Anti-sortilin antibodies and methods of use thereof

Abstract

Antibodies that specifically bind to one or more epitopes within human or mammalian sortilin are provided. [Solution] An isolated anti-Sortilin antibody that binds to human Sortilin, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising HVR-L1, HVR-L2, and HVR-L3 comprising amino acid sequences consisting of specific sequences, and the heavy chain variable domain comprising HVR-H1, HVR-H2, and HVR-H3 comprising amino acid sequences consisting of specific sequences. Also provided is a pharmaceutical for increasing extracellular levels of progranulin, decreasing intracellular levels of sortilin in one or more cells, and / or decreasing expression of one or more pro-inflammatory mediators in one or more cells, the pharmaceutical comprising the anti-Sortilin antibody.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 144,270, filed April 7, 2015, which is incorporated herein 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: 735022000240SEQLIST.TXT, Date Recorded: April 6, 2016, Size: 345 KB).

[0003] The present disclosure relates to anti-Sortilin antibodies and therapeutic uses of such 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 has a large extracellular domain that is homologous to yeast VPS10P and is part of the VPS10 family, containing a 10-bladed β-propeller structure and a cysteine-rich 10CC module (Nykjaer, A et al., (2012) Trends Neurosci 35:261-270, and Zheng, Y et al., (2011) PLoS One 6:e21023). A small fraction of sortilin can be released by the activity of ADAM10 or gamma-secretase (<5%) (Nykjaer, A et al., (2012) Trends Neurosci 35:261-270, and Willnow, TE et al., (2011) Curr Opin Lipidol 22:79-85).

[0005] Sortilin binds to the secreted protein progranulin (PGRN) and targets it for lysosomal degradation, thereby negatively regulating the extracellular levels of PGRN (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) 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).

[0006] 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).

[0007] Sortilin also binds directly to proneurotrophins, such as nerve growth factor precursor (pro-NGF), pro-BDNF, proneurotrophin-3, which have prodomains and are typically pro-apoptotic. These proneurotrophin precursors are released under stress, and sortilin is involved in regulating their release, binding to receptor cells, and stimulating apoptosis in conjunction with p75NTR (Willnow, TE et al., (2008) Nat Rev Neurosci 9:899-909; Nykjaer, A et al., Trends Neurosci 35:261-270; and Nykjaer, A et al., (2004) Nature 427:843-848; Hiroko Yano et al., (2009) J Neurosci.;29:14790-14802; Teng HK, et al., J. Neurosci. 25:5455-5463 (2005)). Sortilin also directly binds to p75NTR (Skeldal S et al., (2012) J Biol Chem.;287:43798). Sortilin also binds to neurotensin in a region that partially overlaps with progranulin binding (Quistgaard, EM et al., (2009) Nat Struct Mol Biol 16:96-98, and Zheng, Y et al., PLoS One 6:e21023). Furthermore, sortilin interacts with Trk receptors NTRK1, NTRK2, and NTRK3 and may regulate their anterograde axonal transport and signal transduction (Vaegter, CB et al., (2011) Nat. Neurosci. 14:54-61). Sortilin also interacts with and regulates the processing and transport of amyloid precursor protein and the resulting production of abnormal beta-amyloid peptides (Gustafsen C et al., (2013). J Neurosci. 2; 33(1): 64-71.

[0008] Sortilin has also been shown to bind to apolipoprotein and lipoprotein lipase, and therefore, its deficiency reduces VLDL release from the liver and cholesterol (Willnow, TE et al., (2011) Curr Opin Lipidol 22:79-85; Kjolby, M et al., (2010) Cell Metab 12:213-223; Nilsson, SK et al., (2007) Biochemistry 46:3896-3904; Nilsson, SK et al., (2008) J Biol Chem 283:25920-25927; and Klinger, SC et al., (2011) J Cell Sci 124:1095-1105). Recently, it has been suggested that sortilin binds directly to APP (Gustafsen, C et al., (2013) J. Neurosc. 33:64-71) and also to the APP-processing enzyme BACE1 (Gustafsen, C et al., (2013) J. Neurosc. 33:64-71, and Finan, GM et al., J Biol Chem 286:12602-12616). Sortilin also binds to apolipoprotein E (APOE), Aβ peptide (Carlo, AS et al., (2013) J. Neurosc. 33:358-370), and PCSK9 (Gustafsen et al., (2014) Cell Metab. 19:310-318). Sortilin has also been shown to increase LDL cholesterol levels by binding to PCSK9, which directs the low-density lipoprotein receptor for degradation in lysosomes, and regulating its extracellular levels (Gustafsen C et al., (2014). Cell Metab. 2014 Feb 4;19(2):310-8).

[0009] When present in intracellular vesicles such as endosomes, sortilin's amino-terminal extracellular domain faces the lumen, where cargo molecules reside. Meanwhile, its carboxy-terminal intracellular / cytoplasmic domain binds to a series of adaptor proteins that regulate transport from the surface and within intracellular compartments. These include AP2 (a clathrin adaptor that regulates endocytosis from the cell surface) and the retromer complex / AP1 (which regulates recycling from early endosomes to the Golgi apparatus), as well as interactions with GGA (Golgi-localized γ-ear-containing ADP-ribosylation factor-binding) family proteins, which direct sortilin from the Golgi apparatus to early endosomes for subsequent degradation, usually via lysosomes. Thus, sortilin can bind ligands via its luminal domain and further bind to cytoplasmic adaptors that determine its intracellular fate, such as degradation of progranulin and other factors.

[0010] 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, amyotrophic lateral sclerosis, 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.

[0011] 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 ligands to treat one or more diseases, disorders, and conditions associated with Sortilin activity.

[0012] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0013] The present disclosure is generally directed to anti-Sortilin antibodies and methods of using such antibodies. The methods provided herein are directed to the treatment of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, Levitra, and the like. The compounds are useful for preventing, reducing the risk of, or treating an individual with dementia with glaucoma, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disease, obesity, insulin resistance, type 2 diabetes, tissue or vascular injury, trauma, intervertebral disc degeneration, or one or more undesirable symptoms of normal aging.

[0014] Certain aspects of the present disclosure are based, at least in part, on the identification of anti-Sortilin antibodies that can block the interaction between Sortilin and Progranulin (see, e.g., Example 4), anti-Sortilin antibodies that can increase extracellular levels of Progranulin secreted from cells in culture and cells in the brain of a mouse model of Alzheimer's disease (see, e.g., Example 5), anti-Sortilin antibodies that can decrease cellular levels of Sortilin in human primary monocytes (see, e.g., Example 25), and anti-Sortilin antibodies that can increase cellular levels of Progranulin in vivo (see, e.g., Example 26). Surprisingly, one class of antibodies was shown to be able to increase extracellular levels of Progranulin without being able to block the interaction between Sortilin and Progranulin (e.g., antibodies S-2, S-15, and S-22), while a second class of antibodies was shown to be able to both block the interaction between Sortilin and Progranulin and increase extracellular levels of Progranulin (e.g., antibodies S-8, S-49, and S-60). Furthermore, anti-Sortilin antibodies (e.g., antibodies S-2, S-8, S-15, S-22, S-49, and S-60) that are able to increase extracellular levels of Progranulin were surprisingly also found to decrease cellular levels of Sortilin, e.g., cell surface levels of Sortilin (see, e.g., Example 5). Moreover, cellular levels of Sortilin were shown to be strongly inversely correlated with increased cellular levels of Progranulin (see, e.g., Figures 10B-10E and Figures 23B and 23C). Anti-Sortilin antibodies capable of increasing extracellular levels of Progranulin can also block pro-NGF binding to Sortilin (see, e.g., Example 6). Other aspects of the present disclosure are based, at least in part, on the identification of anti-Sortilin antibodies (e.g., antibody S-30 and Example 30) that block the interaction between Sortilin and Progranulin and can increase extracellular levels of Progranulin without decreasing cellular levels of Sortilin.Other aspects of the present disclosure are based, at least in part, on the identification of anti-Sortilin antibodies (e.g., antibodies S-5 and S-64 and Example 5) that block the interaction between Sortilin and Progranulin without increasing extracellular levels of Progranulin or decreasing cellular levels of Sortilin.

[0015] Accordingly, certain aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody has a property selected from the group consisting of increasing extracellular levels of Progranulin, increasing cellular levels of Progranulin, decreasing cellular levels of Sortilin, inhibiting the interaction between Sortilin and Progranulin, and any combination thereof.

[0016] In certain embodiments that may be combined with any of the preceding embodiments, the antibody reduces cell surface levels of Sortilin, reduces intracellular levels of Sortilin, reduces total levels of Sortilin, or any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody induces Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin and inhibits the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin and increases cellular levels of Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases cellular levels of Progranulin and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and increases cellular levels of Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases Progranulin levels in vivo. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases Progranulin levels in vivo without decreasing Sortilin cellular levels. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases Progranulin levels in the brain.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases cellular levels of Progranulin in the blood. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases cellular levels of Progranulin in one or more peripheral organs. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases levels of Progranulin in the brain, blood, one or more peripheral organs, or any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin in vivo. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin in the brain. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin in one or more peripheral organs. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces cellular levels of Sortilin in the brain, one or more peripheral organs, or any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and does not reduce cellular levels of Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases cellular levels of Progranulin and does not reduce cellular levels of Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases extracellular levels of Progranulin and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases extracellular levels of Progranulin and does not inhibit the interaction between Sortilin and Progranulin.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the extracellular level of Progranulin, and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the extracellular level of Progranulin, and inhibits the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the cellular level of Progranulin, and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the cellular level of Progranulin, and inhibits the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the extracellular level of Progranulin, increases the cellular level of Progranulin, and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the extracellular level of Progranulin, inhibits the interaction between Sortilin and Progranulin, and does not increase the cellular level of Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the cellular level of Progranulin, inhibits the interaction between Sortilin and Progranulin, and does not increase the extracellular level of Progranulin.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody increases the cellular level of Progranulin, increases the extracellular level of Progranulin, inhibits the interaction between Sortilin and Progranulin, and does not decrease the cellular level of Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the extracellular level of Progranulin, does not increase the cellular level of Progranulin, and does not inhibit the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody decreases the cellular level of Sortilin, increases the cellular level of Progranulin, increases the extracellular level of Progranulin, and inhibits the interaction between Sortilin and Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, the cellular levels of Progranulin, the extracellular levels of Progranulin, the cellular levels of Sortilin, or any combination thereof, are measured using an in vitro assay. In certain embodiments that may be combined with any of the preceding embodiments, the cellular levels of Progranulin, the extracellular levels of Progranulin, the cellular levels of Sortilin, or any combination thereof, are measured using a cellular assay. In certain embodiments that may be combined with any of the preceding embodiments, the cellular levels of Progranulin, the extracellular levels of Progranulin, the cellular levels of Sortilin, or any combination thereof, are measured using an in vivo model. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody further inhibits the interaction between Sortilin and nerve growth factor precursor (pro-NGF).In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody further inhibits interaction between Sortilin and one or more proteins selected from the group consisting of proneurotrophin, neurotrophin, nerve growth factor (NGF), brain-derived neurotrophic factor precursor (pro-BDNF), brain-derived neurotrophic factor (BDNF), proneurotrophin-3, neurotrophin-3, proneurotrophin-4 / 5, neurotrophin-4 / 5, neurotensin, neurotensin, p75, sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP). In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody further inhibits interaction between Sortilin and one or more proteins by a) reducing the effective level of Sortilin available for interaction with the one or more proteins, b) inducing degradation of Sortilin, or both. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody inhibits cellular secretion of PCSK9, Aβ peptide production, or both. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody specifically binds to human Sortilin, mouse Sortilin, or both. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is a human antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that may be combined with any of the preceding embodiments, the first antigen is sortilin and the second antigen is an antigen that promotes transport across the blood-brain barrier.In certain embodiments that may be combined with any of the preceding embodiments, the second antigen is selected from the group consisting of sortilin, transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, llama single-domain antibody, TMEM30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptides, angiopep peptides, basigin, Glut1, and CD98hc and ANG1005. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein. In certain embodiments that may be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody (a) induces one or more progranulin activities; (b) inhibits progranulin activity; and (c) increasing the effective concentration of progranulin.

[0017] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to a discontinuous Sortilin epitope. In certain embodiments that may be combined with any of the preceding embodiments, the discontinuous Sortilin epitope comprises two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or ten or more peptides. In certain embodiments that may be combined with any of the preceding embodiments, each of the peptides comprises five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eight or more, nine or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more, twenty-five or more, twenty-six or more, twenty-seven or more, twenty-eight or more, twenty-nine or more, or ten ... and / or 30 or more amino acid residues, or 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 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, or 30 or more amino acid residues on a mammalian Sortilin protein corresponding to the amino acid sequence of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to a conformational epitope of Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is selected from the group consisting of: i. amino acid residues 740-749 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 740-749 of SEQ ID NO:1; ii. amino acid residues 623-632 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 623-632 of SEQ ID NO:1; iii. amino acid residues 429-443 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 429-443 of SEQ ID NO:1; iv.amino acid residues 367 to 391 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 367 to 391 of SEQ ID NO: 1; v. amino acid residues 314 to 338 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 314 to 338 of SEQ ID NO: 1; vi. amino acid residues 297 to 317 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 297 to 317 of SEQ ID NO: 1; vii. amino acid residue 237 of SEQ ID NO: 1 amino acid residues 237 to 260 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 260 of SEQ ID NO: 1; viii. amino acid residues 237 to 260 and 297 to 317 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 260 and 297 to 317 of SEQ ID NO: 1; ix. amino acid residues 237 to 247 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 247 of SEQ ID NO: 1; x. amino acid residues of SEQ ID NO: 1 residues 237 to 247 and 314 to 338 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 247 and 314 to 338 of SEQ ID NO: 1; xi. amino acid residues 233 to 243 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 233 to 243 of SEQ ID NO: 1; xii. amino acid residues 212 to 221 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 212 to 221 of SEQ ID NO: 1; xiii. SEQ ID NO: 1 or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 227 of SEQ ID NO: 1; xiv. amino acid residues 207 to 227 and 237 to 260 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 227 and 237 to 260 of SEQ ID NO: 1; xv. amino acid residues 207 to 231 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 231 of SEQ ID NO: 1; xvi.xvii. amino acid residues 175-181 of SEQ ID NO: 1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 175-181 of SEQ ID NO: 1, and xvii. amino acid residues 131-138 of SEQ ID NO: 1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 131-138 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to one or more amino acids selected from the group consisting of H131, V132, P133, L134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386, and S595 of SEQ ID NO: 1. The amino acid residues bind to one or more amino acid residues on a mammalian sortilin protein corresponding to amino acid residues selected from the group consisting of H131, V132, P133, L134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386, and S595 of SEQ ID NO: 1.

[0018] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-5, S-6, S-8, S-45, S-49, S-60, S-63, S-64, S-65, S-72, and S-83. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 9-12, 14, and 15; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 29, 30, and 32; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 48, 85, 89, 100, 103-105, 112, and 123. L3, (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 127, 136, 140, 142, 145 and 148, (e) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 152, 163, 166, 169, 170, 173 and 175, or (f) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 183, 185, 219, 223, 233, 236, 237, 244 and 254.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 9-12, 14, and 15, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 9-12, 14, and 15; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 29, 30, and 32. or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 29, 30, and 32; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 48, 85, 89, 100, 103 to 105, 112, and 123, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 48, 85, 89, 100, 103 to 105, 112, and 123, The heavy chain variable domain comprises: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 127, 136, 140, 142, 145, and 148, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 127, 136, 140, 142, 145, and 148; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 152, 163, 166, 169, 170, 173, and 175, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 152, 163, 166, 169, 170, 173, and 175. , 170, 173 and 175; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 183, 185, 219, 223, 233, 236, 237, 244 and 254, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 183, 185, 219, 223, 233, 236, 237, 244 and 254.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 324, 326, 330, 401, 409, 430, 436, 438, 439, 453, and 474, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 325, 327, 331, 402, 410, 431, 437, 440, 454, and 475.

[0019] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-2, S-14, S-15, S-18, S-19, S-20, S-21, S-22, S-29, S-51, S57, S-61, and S-82. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10, 13, and 14, (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31 and 33-35, or (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 42, 54, 55, 58, 59, 60, 61, 62, 69, 91, 97, 101, and 122. (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 129, 130, 135, 140, 142 and 147; (e) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 155 to 158, 162, 166, 169 and 173; or (f) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 180, 190, 193 to 197, 203, 225, 231, 234 and 253.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10, 13, and 14, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10, 13, and 14; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31 and 33-35, (c) an HVR-L2 comprising an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 42, 54, 55, 58, 59, 60, 61, 62, 69, 91, 97, 101, and 122, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 42, 54, 55, 58, 59, 60, 61, 62, 69, 91, 97, 101, and 122. and R-L3, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 129, 130, 135, 140, 142, and 147, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 129, 130, 135, 140, 142, and 147; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 155 to 158, 162, 166, 169, and 173, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 155 to 158, 162, 166, 169, and 173. and (c) an HVR-H2 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 180, 190, 193-197, 203, 225, 231, 234, and 253, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 180, 190, 193-197, 203, 225, 231, 234, and 253.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 319, 341, 343, 348, 350, 352, 354, 356, 370, 413, 425, 430, and 472, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 320, 342, 349, 351, 353, 355, 357, 369, 414, 426, 431, and 473.

[0020] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-5, S-30, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 70, and 100; (d) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 136, and 142; (e) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 163, and 170; or (f) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 204, and 233.In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 10; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 30; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 70, and 100, or an amino acid sequence having at least about 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 70, and 100; The HVR-H1 comprises: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 136, and 142, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 136, and 142; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 163, and 170, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 163, and 170; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 204, and 233, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 204, and 233. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 324, 371, and 430, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 325, 372, and 431.

[0021] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40. and (c) an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101. and HVR-L3 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149. (b) HVR-H1 comprising an amino acid sequence having homology thereto; and (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178; and (c) SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208,and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256.

[0022] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-6, S-8, S-49, S-60, S-63, S-72, S-83, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-45, S-64, S-65, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-30, S-60, and any combination thereof.

[0023] Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody is selected from the group consisting of S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-10, S-12, S-14, S-15, S-16, S-18, S-19, S-20, S-21, S-22, S-24, S-25, S-26, S-28, S-29, S-30, S-32, S-34, S-39, S-40, S-42, S-43, S-44, S-45, S-46, S-47, S-48, S-49, S-50, S-51, S-52, S-53, S-54, S-55, S-56, S-57, S-58, S-59, S-60, S-61, S-62, S-63, S-64, S-65, S-66, S-67, S-68, S-69, S-70, S-71, S-72, S-73, S-74, S-75, S-76, S-77, S-78, S-79, S-80, S-81, S-82, S-83, S-84, S-85, S-86, S-87, S-88, S-89, S-90, S-91, S-92, S-93, S-94, S-95, S-96, S-97, S-98, S-99, S-100, S-101, S-102, S-103, S-104, S-105, S-106, and S-3, S-44, S-45, S-48, S-49, S-50, S-51, S-55, S-57, S-58, S-59, S-60, S-61, S-63, S-64, S-65, S-66, S-67, S-69, S-71, S-72, S-73, S-74, S-75, S-76, S-78, S-81, S-82, S-83, S-84, and S-85. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is selected from the group consisting of: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 to 16, 20 to 22, and 24 to 25; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40; or (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125. (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149; (e) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178; or (f) SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247;and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40, or (c) an HVR-L2 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40; and (d) an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80. and HVR-L3 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147. (b) HVR-H1 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178; and (c) SEQ ID NOs: 179 to 186.188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191 , 193-197, 199-201, 203-204, 206, 208, 213-214, 216-219, 222-225, 229, 231-234, 236-239, 241, 243-247, 249, and 252-256, and HVR-H3 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 317-334, 337-338, 341-345, 348-357, 360-365, 368-372, 375-376, 379-380, 389-392, 395-402, 407-414, 421-422, 425-433, 436-444, 447-448, 451-461, 464-465, and 470-479.

[0024] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-2, S-16, S-18, S-19, S-20, S-21, S-22, S-28, S-29, S-82, and any combination thereof. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibodies compete for binding to Sortilin with one or more antibodies selected from the group consisting of S-1, S-3, S-4, S-6, S-7, S-9, S-10, S-14, S-15, S-26, S-32, S-48, S-51, S-55, S57, S-58, S-59, S-61, S-69, S-71, S-73, S-74, S-75, S-85, and any combination thereof. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-12, S-24, S-25, S-30, S-34, S-39, S-40, S-42, S-43, S-44, S-45, S-60, S-63, S-64, S-65, S-66, S-67, S-72, S-76, S-78, S-81, S-83, S-84, and any combination thereof. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-8, S-49, S-50, and any combination thereof.Other aspects of the present disclosure include S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-10, S-12, S-14, S-15, S-16, S-18, S-19, S-20, S-21, S-22, S-24, S-25, S-26, S-28, S-29, S-30, S-32, S-34, S-39, S-40, S-42, S-43, S-44, S-45, S-48, S-49, S-50, S-51, S-52, S-53, S-54, S-55, S-56, S-57, S-58, S-59, S-60, S-61, S-62, S-63, S-64, S-65, S-66, S-67, S-68, S-69, S-70, S-71, S-72, S-73, S-74, S-75, S-76, S-77, S-78, S-79, S-80, S-81, S-82, S-83, S-84, S-85, S-86, S-87, S-88, S-89, S-90, S-91, S-92, S-93, S-94, S-95, S-96, S-97, S-98, S-99, S-100, S-101, S-102, S-103, S-104, S-105, S-106, S-107, S-108, S-109, S-110, S-111, S-112, S-113, S-11

[0023] The present invention relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that essentially binds to the same Sortilin epitope as an antibody selected from the group consisting of S-55, S-57, S-58, S-59, S-60, S-61, S-63, S-64, S-65, S-66, S-67, S-69, S-71, S-72, S-73, S-74, S-75, S-76, S-78, S-81, S-82, S-83, S-84, and S-85.

[0025] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-41. and (c) an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, and HVR-L3 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149. (b) HVR-H1 comprising an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178, or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178; and (c) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201,and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256.

[0026]

[0014] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin, increases Progranulin levels, and decreases cellular levels of Sortilin, wherein the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-8, S-49, and S-60. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 185. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 89, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 140, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 166, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 223. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 147, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233.Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin, increases the level of Progranulin, and decreases the cellular level of Sortilin, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-8, S-49, S-60, and any combination thereof. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin, increases the level of Progranulin, and decreases the cellular level of Sortilin, wherein the anti-Sortilin antibody binds to one or more amino acids within an amino acid residue selected from the group consisting of: i. amino acid residues 429-443 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein that correspond to amino acid residues 429-443 of SEQ ID NO:1; ii. amino acid residues 232-243 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein that correspond to amino acid residues 232-243 of SEQ ID NO:1; and iii. amino acid residues 207-231 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein that correspond to amino acid residues 207-231 of SEQ ID NO:1.

[0027]

[0014] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that increases Progranulin levels and decreases cellular Sortilin levels without inhibiting the interaction between Sortilin and Progranulin, wherein the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-2, S-19, and S-22. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:7, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:126, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:150, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:180. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 35, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 157, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 196.Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that increases Progranulin levels and decreases cellular levels of Sortilin without inhibiting the interaction between Sortilin and Progranulin, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-2, S-19, S-22, and any combination thereof. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that increases Progranulin levels and decreases cellular levels of Sortilin without inhibiting the interaction between Sortilin and Progranulin, wherein the anti-Sortilin antibody binds to one or more amino acids within an amino acid residue selected from the group consisting of: i. amino acid residues 237-260 and 297-317 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 237-260 and 297-317 of SEQ ID NO:1; and ii. amino acid residues 207-227 and 237-260 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 207-227 and 237-260 of SEQ ID NO:1.

[0028]

[0014] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin without increasing Progranulin levels and without decreasing cellular levels of Sortilin, wherein the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-5 and S-64. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 126, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 151, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 15, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 104, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 169, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 236. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin without increasing the level of Progranulin and without decreasing the cellular level of Sortilin, wherein the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-64, and any combination thereof.

[0029] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin and increases Progranulin levels without decreasing cellular levels of Sortilin, wherein the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of antibody S-30. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 30, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 70, and the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 136, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 163, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 204. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-Sortilin antibody that inhibits the interaction between Sortilin and Progranulin and increases the levels of Progranulin without decreasing the cellular levels of Sortilin, wherein the anti-Sortilin antibody competes with antibody S-30 for binding to Sortilin.

[0030] Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO: 7); (b) an HVR-L2 comprising the amino acid sequence of AASSLQS (SEQ ID NO: 27); and (c) an HVR-L3 comprising the amino acid sequence of QQSDVSPIT (SEQ ID NO: 42); and / or the heavy chain variable domain comprises (a) YTFX1X2YX3MX4 (wherein X1 is T, G, V, P, L, F, A, or R and X2 is G, A, or S). X1 is W, I, or G, X2 is I, V, or T, X3 is N, G, or L, X4 is N, S, V, or M, X5 is S, G, W, or Q, X6 is G, F, A, Y, S, N, or R, and X7 is N, R, S, or M) (SEQ ID NO: 481); and (c) an HVR-H3 comprising the amino acid sequence of ARGKRSSGWYEGYGMDV (SEQ ID NO: 180). In certain embodiments, the anti-Sortilin antibody comprises: (i) a HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15; (ii) a HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15; (iii) HVR-L2 comprising any amino acid sequence of HVR-L2 sequences derived from antibodies selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15;(iv) HVR-L3 comprising any amino acid sequence of HVR-L3 sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14 and S-2-15; (v) HVR-H1 comprising any amino acid sequence of HVR-H1 sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14 and S-2-15; and (vi) an HVR-H3 comprising an amino acid sequence of any of the HVR-H3 sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15. In certain embodiments, the anti-Sortilin antibody comprises any one of the antibody sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15. and / or a heavy chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-2, S-2-1, S-2-2, S-2-3, S-2-4, S-2-5, S-2-6, S-2-7, S-2-8, S-2-9, S-2-10, S-2-11, S-2-12, S-2-13, S-2-14, and S-2-15. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain isand / or a heavy chain variable domain comprising: (a) an HVR-L1 comprising the amino acid sequence of RASQSX1X2SNLA (wherein X1 is V or I, and X2 is S or G) (SEQ ID NO: 508); (b) an HVR-L2 comprising the amino acid sequence of GASTRAT (SEQ ID NO: 29); and (c) an HVR-L3 comprising the amino acid sequence of QQARLGPWT (SEQ ID NO: 55); and / or a heavy chain variable domain comprising: (a) YTX1X2X3X4X5X6S (wherein X1 is F or L, X2 is T or A, X3 is S or K, and X4 is Y, T, R, L, T, G, Q, or or H, X5 is Y, T, or L, and X6 is M or I (SEQ ID NO: 509); (b) HVR-H2 comprising the amino acid sequence of X1INPx2GGX3X4SYAX5X6FX7G (wherein X1 is I or V, X2 is S, W, Y, V, F, L, or I, X3 is S or T, X4 is T or A, X5 is Q or R, X6 is K or R, and X7 is Q or R) (SEQ ID NO: 510); and (c) X1RDPX2GX3X4X5X6X7PX8X9RX, 10 X 11 X 12 GX 13 DV (wherein X1 is A, V or T, X2 is S, F or G, X3 is I or A, X4 is A or G, X5 is A, L or V, X6 is A, L or P, X7 is G, F or Y, X8 is A, G or F, X9 is S, G or A, and X 10 is Y, G, P, H or S, and X 11 is Y or N, and X 12 is Y, L, Q or R, and X 13and HVR-H3 comprising the amino acid sequence of: (SEQ ID NO: 511) In certain embodiments, the anti-Sortilin antibody is (i) S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15- 10-2, S-15-10-3, S-15-10-4, S-15-10-5, S-15-10-6, S-15-10-7, S-15- 10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S -15-10-14, S-15-10-15, S-15-10-16, S-15-10-17, S-15-10-18, S-15-1 0-19, S-15-10-20, S-15-10-21, S-15-11, S-15-12, S-15-13, S-15-14, S (ii) an HVR-L1 comprising any amino acid sequence of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-15, S-15-15, and S-15-16; (ii) S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13; S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15-10-3, S -15-10-4, S-15-10-5, S-15-10-6, S-15-10-7, S-15-10-8, S-15-10-9, S -15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-1 0-15, S-15-10-16, S-15-10-17, S-15-10-18, S-15-10-19, S-15-10-20,(iii) HVR-L2 comprising any amino acid sequence of HVR-L2 sequences derived from antibodies selected from the group consisting of S-15-10-21, S-15-11, S-15-12, S-15-13, S-15-14, S-15-15, and S-15-16; S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-1 5-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15- 10-3, S-15-10-4, S-15-10-5, S-15-10-6, S-15-10-7, S-15-10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-10-15, S-15-10-16, S-15-10-17, S-15-10-18, S-15-10-19, S-15-10-20, S-15-10-21, S-15-11, S-15-12, S-15- (iv) an HVR-L3 comprising any amino acid sequence selected from the group consisting of S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-14, S-15-15, and S-15-16; 10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15-10-3, S-15-10-4, S-15-10 -5, S-15-10-6, S-15-10-7, S-15-10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-10-15,S-15-10-16、S-15-10-17、S-15-10-18、S-15-10-19、S-15、 (v) an HVR-H1 comprising any amino acid sequence of the HVR-H1 sequences derived from an antibody selected from the group consisting of S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-10-21, S-15-11, S-15-12, S-15-13, S-15-14, S-15-15, and S-15-16; -15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-7, S-15-8, S-15-9, S- 15-10, S-15-10-1, S-15-10-2, S-15-10-3, S-15-10-4, S-15-10-5, S-15-10 -6, S-15-10-7, S-15-10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10 -12, S-15-10-13, S-15-10-14, S-15-10-15, S-15-10-16, S-15-10-17, S-15 and (vi) an HVR-H2 comprising any amino acid sequence of an HVR-H2 sequence derived from an antibody selected from the group consisting of S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-7, S-15-8, S-15-9, S-15-10-11, S-15-12, S-15-13, S-15-14, S-15-15, and S-15-16. -15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6 -13, S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15-10-3, S-15-10-4, S-15-10-5, S-15-10-6, S-15-10-7, S-15-10-8, S-15-10-9, S-1 5-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-10-15,It has at least one, two, three, four, five or six HVRs selected from HVR-H3s comprising any amino acid sequence of HVR-H3 sequences derived from antibodies selected from the group consisting of S-15-10-16, S-15-10-17, S-15-10-18, S-15-10-19, S-15-10-20, S-15-10-21, S-15-11, S-15-12, S-15-13, S-15-14, S-15-15 and S-15-16. In certain embodiments, the anti-Sortilin antibody is S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15 -7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15-10-3, S-15-10-4, S-15-10-5, S-15-10-6, S-15-10-7, S-1 5-10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-10-15, S-15-10-16, S-15- any one of the light chain variable regions of the antibody sequences derived from an antibody selected from the group consisting of S-15, S-15-1, S-15-2, S-15-3, S-15-4, S-15-5, S-15-6, S-15-7, S-15-8, S-15-9, S-15-10-11, S-15-12, S-15-13, S-15-14, S-15-15, and S-15-16; 5-6-1, S-15-6-2, S-15-6-3, S-15-6-4, S-15-6-5, S-15-6-6, S-15-6-7, S-15-6-8, S-15-6-9, S-15-6-10, S-15-6-11, S-15-6-12, S-15-6-13, S-15-7, S-15-8, S-15-9, S-15-10, S-15-10-1, S-15-10-2, S-15-10-3, S-15-10-4, S-15-10-5,The heavy chain variable region comprises any one of the antibody sequences derived from an antibody selected from the group consisting of S-15-10-6, S-15-10-7, S-15-10-8, S-15-10-9, S-15-10-10, S-15-10-11, S-15-10-12, S-15-10-13, S-15-10-14, S-15-10-15, S-15-10-16, S-15-10-17, S-15-10-18, S-15-10-19, S-15-10-20, S-15-10-21, S-15-11, S-15-12, S-15-13, S-15-14, S-15-15, and S-15-16. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of RASQSISSWLA (SEQ ID NO: 8); (b) an HVR-L2 comprising the amino acid sequence of KASSLES (SEQ ID NO: 28); and (c) an HVR-L3 comprising the amino acid sequence of QQADGHIT (SEQ ID NO: 62); and / or the heavy chain variable domain comprises (a) X1TFX2X3YAX4X5 (wherein X1 is G or Y and X2 is S). X1PX2X3GX4AX5YAQKFQG (wherein X1 is I or V, X2 is I, R, G, A, S, T or Q, X3 is F or G, X4 is T, R or W, and X5 is S, N, Q or W) (SEQ ID NO: 566); and (c) an HVR-H3 comprising the amino acid sequence of ARQGRKTGYYYYYGMDV (SEQ ID NO: 197). In certain embodiments, the anti-Sortilin antibody comprises: (i) an HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9; (ii) any of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7,(iii) an HVR-L3 comprising any amino acid sequence of an HVR-L3 sequence derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9; (iv) an HVR-H1 sequence derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9; (v) an HVR-H2 comprising the amino acid sequence of any of the HVR-H2 sequences derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9; and (vi) an HVR-H3 comprising the amino acid sequence of any of the HVR-H3 sequences derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9. In certain embodiments, the anti-Sortilin antibody comprises a light chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9, and / or a heavy chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-22, S-22-1, S-22-2, S-22-3, S-22-4, S-22-5, S-22-6, S-22-7, S-22-8, and S-22-9. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain is selected from the group consisting of: (a) RSSQX1LLX2SNGYNYLD, wherein X1 is S or G;and (c) an HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 100); and / or the heavy chain variable domain comprises (a) an HVR-H1 comprising the amino acid sequence of YSISSX1X2YWG (wherein X1 is G or V and X2 is Y or R) (SEQ ID NO: 582); (b) an HVR-H2 comprising the amino acid sequence of X1IYX2SGSTYYNPSLKS (wherein X1 is T, S, or A and X2 is H or P) (SEQ ID NO: 583); and (c) an HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 233). In certain embodiments, the anti-Sortilin antibody comprises: (i) an HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9; (ii) an HVR-L2 comprising the amino acid sequence of any of the HVR-L2 sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9; (iv) an HVR-L3 comprising any amino acid sequence of the HVR-L3 sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9; (iv) an HVR-H1 comprising any amino acid sequence of the HVR-H1 sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9; (v) an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9; and (vi) an HVR-H3 comprising an amino acid sequence of any of the HVR-H3 sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9. In certain embodiments, the anti-Sortilin antibody comprises a light chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9, and / or a heavy chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-Sortilin antibodies, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14), (b) an HVR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26), and (c) an HVR-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122), and / or the heavy chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of X1SIX2SX3X4YYWG (sequence X1 is G or Y, X2 is S, V, Y, K, or P, X3 is S or R, and X4 is D or E (SEQ ID NO: 589), (a) an HVR-H2 comprising the amino acid sequence of X1IYX2X3GSTX4YNPSLKS (wherein X1 is S, G, Q, or L, X2 is Y, W, or R, X3 is S, R, K, or A, and X4 is Y or V) (SEQ ID NO: 590), and (c) an HVR-H3 comprising the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253).In certain embodiments, the anti-Sortilin antibody comprises: (i) an HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; (ii) an HVR-L1 comprising the amino acid sequence of any of the HVR-L1 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; (iii) an HVR-L2 comprising any amino acid sequence of the HVR-L2 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; (iv) an HVR-L3 comprising any amino acid sequence of the HVR-L3 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; (v) HVR-H1 comprising any amino acid sequence of HVR-H1 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; (v) HVR-H1 comprising any amino acid sequence of HVR-H1 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8; and (vi) an HVR-H3 comprising an amino acid sequence of any of the HVR-H3 sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8.In certain embodiments, the anti-Sortilin antibody comprises a light chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8, and / or a heavy chain variable region of any one of the antibody sequences derived from an antibody selected from the group consisting of S-82, S-82-1, S-82-2, S-82-3, S-82-4, S-82-5, S-82-6, S-82-7, and S-82-8.

[0031] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody has a human or mouse IgG1 isotype and has the following residues in the Fc region: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S , T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; (b) the anti-Sortilin antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or (c) the anti-Sortilin antibody has an IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering. and one or more amino acid substitutions at residue positions selected from the group consisting of 33P, F234V, L234A / F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.In certain embodiments that may be combined with any of the preceding embodiments, (a) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, where the residue numbering is according to EU or Kabat numbering; (b) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where the residue numbering is according to EU or Kabat numbering; or (c) the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody reduces expression of one or more pro-inflammatory mediators selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, and CCL5. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody has a dissociation constant (K) for human Sortilin, mouse Sortilin, or both that ranges from about 100 nM to about 0.005 nM, or less than 0.005 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody has a dissociation constant (K) for human Sortilin that ranges from about 70.4 nM to about 0.005 nM, or less than 0.005 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody has a dissociation constant (K) for mouse Sortilin ranging from about 40.3 nM to about 0.07 nM, or less than 0.07 nM. D )

[0032] Other aspects of the present disclosure relate to an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-Sortilin antibody of any of the foregoing embodiments. Other aspects of the present disclosure relate to a vector comprising the nucleic acid of any of the foregoing embodiments. Other aspects of the present disclosure relate to an isolated host cell comprising the vector of any of the foregoing embodiments. Other aspects of the present disclosure relate to a method of producing an anti-Sortilin antibody, the method comprising culturing the host cell of any of the foregoing embodiments such that the anti-Sortilin antibody is produced. In certain embodiments, the method further comprises recovering the anti-Sortilin antibody produced by the host cell. Other aspects of the present disclosure relate to an isolated anti-Sortilin antibody produced by the method of any of the foregoing embodiments. Other aspects of the present disclosure relate to a pharmaceutical composition comprising the anti-Sortilin antibody of any of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0033] Another aspect of the present disclosure relates to a method of increasing progranulin levels in the brain of an individual in need thereof, the method comprising administering a therapeutically effective amount of an anti-Sortilin antibody to the individual. Another aspect of the present disclosure relates to an anti-Sortilin antibody for use in increasing progranulin levels in the brain of an individual in need thereof. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody in the manufacture of a medicament for increasing progranulin levels in the brain of an individual in need thereof. Another aspect of the present disclosure relates to a method of increasing progranulin levels in an individual in need thereof, the method comprising administering a therapeutically effective amount of an anti-Sortilin antibody to the individual. Another aspect of the present disclosure relates to an anti-Sortilin antibody for use in increasing progranulin levels in an individual in need thereof. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody in the manufacture of a medicament for increasing progranulin levels in an individual in need thereof. In certain embodiments that may be combined with any of the preceding embodiments, the level of progranulin is increased in the brain, blood, and / or one or more peripheral organs of the individual. In certain embodiments that may be combined with any of the preceding embodiments, the level of progranulin is increased without decreasing the cellular level of sortilin.

[0034] Another aspect of the present disclosure relates to a method of increasing extracellular levels of Progranulin from one or more cells, the method comprising contacting the one or more cells with an anti-Sortilin antibody. Another aspect of the present disclosure relates to an anti-Sortilin antibody for use in increasing extracellular levels of Progranulin from one or more cells. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody in the manufacture of a medicament for increasing extracellular levels of Progranulin from one or more cells. In certain embodiments that may be combined with any of the preceding embodiments, the level of Progranulin is increased without a decrease in the cellular level of Sortilin. Another aspect of the present disclosure relates to a method of reducing cellular levels of Sortilin in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody. Another aspect of the present disclosure relates to an anti-Sortilin antibody for use in reducing cellular levels of Sortilin in an individual in need thereof. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody in the manufacture of a medicament for reducing cellular levels of Sortilin in an individual in need thereof. In certain embodiments that may be combined with any of the preceding embodiments, the level of Sortilin is decreased in the brain and / or one or more peripheral organs of the individual. Other aspects of the present disclosure relate to methods of decreasing the cellular level of Sortilin in one or more cells, the method comprising contacting the one or more cells with an anti-Sortilin antibody. Other aspects of the present disclosure relate to anti-Sortilin antibodies for use in decreasing the cellular level of Sortilin in one or more cells. Other aspects of the present disclosure relate to the use of an anti-Sortilin antibody in the manufacture of a medicament for decreasing the cellular level of Sortilin in one or more cells.

[0035] Another aspect of the present disclosure relates to a method for inhibiting one or more interactions between a Sortilin protein and one or more proteins selected from the group consisting of Progranulin, Neurotensin, p75, Sortilin propeptide (Sort-pro), Amyloid precursor protein (APP), Aβ peptide, Lipoprotein lipase (LpL), Apolipoprotein AV (APOA5), Apolipoprotein E (APOE), PCSK9, and Receptor-Associated Protein (RAP), the method comprising contacting the Sortilin protein with an anti-Sortilin antibody that binds to an epitope comprising SEQ ID NO:4. Another aspect of the present disclosure relates to an anti-Sortilin antibody that binds to an epitope comprising SEQ ID NO: 4 for use in inhibiting one or more interactions between a Sortilin protein and one or more proteins selected from the group consisting of Progranulin, Neurotensin, p75, Sortilin propeptide (Sort-pro), Amyloid precursor protein (APP), Aβ peptide, Lipoprotein lipase (LpL), Apolipoprotein AV (APOA5), Apolipoprotein E (APOE), PCSK9, and Receptor-Associated Protein (RAP). Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody that binds to an epitope comprising SEQ ID NO: 4 in the manufacture of a medicament for inhibiting one or more interactions between a Sortilin protein and one or more proteins selected from the group consisting of Progranulin, Neurotensin, p75, Sortilin propeptide (Sort-pro), Amyloid precursor protein (APP), Aβ peptide, Lipoprotein lipase (LpL), Apolipoprotein AV (APOA5), Apolipoprotein E (APOE), PCSK9, and Receptor-Associated Protein (RAP).

[0036] In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody has a property selected from the group consisting of increasing extracellular levels of Progranulin, increasing cellular levels of Progranulin, decreasing cellular levels of Sortilin, inhibiting the interaction between Sortilin and Progranulin, and any combination thereof; and (b) the anti-Sortilin antibody decreases cell surface levels of Sortilin, decreases intracellular levels of Sortilin, decreases total levels of Sortilin, or decreases any combination thereof. (c) the anti-Sortilin antibody induces Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof; (d) the anti-Sortilin antibody decreases the cellular level of Sortilin and does not inhibit the interaction between Sortilin and Progranulin; (e) the anti-Sortilin antibody decreases the cellular level of Sortilin and inhibits the interaction between Sortilin and Progranulin; (f) the anti-Sortilin antibody decreases the cellular level of Sortilin and increases the cellular level of Progranulin; and (g) the anti-Sortilin antibody (h) an anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and increases the cellular level of Progranulin; (i) an anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and does not decrease the cellular level of Sortilin; (j) an anti-Sortilin antibody increases the cellular level of Progranulin and does not decrease the cellular level of Sortilin; and (k) an anti-Sortilin antibody inhibits the interaction between Sortilin and nerve growth. (l) anti-Sortilin antibodies further inhibit the interaction between Sortilin and proneurotrophin, neurotrophin, nerve growth factor (NGF), brain-derived neurotrophic factor precursor (pro-BDNF), brain-derived neurotrophic factor (BDNF), proneurotrophin-3, neurotrophin-3, proneurotrophin-4 / 5, neurotrophin-4 / 5, neurotensin, neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide,and (m) an anti-Sortilin antibody further inhibits the interaction between Sortilin and one or more proteins selected from the group consisting of lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP), and (m) an anti-Sortilin antibody inhibits the interaction between Sortilin and pro-neurotrophins, neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor precursor (pro-BDNF), brain-derived neurotrophic factor (BDNF), pro-neurotrophin-3, neurotrophin-3, pro-neurotrophin-4 / 5, neurotrophin-4 / 5, neurotrophin-5, neurotrophin-6, neurotrophin-7, neurotrophin-8, neurotrophin-9, neurotrophin-10, neurotrophin-11, neurotrophin-12, neurotrophin-13, neurotrophin-14, neurotrophin-15, neurotrophin-16, neurotrophin-17, neurotrophin-18, neurotrophin-19, neurotrophin-20, neurotrophin-21, neurotrophin-22, neurotrophin-23, neurotrophin-24, neurotrophin-25, neurotrophin-26, neurotrophin-27, neurotrophin-28, neurotrophin-29, neurotrophin-30, neurotrophin-31, neurotrophin-32, neurotrophin-33, neurotrophin-34, neurotrophin-35, neurotrophin-36, neurotrophin-37, neurotrophin-38, neurotrophin-39 ... (n) the anti-Sortilin antibody inhibits cellular secretion of PCSK9, Aβ peptide production, or both; (o) the anti-Sortilin antibody induces one or more Progranulin activities; (p) the anti-Sortilin antibody decreases endosomal internalization of Progranulin or a fragment thereof; and / or (q) the anti-Sortilin antibody increases the effective concentration of Progranulin. In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody specifically binds to human Sortilin, mouse Sortilin, or both; (b) the anti-Sortilin antibody is a human antibody; (c) the anti-Sortilin antibody is a humanized antibody; (d) the anti-Sortilin antibody is a bispecific antibody; (e) the anti-Sortilin antibody is a bispecific antibody that recognizes a first antigen and a second antigen; (f) the anti-Sortilin antibody is a bispecific antibody that recognizes a first antigen and a second antigen, wherein the first antigen is a Sortilin protein and the second antigen is an antigen that facilitates transport across the blood-brain barrier, and optionally, the second antigen is selected from the group consisting of Sortilin, Transferrin Receptor (TR),(g) the anti-Sortilin antibody is selected from the group consisting of insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopep peptide, basigin, Glut1, CD98hc, and ANG1005; (g) the anti-Sortilin antibody is a multivalent antibody; and (h) the anti-Sortilin antibody is a covalent antibody. (i) the anti-Sortilin antibody is a chimeric antibody; (j) the anti-Sortilin antibody is an antibody; (k) the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein; or (l) the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein, and optionally, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0037] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to a discontinuous Sortilin epitope. In certain embodiments that may be combined with any of the preceding embodiments, the discontinuous Sortilin epitope comprises two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or ten or more peptides. In certain embodiments that may be combined with any of the preceding embodiments, each of the peptides comprises five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eight or more, nine or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more, twenty-five or more, twenty-six or more, twenty-seven or more, twenty-eight or more, twenty-nine or more, or ten ... and / or 30 or more amino acid residues, or 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 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, or 30 or more amino acid residues on a mammalian Sortilin protein corresponding to the amino acid sequence of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to a conformational epitope of Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is selected from the group consisting of: i. amino acid residues 740-749 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 740-749 of SEQ ID NO:1; ii. amino acid residues 623-632 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 623-632 of SEQ ID NO:1; iii. amino acid residues 429-443 of SEQ ID NO:1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 429-443 of SEQ ID NO:1; iv. amino acid residues 367-391 of SEQ ID NO:1;or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 367 to 391 of SEQ ID NO: 1; v. amino acid residues 314 to 338 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 314 to 338 of SEQ ID NO: 1; vi. amino acid residues 297 to 317 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 297 to 317 of SEQ ID NO: 1; vii. amino acid residues 237 to 260 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 260 of SEQ ID NO: 1. amino acid residues on a mammalian sortilin protein; viii. amino acid residues 237 to 260 and 297 to 317 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 260 and 297 to 317 of SEQ ID NO: 1; ix. amino acid residues 237 to 247 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237 to 247 of SEQ ID NO: 1; x. amino acid residues 237 to 247 and 314 to 338 of SEQ ID NO: 1, or amino acid residues 237 to 247 and 314 of SEQ ID NO: 1 amino acid residues 233 to 243 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 233 to 243 of SEQ ID NO: 1; xii. amino acid residues 212 to 221 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 212 to 221 of SEQ ID NO: 1; xiii. amino acid residues 207 to 227 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 227 of SEQ ID NO: 1. xiv. amino acid residues 207 to 227 and 237 to 260 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 227 and 237 to 260 of SEQ ID NO: 1; xv. amino acid residues 207 to 231 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207 to 231 of SEQ ID NO: 1; xvi. amino acid residues 175 to 181 of SEQ ID NO: 1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 175 to 181 of SEQ ID NO: 1;and vii. binds to one or more amino acids within an amino acid residue selected from the group consisting of amino acid residues 131-138 of SEQ ID NO: 1, or amino acid residues on a mammalian Sortilin protein corresponding to amino acid residues 131-138 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody binds to one or more amino acids within an amino acid residue selected from the group consisting of H131, V132, P133, L134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386, and S595 of SEQ ID NO: 1. or one or more amino acid residues on a mammalian sortilin protein corresponding to amino acid residues H131, V132, P133, L134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386 and S595 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-10, S-12, S-14, S-15, S-16, S-18, S-19, S-20, S-21, S-22, S-24, S-25, S-26, S-28, S-29, S-30, S-32, S-34, S-39, S-40, S-42, S-43, S-44, S-45, S-46, S-47, S-48, S-49, S-50, S-51, S-52, S-53, S-54, S-55, S-56, S-57, S-58, S-59, S-60, S-61, S-62, S-63, S-64, S-65, S-66, S-67, S-68, S-69, S-70, S-71, S-72, S-73, S-74, S-75, S-76, S-77, S-78, S-79, S-80, S-81, S-82, S-83, S-84, S-85, S-86, S-87, S-88, S-89, S-90, S-91, S-92, S-93, S-94, S-95, S-96, S-97, S-98, S-99, S-100, S-101, S-102, S-103, S-104, S-105, S-106, S-107, S-108, S-109, S- In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of S-44, S-45, S-48, S-49, S-50, S-51, S-55, S-57, S-58, S-59, S-60, S-61, S-63, S-64, S-65, S-66, S-67, S-69, S-71, S-72, S-73, S-74, S-75, S-76, S-78, S-81, S-82, S-83, S-84, and S-85. ...1, S-42, S-43, S-44, S-45, S-48, S-49, S-50, S-51, S-55, S-57, S-58, S-(b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40; (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125; (d) HVR-L4 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 150; (e) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175 and 177-178; or (f) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 179-186, 188, 190-191, 193-197, 199-201, 203-204, 206, 208, 213-214, 216-219, 22. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; and (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40. and (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116, 118, and 121 to 125, or SEQ ID NOs: 41 to 50, 52, 54 to 56, 58 to 62, 64 to 66, 68 to 70, 72, 74, 79 to 80, 82 to 85, 88 to 91, 95, 97 to 101, 103 to 107, 109, 111 to 116,and HVR-L3 comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 to 145, and 147 to 149, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 to 127, 129 to 130, 133 to 140, 142, 144 and (b) an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178, or an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 to 153, 155 to 158, 160 to 166, 169 to 175, and 177 to 178. and (c) an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256. or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 to 186, 188, 190 to 191, 193 to 197, 199 to 201, 203 to 204, 206, 208, 213 to 214, 216 to 219, 222 to 225, 229, 231 to 234, 236 to 239, 241, 243 to 247, 249, and 252 to 256.

[0038] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein (a) the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO: 7), HVR-L2 comprising the amino acid sequence of AASSLQS (SEQ ID NO: 27), and HVR-L3 comprising the amino acid sequence of QQSDVSPIT (SEQ ID NO: 42); and / or the heavy chain variable domain comprises YTFX1X2YX3MX4 (wherein X1 is T, G, V, P, L, F, A, or X1 is R, X2 is G, A, or S, X3 is Y, M, or L, and X4 is H or W (SEQ ID NO: 480), and HVR-H2 is an amino acid sequence of X1X2X3PX4X5GX6TX7YAQKFQG (wherein Xi is W, I, or G, X2 is I, V, or T, X3 is N, G, or L, X4 is N, S, V, or M, X5 is S, G, W, or Q, X6 is G, F, A, Y, S, N, or R, and X7 is N, R, S, or M) (SEQ ID NO: 481), and and (b) a light chain variable domain comprising an HVR-L1 comprising the amino acid sequence of RASQSX1X2SNLA (wherein X1 is V or I, and X2 is S or G) (SEQ ID NO: 508), an HVR-L2 comprising the amino acid sequence of GASTRAT (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence of QQARLGPWT (SEQ ID NO: 55); and / or a heavy chain variable domain comprising an HVR-L1 comprising the amino acid sequence of YTX1X2X3X4X5X6S (wherein X1 is F or L, and X2 is T). or A, X3 is S or K, X4 is Y, T, R, L, T, G, Q or H, X5 is Y, T or L, and X6 is M or I (SEQ ID NO: 509); and HVR-H2 comprising the amino acid sequence of X1INPx2GGX3X4SYAX5X6FX7G (wherein Xi is I or V, X2 is S, W, Y, V, F, L or I, X3 is S or T, X4 is T or A, X5 is Q or R, X6 is K or R, and X7 is Q or R) (SEQ ID NO: 510).X1RDPX2GX3X4X5X6X7PX8X9RX, 10 X 11 X 12 GX 13 DV (wherein X1 is A, V or T, X2 is S, F or G, X3 is I or A, X4 is A or G, X5 is A, L or V, X6 is A, L or P, X7 is G, F or Y, X8 is A, G or F, X9 is S, G or A, and X 10 is Y, G, P, H or S, and X 11 is Y or N, and X 12 is Y, L, Q or R, and X 13(c) a light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of RASQSISSWLA (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence of KASSLES (SEQ ID NO: 28), and an HVR-L3 comprising the amino acid sequence of QQADGHIT (SEQ ID NO: 62); and / or a heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of X1TFX2X3YAX4X5 (wherein X1 is G or Y, X2 is S, R, G, or T, X3 is S, G, or N, and X4 is I or M). and X5 is S or A) (SEQ ID NO: 565), an HVR-H2 comprising the amino acid sequence of GIX1PX2X3GX4AX5YAQKFQG (wherein X1 is I or V, X2 is I, R, G, A, S, T, or Q, X3 is F or G, X4 is T, R, or W, and X5 is S, N, Q, or W) (SEQ ID NO: 566), and an HVR-H3 comprising the amino acid sequence of ARQGRKTGYYYYYGMDV (SEQ ID NO: 197); and (d) a light chain variable domain comprising RSSQX1LLX2SNGYNY and / or a heavy chain variable domain comprising an HVR-L1 comprising the amino acid sequence of LD (wherein X1 is S or G, and X2 is H or R) (SEQ ID NO: 580), an HVR-L2 comprising the amino acid sequence of LGSNRXS (wherein X is A or V) (SEQ ID NO: 581), and an HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 100); and / or a heavy chain variable domain comprising an HVR-H1 comprising the amino acid sequence of YSISSX1X2YWG (wherein X1 is G or V, and X2 is Y or R) (SEQ ID NO: 582), and an HVR-L3 comprising the amino acid sequence of X1IYX2SGSTYYNPSL and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 233); or (e) the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14), HVR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26), and HVR-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122); and / or the heavy chain variable domain comprisesIt comprises an HVR-H1 comprising the amino acid sequence of X1SIX2SX3X4YYWG (in the sequence, X1 is G or Y, X2 is S, V, Y, K, or P, X3 is S or R, and X4 is D or E) (SEQ ID NO: 589), an HVR-H2 comprising the amino acid sequence of X1IYX2X3GSTX4YNPSLKS (in the sequence, X1 is S, G, Q, or L, X2 is Y, W, or R, X3 is S, R, K, or A, and X4 is Y or V) (SEQ ID NO: 590), and an HVR-H3 comprising the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253). In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-6, S-8, S-49, S-60, S-63, S-72, S-83, and any combination thereof; (b) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-45, S-64, S-65, and any combination thereof; (c) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-5, S-30, S-60, and any combination thereof; and (d) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-2, S-16, S-18, S-19, S-20, S-21, S-22, S-28, S-30, S-32, S-34, S-36, S-38, S-39, S-40, S-41, S-42, S-43, S-44, S-45, S-50, S-51, S-52, S-53, S-54, S-55, S-56, S-57, S-58, S-59, S-60, S-61, S-62, S-63, S-64, S-65, S-65, S-72, S-83, S-84, S-75, S-85, S-86, S-87, S-88, S-89, S-90, S-91, S-92, S-93, S-94, S-95, S-96, S-97, S-98, S-99, S-100, S-101, (e) the anti-Sortilin antibody competes with one or more antibodies selected from the group consisting of S-1, S-3, S-4, S-6, S-7, S-9, S-10, S-14, S-15, S-26, S-32, S-48, S-51, S-55, S57, S-58, S-59, S-61, S-69, S-71, S-73, S-74, S-75, S-76, S-77, S-78, S-79, S-80, S-81, S-82, S-83, S-84, S-85, S-86, S-87, S-88, S-89, S-90, S-91, S-92, S-93, S-94, S-95, S-96, S-97, S-98, S-99, S-100, S-101, S-102, S-103, S-104, S-105, S-106, S-107, S-108, S-109, S-110, S-111, S-112, S-113, S-114, S-115, S-116, S-117, S-118, S-119, S-120, S-121, S-122, S-123, S-124, S-125, S-126, S-127, S-128, S-129, S-130, S-131, S-132, S-133, S-134, S-135, S-136, S-137, S-138, S-139, S-140, S-141, S-142, S (f) the anti-Sortilin antibody competes with one or more antibodies selected from the group consisting of S-5, S-12, S-24, S-25, S-30, S-34, S-39, S-40, S-42, S-43, S-44, S-45, S-60, S-63, S-64, S-65, S-66, S-67, S-72, S-76, S-78, S-81, S-83,(g) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-8, S-49, S-50, and any combination thereof; or (h) the anti-Sortilin antibody competes for binding to Sortilin with one or more antibodies selected from the group consisting of S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-10, S-12, S-14, S-15, S-16, S-18, S-19, S-20, S-21, S-22, S-24, S-25, S-26, S-28, S-29, S-30, S-32, S-34, S-39, S-40, S-42, S-43, S- 44, S-45, S-48, S-49, S-50, S-51, S-55, S-57, S-58, S-59, S-60, S-61, S-63, S-64, S-65, S -66, S-67, S-69, S-71, S-72, S-73, S-74, S-75, S-76, S-78, S-81, S-82, S-83, S-84 and S-85 In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is an antibody that binds essentially to the same Sortilin epitope as an antibody selected from the group consisting of: In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody is of the IgG class, the IgM class, or the IgA class, or (b) the anti-Sortilin antibody has an IgG1, IgG2, IgG3, or IgG4 isotype, or (c) the anti-Sortilin antibody has a human or mouse IgG1 isotype and includes any of the following amino acids in the Fc region: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D,(d) the anti-Sortilin antibody has an IgG2 isotype and comprises one or more amino acid substitutions at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering; or (e) the anti-Sortilin antibody has an IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L234A / F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region of one or more of (c), (d), and (e) further comprises: (a) one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, where residue numbering is according to EU or Kabat numbering; (b) one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where residue numbering is according to EU or Kabat numbering; or (c) an amino acid substitution of S228P according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, (a) the anti-Sortilin antibody has a dissociation constant (K) for human Sortilin, mouse Sortilin, or both, in the range of about 100 nM to about 0.005 nM, or less than 0.005 nM. D ), and (b) the anti-Sortilin antibody has a dissociation constant (K) of about 70.4 nM to about 0.005 nM, or less than 0.005 nM, with respect to human Sortilin. D ), or (c) the anti-Sortilin antibody has a dissociation constant (K) of about 40.3 nM to about 0.07 nM, or less than 0.07 nM, with respect to mouse Sortilin. DIn certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody is the anti-Sortilin antibody of any of the preceding embodiments.

[0039] Other aspects of the present disclosure include the treatment of conditions such as frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive nuclear

[0014] A method of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of epilepsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric diseases, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disease, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, trauma, and one or more undesirable symptoms of normal aging, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any of the preceding embodiments.Other aspects of the present disclosure include the treatment of conditions such as frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, degenerative disc disease, Shy-Dore syndrome, and the like. and one or more undesirable symptoms of normal aging.Other aspects of the present disclosure include the treatment of diseases such as frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, and the like. and one or more undesirable symptoms of normal aging. Another aspect of the present disclosure relates to a method of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury 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, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any of the preceding embodiments.Another aspect of the disclosure relates to an anti-Sortilin antibody of any of the preceding embodiments for use in preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury 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. Another aspect of the disclosure relates to the use of an anti-Sortilin antibody of any of the preceding embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury 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.

[0040] Other aspects of the present disclosure relate to methods of inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal outgrowth and abnormal branching, microglial activation, and an inflammatory response, comprising administering a therapeutically effective amount of an anti-Sortilin antibody of any of the preceding embodiments to an individual. Other aspects of the present disclosure relate to an anti-Sortilin antibody of any of the preceding embodiments for use in inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal outgrowth and abnormal branching, microglial activation, and an inflammatory response. Other aspects of the present disclosure relate to the use of an anti-Sortilin antibody of any of the preceding embodiments in the manufacture of a medicament for inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal outgrowth and abnormal branching, microglial activation, and an inflammatory response. Other aspects of the present disclosure relate to methods of promoting one or more of wound healing, autophagy, and clearance of aggregated proteins, comprising administering a therapeutically effective amount of an anti-Sortilin antibody of any of the preceding embodiments to an individual. Other aspects of the present disclosure relate to an anti-Sortilin antibody of any of the foregoing embodiments for use in promoting one or more of wound healing, autophagy, and clearance of aggregated proteins. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody of any of the foregoing embodiments in the manufacture of a medicament for promoting one or more of wound healing, autophagy, and clearance of aggregated proteins. Another aspect of the present disclosure relates to a method of preventing, reducing the risk of, or treating an individual with arthritis, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any of the foregoing embodiments. Another aspect of the present disclosure relates to an anti-Sortilin antibody of any of the foregoing embodiments for use in preventing, reducing the risk of, or treating an individual with arthritis. Another aspect of the present disclosure relates to the use of an anti-Sortilin antibody of any of the foregoing embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual with arthritis. Another aspect of the present disclosure relates to a method of reducing the expression of one or more pro-inflammatory mediators, comprising administering to an individual a therapeutically effective amount of an anti-Sortilin antibody of any of the foregoing embodiments.Another aspect of the disclosure relates to an anti-Sortilin antibody of any of the preceding embodiments for use in reducing expression of one or more pro-inflammatory mediators. Another aspect of the disclosure relates to the use of an anti-Sortilin antibody of any of the preceding embodiments in the manufacture of a medicament for reducing expression of one or more pro-inflammatory mediators. In certain embodiments, the one or more pro-inflammatory mediators are selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, and CCL5.

[0041] In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody comprises two or more anti-Sortilin antibodies.

[0042] This patent and this application document contains at least one color drawing. Copies of this patent or this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0043] [Figure 1] Figure 1 shows several diagrams of the human sortilin protein, showing the sortilin binding sites for anti-sortilin antibodies S-1, S-65, S-49, S-78, S-44, and S-8. The sortilin backbone is shown in transparent gray. The linear binding regions identified for antibodies S-1 (green), S-65 (red), S-49 (blue), S-78 (yellow), S-44 (pink), and S-8 (purple) are highlighted in color. The binding sites are found within the flexible loop regions of sortilin. [Figure 2A]Figures 2A-2C show characterization of the interaction between sortilin and progranulin using surface plasmon resonance (SPR) and ELISA. Figure 2A shows kinetic analysis of progranulin (PGRN) binding to His-captured sortilin 1 (SORT1) using Biacore SPR. Figure 2B shows binding of biotinylated human PGRN to immobilized human SORT1 on an ELISA plate. Figure 2C shows binding of biotinylated mouse PGRN to immobilized mouse SORT1 on an ELISA plate. [Figure 2B] Figures 2A-2C show characterization of the interaction between sortilin and progranulin using surface plasmon resonance (SPR) and ELISA. Figure 2A shows kinetic analysis of progranulin (PGRN) binding to His-captured sortilin 1 (SORT1) using Biacore SPR. Figure 2B shows binding of biotinylated human PGRN to immobilized human SORT1 on an ELISA plate. Figure 2C shows binding of biotinylated mouse PGRN to immobilized mouse SORT1 on an ELISA plate. [Figure 2C] Figures 2A-2C show characterization of the interaction between sortilin and progranulin using surface plasmon resonance (SPR) and ELISA. Figure 2A shows kinetic analysis of progranulin (PGRN) binding to His-captured sortilin 1 (SORT1) using Biacore SPR. Figure 2B shows binding of biotinylated human PGRN to immobilized human SORT1 on an ELISA plate. Figure 2C shows binding of biotinylated mouse PGRN to immobilized mouse SORT1 on an ELISA plate. [Figure 3A] Antibody avidity binding to human sortilin (bH Sort) on a sensor chip and competition with anti-sortilin antibody (IgG) are shown. [Figure 3B]Characterization of the interaction between sortilin (SORT) and progranulin (PGRN) and competition with anti-sortilin antibody (IgG) using Forte Bio analysis. Left column: Biotinylated progranulin peptide is immobilized on a sensor chip, and SORT is added to the solution, followed by IgG. Middle column: Biotinylated recombinant human SORT is immobilized on a sensor chip, and recombinant PGRN is added to the solution, followed by IgG. Right column: Biotinylated recombinant PGRN is immobilized on a sensor chip, and human SORT is added to the solution, followed by IgG. (SORT = sortilin, PGRN = progranulin, b = biotinylated, H = human, mono = monomeric) [Figure 4A] Examples of different classes of anti-Sortilin antibodies that block Progranulin binding in different ForteBio configurations (as depicted in Figure 3B) are shown. The left column shows competitive binding using human SORT binding to PGRN peptide immobilized on a sensor chip. The middle column shows competitive binding using native PGRN protein binding to human SORT immobilized on a sensor chip. The right column shows competitive binding using native SORT protein binding to native PGRN protein immobilized on a sensor chip. [Figure 4B] Binding of anti-Sortilin antibodies to His-trapped Sortilin (SORT1) using Biacore SPR at pH 6.4 and pH 7.4 is shown. [Figure 5A-B] Figures 5A-5D show characterization of the interaction between sortilin and progranulin on cells. Figure 5A shows a FACS plot showing the binding level of human PGRN-Bio to HEK293T cells expressing human SORT. Figure 5B shows a FACS plot showing the binding level of human PGRN-Bio to control cells. Figure 5C shows the mean fluorescence intensity (MFI) plotted against the concentration of human PGRN bound to HEK293T cells expressing human SORT (circles) or control cells (squares). Figure 5D shows the MFI plotted against the concentration of mouse PGRN bound to HEK293T cells expressing mouse SORT (circles) or control cells (squares). [Figure 5C]Figures 5A-5D show characterization of the interaction between sortilin and progranulin on cells. Figure 5A shows a FACS plot showing the binding level of human PGRN-Bio to HEK293T cells expressing human SORT. Figure 5B shows a FACS plot showing the binding level of human PGRN-Bio to control cells. Figure 5C shows the mean fluorescence intensity (MFI) plotted against the concentration of human PGRN bound to HEK293T cells expressing human SORT (circles) or control cells (squares). Figure 5D shows the MFI plotted against the concentration of mouse PGRN bound to HEK293T cells expressing mouse SORT (circles) or control cells (squares). [Figure 5D] Figures 5A-5D show characterization of the interaction between sortilin and progranulin on cells. Figure 5A shows a FACS plot showing the binding level of human PGRN-Bio to HEK293T cells expressing human SORT. Figure 5B shows a FACS plot showing the binding level of human PGRN-Bio to control cells. Figure 5C shows the mean fluorescence intensity (MFI) plotted against the concentration of human PGRN bound to HEK293T cells expressing human SORT (circles) or control cells (squares). Figure 5D shows the MFI plotted against the concentration of mouse PGRN bound to HEK293T cells expressing mouse SORT (circles) or control cells (squares). [Figure 6A] Figures 6A-6E show dose-dependent inhibition of biotinylated Progranulin binding to cells expressing Sortilin by anti-Sortilin antibodies. Figures 6A and 6B show antibody inhibition of human Progranulin binding to human Sortilin. Figures 6C and 6D show antibody inhibition of mouse Progranulin binding to mouse Sortilin. Figure 6E shows inhibition of biotinylated human Progranulin binding to cells expressing human Sortilin by 67 nM anti-Sortilin antibody. [Figure 6B]Figures 6A-6E show dose-dependent inhibition of biotinylated Progranulin binding to cells expressing Sortilin by anti-Sortilin antibodies. Figures 6A and 6B show antibody inhibition of human Progranulin binding to human Sortilin. Figures 6C and 6D show antibody inhibition of mouse Progranulin binding to mouse Sortilin. Figure 6E shows inhibition of biotinylated human Progranulin binding to cells expressing human Sortilin by 67 nM anti-Sortilin antibody. [Figure 6C] Figures 6A-6E show dose-dependent inhibition of biotinylated Progranulin binding to cells expressing Sortilin by anti-Sortilin antibodies. Figures 6A and 6B show antibody inhibition of human Progranulin binding to human Sortilin. Figures 6C and 6D show antibody inhibition of mouse Progranulin binding to mouse Sortilin. Figure 6E shows inhibition of biotinylated human Progranulin binding to cells expressing human Sortilin by 67 nM anti-Sortilin antibody. [Figure 6D] Figures 6A-6E show dose-dependent inhibition of biotinylated Progranulin binding to cells expressing Sortilin by anti-Sortilin antibodies. Figures 6A and 6B show antibody inhibition of human Progranulin binding to human Sortilin. Figures 6C and 6D show antibody inhibition of mouse Progranulin binding to mouse Sortilin. Figure 6E shows inhibition of biotinylated human Progranulin binding to cells expressing human Sortilin by 67 nM anti-Sortilin antibody. [Figure 6E] Figures 6A-6E show dose-dependent inhibition of biotinylated Progranulin binding to cells expressing Sortilin by anti-Sortilin antibodies. Figures 6A and 6B show antibody inhibition of human Progranulin binding to human Sortilin. Figures 6C and 6D show antibody inhibition of mouse Progranulin binding to mouse Sortilin. Figure 6E shows inhibition of biotinylated human Progranulin binding to cells expressing human Sortilin by 67 nM anti-Sortilin antibody. [Figure 7]Figure 1 shows a test of the synergistic effect of antibody combinations on the binding of biotinylated progranulin to sortilin expressed on HEK293T cells. S-49, S-64 (bin 4), and S-16 (bin 1) were combined with an isotype control antibody or each other. [Figure 8A]

[0049] Figure 1 shows the results of an imaging assay for the time-dependent binding and endocytosis of fluorescently labeled Progranulin (PGRN) by 10 μM Sortilin propeptide, which competes with Progranulin (PGRN), and its blockade. Cells transfected with either human Sortilin (hSort) or lacZ were incubated with Progranulin (PGRN) for 4, 15, 30, or 60 minutes and then imaged. This assay is designed to test the ability of anti-Sortilin antibodies to prevent the binding and endocytosis of Progranulin (PGRN) by Sortilin (Sort). [Figure 8B] 1 shows the results of a FACS graph showing the time-dependent binding and endocytosis of PGRN-DyLight650 by cells expressing human Sortilin. The assay is designed to test the ability of anti-Sortilin antibodies to prevent the binding and endocytosis of fluorescently labeled Progranulin by human Sortilin. [Figure 8C] Figure 8B shows the results of a FACS graph demonstrating the time-dependent binding and endocytosis of PGRN-DyLight650 by cells expressing mouse Sortilin. The assay is designed to test the ability of anti-Sortilin antibodies to prevent the binding and endocytosis of fluorescently labeled Progranulin by mouse Sortilin. Human PGRN-DyLight650 is added to human Sort (Figure 8B) or mouse Sort (Figure 8C) or control HEK293T cells, and the amount of bound and endocytosed PGRN is quantified by FACS. [Figure 8D] 1 shows the results of a FACS assay demonstrating the ability of the human PGRN inhibitor Sort propeptide to prevent binding and endocytosis of fluorescently labeled PGRN by human sortilin. [Figure 8E]1 shows the results of a FACS assay demonstrating the ability of the mouse PGRN inhibitor Sort propeptide to prevent binding and endocytosis of fluorescently labeled PGRN by mouse sortilin. [Figure 9A] Figures 9A-9D show the results of an assay demonstrating the ability of anti-Sortilin antibodies to increase endogenous secreted levels of progranulin in the culture medium of the human astrocyte cell line U-251, which expresses endogenous human sortilin. Figure 9A shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9B shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Figure 9C shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9D shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Progranulin levels in the culture medium were quantified by ELISA analysis. Means of two independent experiments are shown. Statistics were performed using ANOVA. Asterisks indicate antibodies that significantly increased progranulin levels. [Figure 9B] Figures 9A-9D show the results of an assay demonstrating the ability of anti-Sortilin antibodies to increase endogenous secreted levels of progranulin in the culture medium of the human astrocyte cell line U-251, which expresses endogenous human sortilin. Figure 9A shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9B shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Figure 9C shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9D shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Progranulin levels in the culture medium were quantified by ELISA analysis. Means of two independent experiments are shown. Statistics were performed using ANOVA. Asterisks indicate antibodies that significantly increased progranulin levels. [Figure 9C]Figures 9A-9D show the results of an assay demonstrating the ability of anti-Sortilin antibodies to increase endogenous secreted levels of progranulin in the culture medium of the human astrocyte cell line U-251, which expresses endogenous human sortilin. Figure 9A shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9B shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Figure 9C shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9D shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Progranulin levels in the culture medium were quantified by ELISA analysis. Means of two independent experiments are shown. Statistics were performed using ANOVA. Asterisks indicate antibodies that significantly increased progranulin levels. [Figure 9D] Figures 9A-9D show the results of an assay demonstrating the ability of anti-Sortilin antibodies to increase endogenous secreted levels of progranulin in the culture medium of the human astrocyte cell line U-251, which expresses endogenous human sortilin. Figure 9A shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9B shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Figure 9C shows the results for U-251 cells incubated with 50 nM anti-Sortilin antibody for 72 hours. Figure 9D shows the results for U-251 cells incubated with 5 nM anti-Sortilin antibody for 72 hours. Progranulin levels in the culture medium were quantified by ELISA analysis. Means of two independent experiments are shown. Statistics were performed using ANOVA. Asterisks indicate antibodies that significantly increased progranulin levels. [Figure 10A]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10B]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10C]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10D]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10E-1]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10E-2]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 10F]Figures 10A-10F show the effect of anti-Sortilin antibodies on sortilin cell surface levels on human U-251 cells or mouse N2A cells, and the ability of the corresponding antibodies to dose-dependently increase secreted levels of endogenous progranulin (PGRN). Cells were incubated with 50 nM blocking IgG for 72 hours, harvested, and stained with an anti-Sortilin antibody that binds to a region on Sortilin distinct from the test antibody. Figure 10A shows sortilin cell surface expression on U-251 cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not show a reduction in sortilin. Black bars indicate control IgG. Figure 10B shows sortilin cell surface expression on N2A cells pretreated with the test antibodies listed on the X-axis as a percent (%) of control levels. Gray bars indicate antibodies that showed a significant reduction in sortilin (ANOVA, p<0.05), while white bars indicate antibodies that did not. Black bars indicate control IgG. Figures 10C and 10D show cell surface sortilin levels in U-251 cells incubated with different concentrations of anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies induce a dose-dependent decrease in cell surface expression of sortilin. The decrease in sortilin levels is indicated by a decrease in the fluorescence intensity (MFI) of S-20 antibody binding to sortilin. Figure 10E shows quantification by ELISA of the corresponding PGRN levels in the medium of U-251 cells from Figure 10B incubated with the listed anti-sortilin antibodies for 72 hours. Anti-sortilin antibodies that decrease sortilin cell surface levels also result in a dose-dependent increase in extracellular PGRN levels. FIG. 10F shows the correlation between the decrease in cell surface levels of sortilin induced by anti-sortilin antibodies and the increase in extracellular levels of progranulin (PGRN). [Figure 11A]Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 11B] Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 11C]Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 11D] Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 11E]Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 11F] Figures 11A-11F show results demonstrating that infusion of anti-Sortilin antibody increases endogenous brain progranulin levels several-fold in the Tg2576 mouse model of Alzheimer's disease. Figure 11A shows progranulin levels in various brain regions contralateral to the site of ICV infusion. Figure 11B shows progranulin levels in various brain regions ipsilateral to the site of ICV infusion. The various brain regions are the hippocampus (Hip), frontal cortex (F Ctx), and occipital cortex (R Ctx). Fourteen-month-old Tg2576 mice were infused ICV with buffer, goat IgG, or goat anti-Sortilin polyclonal antibody (n = 3 / group). Figure 11C shows the levels of anti-Sortilin antibody in three different brain regions. Figure 11D shows a strong positive correlation between anti-Sortilin antibody levels and endogenous progranulin (PGRN) levels (r = 0.92). Higher levels of anti-Sortilin antibody result in a dose-dependent increase in brain PGRN. Figure 11F shows the levels of Aβ42 peptide in the soluble protein fraction after ICV infusion with anti-Sortilin antibody. [Figure 12A]

[0023] Figure 1 shows a surface plasmon resonance (SPR) biacore assay monitoring competition between pro-NGF and an anti-sortilin antibody for binding to sortilin. The assay shows human sortilin captured on a Biacore chip, followed by binding of pro-NGF to sortilin, followed by binding of the anti-sortilin antibody to sortilin. [Figure 12B] A non-blocking control is shown. If pro-NGF and a given anti-Sortilin antibody bind to the same region on Sortilin, binding of pro-NGF will inhibit subsequent binding of the anti-Sortilin antibody. Thus, as shown in FIG. 12B, if a given antibody binds to Sortilin to the same extent in the presence (dashed line) or absence (solid line) of pro-NGF, such antibody will not block pro-NGF binding to Sortilin. FIG. 12C shows binding of anti-Sortilin antibodies to Sortilin in the presence (dashed line) or absence (solid line) of pro-NGF. The antibodies shown are partially blocked by the presence of pro-NGF bound to Sortilin. Antibodies S-1 and S-65 are strongly affected. The solid line corresponds to binding of the antibody to Sortilin in the absence of pro-NGF. The dashed line corresponds to binding of the antibody to Sortilin in the presence of pro-NGF. The grey line corresponds to the binding of pro-NGF to sortilin in the presence of pro-NGF (maximal competition). [Figure 12C-1]A non-blocking control is shown. If pro-NGF and a given anti-Sortilin antibody bind to the same region on Sortilin, binding of pro-NGF will inhibit subsequent binding of the anti-Sortilin antibody. Thus, as shown in FIG. 12B, if a given antibody binds to Sortilin to the same extent in the presence (dashed line) or absence (solid line) of pro-NGF, such antibody will not block pro-NGF binding to Sortilin. FIG. 12C shows binding of anti-Sortilin antibodies to Sortilin in the presence (dashed line) or absence (solid line) of pro-NGF. The antibodies shown are partially blocked by the presence of pro-NGF bound to Sortilin. Antibodies S-1 and S-65 are strongly affected. The solid line corresponds to binding of the antibody to Sortilin in the absence of pro-NGF. The dashed line corresponds to binding of the antibody to Sortilin in the presence of pro-NGF. The grey line corresponds to the binding of pro-NGF to sortilin in the presence of pro-NGF (maximal competition). [Figure 12C-2] A non-blocking control is shown. If pro-NGF and a given anti-Sortilin antibody bind to the same region on Sortilin, binding of pro-NGF will inhibit subsequent binding of the anti-Sortilin antibody. Thus, as shown in FIG. 12B, if a given antibody binds to Sortilin to the same extent in the presence (dashed line) or absence (solid line) of pro-NGF, such antibody will not block pro-NGF binding to Sortilin. FIG. 12C shows binding of anti-Sortilin antibodies to Sortilin in the presence (dashed line) or absence (solid line) of pro-NGF. The antibodies shown are partially blocked by the presence of pro-NGF bound to Sortilin. Antibodies S-1 and S-65 are strongly affected. The solid line corresponds to binding of the antibody to Sortilin in the absence of pro-NGF. The dashed line corresponds to binding of the antibody to Sortilin in the presence of pro-NGF. The grey line corresponds to the binding of pro-NGF to sortilin in the presence of pro-NGF (maximal competition). [Figure 13A]Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13B] Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13C] Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13D]Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13E] Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13F] Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 13G]Figures 13A-13G show the levels of sortilin cell surface expression after 72 hours of incubation with anti-sortilin antibodies at concentrations of 20 nM, 5 nM, or 1.25 nM. Figures 13A, 13B, 13C, and 13D show sortilin cell surface expression on human U-251 cells. Figures 13E, 13F, and 13G show sortilin cell surface expression on mouse N2A cells. The results show that affinity-matured antibodies induced an increased decrease in cell surface levels of sortilin, especially when used at the lowest concentration of 1.25 nM. [Figure 14] Figure 1 shows the inhibition of progranulin binding to sortilin-expressing HEK293T cells (% PGRN blockade) by 150 nM of affinity-matured anti-sortilin antibodies derived from antibody S-15. Affinity-matured antibody S-15-6 showed improved PGRN blockade. [Figure 15A] Figures 15A and 15B show mass spectrometry profiles of antibody S-2-11 binding to Sortilin in the absence (Figure 15A) or presence (Figure 15B) of peptides derived from Sortilin digestion. The peptides did not compete with antibody binding to Sortilin. A similar lack of peptide competition was observed for other anti-Sortilin antibodies. [Figure 15B] Figures 15A and 15B show mass spectrometry profiles of antibody S-2-11 binding to Sortilin in the absence (Figure 15A) or presence (Figure 15B) of peptides derived from Sortilin digestion. The peptides did not compete with antibody binding to Sortilin. A similar lack of peptide competition was observed for other anti-Sortilin antibodies. [Figure 16A]

[0023] Figure 1 shows a schematic representation of peptide coverage after enzymatic proteolysis of Sortilin. The peptides generated by proteolysis included 94.78% of the Sortilin extracellular domain (ECD) (SEQ ID NO: 714). [Figure 16B] Figure 1 shows reduced binding of S-30 antibodies to specific Sortilin mutants in which human amino acids are substituted with mouse Sortilin amino acids. The results indicate that S-30 binding requires amino acid HVPLVIMT131 or a subset thereof. [Figure 16C]Figure 1 shows reduced binding of S-60 antibodies to specific sortilin mutants in which human amino acids were substituted with mouse sortilin amino acids. The results showed that S-60 binding requires the S595 amino acid. [Figure 17A] Figures 17A-17E show surface plasmon resonance traces. Figure 17A shows the binding level of progranulin (PGRN) to sortilin in the presence or absence of neurotensin (NTS). Figure 17B shows the binding level of anti-sortilin antibody S-15 to sortilin in the presence or absence of NTS. Figure 17C shows the binding level of anti-sortilin antibody S-22 to sortilin in the presence or absence of NTS. Figure 17D shows the binding level of anti-sortilin antibody S-49 to sortilin in the presence or absence of NTS. Figure 17E shows the binding level of anti-sortilin antibody S-60 to sortilin in the presence or absence of NTS. NTS did not affect the binding of the antibodies to sortilin, indicating that the anti-sortilin antibodies do not bind to the NTS binding site. [Figure 17B] Figures 17A-17E show surface plasmon resonance traces. Figure 17A shows the binding level of progranulin (PGRN) to sortilin in the presence or absence of neurotensin (NTS). Figure 17B shows the binding level of anti-sortilin antibody S-15 to sortilin in the presence or absence of NTS. Figure 17C shows the binding level of anti-sortilin antibody S-22 to sortilin in the presence or absence of NTS. Figure 17D shows the binding level of anti-sortilin antibody S-49 to sortilin in the presence or absence of NTS. Figure 17E shows the binding level of anti-sortilin antibody S-60 to sortilin in the presence or absence of NTS. NTS did not affect the binding of the antibodies to sortilin, indicating that the anti-sortilin antibodies do not bind to the NTS binding site. [Figure 17C]Figures 17A-17E show surface plasmon resonance traces. Figure 17A shows the binding level of progranulin (PGRN) to sortilin in the presence or absence of neurotensin (NTS). Figure 17B shows the binding level of anti-sortilin antibody S-15 to sortilin in the presence or absence of NTS. Figure 17C shows the binding level of anti-sortilin antibody S-22 to sortilin in the presence or absence of NTS. Figure 17D shows the binding level of anti-sortilin antibody S-49 to sortilin in the presence or absence of NTS. Figure 17E shows the binding level of anti-sortilin antibody S-60 to sortilin in the presence or absence of NTS. NTS did not affect the binding of the antibodies to sortilin, indicating that the anti-sortilin antibodies do not bind to the NTS binding site. [Figure 17D] Figures 17A-17E show surface plasmon resonance traces. Figure 17A shows the binding level of progranulin (PGRN) to sortilin in the presence or absence of neurotensin (NTS). Figure 17B shows the binding level of anti-sortilin antibody S-15 to sortilin in the presence or absence of NTS. Figure 17C shows the binding level of anti-sortilin antibody S-22 to sortilin in the presence or absence of NTS. Figure 17D shows the binding level of anti-sortilin antibody S-49 to sortilin in the presence or absence of NTS. Figure 17E shows the binding level of anti-sortilin antibody S-60 to sortilin in the presence or absence of NTS. NTS did not affect the binding of the antibodies to sortilin, indicating that the anti-sortilin antibodies do not bind to the NTS binding site. [Figure 17E]Figures 17A-17E show surface plasmon resonance traces. Figure 17A shows the binding level of progranulin (PGRN) to sortilin in the presence or absence of neurotensin (NTS). Figure 17B shows the binding level of anti-sortilin antibody S-15 to sortilin in the presence or absence of NTS. Figure 17C shows the binding level of anti-sortilin antibody S-22 to sortilin in the presence or absence of NTS. Figure 17D shows the binding level of anti-sortilin antibody S-49 to sortilin in the presence or absence of NTS. Figure 17E shows the binding level of anti-sortilin antibody S-60 to sortilin in the presence or absence of NTS. NTS did not affect the binding of the antibodies to sortilin, indicating that the anti-sortilin antibodies do not bind to the NTS binding site. [Figure 18A] 1 shows reduction of sortilin protein levels in human primary macrophages by both full-length anti-sortilin antibody (IgG) and antibody Fab. [Figure 18B] Figure 1 shows reduction of sortilin protein levels in human primary dendritic cells by full-length antibody (IgG). 15 μg of protein was loaded onto a gel, blotted, and stained with antibodies against sortilin and β-actin. [Figure 19A] Figures 19A and 19B show measurements of anti-Sortilin antibody half-life in vivo following intraperitoneal (IP) injection of 40 mg / kg on day 0. Figure 19A shows injection of human anti-Sortilin IgG1 N297A antibody (n=4-5 / group). Figure 19B shows injection of mouse anti-Sortilin IgG1 N297A antibody. Data were fitted using a one-phase decay function (Graph Pad Prism). Anti-Sortilin antibodies have shorter half-lives than control IgG. [Figure 19B]Figures 19A and 19B show measurements of anti-Sortilin antibody half-life in vivo following intraperitoneal (IP) injection of 40 mg / kg on day 0. Figure 19A shows injection of human anti-Sortilin IgG1 N297A antibody (n=4-5 / group). Figure 19B shows injection of mouse anti-Sortilin IgG1 N297A antibody. Data were fitted using a one-phase decay function (Graph Pad Prism). Anti-Sortilin antibodies have shorter half-lives than control IgG. [Figure 20A] Figures 20A-20D show measurements of mouse progranulin (PGRN) protein levels in mouse plasma samples at various times after injection of 40 mg / kg of anti-Sortilin antibody. Figures 20A and 20B show results with mouse anti-Sortilin IgG1 N297A antibody. Figures 20C and 20D show results with human anti-Sortilin IgG1 N297A antibody. Figures 20B and 20D summarize statistical analysis using one-way ANOVA with Tukey post-hoc test. Asterisks indicate significance levels compared to the ms or hu IgG1 isotype control groups: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Anti-Sortilin antibody induces an increase in plasma PGRN protein levels, and the duration of effect correlates with the antibody half-life. [Figure 20B] Figures 20A-20D show measurements of mouse progranulin (PGRN) protein levels in mouse plasma samples at various times after injection of 40 mg / kg of anti-Sortilin antibody. Figures 20A and 20B show results with mouse anti-Sortilin IgG1 N297A antibody. Figures 20C and 20D show results with human anti-Sortilin IgG1 N297A antibody. Figures 20B and 20D summarize statistical analysis using one-way ANOVA with Tukey post-hoc test. Asterisks indicate significance levels compared to the ms or hu IgG1 isotype control groups: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Anti-Sortilin antibody induces an increase in plasma PGRN protein levels, and the duration of effect correlates with the antibody half-life. [Figure 20C]Figures 20A-20D show measurements of mouse progranulin (PGRN) protein levels in mouse plasma samples at various times after injection of 40 mg / kg of anti-Sortilin antibody. Figures 20A and 20B show results with mouse anti-Sortilin IgG1 N297A antibody. Figures 20C and 20D show results with human anti-Sortilin IgG1 N297A antibody. Figures 20B and 20D summarize statistical analysis using one-way ANOVA with Tukey post-hoc test. Asterisks indicate significance levels compared to the ms or hu IgG1 isotype control groups: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Anti-Sortilin antibody induces an increase in plasma PGRN protein levels, and the duration of effect correlates with the antibody half-life. [Figure 20D] Figures 20A-20D show measurements of mouse progranulin (PGRN) protein levels in mouse plasma samples at various times after injection of 40 mg / kg of anti-Sortilin antibody. Figures 20A and 20B show results with mouse anti-Sortilin IgG1 N297A antibody. Figures 20C and 20D show results with human anti-Sortilin IgG1 N297A antibody. Figures 20B and 20D summarize statistical analysis using one-way ANOVA with Tukey post-hoc test. Asterisks indicate significance levels compared to the ms or hu IgG1 isotype control groups: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Anti-Sortilin antibody induces an increase in plasma PGRN protein levels, and the duration of effect correlates with the antibody half-life. [Figure 21A]Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 21B] Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 21C]Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 21D] Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 21E]Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 21F] Figures 21A-21F show measurement of sortilin protein levels using Western blot analysis of leukocyte lysates from mice. Anti-β-actin was used as a loading control and for normalization. Figures 21A and 21B show protein levels on day 5. Figures 21C and 21D show protein levels on day 12. Anti-sortilin antibodies S-20, S-15-6, and S-2-11 induce a significant decrease in sortilin protein levels on day 5 (one-way ANOVA with Tukey's post-hoc test; asterisks indicate significance levels: **p<0.01, ***p<0.001). Antibody S-15-6 induced a decrease in sortilin protein levels in two of three mice on day 12. Figures 21E and 21F show protein levels in leukocytes after mice were IP injected once weekly with 20, 40, or 80 mg / kg of the anti-sortilin antibody S15-6 for a chronic 6-week course. All three doses result in a strong and statistically significant downregulation of sortilin in leukocytes (****p<0.0001 compared to control IgG, one-way ANOVA). [Figure 22A]Figures 22A-22D show a positive correlation between anti-Sortilin antibody IgG levels and progranulin (PGRN) protein levels in brain samples from wild-type (WT) mice after 2 weeks of ICV infusion. There was no significant correlation with the isotype control antibody. Figure 22A shows antibody S-15. Figure 22B shows antibody S-20. Figure 22C shows antibody S-30. Figure 22D shows the isotype control antibody. [Figure 22B] Figures 22A-22D show a positive correlation between anti-Sortilin antibody IgG levels and progranulin (PGRN) protein levels in brain samples from wild-type (WT) mice after 2 weeks of ICV infusion. There was no significant correlation with the isotype control antibody. Figure 22A shows antibody S-15. Figure 22B shows antibody S-20. Figure 22C shows antibody S-30. Figure 22D shows the isotype control antibody. [Figure 22C] Figures 22A-22D show a positive correlation between anti-Sortilin antibody IgG levels and progranulin (PGRN) protein levels in brain samples from wild-type (WT) mice after 2 weeks of ICV infusion. There was no significant correlation with the isotype control antibody. Figure 22A shows antibody S-15. Figure 22B shows antibody S-20. Figure 22C shows antibody S-30. Figure 22D shows the isotype control antibody. [Figure 22D] Figures 22A-22D show a positive correlation between anti-Sortilin antibody IgG levels and progranulin (PGRN) protein levels in brain samples from wild-type (WT) mice after 2 weeks of ICV infusion. There was no significant correlation with the isotype control antibody. Figure 22A shows antibody S-15. Figure 22B shows antibody S-20. Figure 22C shows antibody S-30. Figure 22D shows the isotype control antibody. [Figure 23A] Figure 1 shows IgG levels measured after IV injection of 40 mg / kg of the anti-sortilin antibody S-15-6 huIgG1 N297A. IgG half-life increases with decreasing sortilin levels, indicating that the relatively short half-life of S-15-6 in wild-type (WT) mice is due to post-target binding degradation rather than immunogenicity or other nonspecific degradation. [Figure 23B] Figure 1 shows elevated baseline progranulin (PGRN) protein levels in sortilin knockout (KO) mice compared to sortilin heterozygous (Het) and wild-type (WT) littermates. PGRN was measured in plasma samples using an ELISA assay. [Figure 23C] Figure 1 shows results showing that antibody S-15-6 induced an increase in progranulin (PGRN) protein levels for up to 8 days after injection in wild-type (WT) and sortilin heterozygous (Het) mice, but not in sortilin knockout (KO) mice. The black arrow indicates injection of S-15-6 antibody on day 7. ****p<0.0001, ns: not significant by one-way ANOVA, KO vs. Het and vs. WT. [Figure 24] 1 shows the results of a collagen-induced arthritis study in mice. Biweekly injections of 40 mg / kg of the anti-sortilin antibody S-15-6 significantly reduced arthritis clinical scores compared to control groups (PBS and MOPC-21 / msIgG1). [Figure 25A] Figure 25A shows serum levels of progranulin in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25B shows the number of peritoneal neutrophils in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25C shows the number of large peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25D shows the number of small peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. The results show elevated levels of progranulin, but there was no significant difference in the numbers of peritoneal neutrophils, large peritoneal macrophages, and small peritoneal macrophages. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 25B] Figure 25A shows serum levels of progranulin in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25B shows the number of peritoneal neutrophils in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25C shows the number of large peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25D shows the number of small peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. The results show elevated levels of progranulin, but there was no significant difference in the numbers of peritoneal neutrophils, large peritoneal macrophages, and small peritoneal macrophages. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 25C] Figure 25A shows serum levels of progranulin in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25B shows the number of peritoneal neutrophils in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25C shows the number of large peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25D shows the number of small peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. The results show elevated levels of progranulin, but there was no significant difference in the numbers of peritoneal neutrophils, large peritoneal macrophages, and small peritoneal macrophages. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 25D]Figure 25A shows serum levels of progranulin in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25B shows the number of peritoneal neutrophils in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25C shows the number of large peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 25D shows the number of small peritoneal macrophages in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. The results show elevated levels of progranulin, but there was no significant difference in the numbers of peritoneal neutrophils, large peritoneal macrophages, and small peritoneal macrophages. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26A]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26B]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26C]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26D]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26E]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26F]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26G]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 26H]Figure 26A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 26H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 27A]Figure 27A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 27B] Figure 27A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 27C]Figure 27A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 27D] Figure 27A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 27E]Figure 27A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Figure 27E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 1.5 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28A]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28B]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28C]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28D]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28E]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28F]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28G]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 28H]Figure 28A shows serum levels of IL-6 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28B shows serum levels of TNFα in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28C shows serum levels of IFNγ in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28D shows serum levels of IL-10 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28E shows serum levels of IL-12p70 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28F shows serum levels of IL-12 / IL-23p40 in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28G shows serum levels of IL-1α in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 28H shows serum levels of IL-1β in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 29A]Figure 29A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 29B] Figure 29A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 29C]Figure 29A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 29D] Figure 29A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. [Figure 29E]Figure 29A shows serum CXCL1 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29B shows serum CCL2 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29C shows serum CCL3 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29D shows serum CCL4 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Figure 29E shows serum CCL5 levels in wild-type and sortilin knockout (Sortilin- / -) mice 6 hours after LPS treatment. Open circles represent wild-type mice, and open squares represent sortilin knockout mice. n = 8-10 mice per group. *p<0.01, **p<0.001, ***p<0.001, and ****p<0.0001 by one-way ANOVA with Tukey's multiple comparison test. DETAILED DESCRIPTION OF THE INVENTION

[0044] general technique The techniques and procedures described or referenced herein are generally well understood by those of skill in the art and may be adapted from conventional methodologies such as those described in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)); Harlow and Lane, eds. (1988); Antibodies, A Laboratory Manual; and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual. notebook (JECellis, ed., 1998) Academic Press, Animal Cell Culture (RIFreshney), ed., 1987), Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons, Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.), Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994), Current Protocols in Immunology (JEColigan et al., eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (CA Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989), Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000), Using Antibodies: A Laboratory Manual (E.Harlow and These are commonly used using widely available methodologies such as those described in D. Lane (Cold Spring Harbor Laboratory Press, 1999), The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995), and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., J.B. Lippincott Company, 1993).

[0045] 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.

[0046] 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.

[0047] 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.

[0048] An "effective amount" refers to at least an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result. An effective amount can be administered in one or more administrations.

[0049] A "therapeutically effective amount" is at least the minimum concentration required to bring about a measurable improvement in a particular disease, disorder, or condition. The therapeutically effective amount, as used herein, may vary depending on factors such as the patient's condition, age, sex, and weight, as well as the ability of the sortilin protein antagonist to elicit a desired response in an individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the sortilin protein antagonist are outweighed by the therapeutically beneficial effects.

[0050] 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.

[0051] 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.

[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) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0053] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. H and V Land form a single antigen-binding site. 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.

[0054] 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 domains. Depending on the amino acid sequence of the constant domain (CH) of their heavy chains, 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; see, e.g., Abbas et al., Cellular and Molecular Immunology, 4 th This is roughly described in Saunders Co., ed. (WBSaunders Co., 2000).

[0055] "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.

[0056] 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.

[0057] 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 LThese domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding sites.

[0058] 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). V 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.

[0059] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, e.g., an 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), which may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against one or more antigenic sites. In some embodiments, antibodies of the present disclosure may be bispecific. 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 one or more antigenic sites. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present disclosure can be generated by a variety of techniques, including, for example, phage display (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Nat'l Acad. Sci. USA 101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132(2004), hybridoma method (e.g., Kohler and Milstein, Nature, 256:495-97(1975), Hongo et al., Hybridoma, 14(3):253-260(1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988), Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567) and techniques for producing human antibodies or human-like antibodies in animals having some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893, WO 1996 / 34096, WO 1996 / 33735, WO 1991 / 10741, Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551 (1993), Jakobovits et al., Nature 362:255-258 (1993), Bruggemann et al., Year in Immunol. 7:33 (1993), U.S. Patent Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, and 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992), Lonberg et al., Nature 368:856-859 (1994), Morrison, Nature 368:812-813 (1994), Fishwild et al., Nature Biotechnol. 14:845-851 (1996), Neuberger, Nature Biotechnol. 14:826 (1996), and Lonberg and See Huszar, Intern. Rev. Immunol. 13:65-93 (1995).

[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. The Fab' fragment is C HF(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation used 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 that have 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 LThe 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, which generally includes 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 combines V domains to achieve inter-chain but not intra-chain V domain pairing, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domains 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 Diabodies are heterodimers of two "crossover" sFv fragments, in which the domains are present on different polypeptide chains. Diabodies are described in further detail in, for example, EP 404,097, WO 93 / 11161, and Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[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 (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). 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 that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in either the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FRs typically will not exceed six in the H chain and not exceed three in the L chain. The humanized antibody also optionally will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986), Riechmann et al., Nature 332:323-329 (1988), and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998), Harris, Biochem. Soc. Transactions 23:1035-1038 (1995), Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994), and U.S. Patent Nos. 6,982,321 and 7,087,409.

[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 produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Human monoclonal antibodies can also be produced using the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be produced by administering an antigen to a transgenic animal, e.g., an immunized xenogeneic mouse, which has been engineered to produce such antibodies in response to antigen challenge and whose endogenous gene locus has been disabled (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006), for human antibodies produced by human B cell hybridoma technology.

[0071] As used herein, the terms "hypervariable region," "HVR," or "HV" refer to regions of an antibody variable domain (e.g., regions of an antibody variable domain of an anti-Sortilin antibody of the present disclosure) that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In natural antibodies, H3 and L3 exhibit the highest diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring superior specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains (see, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996)).

[0072] Many HVR descriptions are used and encompassed herein. HVRs, either EU or Kabat complementarity-determining regions (CDRs), are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia, rather, refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). 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. "Contact" HVRs are based on analysis of available complex crystal structures. The residues of each of these HVRs are described below. TIFF0007648584000001.tif50170

[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 EU or 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] The phrases "variable domain residue numbering as in EU or Kabat" or "amino acid position numbering as in EU or Kabat," and variations thereof, refer to the numbering system used in EU or Kabat et al. (supra) for the heavy or light chain variable domains of an antibody sequence. When using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FR or HVR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and may also contain inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The EU or Kabat numbering of residues may be determined for a given antibody by alignment of the antibody sequence with the "standard" Kabat-numbered sequence at the regions of homology.

[0076] The EU or Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU or Kabt numbering system" or "EU index" is generally used when referring to residues in the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless otherwise specified herein, references to residue numbers in the variable domain of an antibody refer to residue numbering according to the Kabat numbering system. Unless otherwise stated herein, references to residue numbers within the constant domain of an antibody refer to residue numbering according to the EU or Kabat numbering system (see, e.g., U.S. Patent Application Publication No. 2010-280227).

[0077] As used herein, an "acceptor human framework" refers to a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or derived from a human consensus framework. An 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 the 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 is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0078] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for VL, the subgroup can be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al. (supra). Furthermore, for VH, the subgroup can be subgroup I, subgroup II, or subgroup III as in Kabat et al. (supra).

[0079] 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.

[0080] 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).

[0081] 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.

[0082] 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.

[0083] A "blocking," "antagonist," or "inhibitory" antibody is an antibody (e.g., an anti-Sortilin antibody of the present disclosure) that inhibits or reduces one or more biological activities of the antigen to which it binds, e.g., its interaction with one or more proteins. In some embodiments, a blocking, antagonist, or inhibitory antibody substantially or completely inhibits one or more biological activities or interactions of the antigen.

[0084] 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.

[0085] 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 or Kabat 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.

[0086] 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.

[0087] 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.

[0088] "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 (see, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991), Capel et al., Immunomethods 4:25-34 (1994), and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those yet to be identified, are encompassed by the term "FcR" herein. FcRs may also extend the serum half-life of antibodies.

[0089] The in vivo binding to FcRn and serum half-life of human FcRn high-affinity binding polypeptides can be assayed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which polypeptides having variant Fc regions are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or reduced binding to FcR. See also, for example, Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0090] 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 amino acid residues 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.

[0091] 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. Isolated nucleic acid molecules are therefore distinguished from nucleic acids encoding the polypeptides and antibodies herein that naturally occur in cells.

[0092] 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 are 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.

[0093] "Polynucleotide" or "nucleic acid," as 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. A polynucleotide may contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can include modification(s) made after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps" that replace one or more of the naturally occurring nucleotides with an analog; internucleotide modifications, such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.); those containing pendant moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.); those with intercalating agents (e.g., acridine, psoralen, etc.); those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.); those containing alkylating agents; those with modified linkages (e.g., alpha anomeric nucleic acids, etc.); and unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present in the sugar may be replaced with, for example, a phosphonate group, a phosphate group, protected with a standard protecting group, or activated to generate additional bonds to additional nucleotides, or conjugated to a solid or semi-solid support. The 5'- and 3'-terminal OH groups can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls may be derivatized to standard protecting groups.Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acrylic acid analogs, and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced with alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C) (optionally containing an ether (-O-) linkage), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages within a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0094] 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.

[0095] As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed to the carrier at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0096] As used herein, the term "apoptosis" refers to the genetically-instructed process of intracellular cell destruction. Apoptosis, distinct from necrosis, involves disruption of the cytoskeleton, shrinkage and condensation of the cytoplasm, expression of phosphatidylserine on the outer surface of the cell membrane, and blebbing, resulting in the formation of membrane-bound vesicles or apoptotic bodies. This process is also referred to as "programmed cell death." During apoptosis, characteristic phenomena are observed, such as a curved cell surface, condensation of nuclear chromatin, fragmentation of chromosomal DNA, and impaired mitochondrial function. Apoptosis can be detected using various known techniques, such as annexin V, propidium iodide, DNA fragmentation assays, and cell staining with YO-PRO-1 (Invitrogen). In some embodiments, staining with annexin V and propidium iodide can be used, and the combined percentage of the annexin V / PI, annexin V / PI, and annexin V / PI populations is considered dead cells.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] Sortilin protein In one aspect, the present disclosure provides an isolated (e.g., monoclonal) antibody that binds to an epitope within a Sortilin protein of the present disclosure, including, but not limited to, mammalian Sortilin protein, human Sortilin protein, mouse Sortilin protein, and rat Sortilin protein.

[0101] Sortilin is variously referred to as sortilin 1, sort1, 100 kDa NT receptor, glycoprotein 95 (GP95), progranulin receptor (PGRN-R), and neurotensin receptor 3 (NT-3 or NTR-3). Sortilin is a protein consisting of 831 amino acids and encodes a type I membrane receptor. Various sortilin homologs are known, including, but not limited to, human sortilin, rat sortilin, and mouse sortilin. The amino acid sequence of human sortilin is shown below as SEQ ID NO: 1 (key amino acid residues predicted to be involved in progranulin binding are shown in bold, and the predicted pro-NGF binding region is underlined). JPEG0007648584000002.jpg134170

[0102] Furthermore, the amino acid sequence of mouse sortilin is shown in SEQ ID NO:2. TIFF0007648584000003.tif58170

[0103] Furthermore, the amino acid sequence of rat sortilin is shown in SEQ ID NO:3. TIFF0007648584000004.tif57170

[0104] In some embodiments, the Sortilin is a preprotein that includes a signal sequence. In some embodiments, the Sortilin is a mature protein. In some embodiments, the mature Sortilin protein does not include a signal sequence. In some embodiments, the mature Sortilin protein is expressed on a cell.

[0105] The sortilin proteins of the present disclosure comprise several domains, including, but not limited to, a signal sequence, a propeptide, a luminal domain, a Vps10p domain, a 10CC domain, a transmembrane domain, and a cytoplasmic domain. Furthermore, the proteins of the present disclosure are expressed at high levels in multiple tissues, including, but not limited to, the brain, spinal cord, heart and skeletal muscle, thyroid, placenta, and testis.

[0106] Sortilin is a member of the Vps10p family of sorting receptors, which includes, but is not limited to, sorting protein-associated receptor with A-type repeats (SorLA), sortilin-related receptor CNS expression type 1 (SorCS1), sortilin-related receptor CNS expression type 2 (SorCS2), and sortilin-related receptor CNS expression type 3 (SorCS3). The luminal region of sortilin is identical to each of the two luminal domains of yeast Vps10p (Vps10p domain). The Vps10p domain is characterized by an amino-terminal propeptide and a carboxy-terminal segment containing 10 conserved cysteine ​​(10CC) residues. Other receptors in the Vps10p family share the amino-terminal Vps10p domain and contain an additional ectodomain.

[0107] The Vps10p family of sorting receptors has diverse functions both within the nervous system and elsewhere. The receptor has been shown to be multifunctional, binding multiple different ligands, including, but not limited to, progranulin (PGRN), nerve growth factor precursor (Pro-NGF), nerve growth factor (NGF), PCSK9, proneurotrophin, neurotrophin, proneurotrophin-3 (pro-NT3), proneurotrophin-4 / 5, brain-derived neurotrophic factor precursor (Pro-BDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin-4 / 5, neurotensin, p75NTR, sortilin propeptide (Sort-pro), amyloid precursor protein (APP), lipoprotein lipase (LpL), apolipoprotein, apolipoprotein AV (APOA5), apolipoprotein E (APOE2, 3, 4), receptor-associated protein (RAP), and components of the plasminogen activator system, and is involved in intracellular sorting, endocytosis, and signal transduction. The sortilin protein of the present disclosure has been shown to mediate rapid endocytosis of lipoprotein lipase, neurotensin, and the precursor form of nerve growth factor, and to target proteins for transport from the Golgi apparatus to late endosomes. Furthermore, the sortilin protein of the present disclosure has been shown to form a complex with p75 on the plasma membrane and to be essential for nerve growth factor precursor (NGF)-induced neuronal cell death. Recently, members of the Vps10p receptor family have been shown to interact with members of the neurotrophin family, including NGF, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 / 5, or the prodomain forms of neurotrophins (pro-neurotrophins). The sortilin protein of the present disclosure has also been shown to increase LDL cholesterol levels by binding to and regulating the extracellular levels of PCSK9, which directs the low-density lipoprotein receptor for degradation in the lysosome.

[0108] Thus, as used herein, a "Sortilin" protein of the present disclosure includes, but is not limited to, mammalian Sortilin protein, human Sortilin protein, primate Sortilin protein, mouse Sortilin protein, and rat Sortilin protein. Furthermore, an anti-Sortilin antibody of the present disclosure may bind to an epitope within one or more of a mammalian Sortilin protein, a human Sortilin protein, a primate Sortilin, a mouse Sortilin protein, and a rat Sortilin protein.

[0109] Sortilin protein domain The sortilin proteins of the present disclosure contain several domains, including a Vps10p domain containing an Asp box motif, a 10-bladed beta-propeller structure and a hydrophobic loop, and a 10CC domain.

[0110] As disclosed herein, the interaction between a Sortilin protein of the disclosure and a proneurotrophin or neurotrophin is mediated by a Vps10p domain containing a 10-bladed β-propeller structure and an Asp-box motif. In certain embodiments, a Sortilin protein of the disclosure contains a Vps10p domain that comprises a 10-bladed β-propeller structure and is located within amino acid residues 78-611 of human Sortilin (SEQ ID NO: 1) or amino acid residues of a mammalian Sortilin that correspond to amino acid residues 78-611 of SEQ ID NO: 1. In certain embodiments, amino acid residues 190-220 of human Sortilin (SEQ ID NO: 1) or amino acid residues of a mammalian Sortilin that correspond to amino acid residues 190-220 of SEQ ID NO: 1 are located within the Vps10p domain.

[0111] The Vps10p domain of the present disclosure can include an Asp box motif. As used herein, an Asp box motif has the following sequence: (S / T)-X-(D / N)-XXXX-(W / F / Y) (SEQ ID NO: 4) or XX-(S / T)-X-(D / N)-XGX-(T / S)-(W / F / Y)-X (SEQ ID NO: 5), where X represents any amino acid. In human sortilin, the Asp box motif is located at amino acid residues 200-207 (SSDFAKNF (SEQ ID NO: 694)). Thus, in certain embodiments, the Asp box motif is located at amino acid residues 200-207 of human sortilin (SEQ ID NO: 1) or amino acid residues in a mammalian sortilin that correspond to amino acid residues 200-207 of SEQ ID NO: 1.

[0112] As disclosed herein, the interaction between the sortilin proteins of the present disclosure and p75 is mediated by the 10CC domain of the hydrophobic loop of the Vps10p domain.

[0113] In certain embodiments, a Sortilin protein of the present disclosure contains a 10CC domain located within amino acid residues 610-757 of human Sortilin (SEQ ID NO: 1) or amino acid residues of a mammalian Sortilin corresponding to amino acid residues 610-757 of SEQ ID NO: 1. In preferred embodiments, amino acid residues 592-593, 610-660, and / or 667-749 of human Sortilin (SEQ ID NO: 1) or amino acid residues of a mammalian Sortilin corresponding to amino acid residues 592-593, 610-660, and / or 667-749 of SEQ ID NO: 1 are located within the 10CC domain of Sortilin.

[0114] In other embodiments, a sortilin protein of the present disclosure contains a hydrophobic loop within the Vps10p domain located within amino acid residues 130-141 of human sortilin (SEQ ID NO:1) or amino acid residues of a mammalian sortilin corresponding to amino acid residues 130-141 of SEQ ID NO:1.

[0115] As one of skill in the art will recognize, the starting and ending residues of the domains of the present disclosure may vary depending on the computer modeling program or method used to determine the domains.

[0116] Sortilin binding partners Sortilin proteins of the present disclosure may interact with (e.g., bind to) one or more proteins including, but not limited to, progranulin protein, proneurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-4 / 5, neurotrophin-4 / 5, neurotrophins such as nerve growth factor precursor (Pro-NGF), nerve growth factor (NGF), brain-derived neurotrophic factor precursor (Pro-BDNF) and brain-derived neurotrophic factor (BDNF), neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), amyloid precursor protein, Aβ peptide, PCSK9, p75NTR, and receptor-associated protein (RAP).

[0117] Progranulin The sortilin proteins of the present disclosure have been shown to directly interact (e.g., bind) with progranulin and mediate the degradation of progranulin (e.g., Zheng, Y et al., (2011) PLoS ONE 6(6):e21023).

[0118] Progranulin is variously referred to as PGRN, proepithelin, granulin-epithelin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a 593-amino acid protein encoding a 68.5 kD secreted glycoprotein with 7.5 repeats of a small 6-25 kDa granulin (epithelin) motif that can be proteolytically cleaved from the precursor PGRN. Examples of progranulin cleavage products include, but are not limited to, granulin A / epithelin 1, granulin B / epithelin 2, granulin C, granulin D, granulin E, granulin F, granulin G, and any other known peptide products derived from progranulin.

[0119] Progranulin is widely expressed and has been implicated in various events in non-neuronal cells, including cell cycle control and cell motility, wound healing, inflammation, induction of growth factors such as vascular endothelial growth factor (VEGF), and tumorigenesis. Progranulin is also widely expressed during early neural development, but later in development, it becomes restricted to distinct neuronal populations, such as cortical neurons, hippocampal pyramidal neurons, and Purkinje cells. However, the role of progranulin in neurons remained unclear until patients with frontotemporal dementia (FTD) were shown to have mutations in the progranulin gene on chromosome 17. Subsequently, progranulin was shown to promote neuronal survival and enhance neurite outgrowth in cortical and motor neurons. Therefore, although progranulin is neither a neurotrophin nor a member of the neurotrophin family, it has been called a neurotrophic factor due to its ability to promote neuronal survival.

[0120] Furthermore, haploinsufficiency of progranulin (containing over 70 different mutations, including loss-of-function mutations) has been shown to be associated with frontotemporal dementia (FTD) associated with TDP-43 pathology. In addition, plasma progranulin levels are reduced in patients with FTD mutations, and progranulin mutations account for 25% of familial FTD cases. Furthermore, low progranulin levels are observed in some FTD patients without progranulin mutations, and progranulin levels are also altered in Alzheimer's disease and ALS. Therefore, it is believed that progranulin may be broadly involved in degenerative diseases.

[0121] Complete deficiency of progranulin has also been shown to lead to the neuronal lipoid fuscinosis (NPL) phenotype. Therefore, individuals with various lysosomal storage diseases may respond to elevated levels of progranulin. Progranulin is widely expressed and produced by neurons and microglia in the central nervous system. Progranulin is also generally believed to play an anti-inflammatory role in macrophages and microglia and a pro-survival role in neurons.

[0122] Thus, anti-Sortilin antibodies of the disclosure that increase progranulin levels, decrease cell surface levels of sortilin, and / or block the interaction (e.g., binding) between sortilin and progranulin may be used to treat conditions such as decreased expression and / or activity levels of progranulin, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, cirrhosis, glaucoma ... In some embodiments, the compounds may be useful in preventing, reducing the risk of, or treating conditions and / or diseases associated with: Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, inflammatory diseases, arthritis, multiple sclerosis, metabolic diseases, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, trauma, and / or one or more undesirable symptoms of normal aging. Furthermore, anti-Sortilin antibodies of the present disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin may inhibit the interaction between Sortilin and Progranulin, may induce one or more Progranulin activities, may decrease endosomal internalization of Progranulin or a fragment thereof, and / or may increase the effective concentration of Progranulin.

[0123] In some embodiments, anti-Sortilin antibodies of the disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin are antibodies that bind to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-39, 370-372, 373-374, 375-376, 377-378, 379-380, 381-382, 383-384, 385-386, 387-388, 389-400, 400-401, 401-402, 402-403, 403-404, 404-405, 405-406, 406-407, 407-410, 411-412, 413-414, 415-416, 417-418, 418-419, 420-421, 421-422, 422-423, 423-424, 424-425, 425-426, 426-427, 427-430, 428-431 1, 429-443, 623-632 and / or 740-749, or one or more amino acids within the amino acid residues of a mammalian sortilin corresponding to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632 and / or 740-749 of SEQ ID NO: 1.In other embodiments, anti-Sortilin antibodies of the disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin bind to amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Ph198, Ph199, Ph200, Ph201, Ph199, Ph202, Ph199, Ph203, Ph199, Ph204, Ph205, Ph206, Ph207, Ph208, Ph209, Ph210, Ph211, Ph212, Ph213, Ph214, Ph215, Ph216, Ph217, Ph218, Ph219, Ph219, Ph219, Ph220, Ph221, Ph222, Ph223, Ph224, Ph225, Ph226, Ph227, Ph228, Ph229, Ph230, Ph231, Ph232, Ph233, Ph234, Ph235, Ph236, Ph237, Ph238, Ph239, Ph240, Ph241, Ph242, Ph243, Ph244, Ph245, Ph246, Ph247, Ph248, Ph249 ... e203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, Lys254, Lys260, Ser305, Phe30 6, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Ty one or more amino acids of r386, Ser595 and / or Glu700, or one or more amino acid residues of SEQ ID NO: 1: His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys2 43, Lys248, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or Glu700 of a mammalian sortilin.

[0124] Neurotrophins The sortilin protein of the present disclosure has been shown to directly interact with (e.g., bind to) pro-neurotrophins (e.g., pro-NGF), which have a prodomain and are typically pro-apoptotic (e.g., Andersen, OS et al. (2010) The Journal of Biological Chemistry, 285, 12210-12222). Such pro-NGF precursors are released under stress, and sortilin proteins have been shown to be involved in regulating their release and binding to recipient cells. This binding may be mediated via a linear epitope on sortilin corresponding to amino acid residues 163-174 of SEQ ID NO: 1.

[0125] Neurotrophins are a family of dimeric peptide hormone proteins that induce the survival, development, and function of neural cells. Neurotrophins belong to a class of growth factors, secreted proteins that transmit signals to specific cells, enabling their survival, differentiation, or growth. Growth factors, such as neurotrophins, that promote neuronal survival are known as neurotrophic factors. Neurotrophic factors are secreted by target tissues and act by preventing associated neurons from initiating programmed cell death. Neurotrophins can also induce the differentiation of progenitor cells to form neurons. The neurotrophins disclosed herein are synthesized intracellularly as 30-35 kDa precursor proteins containing a signal peptide and glycosylation sites. Further processing of the precursor protein occurs within the Golgi apparatus, where it is cleaved at a dibasic cleavage site by the calcium-dependent serine protease furin and other members of the prohormone convertase family. The N-terminal portion of this cleavage is the mature neurotrophin, consisting of 118-120 amino acids, and the biologically active 12-14 kDa C-terminal product (Seidah et al., Biochem. J. (1996) 314:951-960). As used herein, "neurotrophin" and "neurotrophic factor" may be used interchangeably. Neurotrophins of the present disclosure include, but are not limited to, the structurally related factors nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). As used herein, "pro-neurotrophin" may refer to any propeptide of the neurotrophin family, such as, but not limited to, pro-NGF, pro-BDNF, proneurotrophin-3, and proneurotrophin-4 / 5.

[0126] Proneurotrophins have been shown to play a pathological role in aging, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury and long-term depression. (For example, Beattie, MS et al., (2002) Neuron 36, 375-386, Volosin, M et al. (2006) J. Neurosci. 26, 7756 -7766, Nykjaer, A et al., (2005) Curr. Opin. Neurobiol. 15, 49-57, Jansen, P et al. al.,(2007)Nat.Neurosci.10,1449-1457, Volosin,M et al.,(2008)J.Neurosci.28,9870-9879,Fahnestock,M et al.,(2001)Mol.Cell Neurosci.18,210-220,Nakamura,K et al.,(2007)Cell Death.Differ.14,1552-1554, Yune,T et al.(2007)J.Neurosci.27,7751-7761,Arnett,MG et al.,(2007)Brain Res.1183,32-42,Wei,Y et al. al., (2007) Neurosci. Lett. 429, 169-174, Provenzano, MJ et al., (2008) Laryngoscope 118, 87-93, and Pang, PT et al., (2004) Science 306, 487-491).

[0127] Nerve growth factor (NGF) is a small secreted protein that homodimerizes and assembles into a large complex. NGF has nerve growth stimulatory activity, and the complex is involved in regulating the growth, maintenance, survival, and differentiation of sympathetic and certain sensory neurons. Mutations in NGF are associated with hereditary sensory autonomic neuropathy type 5 (HSAN5), and dysregulation of NGF expression is associated with allergic rhinitis. Without being bound by theory, it is also believed that pro-NGF may induce apoptosis and long-term depression.

[0128] Brain-derived neurotrophic factor (BDNF) is a secreted protein derived from cortical neurons and is required for the survival of striatal neurons in the brain. BDNF expression is reduced in both Alzheimer's disease and Huntington's disease patients. BDNF may be involved in the regulation of stress responses and the biology of mood disorders. Numerous transcript variants encoding different isoforms have been described for this gene. Without wishing to be bound by theory, it is believed that pro-BDNF may also induce apoptosis and long-term depression.

[0129] Neurotrophin-3 is a secreted protein required for the survival and function of many peripheral and central nervous system neurons. Neurotrophin-3 gene variants are associated with severe forms of schizophrenia, and pro-neurotrophin-3 (pro-NT3) induces sympathetic neuron death.

[0130] Accordingly, anti-Sortilin antibodies of the present disclosure can also inhibit (e.g., block) the interaction between Sortilin and a neurotrophin (e.g., proneurotrophin) of the present disclosure. Such antibodies can be used to treat conditions such as decreased expression and / or activity levels of neurotrophins, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Bechet's disease, and the like. Anti-Sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between Sortilin and a neurotrophin (e.g., proneurotrophin) of the present disclosure may also be useful in preventing, reducing the risk of, or treating conditions and / or diseases associated with: Streptococcus aureus, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric diseases, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, inflammatory diseases, arthritis, multiple sclerosis, metabolic diseases, obesity, insulin resistance, type 2 diabetes, tissue or vascular injury, trauma, and / or one or more undesirable symptoms of normal aging. Anti-Sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between Sortilin and a neurotrophin (e.g., proneurotrophin) of the present disclosure may also prevent proneurotrophin-induced cell death (e.g., apoptosis).

[0131] In some embodiments, an anti-Sortilin antibody of the disclosure that inhibits (e.g., blocks) the interaction between Sortilin and a neurotrophin of the disclosure is selected from the group consisting of amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632, and / or 640-644 of human Sortilin (SEQ ID NO: 1). binds to one or more amino acids within amino acid residues 740-749, or one or more amino acids within amino acid residues of a mammalian sortilin corresponding to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632 and / or 740-749 of SEQ ID NO: 1.In other embodiments, anti-Sortilin antibodies of the disclosure that inhibit (e.g., block) the interaction between Sortilin and a neurotrophin of the disclosure are those that inhibit (e.g., block) the interaction between Sortilin and a neurotrophin of the disclosure by isoforms of amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Th211, Th212, Th214, Th216, Th218, Th219, Th220, Th221, Th222, Th223, Th224, Th225, Th226, Th227, Th228, Th229, Th230, Th231, Th232, Th233, Th234, Th235, Th236, Th237, Th238, Th240, Th241, Th242, Th243, Th244, Th245, Th246, Th247, Th248, Th249, Th250, Th251, Th252, Th253, Th254, Th255, Th256, Th257, Th258, Th259, Th260, Th261, Th262, Th263, Th264, Th265, Th266, Th267, Th268, Th269, Th270, Th271, Th272, Th273, Th274, Th275, Th276, Th277, Th278, Th279, Th280, Th281, Th282, Th283, Th284 r218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or one or more amino acids of Glu700, or one or more amino acid residues of SEQ ID NO: 1: His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248 , Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or Glu700 of a mammalian sortilin.

[0132] Neurotensin The sortilin protein of the present disclosure has been shown to interact (e.g., bind) with neurotensin within the beta-propeller structure of sortilin, with a key contact shown to be serine 283 in human sortilin (e.g., Quistgaard, EM, et al. (2009) Nature Structural and Molecular Biology, 16 p96-98). This residue has also been shown to be important for progranulin binding. The neurotensin binding site is located within a tunnel located in the center of the beta-propeller structure of sortilin, while the proneurotrophin domain is on the surface of the beta-propeller structure. Proneurotrophin binding to sortilin is partially inhibited by neurotensin because the binding regions are not far apart.

[0133] Neurotensin is a 13-amino acid neuropeptide involved in the regulation of luteinizing hormone and prolactin release. Neurotensin has been shown to have significant interactions with the dopaminergic system. It is synthesized as part of a 169-170 amino acid precursor protein that also contains the related neuropeptide neuromedin N. The peptide-coding domains are arranged in tandem near the carboxyl terminus of the precursor, adjacent to and separated by paired basic amino acid (lysine-arginine) processing sites. Neurotensin shares significant sequence similarity with several other neuropeptides, including neuromedin N, in its six C-terminal amino acid residues. While this C-terminal region is responsible for the full biological activity, the N-terminal portion plays a regulatory role. In the central nervous system, neurotensin has dual functions as a neuromodulator of dopamine transmission and an anterior pituitary hormone secretion regulator. It also exhibits potent hypothermic and analgesic effects in the brain. Neurotensin has also been implicated in the pathophysiology of schizophrenia, Huntington's disease, and Parkinson's disease. Neurotensin has also been shown to confer neuroprotection in experimental models of cerebral ischemia.

[0134] Thus, the anti-Sortilin antibodies of the present disclosure can also inhibit (e.g., block) the interaction between Sortilin and neurotensin. Such antibodies can be beneficial in preventing, reducing the risk of, or treating conditions and / or diseases associated with reduced expression and / or activity levels of neurotensin, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, and / or undesirable symptoms of normal aging.

[0135] In some embodiments, anti-Sortilin antibodies of the disclosure that inhibit (e.g., block) the interaction between Sortilin and Neurotensin are antibodies that bind to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632, and / or 633-634 of human Sortilin (SEQ ID NO: 1). or 740 to 749, or one or more amino acids within the amino acid residues of a mammalian sortilin corresponding to amino acid residues 131 to 138, 175 to 181, 190 to 220, 199 to 220, 190 to 211, 196 to 207, 196 to 199, 200 to 207, 203 to 207, 207 to 231, 207 to 227, 212 to 221, 233 to 243, 237 to 247, 237 to 260, 297 to 317, 314 to 338, 367 to 391, 429 to 443, 623 to 632, and / or 740 to 749 of SEQ ID NO: 1.In other embodiments, anti-Sortilin antibodies of the disclosure that inhibit (e.g., block) the interaction between Sortilin and neurotensin are those that bind to amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr211, and Thr212 of human Sortilin (SEQ ID NO: 1). 8, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595, and / or Gly one or more amino acids of u700, or one or more amino acid residues of SEQ ID NO: 1: His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, and binding to one or more amino acids of the amino acid residues of a mammalian sortilin corresponding to Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or Glu700.

[0136] Low-affinity nerve growth factor receptor (p75) The Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) the low-affinity nerve growth factor (NGF) receptor (p75) within a hydrophobic loop in the 10CC domain of Sortilin or the Vps10p domain of Sortilin. As disclosed herein, the Sortilin proteins of the present disclosure can function as co-receptors for proneurotrophins together with p75, thereby inducing apoptotic signaling.

[0137] The low-affinity NGF receptor is p75, p75 neurotrophin receptor, p75NGF receptor, p75 NTR , LNGFR, NGFR, CD271, Gp80-LNGFR and TNFRSF16 and p75 NTR p75 is variously referred to as "p75 receptor." p75 is one of two receptor types for neurotrophins of the present disclosure. p75 has been shown to bind to neurotrophins and function as a "sink" for neurotrophins. However, in the absence of co-expressed TrkA (the other receptor type for neurotrophins), p75 has been shown to be able to induce cell death (e.g., apoptosis) in cells. Therefore, without being bound by theory, it is believed that blocking the interaction between sortilin and p75 reduces the generation of p75 immunogenic cell death-dependent cell death signals.

[0138] Therefore, inhibiting sortilin's interaction (eg, binding) with p75 would reduce the effective concentration of proneurotrophins, thereby reducing the resulting neuronal cell death.

[0139] Thus, anti-Sortilin antibodies of the present disclosure may also inhibit (e.g., block) the interaction between Sortilin and p75. Such antibodies may be beneficial in preventing, reducing the risk of, or treating conditions and / or diseases associated with reduced expression and / or activity levels of p75, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depress...

Claims

1. 1. An isolated anti-Sortilin antibody that binds to human Sortilin, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, HVR-L2 comprising the amino acid sequence of SEQ ID NO:29, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:55, and the heavy chain variable domain comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO:520, HVR-H2 comprising the amino acid sequence of SEQ ID NO:533, and HVR-H3 comprising the amino acid sequence of SEQ ID NO:

553.

2. 1. An isolated anti-Sortilin antibody that binds to human Sortilin, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising the amino acid sequence of SEQ ID NO:343, and the heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:

648.

3. The anti-Sortilin antibody of claim 1 or 2, wherein the anti-Sortilin antibody increases extracellular levels of Progranulin and decreases cellular levels of Sortilin, and the decrease in cellular levels of Sortilin is a decrease in cell surface levels of Sortilin, a decrease in intracellular levels of Sortilin, a decrease in total levels of Sortilin, or any combination thereof.

4. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody induces Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof.

5. 5. The anti-Sortilin antibody of any one of claims 1 to 4, wherein the anti-Sortilin antibody inhibits the interaction between Sortilin and the one or more proteins by a) reducing the effective level of Sortilin available for interaction with one or more proteins, b) inducing degradation of Sortilin, or c) both a) and b).

6. The anti-Sortilin antibody of claim 5, wherein the anti-Sortilin antibody inhibits the interaction between Sortilin and nerve growth factor precursor (pro-NGF).

7. The anti-sortilin antibody has a dissociation constant (K Ｄ The anti-Sortilin antibody of any one of claims 1 to 6, which binds at the ribosome-specific cleavage site.

8. The anti-Sortilin antibody according to any one of claims 1 to 7, wherein the anti-Sortilin antibody specifically binds to human Sortilin and mouse Sortilin.

9. The anti-sortilin antibody has a dissociation constant (K Ｄ 9. The anti-Sortilin antibody of claim 8, which binds at the nucleotide sequence 114 of the present invention.

10. The anti-Sortilin antibody of any one of claims 1 to 9, wherein the anti-Sortilin antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.

11. The anti-Sortilin antibody according to any one of claims 1 to 10, wherein the anti-Sortilin antibody is a multivalent antibody that recognizes a second antigen.

12. The anti-Sortilin antibody of claim 11, wherein the second antigen is an antigen that promotes transport across the blood-brain barrier.

13. 13. The anti-Sortilin antibody of claim 12, wherein the second antigen is selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low density lipoprotein receptor-related protein 1 (LPR-1) and low density lipoprotein receptor-related protein 2 (LPR-2), diphtheria toxin receptor, CRM197, TMEM30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptides, angiopep peptides, and ANG1005.

14. The anti-Sortilin antibody of any one of claims 1 to 13, wherein the anti-Sortilin antibody is an antibody fragment that binds to an epitope that includes amino acid residues on a human Sortilin or mammalian Sortilin protein.

15. The antibody fragment is Fab, Fab', Fab'-SH, F(ab') ２ 15. The anti-Sortilin antibody of claim 14, which is an Fv or scFv fragment.

16. The anti-sortilin antibody, (a) inducing one or more progranulin activities; (b) reducing endosomal internalization of Progranulin or a fragment thereof; or (c) increasing the effective concentration of progranulin; The anti-sortilin antibody according to any one of claims 1 to 15.

17. The anti-Sortilin antibody of any one of claims 1 to 16, wherein the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin expressed on a cell.

18. The anti-Sortilin antibody of any one of claims 1 to 17, wherein the anti-Sortilin antibody has an IgG1 or IgG4 isotype.

19. (a) the anti-Sortilin antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, where the numbering of the residues is according to EU numbering; or (b) the anti-Sortilin antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L234A / F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering. The anti-sortilin antibody of claim 18.

20. (a) the IgG1 Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, where the numbering of the residues is according to EU numbering; (b) the IgG1 or IgG4 Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where the numbering of the residues is according to EU numbering; or (c) the IgG4 Fc region further comprises an amino acid substitution of S228P according to EU numbering; The anti-sortilin antibody of claim 19.

21. 19. The anti-Sortilin antibody of claim 18, wherein the anti-Sortilin antibody has a human IgG1 isotype and contains amino acid substitutions at residue positions L234A, L235A and P331S, where the numbering of the residue positions is according to EU numbering.

22. The anti-sortilin antibody, (i) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 343 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 648; (ii) having a human IgG1 isotype; The anti-sortilin antibody according to any one of claims 1 to 18.

23. 23. The anti-Sortilin antibody of claim 22, wherein the anti-Sortilin antibody comprises amino acid substitutions at residue positions L234A, L235A and P331S, where the numbering of the residue positions is according to EU numbering.

24. An isolated nucleic acid comprising a nucleic acid sequence encoding an anti-Sortilin antibody according to any one of claims 1 to 23.

25. A vector comprising the nucleic acid of claim 24.

26. 26. An isolated host cell comprising the vector of claim 25.

27. 27. A method for producing an anti-Sortilin antibody, comprising culturing the host cell of claim 26 so that the anti-Sortilin antibody is produced.

28. 28. The method of claim 27, further comprising recovering the anti-Sortilin antibody produced by the host cell.

29. 29. An isolated anti-Sortilin antibody produced by the method of claim 27 or 28.

30. 30. A pharmaceutical composition comprising the anti-Sortilin antibody of any one of claims 1 to 23 or 29 and a pharma- ceutically acceptable carrier.

31. 30. A medicament for increasing extracellular levels of progranulin, for decreasing cellular levels of sortilin in one or more cells, and / or for decreasing expression of one or more pro-inflammatory mediators in one or more cells, the medicament comprising an anti-sortilin antibody according to any one of claims 1 to 23 or 29.

32. The pharmaceutical composition of claim 31, wherein the one or more pro-inflammatory mediators are selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4 and CCL5.

33. 30. A medicament for preventing, reducing the risk of, or treating a disease, disorder, or injury 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 an individual in need thereof, comprising a therapeutically effective amount of the anti-Sortilin antibody of any one of claims 1 to 23 or 29.

34. 30. A medicament for preventing, reducing the risk of, or treating frontotemporal dementia in an individual in need thereof, comprising a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1-23 or 29.

35. 30. A medicament for preventing, reducing the risk of, or treating Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis in an individual in need thereof, comprising a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1-23 or 29.

36. 30. A medicament for inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal outgrowth and abnormal branching, microglial activation and inflammatory response in an individual, and / or promoting one or more of wound healing, autophagy and clearance of aggregated proteins, the medicament comprising a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 23 or 29.

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