGTQFTLTISGVQSDDSATYYCQGTYFSSGWSWAFGGGTEVVVKRAD AAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSK DSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECGGGGQGGGGQGGG GQGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQ VDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNS VGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTR CITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPN ATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGY TCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAH LSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQ LPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGH FCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQLLSEQ ID NO: 38 - 10E10 T52G PGRN Light Chain (1000 nM)AIDMTQTASPVSAAVGGTVTINCQSSQSVYNNNRLAWYQQKPGQPPKLLIYGASTLAS GVPSRFKGSGSGTQFTLTISGVQCDDSATYYCQGTYFSSGWSWAFGGGTEVVVKRAD AAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSK DSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECGGGGQGGGGQGGG GQGGGGQGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQ VDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNS VGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTR CITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPN ATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGY TCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAH LSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTC VAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQ LPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGH FCHDNQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWD APLRDPALRQLLKnob and HoleSEQ ID NO: 39 - scFv 8D3-hIgGl - LAL A knobEVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKCLEWIAMIYYDSSK MNYADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVS VTVSSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDI GNWLAWYQQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQFSLKISRVQVEDIGIYYC LQAYNTPWTFGCGTKLELKGGGGQGGGGQGGGGQDKTHTCPPCPAPEAAGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 40 - hlgGl LAL A hole-PGRNDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI<TI SKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGS GGGGSTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSA GHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPD SQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHP LAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHL HCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSG AWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQA LKRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQ RGSEIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCC EDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQT CCRDNRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPA LRQLLSEQ ID NO: 41 - 3F5 Light ChainAEVVMTQTPSSVSAAVGGTVTIKCQASQNINSWLSWYQQKPGQRPKLLIYSASTLASG VPSRFEGSGSGTEYTLTISDLECDDAATYYCQSSYGSSYDFGGGTEVVVKGDLVAPTVL IFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLS STLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDCSEQ ID NO: 42 - 3F5 hlgGl LALA knobQVQLVQSGAEVKKPGSSVKVSCTASGFSFSSGYWICWVRQAPGQGLEWMGCIHSVRS HMTYYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARDASGVWNYFTLWG QGTLVTVSSASTKGPCVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFP AVLQ S SGL YSLS S VVT VP S S SLGTKT YTCNVDHKP SNTKVDKRVESK YCPPCP AP EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 43 - stump hlgGl TV LALA knobTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSAGHSCIF TVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECP DFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHPLAKKL PAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGC CPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRD VPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEI VAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRD NRQGWACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQL LGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKSEQ ID NO: 44 - stump hlgGl LALA knobDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<APAPIEI<TIS KAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKTfRl Binding Domain Complementary Determining RegionsSEQ ID NO: 45 - Heavy Chain VH CDR1 - NorthVASGFTFSSYSMNSEQ ID NO: 46 - Heavy Chain VH CDR2 - KabatSIS S S S S YIYYAD S VKGSEQ ID NO: 47 - Heavy Chain VH CDR3 - NorthARRHGYSNSDAFDNSEQ ID NO: 48 - Light Chain Kappa CDR1 - NorthRASQGISHYLVSEQ ID NO: 49 - Light Chain Kappa CDR2 - NorthYAASSLQSSEQ ID NO: 50 - Light Chain Kappa CDR3 - NorthLQHNSYPWTAlbumin Binding Domain Complementary Determining RegionsSEQ ID NO: 51 - C90.43 CDR1AASGRYIDETAVASEQ ID NO: 52 - C90.43 CDR2GIGGGVDITYYADSVKGSEQ ID NO: 53 - C90.43 CDR3GARPGRPLITSKVADLYPYTfRl Binding Domain Variable HeavySEQ ID NO: 54 - H09 Fab VH(HCVR)E VQLVESGGGL VKPGGSLRLSC VASGFTF S S YSMNWVRQ APGKGLEW VS SIS S S S S YIY YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRHGYSNSDAFDNWGQGT LVTVSSOther SequencesSEQ ID NO: 55 - His-Tagged PGRNHHHHHHGGGGQGGGGQGGGGQENLYFQSGGGGQTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSR CPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCPQDTVCDLIQSKCLSKENATTDLLT KLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSCPSSDTCCQLTSGEW GCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRASLSHPRDIGC DQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRH CCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQLLAdditional Definitions of the TfRl Binding Domain Complementary Determining RegionsSEQ ID NO: 56 - Heavy Chain VH CDR2 - NorthSISSSSSYIYSEQ ID NO: 57- Heavy Chain VH CDR1 - KabatSYSMNSEQ ID NO: 58- Heavy Chain VH CDR3 - KabatRHGYSNSDAFDNSEQ ID NO: 59 - Light Chain Kappa CDR1 - Kabat RASQGISHYLVSEQ ID NO: 60 - Light Chain Kappa CDR2 - Kabat AASSLQSSEQ ID NO: 61 - Light Chain Kappa CDR3 - Kabat LQHNSYPWTSEQ ID NO: 62 - Heavy Chain VH CDR1 - IMGT GFTFSSYSSEQ ID NO: 63- Heavy Chain VH CDR2 - IMGT ISSSSSYISEQ ID NO: 64- Heavy Chain VH CDR3 - IMGT ARRHGYSNSDAFDNSEQ ID NO: 65 - Light Chain Kappa CDR1 - IMGT QGISHYSEQ ID NO: 66 - Light Chain Kappa CDR2 - IMGTAASSEQ ID NO: 67 - Light Chain Kappa CDR3 - IMGTLQHNSYPWTSEQ ID NO: 68 - Heavy Chain VH CDR1 - ChothiaGFTFSSYSEQ ID NO: 69 - Heavy Chain VH CDR2 - ChothiaSSSSSYSEQ ID NO: 70 - Heavy Chain VH CDR3 - ChothiaRHGYSNSDAFDNSEQ ID NO: 71 - Light Chain Kappa CDR1 - ChothiaRASQGISHYLVSEQ ID NO: 72 - Light Chain Kappa CDR2 - ChothiaAASSLQSSEQ ID NO: 73 - Light Chain Kappa CDR3 - ChothiaLQHNSYPWT

Claims

PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO51CLAIMSWhat is claimed is:

1. A method of preventing, delaying onset of, or reducing the risk of developing a neurogenerative disease in a patient, the method comprising administering to the patient a compound, the compound comprising:(a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and(b) a transferrin receptor 1 (TfRl) binding domain.

2. The method of claim 1, wherein the TfRl binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein the amino acid sequence of HCDR1 is SEQ ID NO: 45, the amino acid sequence of HCDR2 is SEQ ID NO: 46, the amino acid sequence of HCDR3 is SEQ ID NO: 47, the amino acid sequence of LCDR1 is SEQ ID NO: 48, the amino acid sequence of LCDR2 is SEQ ID NO: 49, and the amino acid sequence of LCDR3 is SEQ ID NO: 50.

3. The method of claim 1 or 2, wherein the compound further comprises an albumin binding domain, wherein the albumin binding domain the comprises complementarity determining regions (CDR) CDR1, CDR2, and CDR3, wherein the amino acid sequence of CDR1 is SEQ ID NO: 51, the amino acid sequence of CDR2 is SEQ ID NO: 52, and the amino acid sequence of CDR3 is SEQ ID NO: 53.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO524. The method of claim 3, wherein the TfRl binding domain is linked to the progranulin domain with a first linker and the albumin binding domain is linked to the progranulin domain or the TfRl binding domain with a second linker.

5. The method of claim 3 or 4, wherein the compound is of the formula:Y_L1-X-L2.ZorZ_L2.Y_L1-Xj andwherein X is the progranulin domain,Y is the TfRl binding domain,Z is the albumin binding domain,Li is the first linker, andL2 is the second linker.

6. The method of any one of claims 1 to 5, wherein the TfRl binding domain comprises:(a) a heavy chain, wherein the amino acid sequence of the heavy chain is SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18, and(b) a light chain, wherein the amino acid sequence of the light chain is SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22.

7. The method of any one of claims 1 to 6, wherein the TfRl binding domain comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 15 and the amino acid sequence of the LC is SEQ ID NO: 19.

8. The method of any one of claims 3 to 7, wherein the albumin binding domain is a VHH antibody fragment.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO539. The method of any one of claims 5 to 8, wherein the albumin binding domain is attached to the C-terminus of the progranulin domain through L2.

10. The method of any one of claims 3 to 9, wherein the amino acid sequence of the albumin binding domain is SEQ ID NO: 23 or SEQ ID NO: 24.

11. The method of any one of claims 5 to 10, wherein Li and L2 are independently selected from a covalent bond, a peptide linker, a PEG linker, a disulfide bond, a thioacetal linkage, or a thioester linkage.

12. The method of any one of claims 5 to 11, wherein Li and L2 are identical.

13. The method of any one of claims 5 to 12, wherein the amino acid sequence of Li and L2 are SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO:10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 14.

14. The method of any one of claims 1 to 13, wherein the progranulin domain comprises a fragment of progranulin, wherein the amino sequence of the fragment of progranulin is SEQ ID NO: 2.

15. The method of any one of claims 1 to 13, wherein the amino acid sequence of the progranulin domain is SEQ ID NO: 1.

16. The method of any one of claims 1 to 13, wherein the compound comprises:(a) a heavy chain, wherein the amino acid sequence of the heavy chain is SEQ ID NO: 25, SEQID NO: 26, or SEQ ID NO: 29; andPCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO54(b) a light chain, wherein the amino acid sequence of the light chain is SEQ ID NO: 19, SEQ ID NO: 32, or SEQ ID NO: 33.

17. The method of claim 16, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 25 and the amino acid sequence of the LC is SEQ ID NO: 19.

18. The method of claim 16, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 26 and the amino acid sequence of the LC is SEQ ID NO: 19.

19. The method of claim 16, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 32.

20. The method of claim 16, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 33.

21. The method of any one of claims 1 to 20, wherein the method comprises modulating tau proteins in the patient.

22. The method of any one of claims 1 to 20, wherein the method comprises reducing the amount of tau proteins in a patient having elevated tau proteins.

23. The method of any one of claims 1 to 20, wherein the method comprises reducing the amount of tau proteins in a patient not having elevated tau proteins.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO5524. The method of any one of claims 1 to 20, wherein the method comprises preventing tau tangles in a patient without elevated tau or in a patient having elevated tau.

25. The method of any one of claims 1 to 20, wherein the method comprises preventing tau levels from becoming elevated in a patient without elevated tau.

26. The method of claim 25, wherein the patient is susceptible to experiencing traumatic brain injury.

27. The method of claim 25, wherein the patient recently experienced a traumatic brain injury.

28. The method of any one of claims 1 to 20, wherein the method comprises preventing a neurodegen erative synucleinopathy or a tauopathy.

29. The method of claim 28, wherein the neurodegenerative synucleinopathy comprises Parkinson’s disease, Alzheimer’s disease, multiple system atrophy, or Lewy body dementia.

30. The method of claim 28, wherein the tauopathy comprises Alzheimer’s disease, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Parkinson’s disease, Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degenerationPCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO56(CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, Tangle-only dementia, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, or globular glial tauopathies (GGT).

31. A method of treating a tauopathy in a patient in need of treatment, the method comprising administering to the patient a compound, the compound comprising:(a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and(b) a transferrin receptor 1 (TfRl) binding domain, wherein the tauopathy is selected from the group consisting of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy,PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO57 myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, and globular glial tauopathies (GGT).

32. The method of claim 31, wherein the TfRl binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein the amino acid sequence of HCDR1 is SEQ ID NO: 45, the amino acid sequence of HCDR2 is SEQ ID NO: 46, the amino acid sequence of HCDR3 is SEQ ID NO: 47, the amino acid sequence of LCDR1 is SEQ ID NO: 48, the amino acid sequence of LCDR2 is SEQ ID NO: 49, and the amino acid sequence of LCDR3 is SEQ ID NO: 50.

33. The method of claim 31 or 32, wherein the compound further comprises an albumin binding domain, wherein the albumin binding domain the comprises complementarity determining regions (CDR) CDR1, CDR2, and CDR3, wherein the amino acid sequence of CDR1 is SEQ ID NO: 51, the amino acid sequence of CDR2 is SEQ ID NO: 52, and the amino acid sequence of CDR3 is SEQ ID NO: 53.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO5834. The method of claim 33, wherein the TfRl binding domain is linked to the progranulin domain with a first linker and the albumin binding domain is linked to the progranulin domain or the TfRl binding domain with a second linker.

35. The method of claim 33 or 34, wherein the compound is of the formula:Y-L1-X-L2-ZorZ-L2-Y-Li-X , and wherein X is the progranulin domain,Y is the TfRl binding domain,Z is the albumin binding domain,Li is the first linker, andL2 is the second linker.

36. The method of any one of claims 31 to 35, wherein the TfRl binding domain comprises:(a) a heavy chain, wherein the amino acid sequence of the heavy chain is SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18, and(b) a light chain, wherein the amino acid sequence of the light chain is SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22.

37. The method of any one of claims 31 to 36, wherein the TfRl binding domain comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 15 and the amino acid sequence of the LC is SEQ ID NO: 19.

38. The method of any one of claims 33 to 37, wherein the albumin binding domain is a VHH antibody fragment.

39. The method of any one of claims 35 to 38, wherein the albumin binding domain is attached to the C-terminus of the progranulin domain through L2.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO5940. The method of any one of claims 33 to 39, wherein the amino acid sequence of the albumin binding domain is SEQ ID NO: 23 or SEQ ID NO: 24.

41. The method of any one of claims 35 to 40, wherein Li and L2 are independently selected from a covalent bond, a peptide linker, a PEG linker, a disulfide bond, a thioacetal linkage, or a thioester linkage.

42. The method of any one of claims 35 to 41, wherein Li and L2 are identical.

43. The method of any one of claims 35 to 42, wherein the amino acid sequence of Li and L2are SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 14.

44. The method of any one of claims 31 to 43, wherein the progranulin domain comprises a fragment of progranulin, wherein the amino sequence of the fragment of progranulin is SEQ ID NO: 2.

45. The method of any one of claims 31 to 43, wherein the amino acid sequence of the progranulin domain is SEQ ID NO: 1.

46. The method of any one of claims 31 to 43, wherein the compound comprises:(a) a heavy chain, wherein the amino acid sequence of the heavy chain is SEQ ID NO: 25, SEQID NO: 26, or SEQ ID NO: 29; and(b) a light chain, wherein the amino acid sequence of the light chain is SEQ ID NO: 19, SEQ ID NO: 32, or SEQ ID NO: 33.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO6047. The method of claim 46, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 25 and the amino acid sequence of the LC is SEQ ID NO: 19.

48. The method of claim 46, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 26 and the amino acid sequence of the LC is SEQ ID NO: 19.

49. The method of claim 46, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 32.

50. The method of claim 46, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 33.

51. The method of any one of claims 31 to 50, wherein the method comprises modulating tau proteins in the patient.

52. The method of any one of claims 31 to 50, wherein the method comprises reducing the amount of tau proteins in a patient having elevated tau proteins.

53. The method of any one of claims 31 to 50, wherein the method comprises reducing the amount of tau proteins in a patient not having elevated tau proteins.

54. The method of any one of claims 31 to 50, wherein the method comprises preventing tau tangles in a patient without elevated tau or in a patient having elevated tau.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO6155. The method of any one of claims 31 to 50, wherein the method comprises preventing tau levels from becoming elevated in a patient without elevated tau.

56. The method of claim 55, wherein the patient is susceptible to experiencing traumatic brain injury.

57. The method of claim 55, wherein the patient recently experienced a traumatic brain injury.

58. Use of a compound to prevent a neurodegenerative disease, the compound comprising:(a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and(b) a transferrin receptor 1 (TfRl) binding domain.

59. Use of a compound to treat a tauopathy, the compound comprising:(a) a progranulin domain, the progranulin domain comprising SEQ ID NO: 1 or SEQ ID NO: 2; and(b) a transferrin receptor 1 (TfRl) binding domain, wherein the tauopathy is selected from the group consisting of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), Pick’s disease (PiD), Familial British dementia, Familial Danish dementia, primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), multiple system tauopathy with presenile dementia (MSTD), neurofibrillary tangle (NFT) dementia, FTD with motor neuron disease, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, Guadeloupean parkinsonism, cerebral amyloid angiopathy, chronic traumatic encephalopathy (CTE), corticobasal degenerationPCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO62(CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down’s syndrome, epilepsy, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Huntington’s disease, inclusion body myositis, lead encephalopathy, Lytico-Bodig disease, meningioangiomatosis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, tangle only dementia, tangle-predominant dementia, ganglioglioma, gangliocytoma, SLC9A6-related mental retardation, subacute sclerosingpan encephalitis, White matter tauopathy with globular glial inclusions, tuberous sclerosis, lipofuscinosis, primary age-related tauopathy (PART), Neurodegeneration with brain iron accumulation, and globular glial tauopathies (GGT).

60. The use of claim 58 or 59, wherein the TfRl binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein the amino acid sequence of HCDR1 is SEQ ID NO: 45, the amino acid sequence of HCDR2 is SEQ ID NO: 46, the amino acid sequence of HCDR3 is SEQ ID NO: 47, the amino acid sequence of LCDR1 is SEQ ID NO: 48, the amino acid sequence of LCDR2 is SEQ ID NO: 49, and the amino acid sequence of LCDR3 is SEQ ID NO: 50.

61. The use of any one of claims 58 to 60, wherein the compound further comprises an albumin binding domain, wherein the albumin binding domain the comprises complementarity determining regions (CDR) CDR1, CDR2, and CDR3, wherein the amino acid sequence of CDR1 is SEQ ID NO: 51, the amino acid sequence of CDR2 is SEQ ID NO: 52, and the amino acid sequence of CDR3 is SEQ ID NO: 53.PCT / US25 / 48126 26 September 2025 (26.09.2025)31172WO6362. The use of any one of claims 58 to 61, wherein the compound comprises:(a) a heavy chain, wherein the amino acid sequence of the heavy chain is SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 29; and(b) a light chain, wherein the amino acid sequence of the light chain is SEQ ID NO: 19, SEQ ID NO: 32, or SEQ ID NO: 33.

63. The use of claim 62, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 25 and the amino acid sequence of the LC is SEQ ID NO: 19.

64. The method of claim 62, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 26 and the amino acid sequence of the LC is SEQ ID NO: 19.

65. The method of claim 62, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 32.

66. The method of claim 62, wherein the compound comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the HC is SEQ ID NO: 29 and the amino acid sequence of the LC is SEQ ID NO: 33.

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