Anti-sortilin antibodies for use in therapy - Patent Application 20070122997

Abstract

To provide methods for treating and / or delaying progression of a disease or injury in an individual.SOLUTION: The present disclosure is directed to methods for the use of compositions that include antibodies, e.g., monoclonal, chimeric, affinity-matured, humanized antibodies, antibody fragments, etc., that specifically bind one or more epitopes within a Sortilin protein, e.g., human Sortilin or mammalian Sortilin, and have improved and / or enhanced functional characteristics, in treating and / or delaying progression of a disease or injury in an individual in need thereof.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 860,207, filed June 11, 2019, U.S. Provisional Application No. 62 / 868,850, filed June 28, 2019, U.S. Provisional Application No. 62 / 874,475, filed July 15, 2019, U.S. Provisional Application No. 62 / 947,503, filed December 12, 2019, and U.S. Provisional Application No. 62 / 961,591, filed January 15, 2020, each of which is incorporated by reference in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing in Computer Readable Form (CRF) (Filename: 735022003040SEQLIST.TXT, Date Recorded: June 9, 2020, Size: 135KB).

[0003] The present disclosure relates to therapeutic uses of anti-Sortilin antibodies. [Background technology]

[0004] Sortilin is a type I transmembrane protein that acts as a receptor for several ligands and also functions in sorting designated cargo molecules from the trans-Golgi network (TGN) to late endosomes and lysosomes for degradation. Sortilin binds to the secretory protein progranulin (PGRN) and targets PGRN for lysosomal degradation, thereby negatively regulating its extracellular levels (Hu, F et al. (2010) Neuron 68, 654-667). Accordingly, the absence of sortilin significantly increases plasma PGRN concentrations in both in vivo mouse models and in vitro human cells (Carrasquillo, MM et al. (2010) Am J Hum Genet 87, 890-897; Lee, WC et al. (2014) Hum Mol Genet 23, 1467-1478). Furthermore, it has been shown that sortilin polymorphisms are strongly associated with PGRN serum concentrations in humans (Carrasquillo MM et al., (2010), Am J Hum Genet. 10; 87(6): 890-7).

[0005] Progranulin (PGRN) is a growth factor-like trophic and anti-inflammatory secreted protein that also acts as an adipokine involved in diet-induced obesity and insulin resistance (Nguyen DA et al., (2013). Trends in Endocrinology and Metabolism, 24, 597-606). Progranulin deficiency accounts for approximately 25% of all inherited forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of-function mutations in PGRN have approximately 50% reduction in extracellular levels of the protein and invariably develop FTD, making PGRN the causative gene for this disease (Baker, M et al., (2006) Nature 442, 916-919; Carecchio M et al., (2011) J Alzheimers Dis 27, 781-790; Cruts, M et al., (2008) Trends Genet 24, 186-194; Galimberti, D et al., (2010) J Alzheimers Dis 19, 171-177). In addition, mutant PGRN alleles have been identified in patients with Alzheimer's disease (Seelaar, H et al., (2011) Journal of neurology, neurosurgery, and psychiatry 82, 476-486).Importantly, PGRN acts protectively in multiple disease models, increasing PGRN levels accelerates behavioral recovery from ischemia (Tao, J et al., (2012) Brain Res 1436, 130-136, Egashira, Y. et al., (2013) J Neuroinflammation 10, 105), suppresses gait impairment in Parkinson's disease models (Van Kampen, JM et al. (2014). PLoS One 9, e97032), alleviates pathology in models of amyotrophic lateral sclerosis (Laird, A. S. et al., (2010). PLoS One 5, e13368), and arthritis (Tang, W. et al., (2011). Science 332, 478-484), and prevents memory impairment in Alzheimer's disease models (Minami, S. S. et al. al.,(2014).Nat Med 20,1157-1164).

[0006] Through various interactions with proteins such as progranulin, sortilin and its many ligands have been shown to be involved in a variety of diseases, disorders and conditions, such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis-frontotemporal dementia phenotype, Alzheimer's disease, Parkinson's disease, depression, neuropsychiatric disorders, vascular dementia, seizures, retinal dystrophies, age-related macular degeneration, glaucoma, traumatic brain injury, aging, seizures, wound healing, stroke, arthritis and atherosclerotic vascular disease.

[0007] Novel therapeutic antibodies targeting sortilin are one solution for treating diseases associated with sortilin activity. Systemically administered monoclonal antibodies typically exhibit a biphasic pharmacokinetic profile, initially being relatively rapidly distributed and then slowly eliminated (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). Circulation of systemically administered antibodies is typically limited to the vasculature and interstitial space (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). This is due to their size, polarity, recycling and clearance kinetics, and typically relatively long half-lives (often 11-30 days in humans) (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552).

[0008] Administration of monoclonal antibodies presents challenges for therapeutic use. Because monoclonal antibodies have limited oral bioavailability, they are typically administered intravenously, subcutaneously, or intramuscularly (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). Of these options, subcutaneous administration is the most convenient because it can be performed at home and often by the patient themselves; however, intravenous administration results in higher systemic exposure. Delivery to the cerebrospinal fluid (CSF) requires a high systemic dose. Therefore, if a treatment needs to affect the CSF, intravenous administration is usually required, as subcutaneous administration cannot deliver a sufficiently high dose.

[0009] However, intravenous administration is particularly challenging for patients with neurodegenerative diseases such as FTD and ALS. These diseases affect patients for long periods of time, requiring regular treatment over many years. Because intravenous administration cannot be performed at home, patients must be transported to an infusion center periodically, placing a burden on both patients and caregivers. Finally, memory loss, mood swings, aggression, and other behavioral symptoms of these diseases make patient compliance difficult.

[0010]

[0006] Thus, there is a need for therapeutic antibodies that specifically bind to the Sortilin protein and block binding of Sortilin to its ligands (such as Progranulin) or otherwise modulate the effective concentration of the ligand to treat one or more diseases, disorders, and conditions associated with Sortilin activity. Furthermore, due to limitations in modes of administration and dosing, there is a further need to identify ways to treat patients with the correct dose and administer that dose in a manner that facilitates patient compliance. All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0011] The present disclosure relates generally to methods of using compositions comprising antibodies, eg, monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind to human sortilin.

[0012] In certain aspects, provided herein are methods of treating and / or delaying the progression of a disease or injury in an individual, comprising intravenously administering to the individual an anti-Sortilin antibody at a dose of at least about 30 mg / kg once every four weeks or more, wherein the antibody comprises: (i) a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); and (ii) a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5), and the amino acid sequence RSSQSLLR a light chain variable region comprising HVR-L1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and (iii) a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33). (iv) a light chain variable region comprising an HVR-L1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6), and an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8);a light chain variable region comprising HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29) and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); and (v) a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), and HVR-L3 comprising the amino acid sequence LGSN a light chain variable region comprising HVR-L2 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); and (vi) a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), and HVR-L3 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29). (vii) a light chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and an HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), -L2, and a light chain variable region comprising HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33); or (viii) a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6), and HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), and HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29);and a light chain variable region comprising HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0013] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0014] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0015] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0016] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58.

[0017] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:59.

[0018] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0019] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58.

[0020] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0021] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:77.

[0022] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:78.

[0023] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:79.

[0024] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:80.

[0025] In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-Sortilin antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60.

[0026] In some embodiments, the antibody is of the IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, where the numbering of residue positions is according to EU numbering.

[0027] In some embodiments, the dose is at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, or at least about 60 mg / kg. In some embodiments, the dose is from about 30 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 60 mg / kg.

[0028] In some embodiments, the anti-Sortilin antibody is administered once every two weeks. In some embodiments, the anti-Sortilin antibody is administered once every three weeks. In some embodiments, the anti-Sortilin antibody is administered once every four weeks.

[0029] In some embodiments, the anti-Sortilin antibody is administered at a dose of about 60 mg / kg once every four weeks.

[0030] In some embodiments, the disease or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis. In some embodiments, the disease or injury is frontotemporal dementia. In some embodiments, the disease or injury is amyotrophic lateral sclerosis.

[0031] In some embodiments, the individual is heterozygous for a mutation in GRN. In some embodiments, the mutation in GRN is a loss-of-function mutation. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion. In some embodiments, the individual shows symptoms of frontotemporal dementia. In some embodiments, the individual does not show symptoms of frontotemporal dementia.

[0032] In some embodiments, the level of PGRN protein in the individual's plasma after administration of an anti-Sortilin antibody is at least 1-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the individual's plasma after administration of an anti-Sortilin antibody is at least 2-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the individual's plasma occurs about 5 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the individual's plasma occurs about 42 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the individual's plasma occurs about 56 days after administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the individual's plasma after administration of the anti-Sortilin antibody is at least 0.25-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody about 40 days after administration of the anti-Sortilin antibody.

[0033] In some embodiments, the level of PGRN protein in the individual's plasma after administration of the anti-Sortilin antibody is at least 2-fold, 3-fold, or 4-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 5 days after the last administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of the anti-Sortilin antibody.

[0034] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 0.8-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 1-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 12 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 24 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 56 days after administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 0.2-fold higher about 42 days after administration of the anti-Sortilin antibody than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody.

[0035] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of an anti-Sortilin antibody is at least two-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 12 days after the last administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 24 days after the last administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 28, 35, 42, 49, or 56 days after the last administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 28, 35, 42, 49, or 56 days after the last administration of the anti-Sortilin antibody.

[0036] In some embodiments, the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced by at least 50% compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody. In some embodiments, the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced by at least 70% compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in peripheral leukocytes of the individual is present about 12 days or more after administration of the anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in peripheral leukocytes of the individual is present about 17 days or more after administration of the anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in peripheral leukocytes of the individual is present about 40 days or more after administration of the anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 12 days or more after the last administration of an anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 17 days or more after the last administration of an anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 40 days or more after the last administration of an anti-Sortilin antibody.

[0037] In some embodiments, the half-life of the anti-Sortilin antibody in plasma is about 5 days. In some embodiments, the half-life of the anti-Sortilin antibody in plasma is about 8 days.

[0038] In some embodiments, individuals are treated for a treatment period of up to 48 weeks. In some embodiments, individuals are treated for a treatment period as long as 48 weeks. In some embodiments, administration of the anti-Sortilin antibody occurs on the first day of the treatment period and every four weeks thereafter. In some embodiments, the anti-Sortilin antibody is administered a total of 13 times during the treatment period.

[0039] In some embodiments, the disease or injury is frontotemporal dementia (FTD) and the plasma neurofilament light chain (NfL) level is reduced by at least 10%. In some embodiments, the disease or injury is frontotemporal dementia (FTD) and the plasma neurofilament light chain (NfL) level is reduced by at least 10% after administration of the anti-Sortilin antibody compared to the plasma neurofilament light chain (NfL) level before administration of the anti-Sortilin antibody.

[0040] In some embodiments, the protein level of CTSB in the individual's CSF is increased by at least about 20% compared to the protein level of CTSB in the individual's CSF before administration of the anti-Sortilin antibody. In some embodiments, the protein level of SPP1 in the individual's CSF is decreased by at least about 10% compared to the protein level of SPP1 in the individual's CSF before administration of the anti-Sortilin antibody. In some embodiments, the protein level of CTSB in the individual's CSF is increased by at least about 20% after administration of the anti-Sortilin antibody compared to the protein level of CTSB in the individual's CSF before administration of the anti-Sortilin antibody. In some embodiments, the protein level of SPP1 in the individual's CSF is decreased by at least about 10% after administration of the anti-Sortilin antibody compared to the protein level of SPP1 in the individual's CSF before administration of the anti-Sortilin antibody. In some embodiments, the protein level of N-acetylglucosamine kinase (NAGK) in the individual's CSF is increased after administration of the anti-Sortilin antibody compared to the protein level of NAGK in the individual's CSF before administration of the anti-Sortilin antibody. In some embodiments, the protein level of one or more inflammatory proteins in the CSF of the individual is decreased after administration of the anti-Sortilin antibody compared to the protein level of the one or more inflammatory proteins in the CSF of the individual before administration of the anti-Sortilin antibody, wherein the one or more inflammatory proteins are selected from the group consisting of 14-3-3 protein epsilon (YWHAE), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86.

[0041] In another aspect, provided herein are methods of monitoring treatment of an individual receiving an anti-Sortilin antibody, the methods comprising measuring the level of one or more proteins in a sample from the individual before and after the individual receives one or more doses of the anti-Sortilin antibody, wherein the one or more proteins are CTSB and / or SPP1. In some embodiments, the methods of monitoring treatment of an individual receiving an anti-Sortilin antibody further comprise assessing activity of the anti-Sortilin antibody in the individual based on the level of the one or more proteins in the sample. In some embodiments, the sample is from the individual's cerebrospinal fluid or the individual's blood. In some embodiments, the sample is from the individual's cerebrospinal fluid.

[0042] In another aspect, provided herein are methods of monitoring treatment of an individual receiving an anti-Sortilin antibody, the methods comprising measuring the level of one or more proteins in a sample from the individual before and after the individual receives one or more doses of the anti-Sortilin antibody, wherein the one or more proteins are selected from the group consisting of CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, and CD86. In some embodiments, the method further comprises assessing the activity of the anti-Sortilin antibody in the individual based on the level of the one or more proteins in the sample. In some embodiments, the sample is from the individual's cerebrospinal fluid. In some embodiments, the anti-Sortilin antibody is determined to be active in the individual if the level of CTSB in the cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is increased compared to the level of CTSB in the cerebrospinal fluid before the individual received one or more doses of the anti-Sortilin antibody. In some embodiments, an anti-Sortilin antibody is determined to be active in an individual if the level of CTSB in the cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is increased by at least about 20% compared to the level of CTSB in the cerebrospinal fluid before the individual received one or more doses of the anti-Sortilin antibody. In some embodiments, an anti-Sortilin antibody is determined to be active in an individual if the level of SPP1 in the cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is decreased compared to the level of SPP1 in the cerebrospinal fluid before the individual received one or more doses of the anti-Sortilin antibody. In some embodiments, an anti-Sortilin antibody is determined to be active in an individual if the level of SPP1 in the cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is decreased by about 10% compared to the level of SPP1 in the cerebrospinal fluid before the individual received one or more doses of the anti-Sortilin antibody. In some embodiments, an anti-Sortilin antibody is determined to be active in an individual if the level of NAGK in cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is increased compared to the level of NAGK in cerebrospinal fluid before the individual receives one or more doses of the anti-Sortilin antibody.In some embodiments, an anti-Sortilin antibody is determined to be active in an individual if the level of one or more inflammatory proteins in cerebrospinal fluid after the individual receives one or more doses of the anti-Sortilin antibody is reduced compared to the level of the one or more inflammatory proteins in cerebrospinal fluid before the individual receives one or more doses of the anti-Sortilin antibody, wherein the one or more inflammatory proteins are selected from the group consisting of 14-3-3 protein epsilon (YWHAE), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86. In some embodiments, the sample is from the individual's blood. [Brief explanation of the drawings]

[0043] [Figure 1A] Figures 1A-1C show a pharmacokinetic and pharmacodynamic study of a single dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS in non-human primates. Figure 1A shows the levels of SORT1 in peripheral leukocytes as a percentage of baseline at the indicated times (hours) after treatment with the indicated anti-sortilin antibody doses. SORT1 expression was reduced at all anti-sortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in both a faster and more prolonged decrease in SORT1 levels compared with lower anti-sortilin antibody doses (5 mg / kg, 20 mg / kg). n=3 animals per dose. [Figure 1B] Figures 1A-1C show pharmacokinetic and pharmacodynamic studies of non-human primates treated with a single dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Figure 1B shows plasma PGRN levels as a percentage of baseline at the indicated times (hours) after treatment with the indicated anti-sortilin antibody doses. PGRN levels increased in a time- and dose-dependent manner. Notably, plasma PGRN levels increased 3- to 4-fold at Cmax compared to baseline levels for all anti-sortilin antibody doses tested, and the increase was maintained for a longer period at higher antibody doses. n = 3 animals per dose. [Figure 1C] Figures 1A-1C show pharmacokinetic and pharmacodynamic studies of non-human primates treated with a single dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Figure 1C shows the levels of PGRN in the CSF as a percentage of baseline at the indicated times (hours) after treatment with the indicated anti-sortilin antibody doses. CSF PGRN levels increased 2- to 3-fold above baseline in animals receiving either 20 mg / kg, 60 mg / kg, or 200 mg / kg. As observed with plasma PGRN levels (Figure 1B), CSF PGRN levels remained elevated over time in the higher antibody dose groups. n = 3 animals per dose. [Figure 2A] Figures 2A-2C show a pharmacokinetic and pharmacodynamic study of repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS in non-human primates. Animals (two males and two females) received four weekly doses of 60 mg / kg of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Days of dosing are represented by vertical dashed lines. Figure 2A shows the mean (+ / - standard deviation) SORT1 concentrations in peripheral white blood cells (WBCs) as a percentage of baseline at the indicated times (days). Peripheral white blood cell SORT1 levels remained reduced throughout the study period. [Figure 2B] Figures 2A-2C show pharmacokinetic and pharmacodynamic studies of non-human primates receiving repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Animals (two males and two females) received four weekly doses of 60 mg / kg of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Days of administration are represented by vertical dashed lines. Figure 2B shows the mean (+ / - standard deviation) plasma PGRN concentrations as a percentage of baseline (normalized) at the indicated times (days). Plasma PGRN levels increased 5-6-fold above baseline at peak levels. A decrease in plasma PGRN was observed after the fourth and final dose of anti-sortilin antibody. However, plasma PGRN levels remained elevated at 2-fold above baseline. [Figure 2C]Figures 2A-2C show pharmacokinetic and pharmacodynamic studies of non-human primates receiving repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Animals (two males and two females) received four weekly doses of 60 mg / kg of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Days of administration are represented by vertical dashed lines. Figure 2C shows the mean (+ / - standard deviation) CSF PGRN concentrations as a percentage of baseline (normalized) at the indicated times (days). CSF PGRN levels increased 3-4-fold above baseline. [Figure 3A] Figures 3A-3C show the effects of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on SORT1 levels in leukocytes and plasma PGRN levels. In Figure 3A, the dashed line represents the SORT1 expression level in peripheral leukocytes (WBCs) as a percent change from baseline at the indicated time in a cohort of five healthy volunteers treated with the anti-sortilin antibody S-60-15.1[N33T]LALAPS at the indicated doses. The solid line represents the plasma (PL) PGRN level as a percent change from baseline at the indicated time in a cohort of five healthy volunteers treated with the anti-sortilin antibody S-60-15.1[N33T]LALAPS at the indicated doses. Administration of the anti-sortilin antibody S-60-15.1[N33T]LALAPS to human subjects reduced SORT1 expression levels in peripheral leukocytes and increased plasma PGRN levels. [Figure 3B] Figures 3A-3C show the effect of the anti-Sortilin antibody S-60-15.1[N33T]LALAPS on SORT1 levels in leukocytes and plasma PGRN levels. Further analysis of SORT1 levels on peripheral leukocytes at the indicated times (days after administration) in human subjects administered the anti-Sortilin antibody S-60-15.1[N33T]LALAPS is provided in Figure 3B. [Figure 3C]Figures 3A-3C show the effects of anti-Sortilin antibody S-60-15.1[N33T]LALAPS on SORT1 levels in leukocytes and plasma PGRN levels. Further analysis of PGRN levels compared to baseline at the indicated times (days post-administration) in human subjects administered anti-Sortilin antibody S-60-15.1[N33T]LALAPS is provided in Figure 3C. The horizontal dashed line indicates a two-fold increase over baseline. [Figure 4A] Figures 4A–4C show the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on CSF PGRN levels. Pharmacodynamic data on CSF PGRN levels were obtained from cohorts of healthy volunteers administered 0 mg / kg (placebo), 15 mg / kg, 30 mg / kg, or 60 mg / kg. CSF samples were collected before antibody administration and approximately 30 hours, 12 days, 24 days, and 42 days after antibody administration. As shown in Figure 4A, statistically significant increases in CSF PGRN levels (compared to PGRN levels observed at baseline) were observed at 30 hours and 12 days in all cohorts. Furthermore, administration of the antibody at 60 mg / kg increased CSF PGRN levels, which were sustained for at least 24 days after a single IV administration of the anti-sortilin antibody. [Figure 4B] Figures 4A-4C show the effects of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on CSF PGRN levels. Pharmacodynamic data on CSF PGRN levels were obtained from cohorts of healthy volunteers administered 0 mg / kg (placebo), 15 mg / kg, 30 mg / kg, or 60 mg / kg. CSF samples were collected before antibody administration and approximately 30 hours, 12 days, 24 days, and 42 days after antibody administration. Figure 4B shows the percent change from baseline in CSF PGRN levels in healthy volunteers administered 0 mg / kg (placebo), 15 mg / kg ("Cohort 3"), 30 mg / kg ("Cohort 4"), or 60 mg / kg ("Cohort 5") on study day 13 (12 days after administration). Asterisks indicate statistical significance (****: P<0.0001, adjusted for multiplicity). [Figure 4C] Figures 4A-4C show the effects of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on CSF PGRN levels. Pharmacodynamic data on CSF PGRN levels were obtained from cohorts of healthy volunteers administered 0 mg / kg (placebo), 15 mg / kg, 30 mg / kg, or 60 mg / kg. CSF samples were collected before antibody administration and approximately 30 hours, 12 days, 24 days, and 42 days after antibody administration. Figure 4C shows the percent change from baseline in CSF PGRN levels on the indicated days after administration in healthy volunteers administered 60 mg / kg (Cohort 5 and Cohort 6 combined). [Figure 5A] 5A-5C show the effects of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN levels in plasma and CSF of aFTD-GRN and FTD-GRN subjects. Figure 5A provides the mean percent change in plasma PGRN levels on the indicated days after administration in one aFTD-GRN subject and three FTD-GRN subjects. [Figure 5B] Figures 5A-5C show the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN levels in plasma and CSF of aFTD-GRN and FTD-GRN subjects. Figure 5B provides the mean percent change from baseline in CSF PGRN levels in one aFTD-GRN subject (study day 13) and three FTD-GRN patients (study day 57). [Figure 5C] Figures 5A-5C show the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN levels in plasma and CSF of aFTD-GRN and FTD-GRN subjects. Figure 5C provides the concentrations of PGRN (ng / mL) in CSF from normal healthy volunteers and three FTD-GRN patients before dosing and on study day 57. [Figure 6]FIG. 1 is a schematic diagram showing the Phase 2 study described in Example 3. CSF = cerebrospinal fluid, GRN = granulin, IV = intravenous, MRI = magnetic resonance imaging, PD = pharmacodynamics, PET = positron emission tomography, q4w = every 4 weeks, TSPO = translocator protein. [Figure 7] FIG. 1 shows the effect of anti-Sortilin antibody S-60-15.1[N33T]LALAPS on plasma PGRN concentrations (ng / mL) in aFTD-GRN and FTD-GRN subjects at the indicated times after antibody administration as described in Example 5. SD = single dose, MD = multiple doses. Median baseline concentrations of PGRN in plasma of healthy volunteers (HV) and FTD patients are indicated by horizontal lines. [Figure 8] Figure 1 shows the effect of anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN concentrations (ng / mL) in the CSF of aFTD-GRN (asymptomatic) and FTD-GRN (symptomatic) subjects at the indicated times after antibody administration. Concentrations of PGRN in the CSF of healthy volunteers (HV) are provided. One symptomatic subject had no reportable CSF PGRN results at baseline. [Figure 9]

[0023] Figure 1 shows the effect of anti-sortilin antibody S-60-15.1[N33T]LALAPS on the CSF protein signature of FTD-GRN patients by SOMASCAN analysis of over 1000 proteins, as described in Example 5. The Y-axis provides the Z-score of the ratio of each protein's level in FTD-GRN patients and healthy volunteers. The X-axis provides the Z-score of the ratio of each protein's level in FTD-GRN patients 57 days after anti-sortilin antibody S-60-15.1[N33T]LALAPS administration and at baseline (before anti-sortilin antibody S-60-15.1[N33T]LALAPS administration). Proteins that were upregulated in FTD-GRN patients and normalized after anti-sortilin antibody S-60-15.1[N33T]LALAPS administration are shown in the upper left quadrant of the scatter plot. Proteins that were downregulated in FTD-GRN patients and restored after administration of the anti-sortilin antibody S-60-15.1[N33T]LALAPS are shown in the lower right quadrant of the scatter plot. [Figure 10A]

[0023] Figure 1 shows NfL plasma levels in patients with FTD-GRN. NfL plasma levels were measured using the SIMOA Nf-Light Advantage assay by Quinterix. NfL plasma levels are shown at various time points as a percentage of baseline levels for each of five patients. [Figure 10B] Figure 10A shows NfL plasma levels in patients with FTD-GRN. NfL plasma levels were measured using the SIMOA Nf-Light Advantage assay by Quinterix. Figure 10B shows NfL plasma levels in patients with FTD-GRN. Geometric means of the data in Figure 10A are shown. [Figure 11A] 1 shows the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on SPP1, a biomarker upregulated in FTD patients. The biomarker SPP1 is upregulated in FTD patients compared to healthy volunteers, demonstrating that treatment of FTD patients with S-60-15.1[N33T]LALAPS reduces SPP1 to normal levels. [Figure 11B] 11A shows the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on CTSB, a biomarker downregulated in FTD patients. Contrary to FIG. 11A, the biomarker CTSB is downregulated in FTD patients compared to healthy volunteers, indicating that treating FTD patients with S-60-15.1[N33T]LALAPS increases CTSB levels to normal. DETAILED DESCRIPTION OF THE INVENTION

[0044] definition As used herein, the term "preventing" includes providing protection against the occurrence or recurrence of a particular disease, disorder or condition in an individual. An individual may be predisposed or susceptible to a particular disease, disorder or condition, or may be at risk of developing such a disease, disorder or condition, but has not been diagnosed with the disease, disorder or condition.

[0045] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms prior to the treatment methods described herein. "At risk" means that an individual has one or more risk factors, which are measurable parameters known in the art that correlate with the development of a particular disease, disorder, or condition. Individuals with one or more of these risk factors are more likely to develop a particular disease, disorder, or condition than individuals without one or more of these risk factors.

[0046] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a clinical pathology in a treated individual. Desirable effects of treatment include reducing the rate of progression of a particular disease, disorder, or condition, ameliorating or alleviating the disease state, and achieving remission or improving the prognosis. An individual is successfully "treated," for example, if one or more symptoms associated with a particular disease, disorder, or condition are reduced or eliminated.

[0047] An "effective amount" refers to an amount at least effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or preventative result. An effective amount can be administered in one or more administrations. A therapeutically effective amount, as used herein, can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the treatment to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as elimination or reduction of risk, reduction in severity, or delay in the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes exhibited during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as a reduction in one or more symptoms attributable to the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dose of other drugs required to treat the disease, an enhancement of the effect of another drug, such as by targeting, a delay in disease progression, and / or an increase in survival time. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment.As understood in clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.Therefore, "effective amount" can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in combination with one or more other agents, desired results can be achieved or are achieved.

[0048] As used herein, administration "in combination with" another compound or composition includes simultaneous administration and / or administration at different times. Co-administration also encompasses administration as a combined preparation or as separate compositions, at different dosing frequencies or intervals, and using the same or different routes of administration.

[0049] An "individual" for purposes of treatment, prevention, or risk reduction refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. Preferably, the individual is a human.

[0050] The terms "Sortilin" or "Sortilin polypeptide" are used interchangeably herein and, unless otherwise indicated, refer to any naturally occurring Sortilin from any mammalian source, including primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses "full-length," unprocessed Sortilin, as well as any form of Sortilin that results from processing in the cell. In some embodiments, the Sortilin is human Sortilin. In some embodiments, the amino acid sequence of an exemplary human Sortilin is SEQ ID NO:81.

[0051] The terms "anti-Sortilin antibody," "antibody that binds to Sortilin," and "antibody that specifically binds to Sortilin" refer to an antibody that can bind to Sortilin with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting Sortilin. In one embodiment, the magnitude of binding of an anti-Sortilin antibody to an unrelated, non-Sortilin polypeptide is less than about 10% of the binding of the antibody to Sortilin, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to Sortilin has a dissociation constant (KD) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 M or less, e.g., 10 M to 10 M, e.g., 10 M to 10 M). In certain embodiments, the anti-Sortilin antibody binds to an epitope of Sortilin that is conserved among Sortilins from different species.

[0052] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody." The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), including those formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0053] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (L) and two identical heavy chains (H). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V H ) followed by several constant domains. Each light chain has a variable domain (V) at one end. L ) at one end and a constant domain at the other end, with the light chain constant domain aligned with the first constant domain of the heavy chain and the light chain variable domain aligned with the heavy chain variable domain. Particular amino acid residues are believed to form an interface between the light chain variable domain and the heavy chain variable domain.

[0054] For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0055] Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domain. Depending on the amino acid sequence of the constant domain (CH) of their heavy chain, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are known and are described generally in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (WB Saunders Co., 2000).

[0056] A "variable region" or "variable domain" of an antibody (e.g., an anti-Sortilin antibody of the present disclosure) refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding sites.

[0057] The term "variable" refers to the fact that certain segments of variable domains differ extensively in sequence among antibodies (e.g., the anti-Sortilin antibodies of the present disclosure). The variable domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Naturally occurring heavy-chain and light-chain variable domains each contain four FR regions primarily in a beta-sheet configuration connected by three HVRs, which form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held together in close proximity by the FR regions and, together with the HVRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as antibody-dependent cellular toxicity.

[0058] An "isolated" antibody (e.g., an anti-Sortilin antibody of the present disclosure) is one that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, an isolated polypeptide is free of association with all other contaminating components from its production environment. Contaminating components from its production environment, such as those resulting from recombinant, transfected cells, are typically substances that would interfere with the research, diagnostic, or therapeutic uses of the antibody and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide is purified (1) until the antibody is greater than 95%, and in some embodiments greater than 99%, by weight, as determined, for example, by the Lowry method; (2) to a degree sufficient to obtain at least 15 N-terminal or internal amino acid sequence residues using a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue staining or, preferably, silver staining. Isolated antibody includes the antibody in situ within recombinant T cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step.

[0059] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, e.g., a monoclonal anti-Sortilin antibody of the present disclosure. That is, the individual antibodies within the population are identical except for naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.), which may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include various antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by a hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to one or more of the following methods: immunization of animals, including but not limited to rats, mice, rabbits, guinea pigs, hamsters, and / or chickens, with one or more species of DNA(s), virus-like particles, polypeptide(s), and / or cell(s); hybridoma methods; B-cell cloning methods; recombinant DNA methods; and techniques for producing human antibodies or human-like antibodies in animals carrying some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0060] The terms "full length antibody," "intact antibody," or "whole antibody" are used interchangeably to refer to an antibody (e.g., an anti-Sortilin antibody of the present disclosure) in its substantially intact form, as opposed to an antibody fragment. Specifically, whole antibodies include those having heavy and light chains, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, intact antibodies may have one or more effector functions.

[0061] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding region and / or the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments, diabodies, linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)), single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0062] Papain digestion of an antibody (e.g., the anti-Sortilin antibody of the present disclosure) produces two identical antigen-binding fragments called "Fab" fragments and one residual "Fc" fragment, a name reflecting its ability to crystallize readily. The Fab fragment contains the entire L chain plus the variable region domain of the H chain (V H ) and the first constant domain of one heavy chain (C H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having several additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0063] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of the antibody are determined by the sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0064] An "Fv" is the minimum antibody fragment containing a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain variable region domain and one light-chain variable region domain in tight, non-covalent association. The folding of these two domains generates six hypervariable loops (three loops each from the H and L chains) that provide the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind to antigen, although with lower affinity than the entire binding site.

[0065] A "single-chain Fv," sometimes abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains linked in a single polypeptide chain. Preferably, the sFv polypeptide comprises a VH domain and a VL domain. H Domains and V L The sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0066] A "functional fragment" of an antibody (e.g., an anti-Sortilin antibody of the present disclosure) includes a portion of an intact antibody, generally including the antigen-binding or variable region of the intact antibody, or the F region of the antibody that retains or has modified FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0067] The term "diabody" refers to a diabody that is a fragment of a V fusion protein that achieves inter-chain but not intra-chain variable domain pairing, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. HDomains and V L These refer to small antibody fragments created by constructing sFv fragments (see previous paragraph) with short linkers (approximately 5-10 residues) between the V domains of two antibodies. H Domain and V L It is a heterodimer of two "crossover" sFv fragments in which the domains are present on different polypeptide chains.

[0068] As used herein, a "chimeric antibody" refers to an antibody (immunoglobulin) (e.g., an anti-Sortilin antibody of the present disclosure) in which a portion of the heavy and / or light chain is identical or homologous to sequences corresponding to antibodies from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is identical or homologous to sequences corresponding to antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. Chimeric antibodies of interest herein include PRIMATIZED® antibodies, in which the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0069] "Humanized" forms of non-human (e.g., murine) antibodies (e.g., anti-Sortilin antibodies of the present disclosure) are chimeric antibodies containing amino acid residues of non-human HVRs and amino acid residues of human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been subjected to humanization.

[0070] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human (e.g., an anti-Sortilin antibody of the present disclosure) and / or an antibody made using any of the techniques for making human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries and yeast-based platform technology. Human antibodies can be made by administering antigen to transgenic animals, e.g., immunized xenogeneic mice, which have been engineered to produce such antibodies in response to antigen challenge and have their endogenous gene loci disabled, and can also be generated through human B-cell hybridoma technology.

[0071] As used herein, the term "hypervariable region," "HVR," or "HV" refers to a region of an antibody variable domain (e.g., a region of an antibody variable domain of an anti-Sortilin antibody of the disclosure) that is hypervariable in sequence and / or forms structurally defined loops. Generally, an antibody contains six HVRs, three of which are V H (H1, H2, H3), and three are V L In natural antibodies, H3 and L3 exhibit the highest diversity among the six HVRs, and H3 in particular is thought to play a unique role in conferring superior specificity to antibodies. Naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains.

[0072] Many HVR descriptions are used and encompassed herein. In some embodiments, HVRs may be Kabat complementarity-determining regions (CDRs), which are based on sequence variability and are the most commonly used (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Chothia refers rather to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, HVRs may be AbM HVRs. AbM HVRs represent a compromise between EU or Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. In some embodiments, HVRs may be "contact" HVRs. "Contact" HVRs are based on analysis of available complex crystal structures. The residues of each of these HVRs are described below. [Table 1]

[0073] HVRs may include the following "extended HVRs": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2) and 93-102, 94-102 or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al. (supra) for each of these extended HVR definitions.

[0074] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0075] As used herein, an "acceptor human framework" refers to a V that is derived from a human immunoglobulin framework or derived from a human consensus framework. L Framework or V HThe acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence as the human immunoglobulin framework or human consensus framework, or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When pre-existing amino acid changes are present in VH, preferred amino acid changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework comprises, in sequence, the following amino acid residues: V L It is identical to a human immunoglobulin framework sequence or a human consensus framework sequence.

[0076] The "human consensus framework" is the V of human immunoglobulins. L Framework sequence or V H A framework is a sequence that represents the most commonly occurring amino acid residues in a selection of framework sequences. L Array or V H The selection of sequences is made from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include V L and the subgroup may be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al. (supra). H For example, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al. (supra).

[0077] An "amino acid modification" at a specified position (e.g., an amino acid modification of an anti-Sortilin antibody of the disclosure) refers to a substitution or deletion of the specified residue, or an insertion of at least one amino acid residue adjacent to the specified residue. An insertion "adjacent to" a specified residue means an insertion within one to two residues thereof. The insertion can be N-terminal or C-terminal to the specified residue. A preferred amino acid modification herein is a substitution.

[0078] An "affinity matured" antibody (e.g., an anti-Sortilin antibody of the disclosure) comprises one or more changes in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody lacking those change(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by techniques known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe affinity maturation by shuffling VH and VL domains. Random mutagenesis of HVR and / or framework residues is described, for example, in Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994), Schier et al. Gene 169:147-155 (1995), Yelton et al. J. Immunol. 155:1994-2004 (1995), Jackson et al., J. Immunol. 154(7):3310-9 (1995), and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0079] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction, such as attraction or binding, between a target and an antibody, i.e., (e.g., an anti-Sortilin antibody of the present disclosure), which allows the presence of the target to be determined in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody (e.g., an anti-Sortilin antibody of the present disclosure) that specifically or preferentially binds to a target or epitope is an antibody that binds to that target or epitope with higher affinity, avidity, more readily, and / or with longer duration than it binds to other targets or other epitopes of that target. By reading this definition, it is also understood that, for example, an antibody (or moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. An antibody that specifically binds to a target has at least about 10 3 M -1 or 10 4 M -1 , possibly about 10 5 M -1 or 10 6 M -1 , in other cases, about 10 6 M -1 or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 or about 10 10 M -1 ~10 11 M -1The antibody may have an association constant equal to or greater than 100 . A variety of immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0080] As used herein, an "interaction" between a sortilin protein and a second protein includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. As used herein, an antibody "inhibits the interaction" between two proteins when the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody or fragment thereof of the present disclosure "inhibits the interaction" between two proteins when the antibody or fragment binds to one of the two proteins.

[0081] An "agonist" or "activating" antibody is an antibody, such as an agonist anti-Sortilin antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0082] A "blocking," "antagonist," or "inhibitory" antibody is an antibody (e.g., an anti-Sortilin antibody of the present disclosure) that inhibits or reduces (e.g., decreases) antigen binding to one or more ligands and / or inhibits or reduces (e.g., decreases) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, a blocking, antagonist, or inhibitory antibody substantially or completely inhibits antigen binding to one or more ligands and / or one or more activities or functions of the antigen.

[0083] Antibody "effector functions" refer to those biological activities attributable to the Fc region of an antibody (a native sequence Fc region or amino acid sequence variant Fc region), and vary depending on the antibody isotype.

[0084] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from amino acid residue position Cys226 or Pro230 to its carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, intact antibody compositions can include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0085] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0086] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or in the Fc region of the parent polypeptide. A variant Fc region herein preferably retains at least about 80% homology with a native-sequence Fc region and / or the Fc region of a parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto.

[0087] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternatively spliced ​​forms of these receptors); FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. Other FcRs, including those yet to be identified, are encompassed by the term "FcR" herein. FcRs may also increase the serum half-life of antibodies. As used herein, "percent amino acid sequence identity" and "percent amino acid sequence homology" with respect to a peptide, polypeptide, or antibody sequence refer to the percentage of amino acid residues in a candidate sequence that are identical to those in a specified peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved by a variety of methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for assessing alignment, including any algorithms known in the art necessary to achieve maximal alignment over the entire length of the sequences being compared.

[0088] An "isolated" cell is a molecule or cell that has been identified and separated from at least one contaminating cell with which it is normally associated in the environment in which it was produced. In some embodiments, an isolated cell is free of association with all components associated with its production environment. An isolated cell is in a form or setting that is different from that in which it is found in nature. An isolated cell is distinct from cells that naturally occur in a tissue, organ, or individual. In some embodiments, an isolated cell is a host cell of the present disclosure.

[0089] An "isolated" nucleic acid molecule encoding an antibody (e.g., an anti-Sortilin antibody of the present disclosure) is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it is produced. Preferably, an isolated nucleic acid is free of association with all components associated with its production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are present in a form that is different from the form or setting in which the nucleic acid molecule is found in nature. Thus, isolated nucleic acid molecules are distinguished from nucleic acids encoding the polypeptides and antibodies herein that naturally occur in cells.

[0090] The term "vector," as used herein, refers to a nucleic acid molecule capable of transporting another nucleic acid molecule to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, in which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and are thereby replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." In general, expression vectors utilized in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector.

[0091] "Polynucleotide" or "nucleic acid," used interchangeably herein, refer to a polymer of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.

[0092] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporating a polynucleotide insert. A host cell includes the progeny of a single host cell, which progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the present disclosure.

[0093] As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals exposed to the carrier at the dosages and concentrations employed.

[0094] The term "about" as used herein refers to a normal error range for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to a value or parameter with "about" includes (and describes) embodiments that are directed to the value or parameter itself.

[0095] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. For example, reference to "antibodies" is a reference to from one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0096] It should be understood that aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0097] Overview The present disclosure relates to methods of treating and / or slowing the progression of a disease or disorder in an individual by administering an anti-Sortilin antibody to the individual. Non-limiting examples of diseases that may be treated or slowed include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As described below, the methods of the present disclosure fulfill a need in the art for identifying ways to treat patients with the correct dose and administering that dose in a way that facilitates patient compliance.

[0098] Advantageously, intravenous administration of a single or repeated dose (e.g., see Example 1) of an anti-Sortilin antibody of the present disclosure to a non-human primate results in a dose-dependent decrease in SORT1 protein on leukocytes and an increase in PGRN protein levels in plasma (e.g., a 2-6-fold increase) and cerebrospinal fluid (CSF) (e.g., a 2-4-fold increase). Furthermore, although the half-life of the anti-Sortilin antibody is relatively short (e.g., up to 73.6 hours), unexpectedly, the decrease in SORT1 protein on leukocytes and the increase in PGRN protein levels in plasma and CSF persist over time (e.g., up to 14 days after the last dose of anti-Sortilin antibody). Moreover, advantageously, exposure increases over time (e.g., day 1 vs. day 22), indicating that anti-Sortilin antibodies have accumulated.

[0099] Similarly, intravenous administration of a single dose of an anti-Sortilin antibody of the present disclosure (see, e.g., Example 2) to healthy humans results in a dose-dependent decrease in SORT1 protein on leukocytes (e.g., a 50% or 70% decrease) and an increase in PGRN protein levels in plasma (e.g., a 1.29- to 2.14-fold increase) and CSF (e.g., a 0.57- to 1.13-fold increase). Furthermore, although the half-life of anti-Sortilin antibodies is relatively short (e.g., up to 190 hours), unexpectedly, the decrease in SORT1 protein on leukocytes (e.g., for 40 days or more) and the increase in PGRN protein levels in plasma (e.g., for 40 to 42 days or more) and CSF persists over time (e.g., for at least 24 days).

[0100] Patients with neurodegenerative diseases such as FTD and ALS are affected by the disease for long periods of time, requiring regular treatment for many years. Because therapeutic intravenous administration is not possible at home, patients must be transported to an infusion center, placing a burden on both patients and caregivers. Finally, memory loss, mood swings, aggression, and other behavioral symptoms of these diseases make patient compliance difficult.

[0101] Advantageously, although the anti-Sortilin antibodies of the present disclosure exhibit relatively short half-lives and therefore would not be expected to be therapeutically useful, when administered in accordance with the methods provided herein, the antibodies exhibit unexpectedly long-lasting pharmacodynamic (PD) effects (e.g., increased PGRN levels in plasma and CSF, and decreased SORT1 levels in WBC and CSF). Thus, the methods provided herein allow for relatively infrequent administration of anti-Sortilin antibodies, which is particularly beneficial for patients with neurodegenerative diseases such as FTD and ALS.

[0102] Thus, in some embodiments, the disclosure further relates to methods of treating and / or delaying the progression of FTD (see, e.g., Example 3) or ALS (see, e.g., Example 4) in an individual by intravenously administering to the individual an anti-Sortilin antibody at a dose of at least about 30 mg / kg at least once every four weeks. In some embodiments, the anti-Sortilin antibody is administered at a dose of about 60 mg / kg once every four weeks.

[0103] All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety.

[0104] therapeutic use The present disclosure provides a method for treating and / or delaying the progression of a disease or injury in an individual, the method comprising administering to the individual an anti-Sortilin antibody, the antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2-3; and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 5-6; and the light chain variable region comprises HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8-27; HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 29-30; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 32.

[0105] As disclosed herein, the anti-Sortilin antibodies of the present disclosure can be used to treat and / or slow the progression of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, limbic-predominant aged TDP43 encephalopathy (LATE), acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, or osteoarthritis. In some embodiments, the disease or injury is frontotemporal dementia or amyotrophic lateral sclerosis. In some embodiments, the anti-Sortilin antibodies of the present disclosure may be used to treat or alleviate TDP43 pathologies, such as, but not limited to, TDP43 pathologies associated with dementia, C9orf72-associated disease, FTD, Alzheimer's disease, ALS, LATE, and Parkinson's disease.

[0106] In some embodiments, the methods of the disclosure include anti-Sortilin antibodies, including two or more anti-Sortilin antibodies.

[0107] Dementia Dementia is a nonspecific syndrome (i.e., a set of signs and symptoms) that manifests in previously unimpaired individuals as a significant loss of global cognitive ability beyond that which can be expected from normal aging. Dementia may be static, resulting from inherent global brain damage. Alternatively, dementia may be progressive, with long-term decline resulting from physical injury or disease. Dementia is more common in the elderly population, but can also develop before age 65. Cognitive domains affected by dementia include, but are not limited to, memory, attention span, language, and problem-solving. Generally, symptoms must be present for at least six months before an individual is diagnosed with dementia.

[0108] Exemplary forms of dementia include, but are not limited to, frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, and dementia with Lewy bodies.

[0109] Without being bound by theory, it is believed that administration of an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of dementia. In some embodiments, administering an anti-Sortilin antibody can induce one or more Progranulin activities (e.g., neurotrophic and / or survival activity for neurons, and anti-inflammatory activity) in an individual with dementia.

[0110] frontotemporal dementia Frontotemporal dementia (FTD) is a condition resulting from the progressive deterioration of the frontal lobes of the brain. Over time, this degeneration can progress to the temporal lobes. FTD is second only to Alzheimer's disease (AD) in prevalence, accounting for 20% of presenile dementia cases. Clinical features of FTD include memory impairment, behavioral abnormalities, personality changes, and language disorders (Cruts, M. & Van Broeckhoven, C., Trends Genet. 24:186-194 (2008); Neary, D., et al., Neurology 51:1546-1554 (1998); Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, JR, Neurology 58:1615-1621 (2002)).

[0111] Although a significant proportion of FTD cases are inherited in an autosomal dominant manner, symptoms, even within a single family, can range from FTD with behavioral disturbances to primary progressive aphasia to corticobasal ganglionic degeneration. Like most neurodegenerative diseases, FTD can be characterized by the pathological presence of specific protein aggregates in affected brains. Historically, the first description of FTD recognized the presence of intraneuronal accumulations of abnormally phosphorylated tau protein in neurofibrillary tangles or Pick's globules. The causal role of the microtubule-associated protein tau has been supported by the identification of mutations in the gene encoding the tau protein in several families (Hutton, M., et al., Nature 393:702-705 (1998)). However, the majority of FTD brains do not show accumulation of abnormally phosphorylated tau but instead show immunoreactivity for ubiquitin (Ub) and the TAR DNA-binding protein (TDP43) (Neumann, M., et al., Arch. Neurol. 64:1388-1394 (2007)). The majority of these FTD cases with Ub inclusions (FTD-U) have been shown to have mutations in the progranulin gene.

[0112] Progranulin mutations cause haploinsufficiency and are known to be present in approximately 50% of familial FTD cases, making them the major genetic cause of FTD. Without being bound by theory, the loss-of-function heterozygous characteristics of progranulin mutations suggest that progranulin expression plays an important, dose-dependent role in protecting healthy individuals from the development of FTD. Therefore, increasing progranulin levels by inhibiting the interaction between sortilin and progranulin can treat FTD and / or slow its progression.

[0113] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of FTD, hi some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with FTD.

[0114] In some embodiments, treating FTD and / or delaying its progression is measured by a change from baseline in a neurocognitive and / or functional test or assessment (i.e., a clinical outcome assessment). Non-limiting examples of neurocognitive and functional tests that can be used to assess treating FTD and / or delaying its progression include the Frontotemporal Dementia Clinical Rating Scale (FCRS), the Frontotemporal Dementia Rating Scale (FRS), the Clinical Global Improvement Index (CGI-I) assessment, the Neuropsychiatric Inventory (NPI) assessment, the Color Trails Test (CTT) Part 2, the Repeated Neuropsychological Testing Task (RBANS) for the Assessment of Higher Brain Function, the Delis-Kaplan Executive Functioning System Color-Word Interference Test, the Interpersonal Reactivity Index, the Winterlight Lab Speech Assessment (WLA), and the Summerlight Lab Speech Assessment (SLA). In some embodiments, treating FTD and / or delaying its progression is measured by a change from baseline in one neurocognitive and / or functional test or assessment. In some embodiments, treating FTD and / or slowing its progression is determined by change from baseline in two or more neurocognitive and / or functional tests or assessments (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or more neurocognitive and / or functional tests or assessments).

[0115] In some embodiments, treating FTD and / or slowing its progression is measured by changes from baseline in global and / or regional brain volume, white matter hyperintensity volume, cerebral perfusion, fractional anisotropy, mean diffusivity, axial radial diffusivity, and radial diffusivity and / or functional brain activity. In certain embodiments, cerebral perfusion is measured by arterial spin-labeling MRI. In certain embodiments, radial diffusivity is measured by diffusion tensor imaging. In certain embodiments, functional brain activity is measured by functional MRI.

[0116] In some embodiments, treating FTD and / or delaying its progression is determined by a change from baseline in markers of neurodegeneration in whole blood, plasma, and CSF. Markers of neurodegeneration include, but are not limited to, neurofilament light chain [NfL], tau, and / or pTau. Neurofilament light chain can be measured by methods such as, but not limited to, assays from Quanterix and / or Roche Diagnostics. In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure reduces NfL levels by at least 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, treating FTD and / or delaying its progression is determined by a change (e.g., an increase) from baseline in a marker of lysosomal function. The marker of lysosomal function may be a cathepsin, such as, but not limited to, cathepsin B (CTSB). In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure increases the level of one or more lysosomal markers, such as CTSB, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of the one or more lysosomal markers, such as CTSB. In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure increases the level of CTSB by at least about 20%, compared to the baseline level of CTSB. Another non-limiting example of a lysosomal marker is N-acetylglucosamine kinase (NAGK). In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure increases the level of NAGK by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of NAGK.

[0117] In some embodiments, treating FTD and / or delaying its progression is measured by a change (e.g., a decrease) from baseline in the level of an inflammatory marker, such as osteopontin (SPP1). In some embodiments, treatment with an anti-Sortilin antibody of the disclosure reduces the level of one or more inflammatory markers, such as SPP1, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of the one or more inflammatory markers, such as SPP1. In some embodiments, treatment with an anti-Sortilin antibody of the disclosure reduces the level of one or more inflammatory markers, such as SPP1, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, compared to the baseline level of the one or more inflammatory markers, such as SPP1. In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure reduces the level of SPP1 by at least about 10% compared to the baseline level of SPP1. Other examples of inflammatory markers include, but are not limited to, YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86.In some embodiments, treatment with an anti-Sortilin antibody of the present disclosure reduces the level of one or more inflammatory markers, such as YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, compared to baseline levels of one or more inflammatory markers, such as YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86.

[0118] In some embodiments, treating and / or delaying the progression of FTD is measured by a change from baseline in a marker of microglial activity. Markers of microglial activity may be, but are not limited to, YKL-40 and / or interleukin-6. In some embodiments, treating and / or delaying the progression of FTD is measured by a change from baseline in messenger ribonucleic acid (mRNA) expression in peripheral cells. In some embodiments, treating and / or delaying the progression of FTD is measured by a change from baseline in an analyte related to FTD disease biology and / or response to an anti-sortilin antibody.

[0119] In some embodiments, the level of one or more proteins (e.g., one or more of YKL-40, IL-6, CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, or CD86) can be measured in a sample obtained from an individual, such as a sample of whole blood, plasma, and / or CSF. Non-limiting examples of methods that can be used to measure the level of one or more proteins (e.g., one or more of YKL-40, IL-6, CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, or CD86) in a sample obtained from an individual include a SOMASCAN assay (e.g., Candia et al. (2017) Sci Rep 7, 14248), Western blot, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) assay.

[0120] In some embodiments, treating FTD and / or delaying its progression is determined by changes from baseline in neuroinflammation and / or microglial activation. Neuroinflammation and / or microglial activation can be measured by any method known in the art. In certain embodiments, neuroinflammation and / or microglial activation can be measured using translocator protein-positron emission tomography (TSPO-PET) imaging. In certain embodiments, [ 18 F]PBR06 and / or [ 11 [C]PBR28 PET is used as a radiotracer for TSPO-PET imaging. 18 [F]PBR06 is used as a radiotracer for TSPO-PET imaging. In certain embodiments, [F]PBR06 is used as a radiotracer for TSPO-PET imaging. 11 [C]PBR28 PET is used as a radiotracer for TSPO-PET imaging.

[0121] In some embodiments, the individual is heterozygous for a mutation in GRN (granulin gene). In some embodiments, the mutation in GRN is a loss-of-function mutation. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion. In some embodiments, the individual exhibits symptoms of FTD. In some embodiments, the individual does not exhibit symptoms of FTD.

[0122] In some embodiments, an individual exhibits symptoms of FTD if they meet the diagnostic criteria for possible behavioral variant FTD (bvFTD), high probability bvFTD, or primary progressive aphasia (PPA). In some embodiments, an individual has one or more of the behavioral / cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky et al., (2011) Brain 134(9):2456-2477). In some embodiments, an individual has mild symptomatology that does not significantly affect activities of daily living (e.g., mild cognitive impairment, mild behavioral impairment). In certain embodiments, an individual has bvFTD or PPa with concomitant motor neuron disease. In some embodiments, an individual has mild severity of FTD as defined by a Clinical Dementia Rating Scale (CDR) global score of 1 or less and box scores of 1 or less in both the language domain and the behavior, comfort, and personality domains of the Frontotemporal Dementia Clinical Rating Scale (FCRS).

[0123] Alzheimer's disease Alzheimer's disease (AD) is the most common form of dementia. There is no cure for the disease, which worsens as it progresses and ultimately leads to death. In most cases, AD is diagnosed in people over the age of 65. However, the less common early-onset form of Alzheimer's disease can develop earlier.

[0124] Common symptoms of Alzheimer's disease include behavioral symptoms such as difficulty recalling recent events, cognitive symptoms, confusion, irritability and aggression, mood swings, language disorders, and long-term memory loss. As the disease progresses, bodily functions are lost and eventually death occurs. Alzheimer's disease develops over an unknown and variable amount of time before becoming fully apparent and may proceed undiagnosed for years.

[0125] Sortilin has been shown to bind to amyloid precursor protein (APP) and the APP-processing enzyme BACE1. Without wishing to be bound by theory, it is believed that these interactions are involved in Alzheimer's disease. Thus, without wishing to be bound by theory, it is believed that the anti-Sortilin antibodies of the present disclosure can be used to inhibit such interactions and prevent, reduce the risk of, or treat Alzheimer's disease in individuals in need thereof.

[0126] In some embodiments, without being bound by theory, anti-Sortilin antibodies of the disclosure that inhibit the interaction between Sortilin and a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), p75, amyloid precursor protein (APP), and / or Aβ peptide, or that inhibit one or more activities of Sortilin, can be used to treat Alzheimer's disease and / or slow the progression of Alzheimer's disease in an individual in need thereof.

[0127] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of Alzheimer's disease, hi some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with Alzheimer's disease.

[0128] vascular dementia Vascular dementia (VaD) is a mild, progressive deterioration of memory and other cognitive functions thought to be due to cerebrovascular disease (vascular disease in the brain). Cerebrovascular disease is a progressive change in the blood vessels (vasculature) of the brain (cerebrum). The most common vascular change associated with aging is the accumulation of cholesterol and other substances in blood vessel walls. This leads to thickening and hardening of the vessel walls and narrowing of the vessels, reducing or even completely stopping blood flow to the brain areas supplied by the affected arteries. Patients with vascular dementia often exhibit symptoms similar to those of Alzheimer's disease (AD). However, the associated brain changes are not due to AD pathology but rather to a chronic reduction in blood flow in the brain that ultimately leads to dementia. VaD is considered one of the most common forms of dementia in the elderly. Symptoms of VaD include memory difficulties, difficulty organizing and solving complex problems, diminished thinking, inattention or "disinterest," difficulty retrieving words from memory, mood or behavioral changes such as depression, irritability or apathy, and hallucinations or delusions.

[0129] Without being bound by theory, it is believed that one or more activities of sortilin, or one or more interactions between sortilin and progranulin, a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, lipoprotein lipase, apolipoprotein AV and / or receptor-associated proteins, are involved in vascular dementia. Thus, without being bound by theory, it is believed that anti-Sortilin antibodies of the disclosure that inhibit the interaction between Sortilin and a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), and / or receptor-associated protein (RAP), or that inhibit one or more activities of Sortilin, can be used to prevent, reduce the risk of, or treat vascular dementia in an individual in need thereof.

[0130] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of VaD, hi some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with VaD.

[0131] Seizures, retinal dystrophy, traumatic brain injury, and spinal cord injury As used herein, retinal dystrophy refers to any disease or condition involving retinal degeneration that can lead to vision loss or complete blindness.

[0132] As used herein, a convulsive seizure, including an epileptic seizure, refers to a transient symptom of abnormal, excessive, or synchronized neural activity in the brain. The outward effects can be dramatic, such as excited thrashing, or mild, such as a slight loss of consciousness. A convulsive seizure can manifest as altered mental status, tonic or clonic movements, convulsions, and various other psychiatric symptoms.

[0133] Traumatic brain injury (TBI) may also be known as intracranial injury. Traumatic brain injury occurs when an external force traumatizes the brain. Traumatic brain injury can be classified based on severity, mechanism (closed or penetrating head injury), or other characteristics (e.g., occurring in a specific location or occurring over a wide area).

[0134] Spinal cord injury (SCI) includes any damage to the spinal cord caused by trauma rather than disease. Symptoms can vary widely, from pain to paralysis to incontinence, depending on where the spinal cord and nerve roots are damaged. Spinal cord injuries are described at various levels, from "incomplete," which can vary from not affecting the patient, to "complete" injury, which means a complete loss of function.

[0135] Pro-neurotrophins (eg, proneurotrophin-4 / 5, neurotrophin-4 / 5, pro-NGF, pro-BDNF, etc.) have been shown to be involved in seizures, retinal dystrophy, traumatic brain injury, and spinal cord injury.

[0136] Thus, without being bound by theory, it is believed that anti-Sortilin antibodies of the disclosure that inhibit the interaction between Sortilin and a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.) or that inhibit one or more activities of Sortilin can be used to prevent, reduce the risk of, or treat seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury in individuals in need thereof.

[0137] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury, hi some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in individuals with seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury.

[0138] Undesirable symptoms of aging As used herein, undesirable symptoms of aging include, but are not limited to, memory loss, behavioral changes, dementia, Alzheimer's disease, retinal degeneration, atherosclerotic vascular disease, hearing loss, and cell degradation.

[0139] In some embodiments, without being bound by theory, it is believed that anti-Sortilin antibodies of the disclosure that inhibit the interaction between Sortilin and Progranulin, a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), and / or receptor-associated protein (RAP), or that inhibit one or more activities of Sortilin, can be used to prevent, reduce the risk of, or treat one or more undesirable symptoms of aging.

[0140] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of one or more undesirable symptoms of aging, hi some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with one or more undesirable symptoms of aging.

[0141] Amyotrophic lateral sclerosis (ALS) As used herein, amyotrophic lateral sclerosis (ALS) or motor neuron disease or Lou Gehrig's disease are used interchangeably and refer to a debilitating disease with various etiologies characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (respiratory impairment).

[0142] PGRN haploinsufficiency due to heterozygous loss-of-function mutations in the GRN gene results in reduced CSF PGRN levels and contributes to the development of frontotemporal dementia (FTD) with TDP-43 pathology (Sleegers et al., (2009) Ann Neurol 65:603, Smith et al., (2012) Am J Hum Genet 90:1102). TDP-43 has also been identified as a major pathological protein in ALS, suggesting similarities between ALS and FTD.

[0143] For example, more than 20 dominant mutations in TDP-43 have been identified in sporadic and familial ALS patients (Lagier-Tourenne et al., (2009) Cell 136:1001), and TDP-43-positive populations are found in approximately 95% of ALS cases (Prasad et al., (2019) Front Mol Neurosci 12:25). Furthermore, ALS risk genes such as MOBP, C9ORF72, MOBKL2B, NSF, and FUS can also cause FTD (Karch et al., (2018) JAMA Neurol 75:860). Furthermore, both PGRN and C9ORF72 mutations are associated with abnormal microglial activation, which is considered another common pathology of FTD and ALS (Haukedal et al., (2019) J Mol Biol 431:1818). Other evidence also suggests that ALS and FTD are closely related conditions with overlapping genetic, neuropathological, and clinical features (Weishaupt et al., (2016) Trends Mol Med 22:769; McCauley et al., (2018) Acta Neuropathol 137:715). Collectively, these results suggest that both diseases may benefit from shared treatments and that genetic variation in PGRN may act as a modifier of the course of ALS.

[0144] Furthermore, aside from demonstrating that loss of PGRN is deleterious in multiple models of acute and chronic neurodegeneration (Boddaert et al., (2018) Methods Mol Biol 1806:233), overexpression of PGRN has been shown to be protective in many animal models of ALS (Laird et al., (2010) PLoS One 5:e13368; Tauffenberger et al., (2013) Hum Mol Genet 22:782; Beel et al., (2018) Mol Neurodegener 13:55; Chang et al., (2017) J Exp Med 214:2611). Furthermore, common variants of GRN are significantly associated with a lower age at onset and shorter survival time in ALS patients (Sleegers et al., (2008) Neurology 71:253).

[0145] In summary, both human genetic and disease model data support a protective function of PGRN in mitigating TDP-43 pathology-associated pathology in ALS patients.

[0146] In some embodiments, without being bound by theory, anti-Sortilin antibodies of the disclosure that inhibit the interaction between Sortilin and Progranulin, a neurotrophin of the disclosure (e.g., proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), and / or receptor-associated protein (RAP), or that inhibit one or more activities of Sortilin, can be used to prevent or treat one or more undesirable symptoms of ALS.

[0147] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of ALS. In some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with ALS. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion.

[0148] In some embodiments, the treatment of ALS and / or delay of its progression is determined by changes from baseline in brain atrophy, brain connectivity, brain free water, and / or brain inflammation. Any method known in the art, including but not limited to MRI, can be used to measure brain atrophy, brain connectivity, brain free water, and / or brain inflammation. In certain embodiments, brain atrophy is measured using structural MRI. In certain embodiments, brain free water and / or brain inflammation is measured using diffusion tensor imaging (DTI).

[0149] In some embodiments, treating ALS and / or slowing its progression is measured by a change from baseline in progranulin, a marker of neurodegeneration, a marker of glial activation, and / or a marker of TDP-43 pathology. In certain embodiments, progranulin is measured using an adipogen immunoassay. In certain embodiments, markers of neurodegeneration include, but are not limited to, neurofilament light chain. Neurofilament light chain can be measured by any method known in the art, such as, but not limited to, assays from Quanterix and / or Roche Diagnostics. In certain embodiments, markers of glial activation include, but are not limited to, YKL-40 (CHI3L), IL-6, and / or GFAP. GFAP can be measured using any method known in the art, such as, but not limited to, assays from Roche Diagnostics.

[0150] Parkinson's disease Parkinson's disease, sometimes called idiopathic or primary parkinsonism, hypokinetic rigidity syndrome (HRS), or paralysis agitans, is a neurodegenerative brain disorder that affects motor system control. The progressive death of dopamine-producing cells in the brain causes the primary symptoms of Parkinson's disease. In most cases, Parkinson's disease is diagnosed in people over the age of 50. In most people, Parkinson's disease is idiopathic (the cause is unknown). However, genetic factors also play a role in the disease.

[0151] Symptoms of Parkinson's disease include, but are not limited to, tremors in the hands, arms, legs, jaw, and face; rigidity of the limbs and trunk; slowness of movement (bradykinesia); impaired postural reflexes; difficulty walking; neuropsychiatric disturbances; changes in speech or behavior; depression; anxiety; pain; psychosis; dementia; hallucinations; and sleep problems.

[0152] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of Parkinson's disease. In some embodiments, administering an anti-Sortilin antibody can induce one or more Progranulin activities in an individual with Parkinson's disease. In some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with Parkinson's disease.

[0153] Multiple sclerosis Multiple sclerosis (MS) is sometimes called disseminated sclerosis or disseminated encephalomyelitis. MS is an inflammatory disease in which the fatty myelin sheath that covers the axons in the brain and spinal cord is damaged, resulting in demyelination and scarring and a wide range of signs and symptoms. See, e.g., www.ninds.nih.gov / Disorders / Patient-Caregiver-Education / Hope-Through-Research / Multiple-Sclerosis-Hope-Through-Research.

[0154] Symptoms of MS include, but are not limited to, sensory changes such as loss of sensation or tingling, tingling or numbness such as hypoesthesia and dysesthesia, muscle weakness, clonus, muscle spasms, difficulty moving, coordination and balance difficulties such as ataxia, speech disorders such as dysarthria or swallowing difficulties such as dysphagia, vision problems such as nystagmus, optic neuritis (including phosphenes) and diplopia, fatigue, acute or chronic pain, and bladder and bowel disorders, varying degrees of cognitive impairment, emotional symptoms of depression or mood lability, Uthoff's phenomenon, in which existing symptoms are aggravated by exposure to temperatures higher than normal ambient temperature, and Lhermitte's sign, in which the person experiences an electrical shock sensation down the back when bending the neck.

[0155] In some embodiments, administering an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of multiple sclerosis. In some embodiments, administering an anti-Sortilin antibody can induce one or more Progranulin activities in an individual with multiple sclerosis. In some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in an individual with multiple sclerosis.

[0156] Glaucoma and macular degeneration Glaucoma describes a group of diseases characterized by, but not limited to, damage to the optic nerve, resulting in visual field loss and blindness. Glaucoma is usually caused by increased fluid pressure in the anterior chamber under the cornea (i.e., pressure inside the eye). Glaucoma results in the progressive loss of retinal ganglion cells, which are important for vision. Age-related macular degeneration usually affects older people and causes visual field loss primarily in the macula, the center of vision. Macular degeneration can cause, but is not limited to, drusen, pigmentary changes, visual field distortion, ocular hemorrhage, atrophy, decreased visual acuity, blurred vision, central scotoma, decreased color vision, and decreased contrast sensitivity.

[0157] Without wishing to be bound by theory, it is believed that administration of an anti-Sortilin antibody of the present disclosure can treat and / or slow the progression of glaucoma and macular degeneration. In some embodiments, administering an anti-Sortilin antibody can induce one or more progranulin activities in individuals with glaucoma and macular degeneration. In some embodiments, administering an anti-Sortilin antibody can modulate one or more Sortilin activities in individuals with glaucoma and macular degeneration.

[0158] Granulin mutations In some embodiments, the individual is heterozygous for a mutation in GRN (the granulin gene). In some embodiments, the mutation in GRN is a loss-of-function mutation.

[0159] In some embodiments, the presence of mutation in GRN is determined by any method known in the art.Non-limiting examples of methods that can be used to determine the presence of mutation in GRN include DNA sequencing, DNA hybridization, polymerase chain reaction (PCR), multiplex PCR, nested PCR, real-time PCR, quantitative PCR, semi-quantitative PCR, DNA microarray, multiplex ligation-dependent probe amplification, single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, heteroduplex analysis, Southern blotting, genetic linkage analysis (e.g., using short tandem repeats and / or variable number tandem repeats), fluorescence in situ hybridization, comparative genomic hybridization, allele-specific amplification, and / or restriction enzyme digestion (e.g., restriction fragment length polymorphism analysis) (Mahdieh et al., Iran J Pediatr (2013) 23 (4): 375-388).

[0160] In some embodiments, the presence of a mutation in a GRN is determined by DNA sequencing (Chang et al., (2010) Arch Neurol 67(2):161-170). In some embodiments, the presence of a mutation in a GRN is determined by DNA sequencing and genotyping (Chang et al., (2010) Arch Neurol 67(2):161-170).

[0161] In some embodiments, low serum progranulin predicts the presence of a mutation in GRN (Schofield et al., (2010) J Alzheimers Dis 22(3):981-4). PGRN levels can be determined as described in the "PGRN Levels" section below.

[0162] C9orf72 mutation In some embodiments, the individual is heterozygous for the C9orf72 hexanucleotide repeat expansion.

[0163] In some embodiments, the presence of a C9orf72 hexanucleotide repeat expansion is determined by any method known in the art. Non-limiting examples of methods that can be used to determine the presence of a C9orf72 hexanucleotide repeat expansion include DNA sequencing, long-read DNA sequencing, DNA hybridization, polymerase chain reaction (PCR), multiplex PCR, nested PCR, real-time PCR, quantitative PCR, semi-quantitative PCR, DNA microarrays, Southern blotting, multiplex ligation-dependent probe amplification, single-strand conformational polymorphism analysis, denaturing gradient gel electrophoresis, heteroduplex analysis, genetic linkage analysis (e.g., using short tandem repeats and / or variable number tandem repeats), fluorescence in situ hybridization, comparative genomic hybridization, allele-specific amplification, and / or restriction enzyme digestion methods (e.g., restriction fragment length polymorphism analysis) (Mahdieh et al., Iran J Pediatr (2013) 23(4):375-388).

[0164] In some embodiments, the presence of the C9orf72 hexanucleotide repeat expansion is determined by DNA sequencing (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, the presence of the C9orf72 hexanucleotide repeat expansion is determined by long-read sequencing (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, the presence of the C9orf72 hexanucleotide repeat expansion is determined using a Pacific Biosciences sequencing platform or an Oxford Nanopore Technologies sequencing platform (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, the presence of the C9orf72 hexanucleotide repeat expansion is determined using a commercially available test. Non-limiting examples of commercially available tests include tests from GeneDx (available at the website www[dot]genedx[dot]com / wp-content / uploads / 2017 / 06 / info_sheet_C9orf72.pdf), Fulgent (available at the website www[dot]fulgentgenetics[dot]com / repeatexpansion-c9orf72), Prevention Genetics (available at the website www[dot]preventiongenetics.[dot]com / testInfo.php?sel=test&val=C9orf72+Gene+Hexanucleotide+Repeat+Expansion), and / or Athena Diagnostics (available at the website www[dot]athenadiagnostics[dot]com / view-full-catalog / c / c9orf72-dna-test).

[0165] Pharmaceutical Dosage The antibodies (and any additional therapeutic agents) provided herein can be administered by any suitable means, including parenteral, intrapulmonary, intranasal, intralesional, intracerebral, intracranial, intraspinal, intrasynovial, intrathecal, oral, topical, or inhalation routes. Parenteral administration includes intravenous, intraarterial, intraarticular, intraperitoneal, or subcutaneous administration, either intramuscularly, as a bolus, or by continuous infusion over time. In some embodiments, administration is intravenous. In some embodiments, administration is subcutaneous. Administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or prolonged. Various administration schedules are contemplated herein, including, but not limited to, single or multiple administrations at various time points, bolus administration, and pulse infusion.

[0166] The antibodies provided herein will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to physicians. While the antibodies are optionally, but not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question, the effective amount of such other agents will depend on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These will generally be used in the same dosages and by any route of administration as described herein, or at about 1-99% of the dosages described herein, or at any dosage and by any route that has been empirically / clinically determined to be appropriate.

[0167] The dosage of a particular anti-Sortilin antibody may be empirically determined in an individual who has been given one or more administrations of the anti-Sortilin antibody. The individual is given gradually increasing doses of the anti-Sortilin antibody. To assess the effectiveness of an anti-Sortilin antibody, clinical symptoms of any disease, disorder, or condition of the disclosure (e.g., frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, and undesirable symptoms of normal aging) can be monitored.

[0168] The appropriate dosage of the antibodies of the invention (when used alone or in combination with one or more other additional therapeutic agents) for preventing or treating disease will depend on the type of disease being treated, the type of antibody, the severity and course of the disease, whether the antibody is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

[0169] Depending on the type and severity of the disease, about 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) of antibody can be an initial candidate dosage for administration to an individual, for example, by one or more separate administrations or by continuous infusion. A typical daily dosage could range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, treatment would generally be sustained until a desired suppression of symptoms occurs. An exemplary dosage of the antibody would be in the range of about 15 mg / kg to about 70 mg / kg. Thus, one or more doses of about 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, or 70 mg / kg (or any combination thereof) can be administered to a patient. Another exemplary dosage of an antibody would be in the range of about 30 mg / kg to about 60 mg / kg. Thus, one or more doses of about 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, or 60 mg / kg (or any combination thereof) can be administered to an individual.

[0170] In some embodiments, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 30 mg / kg. In some embodiments, the dose is at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, or at least about 60 mg / kg. In some embodiments, the dose is from about 30 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 60 mg / kg.

[0171] Such doses may be administered intermittently, e.g., weekly or every three weeks (e.g., so that an individual receives about 2-20 doses of antibody, or, e.g., about 6 doses). In certain embodiments, the dosing frequency is three times a day, twice a day, once a day, once every other day, once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once a month, once every two months, once every three months, or more. In some embodiments, the dose is administered about once a month. In some embodiments, the dosing frequency is q2w or more (i.e., the dose is administered once every two weeks or less frequently than once every two weeks), q3w or more, q4w or more, q5w or more, q6w or more, q7w or more, or q8w or more.

[0172] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 30 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg once every four weeks.

[0173] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 35 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg once every four weeks.

[0174] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 40 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg once every four weeks.

[0175] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 45 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg once every four weeks.

[0176] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 50 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg once every four weeks.

[0177] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least about 55 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg once every four weeks.

[0178] In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg once every four weeks or more. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 60 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg once every four weeks.

[0179] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 30 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg once every four weeks.

[0180] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 35 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg once every four weeks.

[0181] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 40 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg once every four weeks.

[0182] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 45 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg once every four weeks.

[0183] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 50 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg once every four weeks.

[0184] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual at a dose of at least 55 mg / kg once every four weeks or more frequently. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg once every four weeks.

[0185] In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg once every four weeks or more. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg once every two weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg once every three weeks. In some embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg once every four weeks.

[0186] In certain embodiments, the anti-Sortilin antibody is administered intravenously to the individual over a period of about 60 minutes.

[0187] In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg over at least about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg over at least 60 minutes.

[0188] In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg over at least about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg over at least 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg over about 60 minutes. In certain embodiments, the anti-Sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg over at least 60 minutes.

[0189] In certain embodiments, the anti-Sortilin antibody is administered intravenously to the individual at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20 times. In certain embodiments, the anti-Sortilin antibody is administered to the individual a total of 13 times.

[0190] In some embodiments, individuals are treated for a treatment period of up to 24 weeks, up to 25 weeks, up to 26 weeks, up to 27 weeks, up to 28 weeks, up to 29 weeks, up to 30 weeks, up to 31 weeks, up to 32 weeks, up to 33 weeks, up to 34 weeks, up to 35 weeks, up to 36 weeks, up to 37 weeks, up to 38 weeks, up to 39 weeks, up to 40 weeks, up to 41 weeks, up to 42 weeks, up to 43 weeks, up to 44 weeks, up to 45 weeks, up to 46 weeks, up to 47 weeks, or up to 48 weeks. In some embodiments, individuals are treated for a treatment period of up to 48 weeks. In some embodiments, individuals are treated for a treatment period as long as 48 weeks.

[0191] In some embodiments, administration of the anti-sortilin antibody occurs on the first day of the treatment period and every four weeks thereafter.

[0192] In some embodiments, the anti-sortilin antibody is administered a total of 13 times during the treatment period.

[0193] An initial higher loading dose, followed by one or more lower doses may be administered. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

[0194] PGRN level In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual, wherein the level of PGRN protein in the individual's plasma after administration of the anti-Sortilin antibody is higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, a 1-fold increase in the level of PGRN protein in the individual's plasma corresponds to a 100% increase in the level of PGRN protein in the individual's plasma. In some embodiments, the level of PGRN protein in the individual's plasma after administration of the anti-Sortilin antibody is at least 1-fold higher, at least 1.25-fold higher, at least 1.5-fold higher, at least 1.75-fold higher, at least 2-fold higher, at least 2.25-fold higher, at least 2.5-fold higher, at least 2.75-fold higher, or at least 3-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the individual's plasma after administration of the anti-Sortilin antibody is at least 1-fold higher than the level of PGRN protein in the individual's plasma before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-Sortilin antibody is at least 2-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody.

[0195] In some embodiments, a 2-fold increase in the level of PGRN protein in the plasma of an individual after administration of an anti-Sortilin antibody corresponds to a 100% increase in the level of PGRN protein in the plasma of the individual compared to the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of an individual after administration of an anti-Sortilin antibody is at least 2-fold, at least 3-fold, or at least 4-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of an individual after administration of an anti-Sortilin antibody is at least 2-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody.

[0196] In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, or about 12 days after administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 5 days after administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 42 days after administration of the anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 56 days after administration of the anti-Sortilin antibody.

[0197] In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, or about 12 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 5 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 28 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 35 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the individual's plasma occurs about 42 days after the last administration of an anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the plasma of the individual occurs about 49 days after the last dose of an anti-Sortilin antibody, hi some embodiments, a doubling of the level of PGRN protein in the plasma of the individual occurs about 56 days after the last dose of an anti-Sortilin antibody.

[0198] In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-Sortilin antibody is at least 0.25-fold higher, at least 0.3-fold higher, at least 0.35-fold higher, at least 0.4-fold higher, at least 0.45-fold higher, at least 0.5-fold higher, at least 0.55-fold higher, at least 0.6-fold higher, at least 0.65-fold higher, at least 0.7-fold higher, at least 0.75-fold higher, at least 0.8-fold higher, at least 0.85-fold higher, at least 0.9-fold higher, at least 0.95-fold higher, at least 1-fold higher, or at least 1.5-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody at about 40 days, about 41 days, or about 42 days after administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-Sortilin antibody is at least 0.25-fold higher about 40 days after administration of the anti-Sortilin antibody than the level of PGRN protein in the plasma of the individual before administration of the anti-Sortilin antibody.

[0199] In some embodiments, the level of PGRN protein in the individual's plasma is determined by drawing blood at multiple time points. In certain embodiments, the level of PGRN protein in the individual's plasma is determined by drawing blood 8 days, 5 days, 3 days, 2 days, 1 day, and / or 0 days before administration of the anti-Sortilin antibody, and 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 18 days, 30 days, 42 days, 43 days, 57 days, 85 days, and / or 113 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of PGRN protein in the individual's plasma is determined by drawing blood 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-Sortilin antibody, and 1, 2, 3, 6, 8, 13, 30, 43, 57, 85, and 113 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of PGRN protein in the individual's plasma is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before the first administration of the anti-Sortilin antibody, on the same day as each administration of the anti-Sortilin antibody, and 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, and / or 70 weeks after the first administration of the anti-Sortilin antibody. In certain embodiments, the level of PGRN protein in the individual's plasma is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first dose of anti-Sortilin antibody, on the same day as each dose of anti-Sortilin antibody, and 61 weeks after the first dose of anti-Sortilin antibody.

[0200] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual, wherein the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, a 1-fold increase in the level of PGRN protein in the cerebrospinal fluid of the individual corresponds to a 100% increase in the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 0.8-fold higher, at least 0.85-fold higher, at least 0.9-fold higher, at least 0.95-fold higher, at least 1-fold higher, or at least 1.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 0.8-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 1-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody.

[0201] In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 12 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 24 days after administration of the anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 56 days after administration of the anti-Sortilin antibody.

[0202] In some embodiments, a 2-fold increase in the level of PGRN protein in the cerebrospinal fluid of an individual corresponds to a 100% increase in the level of PGRN protein in the cerebrospinal fluid of the individual. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of an anti-Sortilin antibody is at least 2-fold higher, at least 2.5-fold higher, at least 3-fold higher, at least 3.5-fold higher, at least 4-fold higher, at least 4.5-fold higher, or at least 5-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of an anti-Sortilin antibody is at least 2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody.

[0203] In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 12 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 24 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 28 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 35 days after the last administration of an anti-Sortilin antibody. In some embodiments, the doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 42 days after the last administration of an anti-Sortilin antibody. In some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 49 days after the last dose of an anti-Sortilin antibody, hi some embodiments, a doubling of the level of PGRN protein in the cerebrospinal fluid of the individual occurs about 56 days after the last dose of an anti-Sortilin antibody.

[0204] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days is at least 0.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is at least 0.2-fold higher about 42 days after administration of the anti-Sortilin antibody than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody.

[0205] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual is determined by performing a lumbar puncture at multiple time points, hi certain embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual is determined by performing a lumbar puncture 8 days, 5 days, 3 days, 2 days, 1 day, and / or 0 days before administration of the anti-Sortilin antibody, and 1 day, 30 hours, 2 days, 12 days, 24 days, and / or 42 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of PGRN protein in the individual's cerebrospinal fluid is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first administration of the anti-Sortilin antibody and at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, and / or at least 60 weeks after the first administration of the anti-Sortilin antibody. In certain embodiments, the level of PGRN protein in the individual's cerebrospinal fluid is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first dose of the anti-Sortilin antibody, and during 25 weeks and 61 weeks after the first dose of the anti-Sortilin antibody.

[0206] In some embodiments, the level of PGRN protein in individual's plasma or cerebrospinal fluid is determined using any method known in the art for quantifying proteins.Non-limiting examples of methods that can be used to quantify PGRN protein include SOMASCAN assay (e.g., Candia et al. (2017) Sci Rep 7,14248), Western blot, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) assay.In certain embodiments, the level of PGRN protein in individual's plasma or cerebrospinal fluid is determined using ELISA assay.

[0207] SORT1 level In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual, where the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody. In some embodiments, the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody. In some embodiments, the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced by at least 50% compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody. In some embodiments, the expression level of SORT1 protein on peripheral leukocytes of the individual after administration of the anti-Sortilin antibody is reduced by at least 70% compared to the expression level of SORT1 protein on peripheral leukocytes of the individual before administration of the anti-Sortilin antibody.

[0208] In some embodiments, the decrease in expression level of SORT1 in peripheral leukocytes of the individual is present about 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or more, 41 or more, 42 or more, 43 or more, 44 or more, or 45 or more days after administration of the anti-Sortilin antibody. In some embodiments, the decrease in expression level of SORT1 in peripheral leukocytes of the individual is present about 12 days or more after administration of the anti-Sortilin antibody. In some embodiments, the decrease in expression level of SORT1 in peripheral leukocytes of the individual is present about 17 days or more after administration of the anti-Sortilin antibody. In some embodiments, the decrease in expression level of SORT1 in peripheral leukocytes of the individual is present about 40 days or more after administration of the anti-Sortilin antibody.

[0209] In some embodiments, the decrease in expression level of SORT1 in peripheral leukocytes of the individual is present about 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or more, 41 or more, 42 or more, 43 or more, 44 or more, or 45 or more days after the last administration of the anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 12 days or more after the last administration of an anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 17 days or more after the last administration of an anti-Sortilin antibody. In some embodiments, the decrease in the expression level of SORT1 in the peripheral leukocytes of the individual is present about 40 days or more after the last administration of an anti-Sortilin antibody.

[0210] In some aspects, the methods of the disclosure comprise intravenously administering an anti-Sortilin antibody to an individual, wherein the level of SORT1 protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is reduced compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is reduced by at least 50% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administration of the anti-Sortilin antibody is reduced by at least 70% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administration of the anti-Sortilin antibody.

[0211] In some embodiments, the level of SORT1 protein on the individual's peripheral leukocytes is determined by drawing blood at multiple time points. In certain embodiments, the level of SORT1 on the individual's peripheral leukocytes is determined by drawing blood 8 days, 5 days, 3 days, 2 days, 1 day, and / or 0 days before administration of the anti-Sortilin antibody, and 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 18 days, 30 days, 42 days, 43 days, 57 days, 85 days, and / or 113 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of SORT1 on peripheral leukocytes of an individual is determined by drawing blood 8 days, 5 days, 3 days, 2 days, 1 day, and / or 0 days prior to administration of the anti-Sortilin antibody, and 1 day, 2 days, 3 days, 6 days, 8 days, 9 days, 13 days, 18 days, 30 days, 43 days, 57 days, 85 days, and 113 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of SORT1 on the individual's peripheral leukocytes is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first dose of anti-Sortilin antibody, on the same day as each dose of anti-Sortilin antibody, and 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, and / or 70 weeks after the first dose of anti-Sortilin antibody. In certain embodiments, the level of SORT1 on the individual's peripheral leukocytes is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first dose of anti-Sortilin antibody, on the same day as each dose of anti-Sortilin antibody, and during the 61st week after the first dose of anti-Sortilin antibody.

[0212] In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual is determined by performing a lumbar puncture at multiple time points, hi certain embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual is determined by performing a lumbar puncture 8 days, 5 days, 3 days, 2 days, 1 day, and / or 0 days before administration of the anti-Sortilin antibody, and 1 day, 30 hours, 12 days, 24 days, and / or 42 days after administration of the anti-Sortilin antibody. In certain embodiments, the level of SORT1 protein in the individual's cerebrospinal fluid is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first administration of the anti-Sortilin antibody and at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, and / or at least 60 weeks after the first administration of the anti-Sortilin antibody. In certain embodiments, the level of SORT1 protein in the individual's cerebrospinal fluid is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days prior to the first dose of the anti-Sortilin antibody, and during 25 weeks and 61 weeks after the first dose of the anti-Sortilin antibody.

[0213] In some embodiments, the level of SORT1 protein on an individual's peripheral leukocytes or the level of soluble SORT1 protein in cerebrospinal fluid is determined using any method known in the art for quantifying proteins. Non-limiting examples of methods that can be used to quantify SORT1 protein include the SOMASCAN assay (e.g., Candia et al. (2017) Sci Rep 7, 14248), Western blot, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) assay. In certain embodiments, the level of SORT1 protein in an individual's peripheral leukocytes or cerebrospinal fluid is determined using an ELISA assay. In certain embodiments, the level of SORT1 protein in an individual's peripheral leukocytes or cerebrospinal fluid is determined using an ELISA assay using an anti-Sortilin antibody-specific anti-idiotype antibody.

[0214] Pharmacokinetics of anti-sortilin antibodies In some embodiments, the half-life of the anti-Sortilin antibody in plasma is about 5 days, about 6 days, about 7 days, about 8 days, or about 9 days. In some embodiments, the half-life of the anti-Sortilin antibody in plasma is about 5 days. In some embodiments, the half-life of the anti-Sortilin antibody in plasma is about 8 days.

[0215] Diagnostic Use The isolated antibodies of the present disclosure (e.g., the anti-Sortilin antibodies described herein) also have diagnostic utility. Accordingly, the present disclosure provides methods of using the antibodies of the present disclosure, or functional fragments thereof, for diagnostic purposes, such as detecting Sortilin protein in an individual or in a tissue sample derived from an individual.

[0216] In some embodiments, the individual is a human. In some embodiments, the individual is a human patient suffering from or at risk of developing a disease, disorder, or injury of the present disclosure. In some embodiments, the diagnostic method involves detecting Sortilin protein in a biological sample, such as a biopsy sample, tissue, or cells. An anti-Sortilin antibody described herein is contacted with the biological sample, and the antibody bound to the antigen is detected. For example, a biopsy sample can be stained with an anti-Sortilin antibody described herein to detect and / or quantitate disease-associated cells. The detection method can include quantitating the antibody bound to the antigen. Antibody detection in a biological sample can be performed by any method known in the art, including immunofluorescence microscopy, immunocytochemistry, immunohistochemistry, ELISA, FACS analysis, immunoprecipitation, or micropositron emission tomography. In certain embodiments, the antibody is, for example, 18 F and then detected using micropositron emission tomography analysis. Antibody binding can also be quantified in individuals by non-invasive techniques such as positron emission tomography (PET), X-ray computed tomography, single photon emission computed tomography (SPECT), computed tomography (CT), and computed axial tomography (CAT).

[0217] In other embodiments, isolated antibodies of the present disclosure (e.g., anti-Sortilin antibodies described herein) can be used to detect and / or quantitate microglia in brain samples taken from preclinical disease models (e.g., non-human disease models). Thus, isolated antibodies of the present disclosure (e.g., anti-Sortilin antibodies described herein) can be useful for assessing therapeutic response following treatment compared to controls in models of nervous system disease or injury, such as frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, atherosclerotic vascular disease, Nasu-Hakola disease, or multiple sclerosis.

[0218] Sortilin antibodies Certain aspects of the present disclosure relate to anti-Sortilin antibodies that comprise one or more improved and / or enhanced functional characteristics. In some embodiments, the anti-Sortilin antibodies of the present disclosure comprise one or more improved and / or enhanced functional characteristics compared to S-60, an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region as described in WO2016164637. In some embodiments, the anti-Sortilin antibodies of the present disclosure have an affinity for Sortilin (e.g., human Sortilin) ​​that is higher than the affinity of a control anti-Sortilin antibody (e.g., a control anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the present disclosure have a lower half-maximal effective concentration (EC) than the control antibody (e.g., a control anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 ) to a greater extent than an anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60. In some embodiments, an anti-Sortilin antibody of the present disclosure improves the maximal reduction in cell surface levels of Sortilin compared to an anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60. In some embodiments, an anti-Sortilin antibody of the present disclosure increases the secretion of extracellular Progranulin (PGRN) compared to an anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60. In some embodiments, an anti-Sortilin antibody of the present disclosure has a lower half-maximal effective concentration (EC 50 ) block PGRN binding to Sortilin to a greater extent than S-60. In some embodiments, the anti-Sortilin antibodies of the disclosure improve maximal blocking of PGRN binding to Sortilin compared to anti-Sortilin antibodies that include heavy chain variable regions and light chain variable regions corresponding to S-60.

[0219] Also contemplated herein are anti-Sortilin antibodies with different Fc variants that exhibit one or more improved and / or enhanced functional characteristics compared to an anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60, such improvements and / or enhancements including half-maximal effective concentration (EC 50 ), decreasing the cell surface level of sortilin, improving the maximum decrease in cell surface level of sortilin, increasing the extracellular secretion of PGRN, and increasing the half-maximal effective concentration (EC 50 ) to block PGRN binding to sortilin, and improving maximal blockade of PGRN binding to sortilin.

[0220] In some embodiments, an anti-Sortilin antibody of the disclosure is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

[0221] In a preferred embodiment, the anti-Sortilin antibodies of the present disclosure are monoclonal antibodies.

[0222] Anti-Sortilin antibody heavy and light chain variable regions A. Heavy chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11-13). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11-13).

[0223] In some embodiments, HVR-H1 comprises the sequence YSISSGYYWG (SEQ ID NO: 1). In some embodiments, HVR-H2 comprises a sequence according to Formula I: TIYHSGSTYYNPSLX1S (SEQ ID NO: 4), where X1 is K or E. In some embodiments, HVR-H2 comprises a sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises a sequence according to Formula II: ARQGSIX1QGYYGMDV (SEQ ID NO: 7). In some embodiments, HVR-H3 comprises a sequence selected from SEQ ID NOs: 5-6.

[0224] In some embodiments, HVR-H1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 1. In some embodiments, HVR-H1 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NO: 1), but retains the ability to bind to sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids have been substituted, inserted, and / or deleted in the HVR-H1 amino acid sequence of SEQ ID NO: 1. In some embodiments, HVR-H2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H2 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 2-3) while still retaining the ability to bind to sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-H2 amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 5-6. In some embodiments, HVR-H3 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 5-6) yet still retains the ability to bind to sortilin.In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids are substituted, inserted, and / or deleted in an HVR-H3 amino acid sequence selected from SEQ ID NOs: 5-6.

[0225] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the sequence according to Formula I, and HVR-H3 comprising the sequence according to Formula II.

[0226] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6.

[0227] In some embodiments, the heavy chain variable region is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof, including HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11-13).

[0228] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region, wherein the heavy chain variable region comprises one or more of the following: (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], at least 85%, at least 86%, or at least 87% of the HVR-H1 amino acids in S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (b) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S]; S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N 33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15 .10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I] , S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or or 100% identical to HVR-H2, and (c) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33R], S-60-15.8[N33D], S-60-15.9[N33H], S-60-15.10[N33T], S-60-15.11[N33S], S-60-15.12[N33G], S-60-15.13[N33R], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15.16[N33H], S-60-15.17[N33R], S-60-15.18[N33D], S-60-15.19[N33H], S-60-15.19[N33R], S-60-15.11[N33R], S-60-15.12[N33D], S-60-15.13[N33S], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15.16[N33H], S-6 .7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-1 5.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60 HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H3 amino acid sequence of S-19 or S-60-24.

[0229] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0230] B. Light chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14-16). In some embodiments, the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14-16).

[0231] In some embodiments, HVR-L1 comprises a sequence according to Formula III: RSSQX1LLX2SX3GYNYLD (SEQ ID NO:28), where Xi is S or G, X2 is R or H, and X3 is N, T, S, G, R, D, H, K, Q, Y, E, W, F, I, V, A, M, or L. In some embodiments, HVR-L1 comprises a sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 comprises a sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 has the sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), RSSQSLLRSTGYNYLD (SEQ ID NO: 9), RSSQSLLRSSGYNYLD (SEQ ID NO: 10), RSSQSLLRSGGYNYLD (SEQ ID NO: 11), RSSQSLLRSRGYNYLD (SEQ ID NO: 12), RSSQSLLRSDGYNYLD (SEQ ID NO: 13), RSSQSLLRSHGYNYLD (SEQ ID NO: 14), RSSQSLLRSKGYNYLD (SEQ ID NO: 15), RSSQSLLRSQGYNYLD (SEQ ID NO: 16), RSSQSLLRSYGYNYLD (SEQ ID NO: 17), RSSQSLLRSYGYNYLD (SEQ ID NO: 18), RSSQSLLRSYGYNYLD (SEQ ID NO: 19), RSSQSLLRSYGYNYLD (SEQ ID NO: 20), RSSQSLLRSYGYNYLD (SEQ ID NO: 21), RSSQSLLRSYGYNYLD (SEQ ID NO: 22), RSSQSLLRSYGYNYLD (SEQ ID NO: 23), RSSQSLLRSYGYNYLD (SEQ ID NO: 24), RSSQSLLRSYGYNYLD (SEQ ID NO: 25), RSSQSLLRSYGYNYLD (SEQ ID NO: 26), RSSQSLLRSYGYNYLD (SEQ ID NO: 27), RSSQSLLRSYGYNYLD (SEQ ID NO: 28), RSSQSLLRSYGYNYLD (SEQ ID NO: 29), RSSQSLLRSYGYNYLD (SEQ ID NO: 30), RSSQSLLRSYGYNYLD (SEQ ID NO: 31), RSSQSLLRSYGYNYLD (SEQ ID NO: 32), SEQ ID NO: 17), RSSQSLLRSEGYNYLD (SEQ ID NO: 18), RSSQSLLRSWGYNYLD (SEQ ID NO: 19), RSSQSLLRSFGYNYLD (SEQ ID NO: 20), RSSQSLLRSIGYNYLD (SEQ ID NO: 21), RSSQSLLRSVGYNYLD (SEQ ID NO: 22), RSSQSLLRSAGYNYLD (SEQ ID NO: 23), RSSQSLLRSMGYNYLD (SEQ ID NO: 24), RSSQSLLRSLGYNYLD (SEQ ID NO: 25), RSSQSLLHSNGYNYLD (SEQ ID NO: 26), or RSSQGLLRSNGYNYLD (SEQ ID NO: 27). In one particular embodiment, HVR-L1 comprises the sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8). In another particular embodiment, HVR-L1 comprises the sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9) (as shown in Table 14).

[0232] In some embodiments, HVR-L2 comprises a sequence according to Formula IV:LGSNRX1S (SEQ ID NO: 31), where X1 is A or V. In some embodiments, HVR-L2 comprises a sequence selected from 29-30.

[0233] In some embodiments, HVR-L3 comprises a sequence according to formula V:MQQQEX1PLT (SEQ ID NO: 34), where X1 is A or T. In some embodiments, HVR-L3 comprises a sequence selected from SEQ ID NOs: 32-33.

[0234] In some embodiments, HVR-L1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 8-27) while still retaining the ability to bind to sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-L1 amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L2 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 29-30) yet still retains the ability to bind to sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-L2 amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 32-33.In some embodiments, the HVR-L3 comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 32-33), yet still retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids are substituted, inserted, and / or deleted in the HVR-L3 amino acid sequence selected from SEQ ID NOs: 32-33.

[0235] In some embodiments, the light chain variable region comprises HVR-L1 comprising a sequence according to Formula III, HVR-L2 comprising a sequence according to Formula IV, and HVR-L3 comprising a sequence according to Formula V. In some embodiments, the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8-27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29-30, and HVR-L3 comprising a sequence selected from SEQ ID NOs: 32-33.

[0236] In some embodiments, the light chain variable region is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof, including HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14-16).

[0237] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region, wherein the light chain variable region comprises one or more of the following: (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], At least 85%, at least 86%, or at least 87% of the HVR-L1 amino acids in S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (b) HVR-L1 comprising an amino acid sequence having 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with any of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S -60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N3 3H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15. 10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I] , S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24, or HVR-L2 comprising an amino acid sequence having 100% identity thereto, and (c) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15 .7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-1 5.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60 and an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L3 amino acid sequence of S-19 or S-60-24.

[0238] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0239] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0240] C. Heavy Chain HVR and Light Chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (shown in Tables 11-13), and a light chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (shown in Tables 14-16). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (shown in Tables 11-13), and the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (shown in Tables 14-16).

[0241] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising a sequence according to Formula I, and HVR-H3 comprising a sequence according to Formula II; the light chain variable region comprises HVR-L1 comprising a sequence according to Formula III, HVR-L2 comprising a sequence according to Formula IV, and HVR-L3 comprising a sequence according to Formula V. In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6; and the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8-27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29-30, and HVR-L3 comprising a sequence selected from SEQ ID NOs: 32-33.

[0242] In some aspects, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2 to 3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5 to 6, and the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8 to 27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29 to 30, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 32.

[0243] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33H], S-60-15.10[N33K], S-60-15.11[N33R], S-60-15.12[N33R], S-60-15.13[N33K], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15.16[N33H], S-60-15.17[N33K], S-60-15.18[N33Q], S-60-15.19[N33R], S-60-15.20[N33R], S-60-15.21[N33R], S-60-15.22[N33R], S-60-15.23[N33R], S-60-15.24[N33R], S-60-15.25[N33R], S-60-15.26[N33R], S-60- HVR-H1, HVR-H2, and HVR-H3 of S-60-15.9 [N33Y], S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof (Tables 11-13) and heavy chain variable regions containing S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H], S-60-15.7 [N33K], S-60-15.8 [N33Q], S-60-15.9 [N33Y], and S-60-15. and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14-16) of S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof.

[0244] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, and the antibody is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N 33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N3 3W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N 33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, or S-60-24; HVR-H1, HVR-H2, HVR-H3, and HVR-L1, HVR-L2, and HVR-L3 (shown in Tables 11 to 16).

[0245] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one or more of the following: (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H] ], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 HVR-H1 amino acids (b) HVR-H1 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the sequence of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], and S-60-15. 3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[ N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.and (c) an HVR-H2 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H2 amino acid sequence of S-60-17 [N33L], S-60-16; S-60-18, S-60-19, or S-60-24; and -60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R] , S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33 Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.1 2[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-6 and an HVR-H3 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H3 amino acid sequence of S-60-10, S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24, wherein the light chain variable region comprises one or more of the following: (a) antibody S-60-10, S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. -11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S -60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D] , S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33 Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.HVR-L1 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L1 amino acids of S-60-13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 ( b)S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-6 0-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S -60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q] , S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[ N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. HVR-L2 containing the amino acid sequence, and (c) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H], S-60-15.7 [N33K], S-60-15.8 [N33Q], S-60-15.9 [N33Y], S-60-15.10 [N33E], and S-60-15.and an HVR-L3 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L3 amino acid sequence of S-60-11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16;S-60-18, S-60-19, or S-60-24.

[0246] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0247] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0248] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0249] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising: HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising: HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0250] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising: HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising: HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0251] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0252] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0253] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6), and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0254] D. Heavy Chain Variable Region In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 54-56) while still retaining the ability to bind to Sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56.

[0255] In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:56.

[0256] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33 [N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 heavy chain variable regions (as shown in Table 25).

[0257] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0258] E. Light Chain Variable Region In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence that includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 57-80) while still retaining the ability to bind to Sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0259] In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 60.

[0260] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33 and S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-15.18, S-60-19, or S-60-24 (as shown in Table 26).

[0261] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0262] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0263] F. Heavy Chain Variable Region and Light Chain Variable Region In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-56, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 57-80. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56, and the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence that includes a substitution (e.g., a conservative substitution, insertion, or deletion relative to an amino acid sequence selected from SEQ ID NOs: 54-56), and a heavy chain variable region that includes an amino acid sequence that includes a substitution (e.g., a conservative substitution, insertion, or deletion relative to an amino acid sequence selected from SEQ ID NOs: 57-80), but still retains the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56, and in certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0264] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-56, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 57-58, 60-78, and 80.

[0265] In some embodiments, the anti-Sortilin antibodies of the disclosure bind to a Sortilin protein and include antibodies comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59 Examples of the variable region include a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 78, a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80.

[0266] In one embodiment, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:56 and a light chain variable region having the amino acid sequence of SEQ ID NO:57.

[0267] In one embodiment, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:56 and a light chain variable region having the amino acid sequence of SEQ ID NO:60.

[0268] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60- heavy chain variable region of S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 The antibody sequences were compared for the following regions (shown in Table 25) and the following antibodies: S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H], S-60-15.7 [N33K], S-60-15.8 [N33Q], S-60 and a light chain variable region of S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (shown in Table 26).

[0269] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 57 and 60. In some embodiments, the antibody comprises the heavy chain variable region of S-60-15[N33(wt)] (shown in Table 25) and the light chain variable region of antibody S-60-15[N33(wt)] (shown in Table 26). In some embodiments, the antibody comprises the heavy chain variable region of S-60-15.1[N33T] (shown in Table 25) and the light chain variable region of antibody S-60-15.1[N33T] (shown in Table 26).

[0270] Exemplary Anti-Sortilin Antibodies In some embodiments, the anti-Sortilin antibody is S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33 and an anti-sortilin monoclonal antibody comprising the heavy chain variable region and the light chain variable region of an antibody selected from S-60-15.3Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60- and an anti-Sortilin monoclonal antibody comprising the heavy and light chains of an antibody selected from S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24.

[0271] (1) S-60-10 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-10. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-10.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-10 or SEQ ID NO: 54, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-10, (b) the HVR-H2 amino acid sequence of antibody S-60-10, and (c) the HVR-H3 amino acid sequence of antibody S-60-10. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein an anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-10 or SEQ ID NO: 57, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-10, (b) the HVR-L2 amino acid sequence of antibody S-60-10, and (c) the HVR-L3 amino acid sequence of antibody S-60-10.

[0272] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 92.

[0273] (2)S-60-11 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO:58. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-11. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-11.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-11 or SEQ ID NO: 54, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-11, (b) the HVR-H2 amino acid sequence of antibody S-60-11, and (c) the HVR-H3 amino acid sequence of antibody S-60-11. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-11 or SEQ ID NO: 58, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-11, (b) the HVR-L2 amino acid sequence of antibody S-60-11, and (c) the HVR-L3 amino acid sequence of antibody S-60-11.

[0274] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 93. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.

[0275] (3) S-60-12 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO:59. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-12. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-12.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-12 or SEQ ID NO: 54, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-12, (b) the HVR-H2 amino acid sequence of antibody S-60-12, and (c) the HVR-H3 amino acid sequence of antibody S-60-12. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-12 or SEQ ID NO: 59, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-12, (b) the HVR-L2 amino acid sequence of antibody S-60-12, and (c) the HVR-L3 amino acid sequence of antibody S-60-12.

[0276] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 94. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 94.

[0277] (4)S-60-13 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO:55; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-13. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-13.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-13 or SEQ ID NO: 55, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-13, (b) the HVR-H2 amino acid sequence of antibody S-60-13, and (c) the HVR-H3 amino acid sequence of antibody S-60-13. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-13 or SEQ ID NO: 57, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-13, (b) the HVR-L2 amino acid sequence of antibody S-60-13, and (c) the HVR-L3 amino acid sequence of antibody S-60-13.

[0278] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89 and a light chain comprising the amino acid sequence of SEQ ID NO: 92.

[0279] (5)S-60-14 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO:55; and / or the light chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO:58. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-14. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-14.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-14 or SEQ ID NO: 55, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-14, (b) the HVR-H2 amino acid sequence of antibody S-60-14, and (c) the HVR-H3 amino acid sequence of antibody S-60-14. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-14 or SEQ ID NO: 58, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-14, (b) the HVR-L2 amino acid sequence of antibody S-60-14, and (c) the HVR-L3 amino acid sequence of antibody S-60-14.

[0280] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 93. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.

[0281] (6)S-60-15 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-15 or SEQ ID NO: 56, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-15, (b) the HVR-H2 amino acid sequence of antibody S-60-15, and (c) the HVR-H3 amino acid sequence of antibody S-60-15. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-15 or SEQ ID NO: 57, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-15, (b) the HVR-L2 amino acid sequence of antibody S-60-15, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.

[0282] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 92. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 92.

[0283] (7) S-60-15.1 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO:60. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15.1. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15.1.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-15.1 or SEQ ID NO: 56, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-15.1, (b) the HVR-H2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-H3 amino acid sequence of antibody S-60-15.1. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-15.1 or SEQ ID NO: 60, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-15.1, (b) the HVR-L2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.1.

[0284] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 95. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0285] (8)S-60-16 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO:77. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-16. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-16.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-16 or SEQ ID NO: 56, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-16, (b) the HVR-H2 amino acid sequence of antibody S-60-16, and (c) the HVR-H3 amino acid sequence of antibody S-60-16. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-16 or SEQ ID NO: 77, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-16, (b) the HVR-L2 amino acid sequence of antibody S-60-16, and (c) the HVR-L3 amino acid sequence of antibody S-60-16.

[0286] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 112. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 112.

[0287] (9)S-60-18 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO:78. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-18. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-18.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-18 or SEQ ID NO: 56, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-18, (b) the HVR-H2 amino acid sequence of antibody S-60-18, and (c) the HVR-H3 amino acid sequence of antibody S-60-18. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-18 or SEQ ID NO: 78, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-18, (b) the HVR-L2 amino acid sequence of antibody S-60-18, and (c) the HVR-L3 amino acid sequence of antibody S-60-18.

[0288] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 113. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 113.

[0289] (10)S-60-19 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO:79. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-19. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-19.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-19 or SEQ ID NO: 54, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-19, (b) the HVR-H2 amino acid sequence of antibody S-60-19, and (c) the HVR-H3 amino acid sequence of antibody S-60-19. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-19 or SEQ ID NO: 79, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-19, (b) the HVR-L2 amino acid sequence of antibody S-60-19, and (c) the HVR-L3 amino acid sequence of antibody S-60-19.

[0290] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 114. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 114.

[0291] (11)S-60-24 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO:80. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-24. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-24.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-24 or SEQ ID NO: 56, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-24, (b) the HVR-H2 amino acid sequence of antibody S-60-24, and (c) the HVR-H3 amino acid sequence of antibody S-60-24. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80, and includes substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-24 or SEQ ID NO: 80, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-24, (b) the HVR-L2 amino acid sequence of antibody S-60-24, and (c) the HVR-L3 amino acid sequence of antibody S-60-24.

[0292] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 115. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 115.

[0293] In some embodiments, an anti-Sortilin antibody of the disclosure binds to essentially the same Sortilin epitope as an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, and S-60-24.

[0294] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-10.

[0295] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-11.

[0296] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-12.

[0297] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-13.

[0298] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-14.

[0299] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-15.

[0300] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-15.1.

[0301] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-16.

[0302] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-18.

[0303] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-19.

[0304] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-24.

[0305] In certain embodiments, the anti-Sortilin antibody is an antagonist antibody. In certain embodiments, the anti-Sortilin antibody is an agonist antibody. In some embodiments, the anti-Sortilin antibody of the present disclosure is of the IgG class, IgM class, or IgA class. In some embodiments, the anti-Sortilin antibody of the present disclosure is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

[0306] Additional anti-Sortilin antibodies, e.g., antibodies that specifically bind to a Sortilin protein of the present disclosure, can be identified, screened, and / or characterized for their physical / chemical properties and / or biological activity by a variety of assays known in the art.

[0307] Certain aspects of the present disclosure relate to the use of two or more anti-Sortilin antibodies that, when utilized together, exhibit additive or synergistic effects compared to the use of a corresponding single anti-Sortilin antibody.

[0308] In some embodiments, the anti-Sortilin antibodies of the present disclosure are antibody fragments that bind to human Sortilin protein.

[0309] In some embodiments, the anti-Sortilin antibodies of the present disclosure are antibody fragments that bind to one or more human proteins selected from the group consisting of human Sortilin, naturally occurring variants of human Sortilin, and disease variants of human Sortilin.

[0310] In some embodiments, the anti-Sortilin antibodies of the disclosure are antibody fragments, and the antibody fragments are Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragments.

[0311] Antibody Framework In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, three or more, or all four) framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4 (see Tables 17-20). In some embodiments, VH FR1 comprises the sequence QVQLQESGPGLVKPSETLSL TCAVSG (SEQ ID NO: 35). In some embodiments, VH FR2 comprises the sequence WIRQPPGKGLEWIG (SEQ ID NO: 36). In some embodiments, VH FR3 comprises a sequence of formula VI: X1VTISVDTSKNQFSLX2LSSVTAADTAVYYC (SEQ ID NO: 39), where X1 is Q or R and X2 is E or K. In some embodiments, VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 37-38. In some embodiments, VH FR4 comprises the sequence WGQGTTVTVSS (SEQ ID NO: 40). In some embodiments, the antibody comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 of Formula VI, and a VH FR4 comprising the sequence of SEQ ID NO: 40.

[0312] In some embodiments, the antibody comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 comprising a sequence selected from SEQ ID NOs: 37-38, and a VH FR4 comprising the sequence of SEQ ID NO: 40.

[0313] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33H], S-60-15.9[N33K], S-60-15.10[N33R], S-60-15.11[N33T], S-60-15.12[N33S], S-60-15.13[N33G], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15.16[N33H], S-60-15.17[N33K], S-60-15.18[N33R], S-60-15.19[N33R], S-60-15.20[N33R], S-60-15.21[N33R], S-60-15.22[N33R], S-60-15.23[N33R], S-60-15.24[N33R], S-60-15.25[N33R], S-60-15.26[N33R], S-60- and S-6...

Claims

1. 1. A pharmaceutical formulation comprising an anti-sortilin antibody, comprising: a) 20 mM histidine or histidine HCl b) 7.5% (w / v) sucrose c) 0.02% (w / v) polysorbate-80 Including; pH is 5.5; The antibody a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); Including, The pharmaceutical preparation.

2. 2. The pharmaceutical formulation of claim 1, wherein the anti-Sortilin antibody is at a concentration of 50 mg / ml.

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

60.

4. 4. The pharmaceutical formulation of claim 1, wherein the antibody is of the IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of residue positions is according to EU numbering.

5. 5. The pharmaceutical formulation of claim 1, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO:

95.

6. 6. A pharmaceutical formulation according to any one of claims 1 to 5 for use in a method for treating and / or delaying the progression of a disease or injury in a human, comprising: the method comprises intravenously administering to the human an anti-Sortilin antibody at a dose of about 60 mg / kg once every four weeks; the disease or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis; The pharmaceutical preparation.

7. 7. The pharmaceutical formulation of claim 6, wherein the disease or disorder is frontotemporal dementia or amyotrophic lateral sclerosis.

8. (a) the human is heterozygous for a mutation in GRN, and optionally, the mutation in GRN is a loss-of-function mutation; or (b) the human is heterozygous for a C9orf72 hexanucleotide repeat expansion; The pharmaceutical formulation according to claim 6 or 7.

9. 9. The pharmaceutical formulation of claim 7 or 8, wherein the human exhibits symptoms of frontotemporal dementia or the human does not exhibit symptoms of frontotemporal dementia.

10. (a) the level of PGRN protein in the human's plasma after administration of the anti-Sortilin antibody is at least 2-fold, 3-fold, or 4-fold higher than the level of PGRN protein in the human's plasma before administration of the anti-Sortilin antibody, and optionally, the doubling of the level of PGRN protein in the human's plasma is present about 5 days after the last administration of the anti-Sortilin antibody and / or about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of the anti-Sortilin antibody; and / or (b) the level of PGRN protein in cerebrospinal fluid of the human after administration of the anti-Sortilin antibody is at least two-fold higher than the level of PGRN protein in cerebrospinal fluid of the human before administration of the anti-Sortilin antibody, and optionally, the doubling of the level of PGRN protein in cerebrospinal fluid of the human is present at about 12 days after the last administration of the anti-Sortilin antibody, and / or at about 24 days after the last administration of the anti-Sortilin antibody, and / or at about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of the anti-Sortilin antibody. The pharmaceutical formulation according to any one of claims 6 to 9.

11. 11. The pharmaceutical formulation of any one of claims 6-10, wherein the expression level of SORT1 protein on peripheral leukocytes of the human after administration of the anti-Sortilin antibody is reduced by at least 50%, or at least 70%, compared to the expression level of SORT1 protein on peripheral leukocytes of the human before administration of the anti-Sortilin antibody, and optionally, the reduction in the expression level of SORT1 on peripheral leukocytes of the human is present at about 12 days or more after the final administration of the anti-Sortilin antibody, at about 17 days or more after the final administration of the anti-Sortilin antibody, or at about 40 days or more after the final administration of the anti-Sortilin antibody.

12. 12. The pharmaceutical formulation of any one of claims 6 to 11, wherein the half-life of the anti-Sortilin antibody in plasma is about 5 days or about 8 days.

13. 13. The pharmaceutical formulation of any one of claims 6-12, wherein the human is treated for a treatment period of up to 48 weeks, or for a treatment period as long as 48 weeks, and optionally, administration of the anti-Sortilin antibody occurs on the first day of the treatment period and every four weeks thereafter.

14. 14. The pharmaceutical formulation of any one of claims 6 to 13, wherein the disease or injury is frontotemporal dementia (FTD), and after administration of the anti-Sortilin antibody, plasma neurofilament light chain (NfL) levels are reduced by at least 10% compared to plasma neurofilament light chain (NfL) levels before administration of the anti-Sortilin antibody.

15. (a) the protein level of CTSB in the cerebrospinal fluid (CSF) of the human is increased by at least about 20% after administration of the anti-Sortilin antibody, compared to the protein level of CTSB in the CSF of the human before administration of the anti-Sortilin antibody; (b) the protein level of SPP1 in the CSF of the human is reduced by at least about 10% after administration of the anti-Sortilin antibody, compared to the protein level of SPP1 in the CSF of the human before administration of the anti-Sortilin antibody; (c) the protein level of N-acetylglucosamine kinase (NAGK) in the human's CSF is increased after administration of the anti-Sortilin antibody compared to the protein level of NAGK in the human's CSF before administration of the anti-Sortilin antibody; and / or (d) the protein level of one or more inflammatory proteins in the CSF of the human is decreased after administration of the anti-Sortilin antibody compared to the protein level of the one or more inflammatory proteins in the CSF of the human before administration of the anti-Sortilin antibody, wherein the one or more inflammatory proteins are selected from the group consisting of 14-3-3 protein epsilon (YWHAE), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86. The pharmaceutical formulation according to any one of claims 6 to 14.

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