Anti-sortilin antibodies and methods of use thereof

Abstract

To provide therapeutic antibodies that specifically bind Sortilin proteins and block the binding of Sortilin to its ligands (such as Progranulin), or otherwise modulate the effective concentration of the ligands, in order to treat one or more diseases, disorders, and conditions associated with Sortilin activity.SOLUTION: The present invention provides compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind one or more epitopes within a Sortilin protein, e.g., human Sortilin or a mammalian Sortilin, and use of such compositions in prevention, risk reduction, or treatment in an individual in need thereof.SELECTED DRAWING: Figure 9A

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 on Apr. 7, 2015, the entire disclosure of which is hereby incorporated by reference herein.

[0002] Submission of Sequence Listing in ASCII Text File The following submission in ASCII text file is hereby incorporated by reference in its entirety herein. Sequence Listing in computer - readable format (CRF) (filename: 735022000240SEQLIST.TXT, date of record: Apr. 6, 2016, size: 345 KB).

[0003] The present disclosure relates to anti - sortilin antibodies and therapeutic uses of such antibodies.

Background Art

[0004] Sortilin is a type I transmembrane protein that acts as a receptor for several ligands and also functions in the sorting of specified cargo molecules from the trans - Golgi network (TGN) to late endosomes and lysosomes for degradation. Sortilin has a large extracellular domain that is part of the VPS10 family and is homologous to yeast VPS10P, and contains a ten - 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 portion of sortilin can be released by the activity of ADAM10 or γ - 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 PGRN for lysosomal degradation, thereby negatively regulating extracellular levels of PGRN (Hu, F et al. (2010) Neuron 68, 654-667). Accordingly, sortilin deficiency significantly increases plasma PGRN concentrations in both in vivo mouse models and in vitro human cells (Carrasquillo, M.M et al., (2010) Am J Hum Genet 87, 890-897, Lee, W.C et al., (2014) 23, 1467-1478). Furthermore, sortilin polymorphisms have been shown to be strongly associated with PGRN serum concentrations in humans (Carrasquillo MM e 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). Deficiency of progranulin accounts for nearly 25% of all genotypes of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of-function mutations in PGRN have approximately a 50% reduction in the 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, PGRN mutant alleles have been identified in Alzheimer's disease patients (Seelaar, H et al., (2011). Journal of neurology, neurosurgery, and psychiatry 82, 476-486).Importantly, PGRN has a protective effect in multiple disease models with increased PGRN levels, accelerating behavioral recovery from ischemia (Tao, J et al., (2012) Brain Res 1436, 130 - 136, Egashira, Y. et al., (2013). J Neuroinflammation 10, 105), suppressing gait disturbances in a Parkinson's disease model (Van Kampen, J.M et al. (2014). PLoS One 9, e97032), alleviating disease conditions 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 preventing memory impairment in an Alzheimer's disease model (Minami, S.S et al., 2014). Nat Med 20, 1157 - 1164).

[0007] Sortilin also binds directly to pro-neurotrophins such as nerve growth factor precursor (pro-NGF), pro-BDNF, and pro-neurotrophin-3, which have a prodomain and are typically apoptosis-promoting. Such pro-neurotrophin precursors are released under stress, and sortilin is involved in the control of their release, as well as their binding to recipient cells and the stimulation of apoptosis associated 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 H.K., et al., J.Neurosci.25:5455-5463(2005)). Sortilin also binds directly 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 can interact with Trk receptors NTRK1, NTRK2, and NTRK3 and control their anterograde axonal transport and signaling (Vaegter, CB et al., (2011) Nat.Neurosci.14:54-61). Sortilin also interacts with and controls the processing and transport of amyloid precursor protein and the resulting production of abnormal β-amyloid peptides (Gustafsen C et al., (2013).J Neurosci.2;33(1):64-71.

[0008] Moreover, sortilin has been shown to bind to apolipoproteins and lipoprotein lipase, and thus, its deficiency leads to a decrease in VLDL release from the liver and a decrease in cholesterol (Willnow, T.E. et al., (2011) Curr Opin Lipidol 22:79 - 85, Kjolby, M. et al., (2010) Cell Metab 12:213 - 223, Nilsson, S.K. et al., (2007) Biochemistry 46:3896 - 3904., Nilsson, S.K. et al., (2008) J Biol Chem 283:25920 - 25927, and Klinger, S.C. et al., (2011) J Cell Sci 124:1095 - 1105). Recently, sortilin has been shown to bind 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, G.M. et al., J Biol Chem 286:12602 - 12616). Sortilin also binds to apolipoprotein E (APOE), Aβ peptide (Carlo, A.S. et al., (2013) J, Neurosc, 33:358 - 370) and PCSK9 (Gustafsen et al, (2014) Cell Metab, 19:310 - 318). Additionally, sortilin has been shown to bind to PCSK9, which directs the low - density lipoprotein receptor to lysosomal degradation, and by controlling its extracellular levels, increase LDL cholesterol concentrations. (Gustafsen C et al., (2014). Cell Metab. 2014 Feb 4;19(2):310 - 8).

[0009] When present in intracellular vesicles such as endosomes, the amino-terminal extracellular domain of sortilin faces the lumen side where the cargo molecules of the vesicle are present. On the other hand, the intracellular / cytoplasmic domain at the carboxy-terminus of sortilin binds to a series of adapter proteins that control transport from the surface and within intracellular compartments. These include AP2 (a clathrin adapter that regulates endocytosis from the cell surface) and the retromer complex / AP1 (which regulates the recycling movement from early endosomes to the Golgi apparatus), and also interactions with GGA (Golgi-localized γ-ear-containing ADP ribosylation factor-binding) family proteins that directly move from the Golgi apparatus to early endosomes and are usually followed by degradation via lysosomes. Thus, sortilin can bind to ligands with its luminal domain and further bind to cytoplasmic adapters that determine its destination to determine intracellular fates such as the degradation of progranulin and other factors.

[0010] Through various interactions with proteins such as progranulin, sortilin and its numerous ligands are involved in various diseases, disorders and pathologies, such as frontotemporal dementia, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis-frontotemporal dementia phenotype, Alzheimer's disease, Parkinson's disease, depression, neuropsychiatric disorders, vascular dementia, epileptic seizures, retinal dystrophy, age-related macular degeneration, glaucoma, traumatic brain injury, aging, epileptic seizures, wound healing, stroke, arthritis and atherosclerotic vascular disease.

[0011] Therefore, there is a need for therapeutic antibodies that specifically bind to the sortilin protein to block its binding to its ligands (such as progranulin) or otherwise regulate the effective concentration of the ligand in order to treat one or more diseases, disorders and pathologies related to 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 generally aims at anti-sorcin antibodies and methods of using such antibodies. The methods provided herein are useful for preventing, reducing the risk of, or treating an individual having frontotemporal dementia, Alzheimer's disease, vascular dementia, seizure disorder, retinal dystrophy, traumatic brain injury, spinal cord injury, prolonged 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, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric disease, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway 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 (see, e.g., Example 4) that can block the interaction between sortilin and progranulin, anti-sortilin antibodies (see, e.g., Example 5) that can increase the extracellular levels of progranulin secreted from cells in culture and from cells in the brains of mouse models of Alzheimer's disease, anti-sortilin antibodies (see, e.g., Example 25) that can decrease the intracellular levels of sortilin in human primary monocytes, and anti-sortilin antibodies (see, e.g., Example 26) that can increase the intracellular levels of progranulin in vivo. Surprisingly, it has been shown that a certain class of antibodies (e.g., antibodies S-2, S-15, and S-22) can increase the extracellular levels of progranulin without blocking the interaction between sortilin and progranulin, while a second class of antibodies (e.g., antibodies S-8, S-49, and S-60) has been shown to be capable of both blocking the interaction between sortilin and progranulin and increasing the extracellular levels of progranulin. Furthermore, anti-sortilin antibodies that can increase the extracellular levels of progranulin (e.g., antibodies S-2, S-8, S-15, S-22, S-49, and S-60) have surprisingly also been found to decrease the intracellular levels of sortilin, e.g., the cell surface levels of sortilin (see, e.g., Example 5). Moreover, it has been shown that there is a strong inverse correlation between the increase in the intracellular levels of progranulin and the intracellular levels of sortilin (see, e.g., FIGS. 10B-10E and FIGS. 23B and 23C). Anti-sortilin antibodies that can increase the extracellular levels of progranulin can also block the binding of pro-NGF 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 can block the interaction between sortilin and progranulin and increase the extracellular levels of progranulin without decreasing the intracellular levels of sortilin.Other aspects of the disclosure are based, at least in part, on the identification of antisortilin antibodies (e.g., antibodies S-5 and S-64 and Example 5) that block the interaction between sortilin and progranulin without causing an increase in the extracellular level of progranulin or a decrease in the intracellular level of sortilin.

[0015] Accordingly, certain aspects of the disclosure relate to an isolated (e.g., monoclonal) antisortilin antibody, wherein the antisortilin antibody has a property selected from the group consisting of an increase in the extracellular level of progranulin, an increase in the intracellular level of progranulin, a decrease in the intracellular level of sortilin, inhibition of the interaction between sortilin and progranulin, and any combination thereof.

[0016] In certain embodiments that can be combined with any of the foregoing embodiments, the antibody decreases the cell surface level of sortilin, decreases the intracellular level of sortilin, decreases the total level of sortilin, or decreases any combination thereof. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody induces sortilin degradation, sortilin cleavage, sortilin internalization, sortilin downregulation, or any combination thereof. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin and inhibits the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin and increases the intracellular level of progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the intracellular level of progranulin and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody inhibits the interaction between sortilin and progranulin and increases the intracellular level of progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the level of progranulin in vivo. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the level of progranulin in vivo without decreasing the intracellular level of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the level of progranulin in the brain.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the intracellular level of progranulin in the blood. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the intracellular level of progranulin in one or more peripheral organs. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the level of progranulin in the brain, blood, one or more peripheral organs, or any combination thereof. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin in vivo. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin in the brain. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin in one or more peripheral organs. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin in the brain, one or more peripheral organs, or any combination thereof. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody inhibits the interaction between sortilin and progranulin and does not decrease the intracellular level of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the intracellular level of progranulin and does not decrease the intracellular level of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the extracellular level of progranulin and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the extracellular level of progranulin and inhibits the interaction between sortilin and progranulin.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the extracellular level of progranulin, and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the extracellular level of progranulin, and inhibits the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the intracellular level of progranulin, and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the intracellular level of progranulin, and inhibits the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the extracellular level of progranulin, increases the intracellular level of progranulin, and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the extracellular level of progranulin, inhibits the interaction between sortilin and progranulin, and does not increase the intracellular level of progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the intracellular level of sortilin, increases the intracellular level of progranulin, inhibits the interaction between sortilin and progranulin, and does not increase the extracellular level of progranulin.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody increases the intracellular level of progranulin, increases the extracellular level of progranulin, inhibits the interaction between sortilin and progranulin, and does not decrease the intracellular level of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin, increases the extracellular level of progranulin, does not increase the intracellular level of progranulin, and does not inhibit the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody decreases the intracellular level of sortilin, increases the intracellular level of progranulin, increases the extracellular level of progranulin, and inhibits the interaction between sortilin and progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, the intracellular level of progranulin, the extracellular level of progranulin, the intracellular level of sortilin, or any combination thereof is measured using an in vitro assay. In certain embodiments that can be combined with any of the foregoing embodiments, the intracellular level of progranulin, the extracellular level of progranulin, the intracellular level of sortilin, or any combination thereof is measured using a cell assay. In certain embodiments that can be combined with any of the foregoing embodiments, the intracellular level of progranulin, the extracellular level of progranulin, the intracellular level of sortilin, or any combination thereof is measured using an in vivo model. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody further inhibits the interaction between sortilin and pro-neurotrophic factor (pro-NGF).In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody further inhibits the interaction between sortilin and one or more proteins selected from the group consisting of pronurotrophin, neurotrophin, nerve growth factor (NGF), pro-brain-derived neurotrophic factor (pro-BDNF), brain-derived neurotrophic factor (BDNF), pronurotrophin-3, neurotrophin-3, pronurotrophin-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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody further inhibits the interaction between sortilin and one or more proteins by a) reducing the effective level of sortilin available for interaction with one or more proteins, b) inducing the degradation of sortilin, or both. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody inhibits the cellular secretion of PCSK9, Aβ peptide production, or both. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody specifically binds to human sortilin, mouse sortilin, or both. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody is a human antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugate antibody, or a chimeric antibody. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing 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 peptide, angiopep peptide, besedin, Glut1, CD98hc, and ANG1005. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human sortilin or mammalian sortilin protein. In certain embodiments that can be combined with any of the foregoing embodiments, the fragment is a Fab, Fab’, Fab’-SH, F(ab’)2, Fv, or scFv fragment. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorti. lin antibody further comprises one or more activities selected from the group consisting of (a) inducing one or more progranulin activities, (b) reducing endosomal internalization of progranulin or a fragment thereof, and (c) increasing the effective concentration of progranulin.

[0017] In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to a discontinuous sortilin epitope. In certain embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing 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, eighteen or more, nineteen 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 thirty or more amino acid residues of the amino acid sequence of SEQ ID NO: 1, or 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, eighteen or more, nineteen 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 thirty or more amino acid residues on the mammalian sortilin protein corresponding to the amino acid sequence of SEQ ID NO: 1. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to a higher-order structure epitope of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to: i. amino acid residues 740-749 of SEQ ID NO: 1, or amino acid residues on the 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 the 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 the mammalian sortilin protein corresponding to amino acid residues 429-443 of SEQ ID NO: 1; iv.The amino acid residues 367 - 391 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 367 - 391 of SEQ ID NO:1, v. the amino acid residues 314 - 338 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 314 - 338 of SEQ ID NO:1, vi. the amino acid residues 297 - 317 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 297 - 317 of SEQ ID NO:1, vii. the amino acid residues 237 - 260 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 237 - 260 of SEQ ID NO:1, viii. the amino acid residues 237 - 260 and 297 - 317 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 237 - 260 and 297 - 317 of SEQ ID NO:1, ix. the amino acid residues 237 - 247 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 237 - 247 of SEQ ID NO:1, x. the amino acid residues 237 - 247 and 314 - 338 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 237 - 247 and 314 - 338 of SEQ ID NO:1, xi. the amino acid residues 233 - 243 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 233 - 243 of SEQ ID NO:1, xii. the amino acid residues 212 - 221 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 212 - 221 of SEQ ID NO:1, xiii. the amino acid residues 207 - 227 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 207 - 227 of SEQ ID NO:1, xiv. the amino acid residues 207 - 227 and 237 - 260 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 207 - 227 and 237 - 260 of SEQ ID NO:1, xv. the amino acid residues 207 - 231 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to the amino acid residues 207 - 231 of SEQ ID NO:1, xvi.It binds to one or more amino acids within the amino acid residues selected from the group consisting of amino acid residues 175 to 181 of SEQ ID NO: 1, or amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 175 to 181 of SEQ ID NO: 1, and xvii. amino acid residues 131 to 138 of SEQ ID NO: 1, or amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 131 to 138 of SEQ ID NO: 1. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to one or more 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, or one or more amino acid residues on the mammalian sortilin protein corresponding to the 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 HV Rs 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody comprises (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 9-12, 14, and 15, (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 29, 30, and 32, (c) 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, (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 can be combined with any of the foregoing 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 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 9-12, 14, and 15, HVR-L1; (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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, 29, 30, and 32, HVR-L2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 48, 85, 89, 100, 103-105, 112, and 123, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 46, 48, 85, 89, 100, 103-105, 112, and 123, HVR-L3; and the heavy chain variable domain comprises: (a) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 127, 136, 140, 142, 145, and 148, HVR-H1; (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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 152, 163, 166, 169, 170, 173, and 175, HVR-H2; (c) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 183, 185, 219, 223, 233, 236, 237, 244, and 254, HVR-H3.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcharin 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 can be combined with any of the foregoing embodiments, the anti-sorcharin antibody comprises at least 1, 2, 3, 4, 5, or 6 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 can be combined with any of the foregoing embodiments, the anti-sorcharin antibody comprises (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10, 13, and 14, (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31 and 33-35, (c) HVR-L3 comprising 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, 155-158, 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, 193-197, 203, 225, 231, 234, and 253.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcharin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-10, 13, and 14, HVR-L1; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31 and 33-35, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31 and 33-35, HVR-L2; (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, or an amino acid sequence having at least about 95% homology with 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, HVR-L3; and the heavy chain variable domain comprises: (a) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 129, 130, 135, 140, 142, and 147, HVR-H1; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 155-158, 162, 166, 169, and 173, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 150, 155-158, 162, 166, 169, and 173, HVR-H2; (c) 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 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 180, 190, 193-197, 203, 225, 231, 234, and 253, HVR-H3.In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcharin 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 HV Rs 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 45, 70, and 100, (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 126, 136, and 142, (e) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 151, 163, and 170, or (f) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 182, 204, and 233.In certain embodiments that can be combined with any of the foregoing 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% homology with 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% homology with 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 70, and 100. The heavy chain variable domain comprises: (a) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 136, and 142; (b) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 151, 163, and 170; and (c) 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% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 182, 204, and 233. In certain embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing embodiments, the anti-sorcharin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) 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 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25, HVR-L1; (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 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40, HVR-L2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, HVR-L3; and the heavy chain variable domain comprises: (a) an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, HVR-H1; (b) 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 an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178, HVR-H2; (c) 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,An amino acid sequence selected from the group consisting of 213-214, 216-219, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, or an amino acid sequence having at least about 95% homology with 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, and includes HVR-H3.

[0022] In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcilin antibody competes for binding to sorcilin 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 can be combined with any of the foregoing embodiments, the anti-sorcilin antibody competes for binding to sorcilin 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 can be combined with any of the foregoing embodiments, the anti-sorcilin antibody competes for binding to sorcilin 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 disclosure relate to isolated (e.g., monoclonal) anti-sorcharin antibodies, where the anti-sorcharin antibody comprises at least 1, 2, 3, 4, 5, or 6 HVRs of an antibody 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 can be combined with any of the foregoing embodiments, the anti-sorcharin antibody 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; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-40; (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149; (e) HVR-H2 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) SEQ ID NOs: 179-186, 188, 190-191, 193-197, 199-201, 203-204, 206, 208, 213-214, 216-219, 222-225, 229, 231-234, 236-239, 241, 243-247,It comprises an HVR-H3 comprising an amino acid sequence selected from the group consisting of 249 and 252 - 256. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcharin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) 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 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 - 16, 20 - 22, and 24 - 25, an HVR-L1; (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 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 - 40, an HVR-L2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 - 50, 52, 54 - 56, 58 - 62, 64 - 66, 68 - 70, 72, 74, 79 - 80, 82 - 85, 88 - 91, 95, 97 - 101, 103 - 107, 109, 111 - 116, 118, and 121 - 125, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 - 50, 52, 54 - 56, 58 - 62, 64 - 66, 68 - 70, 72, 74, 79 - 80, 82 - 85, 88 - 91, 95, 97 - 101, 103 - 107, 109, 111 - 116, 118, and 121 - 125, an HVR-L3, and the heavy chain variable domain comprises: (a) an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 - 127, 129 - 130, 133 - 140, 142, 144 - 145, and 147 - 149, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126 - 127, 129 - 130, 133 - 140, 142, 144 - 145, and 147 - 149, an HVR-H1; (b) 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 an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 150 - 153, 155 - 158, 160 - 166, 169 - 175, and 177 - 178, an HVR-H2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 179 - 186,An amino acid sequence selected from the group consisting of 188, 190-191, 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, or an amino acid sequence having at least about 95% homology with 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, comprising HVR-H3. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sorcharin antibodies, wherein the anti-sorcharin antibodies comprise 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] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies, where 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 disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies, where the anti-sortilin antibody competes 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, where 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, where 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 disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that bind essentially to the same sortilin epitope as an antibody 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.

[0025] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sorcharin antibodies, where the anti-sorcharin antibody comprises a light chain variable domain and a heavy chain variable domain, where the light chain variable domain comprises: (a) 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, HVR-L1; (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, HVR-L2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, 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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, HVR-L3; or the heavy chain variable domain comprises: (a) an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, 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: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, HVR-H1; (b) 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 an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178, HVR-H2; (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 179-186, 188, 190-191, 193-197, 199-201,An amino acid sequence selected from the group consisting of 203~204, 206, 208, 213~214, 216~219, 222~225, 229, 231~234, 236~239, 241, 243~247, 249 and 252~256, or an amino acid sequence having at least about 95% homology with 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, 222~225, 229, 231~234, 236~239, 241, 243~247, 249 and 252~256, and comprising HVR-H3.

[0026] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that inhibit the interaction between sortilin and progranulin, increase the level of progranulin, and decrease the intracellular level of sortilin, where the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (b) HVR-L2 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, (b) HVR-L2 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L2 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.Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that inhibit the interaction between sortilin and progranulin, increase the level of progranulin, and decrease the intracellular level of sortilin, where 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. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that inhibit the interaction between sortilin and progranulin, increase the level of progranulin, and decrease the intracellular level of sortilin, where the anti-sortilin antibody binds to one or more amino acids within the amino acid residues selected from the group consisting of: i. amino acid residues 429-443 of SEQ ID NO: 1, or amino acid residues on the mammalian sortilin protein corresponding 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 the mammalian sortilin protein corresponding 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 the mammalian sortilin protein corresponding to amino acid residues 207-231 of SEQ ID NO: 1.

[0027] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that increase progranulin levels and decrease intracellular levels of sortilin without inhibiting the interaction between sortilin and progranulin, where the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 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, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 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.Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that increase the level of progranulin and decrease the intracellular level of sortilin without inhibiting the interaction between sortilin and progranulin, where 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. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that increase the level of progranulin and decrease the intracellular level of sortilin without inhibiting the interaction between sortilin and progranulin, where the anti-sortilin antibody binds to one or more amino acids within the amino acid residues 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 the 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 the mammalian sortilin protein corresponding to amino acid residues 207-227 and 237-260 of SEQ ID NO: 1.

[0028] Other aspects of the disclosure relate 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 intracellular level of sortilin, wherein the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 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-L2 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-L2 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. Other aspects of the disclosure relate 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 intracellular 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] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that inhibit the interaction between sortilin and progranulin and increase the level of progranulin without decreasing the intracellular level of sortilin, where the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5, or 6 HVRs of antibody S-30. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-L2 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. Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies that inhibit the interaction between sortilin and progranulin and increase the level of progranulin without decreasing the intracellular level of sortilin, where the anti-sortilin antibody competes with antibody S-30 for binding to sortilin.

[0030] Other aspects of the disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies, where the anti-sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, where the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence RASQSISSYLN (SEQ ID NO: 7), (b) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 27), and (c) HVR-L3 comprising the amino acid sequence QQSDVSPIT (SEQ ID NO: 42), and / or the heavy chain variable domain comprises (a) YTFX 1 X 2 YX 3 MX 4 (in the sequence, X 1 is T, G, V, P, L, F, A, or R, X 2 is G, A, or S, X 3 is Y, M, or L, X 4HVR-H1 containing the amino acid sequence of (SEQ ID NO: 480) which is H or W, and (b) X 1 X 2 X 3 PX 4 X 5 GX 6 TX 7 YAQKFQG (in the sequence, X 1 is W, I or G, and X 2 is I, V or T, and X 3 is N, G or L, and X 4 is N, S, V or M, and X 5 is S, G, W or Q, and X 6 is G, F, A, Y, S, N or R, and X 7It comprises HVR-H2 containing the amino acid sequence of N, R, S or M)(SEQ ID NO: 481), and (c) HVR-H3 containing the amino acid sequence of ARGKRSSGWYEGYGMDV (SEQ ID NO: 180). In certain embodiments, the anti-sortilin antibody comprises (i) HVR-L1 containing any amino acid sequence of the HVR-L1 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, (ii) HVR-L2 containing any amino acid sequence of the 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, (iii) HVR-L3 containing any amino acid sequence of the HVR-L3 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-H1 containing any amino acid sequence of the HVR-H1 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, (v) HVR-H2 containing any amino acid sequence of the HVR-H2 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, and (vi) 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,Having at least 1, 2, 3, 4, 5 or 6 HV Rs selected from HV R-H3 comprising an amino acid sequence of any one of the HV R-H3 sequences derived from an antibody selected from the group consisting of S-2-14 and S-2-15. In certain embodiments, the anti-sortilin antibody comprises any one light chain variable region 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 any one heavy chain variable region 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. Another aspect of the 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) HV R-L1 comprising the amino acid sequence of RASQSX, 1 X 2 SNLA (wherein in the sequence, X 1 is V or I and X 2 is S or G) (SEQ ID NO: 508), (b) HV R-L2 comprising the amino acid sequence of GASTRAT (SEQ ID NO: 29), and (c) HV R-L3 comprising the amino acid sequence of QQARLGPWT (SEQ ID NO: 55), and / or the heavy chain variable domain comprises (a) YTX 1 X 2 X 3 X 4 X 5 X 6 S (wherein in the sequence, X 1 is F or L, X 2 is T or A, X 3 is S or K, X 4 is Y, T, R, L, T, G, Q or H, X 5 is Y, T or L, X 6HVR-H1 comprising the amino acid sequence of (being M or I)(SEQ ID NO: 509), and (b) X 1 INPx 2 GGX 3 X 4 SYAX 5 X 6 FX 7 G (in the sequence, X 1 is I or V, and X 2 is S, W, Y, V, F, L or I, and X 3 is S or T, and X 4 is T or A, and X 5 is Q or R, and X 6 is K or R, and X 7 HVR-H2 comprising the amino acid sequence of (being Q or R)(SEQ ID NO: 510), and (c) X 1 RDPX 2 GX 3 X 4 X 5 X 6 X 7 PX 8 X 9 RX 10 X 11 X 12 GX 13 DV (in the sequence, X 1 is A, V or T, and X 2 is S, F or G, and X 3 is I or A, and X 4 is A or G, and X 5 is A, L or V, and X 6 is A, L or P, and X 7 is G, F or Y, and X 8 is A, G or F, and X 9 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 13It includes HVR-H3 containing the amino acid sequence of (is M or L)(SEQ ID NO: 511). In certain embodiments, the anti-sorcharin antibody comprises (i) HVR-L1 containing any amino acid sequence of the HVR-L1 sequences derived from antibodies 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-15-7, 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-15-13, S-15-14, 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-15-10-15, S-15-10-16, S-15-10-17, S-15-10-18, S-15-10-19, S-15-10-20,HVR-L2 containing any amino acid sequence of the HVR-L2 sequences derived from an antibody 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, (iii) HVR-L3 containing any amino acid sequence of the HVR-L3 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-15-6-11, 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-15-13, S-15-14, S-15-15 and S-15-16, (iv) 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-15-10-19, S-15, -10-20, S-15-10-21, S-15-11, S-15-12, S-15-1 HVR-H1 comprising any amino acid sequence of the HVR-H1 sequences derived from an antibody selected from the group consisting of S-15-14, S-15-15, and S-15-16; (v) HVR-H2 comprising any amino acid sequence of the HVR-H2 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-15-6-11, 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-15-13, S-15-14, S-15-15, and S-15-16; and (vi) 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,It has at least 1, 2, 3, 4, 5, or 6 HVRs selected from HVR-H3 containing any amino acid sequence among the HVR-H3 sequences derived from antibodies selected from the group consisting of 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-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, any one light chain variable region of the antibody sequences derived from antibodies selected from the group consisting of, and / or 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,It comprises any one of the heavy chain variable regions of antibody sequences derived from antibodies selected from the group consisting of 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. 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) HVR-L1 comprising the amino acid sequence of RASQSISSWLA (SEQ ID NO: 8), (b) HVR-L2 comprising the amino acid sequence of KASSLES (SEQ ID NO: 28), (c) HVR-L3 comprising the amino acid sequence of QQADGHIT (SEQ ID NO: 62), and / or the heavy chain variable domain comprises (a) X, 1 TFX 2 X 3 YAX 4 X 5 (In the sequence, X 1 is G or Y, X 2 is S, R, G or T, X 3 is S, G or N, X 4 is I or M, X 5 is S or A) (SEQ ID NO: 565) and comprises the amino acid sequence of HVR-H1, (b) GIX 1 PX 2 X 3 GX 4 AX 5 YAQKFQG (in the sequence, X 1 is I or V, X 2 is I, R, G, A, S, T or Q, X 3 is F or G, X 4 is T, R or W, X 5It comprises an HVR-H2 containing the amino acid sequence of (SEQ ID NO: 566) which is S, N, Q or W, and an HVR-H3 containing the amino acid sequence of ARQGRKTGYYYYYGMDV (SEQ ID NO: 197). In certain embodiments, the anti-sorcharin antibody has at least one, two, three, four, five or six HVRs selected from: (i) an HVR-L1 containing any of the amino acid sequences of the HVR-L1 sequences derived from antibodies 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) an HVR-L2 containing any of the amino acid sequences of the HVR-L2 sequences derived from antibodies 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; (iii) an HVR-L3 containing any of the amino acid sequences of the HVR-L3 sequences derived from antibodies 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 containing any of the amino acid sequences of the HVR-H1 sequences derived from antibodies 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 containing any of the amino acid sequences of the HVR-H2 sequences derived from antibodies 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 containing any of the amino acid sequences of the HVR-H3 sequences derived from antibodies 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-sorcharin antibody comprises any one light chain variable region of antibody sequences derived from antibodies 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 any one heavy chain variable region of antibody sequences derived from antibodies 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 disclosure relate to isolated (e.g., monoclonal) anti-sorcharin antibodies, wherein the anti-sorcharin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises (a) RSSQX. 1 LLX 2 SNGYNYLD (wherein in the sequence, X 1 is S or G, and X 2 is H or R) (SEQ ID NO: 580) and HVR-L1 comprising the amino acid sequence of, (b) LGSNRXS (wherein in the sequence, X is A or V) (SEQ ID NO: 581) and HVR-L2 comprising the amino acid sequence of, (c) MQQQETPLT (SEQ ID NO: 100) and HVR-L3 comprising the amino acid sequence of, and / or the heavy chain variable domain comprises (a) YSISSX 1 X 2 YWG (wherein in the sequence, X 1 is G or V, and X 2 is Y or R) (SEQ ID NO: 582) and HVR-H1 comprising the amino acid sequence of, (b) X 1 IYX 2 SGSTYYNPSLKS (wherein X 1 is T, S or A, and X 2It includes HVR-H2 containing the amino acid sequence of (which is H or P) (SEQ ID NO: 583), and HVR-H3 containing the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 233). In certain embodiments, the anti-sorcharin antibody is (i) HVR-L1 containing any amino acid sequence of the HVR-L1 sequences derived from antibodies 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) HVR-L2 containing any amino acid sequence of the HVR-L2 sequences derived from antibodies 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, (iii) HVR-L3 containing any amino acid sequence of the HVR-L3 sequences derived from antibodies 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) HVR-H1 containing any amino acid sequence of the HVR-H1 sequences derived from antibodies 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) HVR-H2 containing any amino acid sequence of the HVR-H2 sequences derived from antibodies 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 HVR-H2 containing any amino acid sequence of the HVR-H2 sequences derived from the antibody and (vi) at least 1, 2, 3, 4, 5, or 6 HV Rs selected from HV R-H3 comprising an amino acid sequence of any one of the HV R-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 any one light chain variable region 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 any one heavy chain variable region 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 disclosure relate to isolated (e.g., monoclonal) anti-sortilin antibodies, where the anti-sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, where the light chain variable domain comprises (a) HV R-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14), (b) HV R-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26), and (c) HV R-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122), and / or the heavy chain variable domain comprises (a) HV R-H1 comprising the amino acid sequence of X 1 SIX 2 SX 3 X 4 YYWG (in the sequence, X 1 is G or Y, X 2 is S, V, Y, K, or P, X 3 is S or R, X 4 is D or E) (SEQ ID NO: 589), (b) X 1 IYX 2 X 3 GSTX 4 YNPSLKS (in the sequence, X 1 is S, G, Q, or L, X 2 is Y, W, or R, X 3is S, R, K or A, and X 4It comprises an HVR-H2 containing the amino acid sequence of (SEQ ID NO: 590) which is Y or V, and an HVR-H3 containing the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253). In certain embodiments, the anti-sorcharin antibody comprises (i) an HVR-L1 containing any amino acid sequence of the HVR-L1 sequences derived from antibodies 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-L2 containing any amino acid sequence of the HVR-L2 sequences derived from antibodies 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-L3 containing any amino acid sequence of the HVR-L3 sequences derived from antibodies 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-H1 containing any amino acid sequence of the HVR-H1 sequences derived from antibodies 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) an HVR-H2 containing any amino acid sequence of the HVR-H2 sequences derived from antibodies 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 containing any amino acid sequence of the HVR-H3 sequences derived from antibodies 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 has at least 1, 2, 3, 4, 5, or 6 HVRs selected from these.In certain embodiments, the anti-sorcharine antibody comprises any one light chain variable region 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 any one heavy chain variable region 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 can be combined with any of the foregoing embodiments, the anti-sorcilin antibody has an IgG1, IgG2, IgG3 or IgG4 isotype. In certain embodiments that can be combined with any of the foregoing embodiments, (a) the anti-sorcilin antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions 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 in the Fc region, wherein the residue numbering follows EU or Kabat numbering; (b) the anti-sorcilin 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 in the Fc region, wherein the residue numbering follows EU or Kabat numbering; or (c) the anti-sorcilin antibody has an IgG4 isotype and comprises one or more amino acid substitutions 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 in the Fc region, wherein the residue numbering follows EU or Kabat numbering.In certain embodiments that can be combined with any of the foregoing embodiments, (a) the 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, wherein the residue numbering follows EU or Kabat numbering, (b) the 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, wherein the residue numbering follows EU or Kabat numbering, or (c) the Fc region further comprises the amino acid substitution of S228P according to EU or Kabat numbering. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody reduces the 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 100 nM to about 0.005 nM, or less than 0.005 nM, for human sortilin, mouse sortilin, or both. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 70.4 nM to about 0.005 nM, or less than 0.005 nM, for human sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 40.3 nM to about 0.07 nM, or less than 0.07 nM, for mouse sortilin.

[0032] Other aspects of the disclosure relate to an isolated nucleic acid comprising a nucleic acid sequence encoding an anti-sortilin antibody of any of the foregoing embodiments. Other aspects of the disclosure relate to a vector comprising a nucleic acid of any of the foregoing embodiments. Other aspects of the disclosure relate to an isolated host cell comprising a vector of any of the foregoing embodiments. Other aspects of the disclosure relate to a method of producing an anti-sortilin antibody, the method comprising culturing a 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 disclosure relate to an isolated anti-sortilin antibody produced by a method of any of the foregoing embodiments. Other aspects of the disclosure relate to a pharmaceutical composition comprising an anti-sortilin antibody of any of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0033] Other aspects of the disclosure relate to methods of doing so in the brain of an individual in need of an increase in prograinulin levels, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody. Other aspects of the disclosure relate to an anti-sortilin antibody for use in doing so in the brain of an individual in need of an increase in prograinulin levels. Other aspects of the disclosure relate to the use of an anti-sortilin antibody in the manufacture of a medicament for doing so in the brain of an individual in need of an increase in prograinulin levels. Other aspects of the disclosure relate to methods of doing so in an individual in need of an increase in prograinulin levels, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody. Other aspects of the disclosure relate to an anti-sortilin antibody for use in doing so in an individual in need of an increase in prograinulin levels. Other aspects of the disclosure relate to the use of an anti-sortilin antibody in the manufacture of a medicament for doing so in an individual in need of an increase in prograinulin levels. In certain embodiments that can be combined with any of the foregoing embodiments, the level of prograinulin is increased in the brain, blood, and / or one or more peripheral organs of the individual. In certain embodiments that can be combined with any of the foregoing embodiments, the level of prograinulin is increased without a decrease in the intracellular level of sortilin.

[0034] Other aspects of the disclosure relate to methods of increasing the extracellular level of progranulin from one or more cells, the method comprising contacting the one or more cells with an anti-sortilin antibody. Other aspects of the disclosure relate to anti-sortilin antibodies for use in increasing the extracellular level of progranulin from one or more cells. Other aspects of the disclosure relate to the use of anti-sortilin antibodies in the manufacture of a medicament for increasing the extracellular level of progranulin from one or more cells. In certain embodiments that may be combined with any of the foregoing embodiments, the level of progranulin increases without a decrease in the intracellular level of sortilin. Other aspects of the disclosure relate to methods of doing so in an individual in need of a decrease in the intracellular level of sortilin, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody. Other aspects of the disclosure relate to anti-sortilin antibodies for use in doing so in an individual in need of a decrease in the intracellular level of sortilin. Other aspects of the disclosure relate to the use of anti-sortilin antibodies in the manufacture of a medicament for doing so in an individual in need of a decrease in the intracellular level of sortilin. In certain embodiments that may be combined with any of the foregoing embodiments, the level of sortilin decreases in the brain and / or one or more peripheral organs of the individual. Other aspects of the disclosure relate to methods of decreasing the intracellular 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 disclosure relate to anti-sortilin antibodies for use in decreasing the intracellular level of sortilin in one or more cells. Other aspects of the disclosure relate to the use of anti-sortilin antibodies in the manufacture of a medicament for decreasing the intracellular level of sortilin in one or more cells.

[0035] Other aspects of the present disclosure relate to a method for inhibiting one or more interactions between 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. Other aspects of the present disclosure relate to an anti-sortilin antibody that binds to an epitope comprising SEQ ID NO: 4 for use in inhibiting one or more interactions between 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). Other aspects of the present disclosure relate 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 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 can be combined with any of the foregoing embodiments, (a) the anti-sortilin antibody has a property selected from the group consisting of an increase in the extracellular level of progranulin, an increase in the intracellular level of progranulin, a decrease in the intracellular level of sortilin, inhibition of the interaction between sortilin and progranulin, and any combination thereof; (b) the anti-sortilin antibody decreases the cell surface level of sortilin, decreases the intracellular level of sortilin, decreases the total level 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 intracellular level of sortilin without inhibiting the interaction between sortilin and progranulin; (e) the anti-sortilin antibody decreases the intracellular level of sortilin and inhibits the interaction between sortilin and progranulin; (f) the anti-sortilin antibody decreases the intracellular level of sortilin and increases the intracellular level of progranulin; (g) the anti-sortilin antibody increases the intracellular level of progranulin without inhibiting the interaction between sortilin and progranulin; (h) the anti-sortilin antibody inhibits the interaction between sortilin and progranulin and increases the intracellular level of progranulin; (i) the anti-sortilin antibody inhibits the interaction between sortilin and progranulin without decreasing the intracellular level of sortilin; (j) the anti-sortilin antibody increases the intracellular level of progranulin without decreasing the intracellular level of sortilin; (k) the anti-sortilin antibody further inhibits the interaction between sortilin and pro-neurotrophin (pro-NGF); (l) the anti-sortilin antibody inhibits the interaction between sortilin and pro-neurotrophin, neurotrophin, nerve growth factor (NGF), pro-brain-derived neurotrophic factor (pro-BDNF), brain-derived neurotrophic factor (BDNF), pro-neurotrophin-3, neurotrophin-3, pro-neurotrophin-4 / 5, neurotrophin-4 / 5, neurotensin, neurotensin, p75, sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide,further inhibits the interaction between sorcin 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) the anti-sorcin antibody reduces the effective level of sorcin available for interaction with one or more proteins, induces the degradation of sorcin, or both, thereby further inhibiting the interaction between sorcin and one or more proteins selected from the group consisting of pro-neurotrophin, neurotrophin, nerve growth factor (NGF), pro-brain-derived neurotrophic factor (pro-BDNF), brain-derived neurotrophic factor (BDNF), pro-neurotrophin-3, neurotrophin-3, pro-neurotrophin-4 / 5, neurotrophin-4 / 5, neurotensin, neurotensin, p75, sorcin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP), (n) the anti-sorcin antibody inhibits the cellular secretion of PCSK9, Aβ peptide production, or both, (o) the anti-sorcin antibody induces one or more progranulin activities, (p) the anti-sorcin antibody reduces the endosomal internalization of progranulin or its fragment, and / or (q) the anti-sorcin antibody increases the effective concentration of progranulin. In certain embodiments that can be combined with any of the foregoing embodiments, (a) the anti-sorcin antibody specifically binds to human sorcin, mouse sorcin, or both, (b) the anti-sorcin antibody is a human antibody, (c) the anti-sorcin antibody is a humanized antibody, (d) the anti-sorcin antibody is a bispecific antibody, (e) the anti-sorcin antibody is a bispecific antibody that recognizes a first antigen and a second antigen, (f) the anti-sorcin antibody is a bispecific antibody that recognizes a first antigen and a second antigen, where the first antigen is the sorcin protein and the second antigen is an antigen that promotes transport across the blood-brain barrier, and optionally, the second antigen is sorcin, transferrin receptor (TR),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, bacitracin, Glut1, CD98hc and ANG1005, (g) the anti-sortilin antibody is a multivalent antibody, (h) the anti-sortilin antibody is a conjugate 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 containing an amino acid residue on human sortilin or mammalian sortilin protein, or (l) the anti-sortilin antibody is an antibody fragment that binds to an epitope containing an amino acid residue on human sortilin or 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to discontinuous sortilin epitopes. In certain embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing 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, eighteen or more, nineteen 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 thirty or more amino acid residues of the amino acid sequence of SEQ ID NO: 1, or 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, eighteen or more, nineteen 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 thirty or more amino acid residues on the mammalian sortilin protein corresponding to the amino acid sequence of SEQ ID NO: 1. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to a higher-order structure epitope of sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to: i. amino acid residues 740-749 of SEQ ID NO: 1, or amino acid residues on the 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 the 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 the 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 the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 367 - 391 of SEQ ID NO:1, v. amino acid residues 314 - 338 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 314 - 338 of SEQ ID NO:1, vi. amino acid residues 297 - 317 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 297 - 317 of SEQ ID NO:1, vii. amino acid residues 237 - 260 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 237 - 260 of SEQ ID NO:1, viii. amino acid residues 237 - 260 and 297 - 317 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 237 - 260 and 297 - 317 of SEQ ID NO:1, ix. amino acid residues 237 - 247 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 237 - 247 of SEQ ID NO:1, x. amino acid residues 237 - 247 and 314 - 338 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 237 - 247 and 314 - 338 of SEQ ID NO:1, xi. amino acid residues 233 - 243 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 233 - 243 of SEQ ID NO:1, xii. amino acid residues 212 - 221 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 212 - 221 of SEQ ID NO:1, xiii. amino acid residues 207 - 227 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 207 - 227 of SEQ ID NO:1, xiv. amino acid residues 207 - 227 and 237 - 260 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 207 - 227 and 237 - 260 of SEQ ID NO:1, xv. amino acid residues 207 - 231 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 207 - 231 of SEQ ID NO:1, xvi. amino acid residues 175 - 181 of SEQ ID NO:1, or the amino acid residues on the mammalian sortilin protein corresponding to amino acid residues 175 - 181 of SEQ ID NO:1,and 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody binds to one or more 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, 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody comprises at least 1, 2, 3, 4, 5 or 6 HVRs of an antibody 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 can be combined with any of the foregoing embodiments, the anti-sortilin antibody 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,(b) An HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40, (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) an 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) an 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) an HVR-H3 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, 203 to 204, 206, 208, 213 to 214, 216 to 219, 22. In certain embodiments that can be combined with any of the foregoing 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 amino acid sequence selected from the group consisting of SEQ ID NOs: 6 to 16, 20 to 22 and 24 to 25, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 to 16, 20 to 22 and 24 to 25, an HVR-L1, (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 26 to 40, an HVR-L2, (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 an amino acid sequence having at least about 95% homology with 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,An HVR-L3 comprising an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of 118 and 121-125, wherein the heavy chain variable domain comprises: (a) an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, or an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, an HVR-H1; (b) 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 an amino acid sequence having at least about 95% homology with an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178, an HVR-H2; (c) 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249, and 252-256, or an amino acid sequence having at least about 95% homology with 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249, and 252-256, an HVR-H3.

[0038] In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sorcharin 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 YTFX 1 X 2 YX 3 MX 4 (In the sequence, X 1 is T, G, V, P, L, F, A or R, X 2 is G, A or S, X 3 is Y, M or L, X 4 is H or W)(SEQ ID NO: 480) and comprises HVR-H1 having the amino acid sequence of, X 1 X 2 X 3 PX 4 X 5 GX 6 TX 7 YAQKFQG (In the sequence, X 1 is W, I or G, X 2 is I, V or T, X 3 is N, G or L, X 4 is N, S, V or M, X 5 is S, G, W or Q, X 6 is G, F, A, Y, S, N or R, X 7 is N, R, S or M)(SEQ ID NO: 481) and HVR-H3 having the amino acid sequence of ARGKRSSGWYEGYGMDV (SEQ ID NO: 180), and (b) the light chain variable domain is RASQSX 1 X 2 SNLA (In the sequence, X 1 is V or I, X 2It includes HVR-L1 containing the amino acid sequence of (being S or G)(SEQ ID NO: 508), HVR-L2 containing the amino acid sequence of GASTRAT (SEQ ID NO: 29), and HVR-L3 containing the amino acid sequence of QQARLGPWT (SEQ ID NO: 55), and / or the heavy chain variable domain is YTX 1 X 2 X 3 X 4 X 5 X 6 S (in the sequence, X 1 is F or L, X 2 is T or A, X 3 is S or K, X 4 is Y, T, R, L, T, G, Q or H, X 5 is Y, T or L, X 6 It includes HVR-H1 containing the amino acid sequence of (being M or I)(SEQ ID NO: 509), X 1 INPx 2 GGX 3 X 4 SYAX 5 X 6 FX 7 G (in the sequence, X 1 is I or V, X 2 is S, W, Y, V, F, L or I, X 3 is S or T, X 4 is T or A, X 5 is Q or R, X 6 is K or R, X 7 It includes HVR-H2 containing the amino acid sequence of (being Q or R)(SEQ ID NO: 510), X 1 RDPX 2 GX 3 X 4 X 5 X 6 X 7 PX 8 X 9 RX 10 X 11 X 12 GX 13 DV (in the sequence, X 1 is A, V or T, X 2 is S, F or G, X 3 is I or A, X4 is A or G, and X 5 is A, L or V, and X 6 is A, L or P, and X 7 is G, F or Y, and X 8 is A, G or F, and X 9 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 comprises HVR-H3 containing the amino acid sequence of )(SEQ ID NO: 511) which is M or L, and (c) the light chain variable domain comprises HVR-L1 containing the amino acid sequence of RASQSISSWLA (SEQ ID NO: 8), HVR-L2 containing the amino acid sequence of KASSLES (SEQ ID NO: 28), and HVR-L3 containing the amino acid sequence of QQADGHIT (SEQ ID NO: 62), and / or the heavy chain variable domain is X 1 TFX 2 X 3 YAX 4 X 5 (In the sequence, X 1 is G or Y, and X 2 is S, R, G or T, and X 3 is S, G or N, and X 4 is I or M, and X 5 comprises HVR-H1 containing the amino acid sequence of )(SEQ ID NO: 565) which is S or A, and GIX 1 PX 2 X 3 GX 4 AX 5 YAQKFQG (In the sequence, X 1 is I or V, and X 2 is I, R, G, A, S, T or Q, and X 3 is F or G, and X 4 is T, R or W, and X 5 is S, N, Q or W)(SEQ ID NO: 566) and comprises HVR-H2 containing the amino acid sequence of, and HVR-H3 containing the amino acid sequence of ARQGRKTGYYYYYGMDV (SEQ ID NO: 197), (d) the light chain variable domain is RSSQX 1 LLX 2SNGYNYLD (in the sequence, X 1 is S or G, and X 2 is H or R) (SEQ ID NO: 580), an HVR-L1 comprising the amino acid sequence of LGSNRXS (in the sequence, X is A or V) (SEQ ID NO: 581), an HVR-L2 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 100), and an HVR-L3, and / or the heavy chain variable domain is YSISSX 1 X 2 YWG (in the sequence, X 1 is G or V, and X 2 is Y or R) (SEQ ID NO: 582), an HVR-H1 comprising the amino acid sequence of X 1 IYX 2 SGSTYYNPSLKS (wherein X 1 is T, S or A, and X 2 is H or P) (SEQ ID NO: 583), an HVR-H2 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 233), and an HVR-H3, or (e) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14), an HVR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26), and an HVR-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122), and / or the heavy chain variable domain is X 1 SIX 2 SX 3 X 4 YYWG (in the sequence, X 1 is G or Y, and X 2 is S, V, Y, K or P, and X 3 is S or R, and X 4 is D or E) (SEQ ID NO: 589), an HVR-H1 comprising the amino acid sequence of X 1 IYX 2 X 3 GSTX 4 YNPSLKS (in the sequence, X 1 is S, G, Q or L, and X 2 is Y, W or R, and X 3 is S, R, K or A, and X 4It comprises HVR-H2 containing the amino acid sequence of (which is Y or V) (SEQ ID NO: 590) and HVR-H3 containing the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253). In certain embodiments that can be combined with any of the foregoing 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; (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-29, S-82 and any combination thereof; (e) the anti-sortilin antibody competes 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; (f) 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; (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 (hS-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-85An anti-sortilin antibody that binds essentially to the same sortilin epitope as an antibody selected from the group consisting of . In certain embodiments that can be combined with any of the foregoing embodiments, 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. In certain embodiments that can be combined with any of the foregoing embodiments, (a) the anti-sortilin antibody is of the IgG class, IgM class, or IgA class, or (b) the anti-sortilin antibody has an IgG1, IgG2, IgG3, or IgG4 isotype, (c) the anti-sortilin antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions 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 residue numbering follows EU or Kabat numbering, (d) the anti-sortilin antibody has an IgG2 isotype and comprises P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252 Y, S254T, T256E, and any combination thereof selected from the group consisting of residues comprising one or more amino acid substitutions at the hinge position, wherein the residue numbering follows EU or Kabat numbering, or (e) the anti-sortilin antibody has an IgG4 isotype and comprises one or more amino acid substitutions 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 residue numbering follows EU or Kabat numbering. In certain embodiments that can be combined with any of the foregoing embodiments, one or more of the Fc regions of (c), (d), and (e) further comprise (a) one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof (wherein the residue numbering follows EU or Kabat numbering), (b) one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof (wherein the residue numbering follows EU or Kabat numbering), or (c) an amino acid substitution of S228P according to EU or Kabat numbering. In certain embodiments that can be combined with any of the foregoing embodiments, (a) the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 100 nM to about 0.005 nM, or less than 0.005 nM, for human sortilin, mouse sortilin, or both, (b) the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 70.4 nM to about 0.005 nM, or less than 0.005 nM, for human sortilin, or (c) the anti-sortilin antibody has a dissociation constant (K D ) in the range of about 40.3 nM to about 0.07 nM, or less than 0.07 nM, for mouse sortilin. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-sortilin antibody is any of the anti-sortilin antibodies of any of the foregoing embodiments.

[0039] Other aspects of the present disclosure relate to a method for preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizure disorders, retinal dystrophy, traumatic brain injury, spinal cord injury, chronic 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, Behçet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous diseases, sarcoidosis, geriatric diseases, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway 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 one or more undesirable symptoms of normal aging, the method comprising administering to the individual a therapeutically effective amount of an anti-sorcilin antibody of any of the foregoing embodiments.Other aspects of the present disclosure relate to the anti-sorticoline antibodies of any of the foregoing 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, Alzheimer's disease, vascular dementia, seizure disorder, retinal dystrophy, traumatic brain injury, spinal cord injury, chronic 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, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric disease, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway 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.Other aspects of the present disclosure relate to the use of an anti-sorcilin antibody of any of the foregoing embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual having a disease, disorder or trauma selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizure, retinal dystrophy, traumatic brain injury, spinal cord injury, chronic depression, atherosclerotic vascular disease, unwanted 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, Behçet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric disease, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disease, obesity, insulin resistance, type 2 diabetes, tissue or vascular injury, trauma and one or more unwanted symptoms of normal aging. Other aspects of the present disclosure relate to a method for preventing, reducing the risk of, or treating an individual having a disease, disorder or trauma selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizure, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis and osteoarthritis, the method comprising administering to the individual a therapeutically effective amount of an anti-sorcilin antibody of any of the foregoing embodiments.Other aspects of the disclosure relate to any of the anti-sorcilin antibodies of the foregoing 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, seizure disorder, 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. Other aspects of the disclosure relate to the use of any of the anti-sorcilin antibodies of the foregoing 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, seizure disorder, 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, axonal disorders characterized by short axonal outgrowth and abnormal branching, microglial activation, and inflammatory responses, the method comprising administering to an individual a therapeutically effective amount of any of the anti-sorutilin antibodies of the foregoing embodiments. Other aspects of the present disclosure relate to any of the anti-sorutilin antibodies of the foregoing embodiments for use in inhibiting one or more of neuroinflammation, axonal disorders characterized by short axonal outgrowth and abnormal branching, microglial activation, and inflammatory responses. Other aspects of the present disclosure relate to the use of any of the anti-sorutilin antibodies of the foregoing embodiments in the manufacture of a medicament for inhibiting one or more of neuroinflammation, axonal disorders characterized by short axonal outgrowth and abnormal branching, microglial activation, and inflammatory responses. Other aspects of the present disclosure relate to methods of promoting one or more of wound healing, autophagy, and clearance of aggregated proteins, the method comprising administering to an individual a therapeutically effective amount of any of the anti-sorutilin antibodies of the foregoing embodiments. Other aspects of the present disclosure relate to any of the anti-sorutilin antibodies of the foregoing embodiments for use in promoting one or more of wound healing, autophagy, and clearance of aggregated proteins. Other aspects of the present disclosure relate to the use of any of the anti-sorutilin antibodies of the foregoing embodiments in the manufacture of a medicament for promoting one or more of wound healing, autophagy, and clearance of aggregated proteins. Other aspects of the present disclosure relate to methods of preventing, reducing the risk of, or treating an individual having arthritis, the method comprising administering to the individual a therapeutically effective amount of any of the anti-sorutilin antibodies of the foregoing embodiments. Other aspects of the present disclosure relate to any of the anti-sorutilin antibodies of the foregoing embodiments for use in preventing, reducing the risk of, or treating an individual having arthritis. Other aspects of the present disclosure relate to the use of any of the anti-sorutilin antibodies of the foregoing embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual having arthritis. Other aspects of the present disclosure relate to methods of decreasing the expression of one or more inflammation-promoting mediators, the method comprising administering to an individual a therapeutically effective amount of any of the anti-sorutilin antibodies of the foregoing embodiments.Other aspects of the disclosure relate to any of the aforementioned anti-sortilin antibodies for use in reducing the expression of one or more pro-inflammatory mediators. Other aspects of the disclosure relate to the use of any of the aforementioned anti-sortilin antibodies in the manufacture of a medicament for reducing the 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, which can be combined with any of the aforementioned embodiments, the anti-sortilin antibody comprises two or more anti-sortilin antibodies.

[0042] This patent and the application documents include at least one color drawing. Copies of this patent or the published patent application that include the color drawing(s) will be provided by the Patent Office upon request and payment of the required fee.

Brief Description of the Drawings

[0043]

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Mode for Carrying Out the Invention

[0044] General Techniques The techniques and procedures described or referenced in this specification are generally well understood by those skilled in the art and are conventional methodologies such as Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)), 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 notebook (J.E. Cellis, ed., 1998) Academic Press, Animal Cell Culture (R.I. Freshney), ed., 1987), Introduction to Cell and Tissue Culture (J.P. Mather and P.E.R. Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993 - 8) J.Wiley and Sons, Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.) are generally used using widely used methodologies such as those described in Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994), Current Protocols in Immunology (J.E. Coligan et al., eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (C.A. 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 D. Lane (Cold Spring Harbor Laboratory Press, 1999), The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995), and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).

[0045] Definition As used herein, the term "prevent" includes providing prophylaxis against the occurrence or recurrence of a particular disease, disorder or condition in an individual. The individual may be susceptible or sensitive to developing a particular disease, disorder or condition, or may be at risk of developing such disease, disorder or condition, but has not been diagnosed as having such disease, disorder or condition.

[0046] As used herein, an "at risk" individual of developing a particular disease, disorder or condition may or may not have a detectable disease or symptom of a disease, and may or may not exhibit a detectable disease or symptom of a disease prior to the methods of treatment described herein. "At risk" means that the individual has one or more risk factors that are measurable parameters known in the art to be correlated with the development of a particular disease, disorder or condition. An individual having one or more of these risk factors is more likely to develop a particular disease, disorder or condition than an individual not having 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 an individual being treated. Desirable effects of treatment include reducing the rate of progression of a particular disease, disorder or condition, restoring or alleviating the disease state, and improving remission or prognosis. An individual "responds to treatment" if, for example, one or more symptoms associated with a particular disease, disorder or condition are reduced or eliminated.

[0048] "Effective amount" refers to an amount that is at least effective to achieve a desired therapeutic or prophylactic result at the required dosage and for the required period. An effective amount may be administered in one or more administrations.

[0049] "Therapeutically effective amount" is at least the minimal concentration required to bring about a measurable improvement in a particular disease, disorder or medical condition. A therapeutically effective amount can vary in the present specification depending on factors such as the patient's medical condition, age, gender and weight, as well as the ability of the sortilin protein antagonist to elicit the desired response in an individual. A therapeutically effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the sortilin protein antagonist.

[0050] As used herein, "co-administration" with another compound or composition includes simultaneous administration and / or administration at different times. Co-administration also encompasses administration as a combination product or as separate compositions, including using different dosing frequencies or intervals and the same or different routes of administration.

[0051] An "individual" for the purposes of treatment, prevention or risk reduction includes any animal classified as a mammal, including humans, domestic and farm animals, as well as zoo, sporting 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" as used herein is used 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, but only if they exhibit the desired biological activity.

[0053] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light chains (L) and two identical heavy chains (H). V H and V LBy pairing together, a single antigen-binding site is formed. For the structures and properties of different classes of antibodies, see, for example, 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] L chains derived from any vertebrate species can be assigned to one of two distinct types called kappa ("κ") and lambda ("λ") based on the amino acid sequences of their constant domains. Depending on the amino acid sequences of their heavy chain constant domains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each having heavy chains designated as alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The γ and α classes are further classified into subclasses (isotypes) based on relatively minor differences in CH sequences and functions. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are known and are generally described, for example, in Abbas et al., Cellular and Molecular Immunology, 4 th ed. (W.B. Saunders Co., 2000).

[0055] A "natural antibody" is usually a heterotetrameric glycoprotein of approximately 150,000 daltons consisting of two identical light chains (L) and two identical heavy chains (H). Each light chain is bound to the heavy chain by one disulfide covalent bond, but the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide cross-links. Each heavy chain has a variable domain (V at one end H) and is followed by several constant domains. Each light chain has a variable domain (V L ) at one end and a constant domain at the other end. The constant domain of the light chain aligns with the first constant domain of the heavy chain, and the variable domain of the light chain aligns with the variable domain of the heavy chain. Certain amino acid residues are thought to form an interface between the variable domain of the light chain and the variable domain of the heavy chain.

[0056] An "isolated" antibody (e.g., an anti-sorcharin antibody of the present disclosure) is one that has been identified, separated, and / or recovered from the components of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free of association with all other contaminating components derived from its production environment. Contaminating components derived from its production environment, such as those resulting from recombinant transfection cells, are typically substances that interfere with the research, diagnostic, or therapeutic use of the antibody, and these can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In a preferred embodiment, the polypeptide is (1) at least 95% by weight, and in some embodiments at least 99% by weight, as determined by, for example, the Lowry method, (2) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by use of a spinning cup sequencer, or (3) purified to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue staining or preferably silver staining. Isolated antibodies include in situ antibodies in recombinant T cells because at least one component of the natural environment of the antibody is absent. However, usually, an isolated polypeptide or antibody is prepared by at least one purification step.

[0057] The "variable region" or "variable domain" of an antibody (e.g., an anti-sorcharin antibody of the present disclosure) refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains are "V H " and "V LIt can be referred to as "". These domains are generally the most variable parts of the antibody (compared to other antibodies of the same class) and contain the antigen-binding site.

[0058] The term "variable" refers to the fact that certain segments of the variable domains vary significantly in sequence among antibodies (e.g., the anti-sorcharin antibodies of the present disclosure). The V domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in the variable domains of both the light and heavy chains. The more highly conserved parts of the variable domains are called framework regions (FRs). The variable domains of the native heavy and light chains each contain four FR regions predominantly in a beta-sheet conformation connected by three HVRs, and these HVRs form loops that connect the beta-sheet structures and in some cases form part of the beta-sheet structures. The HVRs of each chain are held together very closely by the FR regions and, together with the HVRs from the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not directly involved in the binding of the antibody to the antigen but exhibit various effector functions such as involvement in antibody-dependent cell cytotoxicity.

[0059] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, e.g., the anti-sorcharin antibodies of the present disclosure. That is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. Monoclonal antibodies are highly specific and target one or more antigenic sites. In some embodiments, the antibodies of the present disclosure can be bispecific antibodies. In contrast to polyclonal antibody preparations, which typically include a variety of antibodies targeting different determinants (epitopes), each monoclonal antibody targets a single determinant on one or more antigenic sites. The modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present disclosure can be made by a variety of techniques, including, for example, phage display methods (see, 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 methods (see, 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, 2d ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), and techniques for the production of human or human-like antibodies in animals having all or a part of a human immunoglobulin locus or gene encoding a human immunoglobulin sequence (see, e.g., WO1998 / 24893, WO1996 / 34096, WO1996 / 33735, WO1991 / 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 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 in its substantially intact form (e.g., the anti-sorcin antibodies of the present disclosure) as contrasted with antibody fragments. Specifically, whole antibodies include those having heavy and light chains that include an Fc region. The constant domains may be the constant domains of the native sequence (e.g., the constant domains of the human native sequence) or amino acid sequence variants thereof. In some cases, intact antibodies may have one or more effector functions.

[0061] "Antibody fragment" includes a portion of an intact antibody, preferably the antigen-binding region and / or variable region of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab' 2 and Fv fragments, diabodies, linear antibodies (see U.S. Patent 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-sorcin antibodies of the present disclosure) produces two identical antigen-binding fragments called "Fab" fragments and one residual "Fc" fragment having a name reflecting its ability to crystallize readily. The Fab fragment consists of the entire L chain in addition to 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., has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab') 2 fragment, which approximately corresponds to two disulfide-linked Fab fragments having different antigen-binding activities and can still cross-link antigens. The Fab' fragment differs from the Fab fragment by having one or more additional residues including one or more cysteines from the antibody hinge region at the carboxy terminus of the C H 1 domain. Fab'-SH is the name herein for a Fab' in which the cysteine residue(s) of the constant domain have free thiol groups. F(ab'2 Antibody fragments were originally produced as pairs of Fab’ fragments that have a hinge cysteine in between. 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 an antibody are determined by the sequence of the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0064] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and antigen-binding site. This fragment consists of a dimer in which one heavy-chain variable domain and one light-chain variable domain are tightly bound non-covalently. The folding of these two domains gives rise to six hypervariable loops (three loops each from the H and L chains) that provide amino acid residues for antigen binding and confer antigen-binding specificity to this antibody. However, even a single variable domain (or half of the Fv containing only three HVRs specific for the antigen) has the ability to recognize and bind the antigen, although with a lower affinity than the whole binding site.

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

[0066] A "functional fragment" of an antibody (e.g., an anti-sorcharin antibody of the present disclosure) includes a portion of the intact antibody, which generally includes the antigen-binding region or variable region of the intact antibody, or the F region of an antibody that retains or has a 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 small antibody fragment created by constructing an sFv fragment (see previous paragraph) using a short linker (about 5-10 residues) between the V H domain and the V L domain to achieve inter-chain rather than intra-chain V domain pairing, thereby obtaining a bivalent fragment, i.e., a fragment having two antigen-binding sites. A bispecific diabody is a heterodimer of two "crossed" sFv fragments in which the V H domains and the V L domains are present on different polypeptide chains. Diabodies are described in more detail, for example, in European Patent No. 404,097, WO93 / 11161, Hollinger et al., Proc. Nat’l Acad. Sci. USA 90:6444-48 (1993).

[0068] As used herein, a "chimeric antibody" is an antibody (immunoglobulin) (e.g., an anti-sortilin antibody of the present disclosure) wherein a portion of the heavy chain and / or light chain is identical or homologous to a sequence corresponding to an antibody derived from a particular species or an antibody belonging to a particular antibody class or subclass, and further wherein the remainder of the chain(s) is identical or homologous to a sequence corresponding to an antibody derived from a different species or an antibody belonging to a different antibody class or subclass, as well as fragments of such antibodies (provided that they exhibit the desired biological activity) (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat’l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies for purposes herein include PRIMATIZED™ antibodies, wherein the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing a cynomolgus monkey with the antigen of interest. As used herein, a "humanized antibody" is used as a subset of "chimeric antibodies".

[0069] The "humanized" form of a non-human (e.g., mouse) antibody (e.g., an anti-sortilin antibody of the present disclosure) is a chimeric antibody that contains minimal sequences derived from non-human immunoglobulins. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the recipient's HVRs are replaced with residues derived from the HVRs of a non-human species (donor antibody) such as a mouse, rat, rabbit, or non-human primate that have the desired specificity, affinity, and / or ability. Optionally, FR residues of the human immunoglobulin are replaced with corresponding non-human residues. Further, a humanized antibody may contain residues not found in either the recipient antibody or the donor antibody. These modifications can be made to further improve antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, typically two, variable domains, where all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin sequence and all or substantially all of the FR regions are of human immunoglobulin sequence, although the FR regions may contain 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 is typically six or fewer in the H chain and three or fewer in the L chain. A humanized antibody also optionally comprises at least a portion of the immunoglobulin constant region (Fc), typically at least a portion 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). Also see, 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 the amino acid sequence of an antibody produced by a human (e.g., the anti-sorcin antibody of the present disclosure), and / or an antibody produced using any of the techniques for producing a human antibody disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain 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). 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) can also be used to produce human monoclonal antibodies. 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 xenomouse, which has been modified to produce such antibodies in response to antigen administration and whose endogenous loci have been inactivated (see, e.g., U.S. Patent 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 the antibody variable domain (e.g., regions of the antibody variable domain of the anti-sorcilin antibodies of the present disclosure) where the sequences are hypervariable and / or form structurally defined loops. Generally, an antibody contains six HVRs, three in VH (H1, H2, H3) and three in VL (L1, L2, L3). In a natural antibody, H3 and L3 exhibit the highest diversity among the six HVRs, and H3 in particular is thought to play a unique role in conferring excellent specificity to the antibody. 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 camel antibodies consisting of only 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 included herein. HVRs that are Complementarity Determining Regions (CDRs) according to EU or Kabat are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia, rather, refers to the positions 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 the analysis of available complex crystal structures. The residues of each of these HVRs are described below. TIFF2025087841000002.tif50170

[0073] The HVRs may include the following "extended HVRs": in VL, 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3), and in VH, 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2) and 93-102, 94-102 or 95-102 (H3). 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 variable domain residues other than the HVR residues defined herein.

[0075] The expressions "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 systems used in EU or Kabat et al. (supra) for the heavy chain variable domain or light chain variable domain of the antibody's makeup. When using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to deletions or insertions in the FR or HVR of the variable domain. For example, the heavy chain variable domain may include one amino acid insertion (residue 52a according to Kabat) after residue 52 of H2, and may also include residues inserted after residue 82 of the heavy chain FR residues (e.g., residues 82a, 82b, and 82c according to Kabat, etc.). The EU or Kabat numbering of residues can be determined for a given antibody by alignment in the homologous regions between the antibody's sequence and the sequence numbered by "standard" Kabat.

[0076] The EU or Kabat numbering system is generally used when referring to residues in the variable domain (generally residues 1 to 107 of the light chain and residues 1 to 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 constant region of the immunoglobulin heavy chain (e.g., the EU index reported by Kabat et al. (supra)). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless otherwise indicated herein, reference to residue numbers within the variable domain of an antibody means residue numbering according to the Kabat numbering system. Unless otherwise indicated herein, reference to residue numbers within the constant domain of an antibody means residue numbering according to the EU or Kabat numbering system (e.g., see U.S. Patent Application Publication No. 2010-280227).

[0077] As used herein, "acceptor human framework" refers to a framework that includes the amino acid sequence of a VL framework or a VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain existing amino acid sequence variations. In some embodiments, the number of existing amino acid variations 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 existing amino acid variations are present in VH, the preferred amino acid variations occur in only 3, 2, or 1 of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions can 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 the human consensus framework sequence.

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

[0079] "Amino acid modification" at a specified position (e.g., amino acid modification of the anti-sorcharin antibody of the present disclosure) refers to substitution or deletion of a specified residue, or insertion of at least one amino acid residue adjacent to the specified residue. "Adjacent" insertion to a specified residue means insertion within one or two residues thereof. The insertion can be on the N-terminal side or C-terminal side of the specified residue. Preferred amino acid modifications herein are substitutions.

[0080] An "affinity matured" antibody (e.g., the anti-sorcharin antibody of the present disclosure) has one or more changes in one or more of its HV Rs, and these changes result in an improvement in the affinity of the antibody for the antigen as compared to the parental antibody that does not have these change(s). In one embodiment, the affinity matured antibody has a nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by methods known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by shuffling of VH and VL domains. Random mutagenesis of HVRs 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 an attractive force or binding, between a target and an antibody (e.g., an anti-sorcin antibody of the present disclosure), by which the presence of the target can be determined in the presence of a heterogeneous population of molecules including biomolecules. For example, an antibody (e.g., an anti-sorcin antibody of the present disclosure) that specifically or preferentially binds to a target or epitope binds to the target or epitope with higher affinity, avidity, more readily, and / or for a longer duration than it binds to other targets or other epitopes of the target. By reading this definition, it is also understood that, for example, an antibody (or portion) 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 exclusive binding (although it may include it). An antibody that specifically binds to a target has at least about 10 3 M -1 or 10 4 M -1 , optionally 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 -1It may have the above association constants. Antibodies that are specifically immunoreactive with a particular protein can be selected using a variety of immunoassay formats. For example, a solid-phase ELISA immunoassay is used by conventional methods to select monoclonal antibodies that are specifically immunoreactive with a protein. For a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0082] As used herein, "interaction" between a sortilin protein and a second protein includes, but is not limited to, protein-protein interaction, physical interaction, chemical interaction, binding, covalent bond, and ionic bond. As used herein, an antibody "inhibits the interaction" between two proteins when the antibody interrupts, 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" antibody, "antagonist" antibody, or "inhibitory" antibody is an antibody that inhibits or reduces one or more biological activities of an antigen to which the antibody binds, for example, an interaction with one or more proteins (e.g., an anti-sortilin antibody of the present disclosure). In some embodiments, the blocking antibody, antagonist antibody, or inhibitory antibody substantially or completely inhibits one or more biological activities or interactions of the antigen.

[0084] The "effector function" of an antibody refers to the biological activity attributed to the Fc region of the antibody (the native sequence Fc region or an amino acid sequence variant Fc region), and varies depending on the isotype of the antibody.

[0085] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including the native sequence Fc region and variant Fc regions. The boundaries of the Fc region of an immunoglobulin heavy chain can vary, but the human IgG heavy chain Fc region is generally defined as extending from amino acid residue 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 recombinant manipulation of the nucleic acid encoding the antibody heavy chain. Thus, the composition of an intact antibody can include an antibody population in which all K447 residues have been removed, an antibody population in which the K447 residues have not been removed, and an antibody population 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" includes 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 region (non-A and A allotypes), native sequence human IgG2 Fc region, native sequence human IgG3 Fc region, and native sequence human IgG4 Fc region, as well as naturally occurring variants thereof.

[0087] A "variant Fc region" includes an amino acid sequence that differs from that of a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions (multiple possible). Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the Fc region of the parent polypeptide, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions, in the native sequence Fc region or the Fc region of the parent polypeptide. The variant Fc regions herein preferably possess at least about 80% homology, most preferably at least about 90% homology, and more preferably at least about 95% homology with the native sequence Fc region and / or the Fc region of the parent polypeptide.

[0088] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. Further preferred FcRs are those that bind to IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternatively spliced forms of these receptors). Among the FcγRII receptors, there are FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that mainly differ in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif ("ITIM") in its cytoplasmic domain (see, for example, M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). For FcRs, see 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 to be identified in the future, are encompassed by the term "FcR" herein. FcRs can also extend the serum half-life of antibodies.

[0089] The in vivo binding of a human FcRn high-affinity binding polypeptide to FcRn and its serum half-life can be assayed, for example, in transgenic mice expressing human FcRn or transfected human cell lines, or in primates administered with a polypeptide having a mutant Fc region. WO2004 / 42072 (Presta) describes antibody variants with improved or reduced binding to FcRs. 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 refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a designated 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. Alignments for the purpose of determining percent amino acid sequence identity can be achieved using a variety of methods within the skill in the art, such as generally available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for evaluating the alignment, including any algorithms known in the art necessary to achieve the maximum alignment over the full length of the sequences being compared.

[0091] An “isolated” nucleic acid molecule encoding an antibody (e.g., an anti-sorcin antibody of the disclosure) is a nucleic acid molecule identified and separated from at least one contaminating nucleic acid molecule with which it is ordinarily associated in the environment in which the nucleic acid molecule is produced. Preferably, the isolated nucleic acid is free of association with all components associated with its production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies of the present specification exist in a form different from the form or setting in which the nucleic acid molecule is found in nature. Thus, isolated nucleic acid molecules are distinguished from the nucleic acids encoding the polypeptides and antibodies of the present specification that are found naturally in cells.

[0092] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid molecule attached thereto. One type of vector is a "plasmid", which refers to circular double-stranded DNA to 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 case the additional DNA segment is ligated into the viral genome. Certain vectors are capable of self-replication in the host cells 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 integrate into the genome of the host cell upon introduction into the host cell and are thus replicated along with the host genome. Furthermore, certain vectors can direct the expression of operably linked genes. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors". Generally, expression vectors utilized in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably since plasmid is the most commonly used form among vectors.

[0093] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length, including DNA and RNA. 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. Polynucleotides may include modified nucleotides such as methylated nucleotides and their analogs. Where present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The nucleotide sequence can be interrupted by non-nucleotide components. Polynucleotides can include modifications (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 analogs, internucleotide modifications, such as those by non-charged bonds (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as by proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), by intercalators (e.g., acridines, psoralens, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, by modified linkages (e.g., α-anomeric nucleic acids, etc.), and the unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups normally present in the sugar can be substituted, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to create additional linkages to additional nucleotides, or conjugated to a solid or semi-solid support. The OH at the 5' and 3' termini can be phosphorylated or replaced with an amine or an organic capping group moiety of 1 to 20 carbon atoms. Other hydroxyls may be derivatized with standard protecting groups.The polynucleotide can also include analogous forms of ribose or deoxyribose sugars generally known in the art, including 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α-anomer 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 bonds may be replaced with alternative linking groups. These alternative linking groups include, but are not limited to, embodiments where the phosphate is replaced with 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-) bond), aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all bonds within the polynucleotide need to 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 a recipient of a vector(s) for incorporation of a polynucleotide insert. Host cells include progeny of a single host cell, and the progeny need not be identical to the original parent cell (either morphologically or in genomic DNA complement) due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with a polynucleotide(s) of the present disclosure.

[0095] As used herein, the term "carrier" includes pharmaceutically acceptable carriers, excipients or stabilizers that are non-toxic to the cells or mammals to which the carrier is exposed at the dosages and concentrations used. In many cases, the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphoric acid, citric acid 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 dextrin, 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 an intracellular cell destruction process directed by a gene. Apoptosis is distinguished from necrosis and includes destruction of the cytoskeleton, cytoplasmic shrinkage and condensation, expression of phosphatidylserine on the outer surface of the cell membrane and bleb formation, whereby vesicles or apoptotic bodies bound to the cell membrane are formed. This process is also called "programmed cell death". During the process of apoptosis, characteristic phenomena such as a curved cell surface, condensation of nuclear chromatin, fragmentation of chromosomal DNA and decreased mitochondrial function are observed. 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 total percentage of the annexin V+ / PI+, annexin V+ / PI- and annexin V- / PI+ populations is considered to be dead cells.

[0097] As used herein, the term "about" refers to the normal error range of each value that would be readily understood by a person of ordinary skill in the art. References to values or parameters herein with "about" attached thereto include (and describe) embodiments 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 unless the context clearly dictates otherwise. For example, reference to "an antibody" refers to a reference to one or more antibodies such as a molar amount, and includes its equivalents known to those of ordinary skill in the art.

[0099] It should be understood that the aspects and embodiments of the present disclosure described herein include aspects and embodiments "comprising", aspects and embodiments "consisting of", and aspects and embodiments "essentially consisting of".

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

[0101] Sortilin is variously called 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 (important amino acid residues predicted to be involved in progranulin binding are shown in bold, and those predicted to be the pro-NGF binding region are underlined). JPEG2025087841000003.jpg148160

[0102] Furthermore, the amino acid sequence of mouse sortilin is shown in SEQ ID NO: 2. TIFF2025087841000004.tif58170

[0103] Furthermore, the amino acid sequence of rat sortilin is shown in SEQ ID NO: 3. TIFF2025087841000005.tif57170

[0104] In some embodiments, sortilin is a preprotein that includes a signal sequence. In some embodiments, 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 the cell surface.

[0105] The sortilin protein of the present disclosure includes 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 protein of the present disclosure is expressed at high levels in a number of 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 further includes, but is not limited to, sorting protein-related receptor with A-type repeats (SorLA), sortilin-related receptor CNS expressed type 1 (SorCS1), sortilin-related receptor CNS expressed type 2 (SorCS2), and sortilin-related receptor CNS expressed type 3 (SorCS3). The luminal region of sortilin coincides with each of the two luminal domains of yeast Vps10p (Vps10p domain). The characteristics of the Vps10p domain are an amino-terminal propeptide and a carboxy-terminal segment containing ten conserved cysteine (10CC) residues. Other receptors of the Vps10p family share the Vps10p domain located at the amino terminus and contain additional ectodomains.

[0107] The Vps10p family of sorting receptors has diverse functions both within the nervous system and elsewhere. The receptors have been shown to be multifunctional and bind to a plurality of different ligands including, but not limited to, progranulin (PGRN), pro-nerve growth factor (Pro-NGF), nerve growth factor (NGF), PCSK9, proneurotrophins, neurotrophins, pro-neurotrophin-3 (pro-NT3), pro-neurotrophin-4 / 5, pro-brain-derived neurotrophic factor (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), apolipoproteins, apolipoprotein AV (APOA5), apolipoprotein E (APOE2, 3, 4), receptor-associated protein (RAP), and elements of the plasminogen activator system, and are involved in sorting, endocytosis, and signaling within the cell. The sortilin protein of the present disclosure has been shown to mediate the rapid endocytosis of the pro-forms of lipoprotein lipase, neurotensin, and nerve growth factor, and to target proteins for transport from the Golgi apparatus to late endosomes. Further, the sortilin protein of the present disclosure has been shown to form a complex with p75 on the cell membrane and to be essential for pro-nerve growth factor (NGF)-induced neuronal cell death. More 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 (proneurotrophins) of the neurotrophins. The sortilin protein of the present disclosure has also been shown to bind to PCSK9, which targets the low density lipoprotein receptor for lysosomal degradation, and to increase LDL cholesterol concentrations by controlling its extracellular levels.

[0108] Accordingly, as used herein, the "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. Further, the anti-sortilin antibodies of the present disclosure can bind to epitopes of one or more of mammalian sortilin protein, human sortilin protein, primate sortilin, mouse sortilin protein, and rat sortilin protein.

[0109] Sortilin protein domain The sortilin protein of the present disclosure contains several domains such as the Asp box motif, the 10-bladed β-propeller structure and the Vps10p domain containing a hydrophobic loop, as well as the 10CC domain.

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

[0111] The Vps10p domain of the present disclosure may include an Asp box motif. As used herein, the Asp box motif has the following sequences: (S / T)-X-(D / N)-X-X-X-X-(W / F / Y) (SEQ ID NO: 4) or X-X-(S / T)-X-(D / N)-X-G-X-(T / S)-(W / F / Y)-X (SEQ ID NO: 5) (in the sequences, 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 of mammalian sortilin corresponding to amino acid residues 200-207 of SEQ ID NO: 1.

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

[0113] In certain embodiments, the 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 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 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, the sortilin protein of the present disclosure contains a hydrophobic loop located within amino acid residues 130-141 of human sortilin (SEQ ID NO: 1) or amino acid residues of mammalian sortilin corresponding to amino acid residues 130-141 of SEQ ID NO: 1 within the Vps10p domain.

[0115] As will be appreciated by those skilled in the art, 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 partner The sortilin proteins of the present disclosure can interact (e.g., bind) with one or more proteins including, but not limited to, progranulin protein, proneurotrophins, pro-neurotrophin-3, neurotrophin-3, pro-neurotrophin-4 / 5, neurotrophin-4 / 5, pro-nerve growth factor (Pro-NGF), nerve growth factor (NGF), pro-brain-derived neurotrophic factor (Pro-BDNF), and brain-derived neurotrophic factor (BDNF) and other neurotrophins, 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 interact directly (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 called PGRN, proepithelin, granulysin-epithelin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a protein consisting of 593 amino acids and encodes a 68.5-kD secreted glycoprotein with a repeat structure of 7.5 small granulin (epithelin) motifs of 6 - 25 kDa 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 is involved in various events in non-neuronal cells, such as cell cycle control and cell motility, wound healing, inflammation, induction of growth factors such as vascular endothelial growth factor (VEGF), and tumor formation. Also, progranulin is widely expressed during early neurodevelopment but becomes restricted to distinct neuronal populations such as cortical neurons, hippocampal pyramidal neurons, and Purkinje cells in the late developmental stage. However, the role of progranulin in neurons was unknown until it was shown that patients with frontotemporal dementia (FTD) have mutations in the progranulin gene on chromosome 17. Subsequently, progranulin has been shown to promote neuronal survival and enhance neurite outgrowth in cortical and motor neurons. Therefore, although progranulin is neither a neurotrophin nor a member of the neurotrophin family, it is called a neurotrophic factor because of its ability to promote neuronal survival.

[0120] Furthermore, haploinsufficiency of progranulin (including over 70 different mutations such as loss-of-function mutations) has been shown to be associated with frontotemporal dementia (FTD) with TDP-43 lesions. In addition, in patients with FTD mutations, plasma concentrations of progranulin are decreased, and progranulin mutations account for 25% of familial FTD. Moreover, low concentrations of progranulin are also observed in some FTD patients without progranulin mutations, and progranulin concentrations also change in Alzheimer's disease and ALS. Therefore, it is considered that progranulin may be widely involved in neurodegenerative diseases.

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

[0122] Accordingly, the anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease the cell surface levels of sortilin, and / or block the interaction (e.g., binding) between sortilin and progranulin are useful for preventing, reducing the risk of, or treating a decrease in the expression and / or activity level of progranulin, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizure, retinal dystrophy, traumatic brain injury, spinal cord injury, prolonged 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, Behçet'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, geriatric disease, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disease, obesity, insulin resistance, type 2 diabetes, tissue or vascular injury, trauma and / or a condition and / or disease associated with one or more undesirable symptoms of normal aging. Further, the anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease the cell surface levels of sortilin, and / or block the interaction (e.g., binding) between sortilin and progranulin can inhibit the interaction between sortilin and progranulin, can induce one or more progranulin activities, can decrease the endosomal internalization of progranulin or a fragment thereof, and / or can increase the effective concentration of progranulin.

[0123] In some embodiments, the anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease the cell surface level of sortilin, and / or block the interaction (e.g., binding) between sortilin and progranulin bind to one or more amino acids within 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 human sortilin (SEQ ID NO: 1), or to one or more amino acids within amino acid residues 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 mammalian sortilin corresponding to SEQ ID NO: 1.In other embodiments, the anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease the cell surface level of sortilin, and / or block the interaction (e.g., binding) between sortilin and progranulin bind to one or more amino acids of amino acid residues 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 human sortilin (SEQ ID NO: 1), or to one or more amino acids of amino acid residues of mammalian sortilin corresponding to one or more amino acid residues 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 SEQ ID NO: 1.

[0124] Neurotrophin The sortilin protein of the present disclosure has been shown to directly interact (e.g., bind) with pro-neurotrophins (e.g., pro-NGF) that 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, but it has been shown that the sortilin protein is involved in the control of its release and its binding to recipient cells. This binding can 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 nerve cells. Neurotrophins belong to a class of growth factors and are secreted proteins that transmit signals to specific cells to enable survival, differentiation, or growth. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissues and act by preventing the associated neurons from initiating programmed cell death. Neurotrophins can also induce the differentiation of progenitor cells to form neurons. The neurotrophins of the present disclosure are synthesized intracellularly as precursor proteins of 30-35 kDa containing a signal peptide and glycosylation sites. The precursor proteins are further cleaved at dibasic cleavage sites in the Golgi apparatus by calcium-dependent serine protease furin and other members of the prohormone convertase family during the processing process. The N-terminal portion of this cleavage is the mature neurotrophin consisting of 118-120 amino acids and is a biologically active C-terminal product (Seidah et al, Biochem. J. (1996) 314:951-960). As used herein, "neurotrophin" and "neurotrophic factor" may be used interchangeably. The neurotrophins of the present disclosure include, but are not limited to, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), which are structurally related factors. As used herein, "pro-neurotrophin" may refer to any propeptide of the neurotrophin family, for example, but not limited to, pro-NGF, pro-BDNF, pro-neurotrophin-3, and pro-neurotrophin-4 / 5.

[0126] Pro-neurotrophins have been shown to play a pathological role in aging, seizure disorders, retinal dystrophy, traumatic brain injury, spinal cord injury, and prolonged 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., (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., (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 is incorporated into a large complex. NGF has nerve growth-stimulating activity and the complex is involved in the control of the growth, maintenance, survival, and differentiation of sympathetic and certain sensory neurons. Mutations in NGF are associated with hereditary sensory and autonomic neuropathy type 5 (HSAN5) and dysregulation of NGF expression is associated with allergic rhinitis. Without being bound by theory, pro-NGF is also thought to be able to induce apoptosis and prolonged depression.

[0128] Brain-derived neurotrophic factor (BDNF) is a secreted protein induced from cortical neurons and is necessary for the survival of striatal neurons in the brain. Expression of BDNF is decreased in both Alzheimer's disease patients and Huntington's disease patients. BDNF may be involved in the control of the stress response and the biology of mood disorders. Multiple transcript variants encoding different isoforms have been described for this gene. Without being bound by theory, pro-BDNF is also thought to be able to induce apoptosis and long-term depression.

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

[0130] Accordingly, the anti-sortilin antibodies of the present disclosure can also inhibit (e.g., block) the interaction between sortilin and the neurotrophins (e.g., pro-neurotrophins) of the present disclosure. Such antibodies can reduce the expression and / or activity levels of neurotrophins, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizure, retinal dystrophy, traumatic brain injury, spinal cord injury, prolonged 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, Behçet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, geriatric disease, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, airway infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disease, obesity, insulin resistance, type 2 diabetes, tissue or vascular injury, trauma and / or one or more undesirable symptoms of normal aging, and can be beneficial for the prevention, risk reduction or treatment of related pathological conditions and / or diseases. The anti-sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between sortilin and the neurotrophins (e.g., pro-neurotrophins) of the present disclosure can also prevent cell death (e.g., apoptosis) induced by pro-neurotrophins.

[0131] In some embodiments, the anti-sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between sortilin and the neurotrophins of the present disclosure bind to one or more amino acids within the 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 human sortilin (SEQ ID NO: 1), or to one or more amino acids within the amino acid residues of 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, the anti-sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between sortilin and the neurotrophins of the present disclosure bind to one or more amino acids of amino acid residues 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 human sortilin (SEQ ID NO: 1), or to one or more amino acids of amino acid residues 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 SEQ ID NO: 1 corresponding to the amino acid residues of mammalian sortilin.

[0132] Neurotensin The sortilin protein of the present disclosure has been shown to interact (e.g., bind) with neurotensin within the β-propeller structure of sortilin, and it has been shown that the important contact is serine 283 of 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 neurotensi...

Claims

1. 1. An isolated anti-Sortilin antibody, 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.

2. 2. The anti-Sortilin antibody of claim 1, wherein the antibody reduces cell surface levels of Sortilin, reduces intracellular levels of Sortilin, reduces total levels of Sortilin, or any combination thereof.

3. 3. The anti-Sortilin antibody of claim 1 or 2, wherein the anti-Sortilin antibody induces Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof.

4. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody reduces intracellular levels of Sortilin and does not inhibit the interaction between Sortilin and Progranulin.

5. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody reduces intracellular levels of Sortilin and inhibits the interaction between Sortilin and Progranulin.

6. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody decreases intracellular levels of Sortilin and increases intracellular levels of Progranulin.

7. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody increases intracellular levels of Progranulin and does not inhibit the interaction between Sortilin and Progranulin.

8. The anti-Sortilin antibody of any one of claims 1 to 3, wherein the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and increases intracellular levels of Progranulin.

9. The anti-Sortilin antibody of any one of claims 1 to 8, wherein the anti-Sortilin antibody increases progranulin levels in vivo.

10. The anti-Sortilin antibody of any one of claims 1 to 8, wherein the anti-Sortilin antibody increases Progranulin levels in vivo without decreasing cellular levels of Sortilin.

11. The anti-Sortilin antibody of claim 9 or 10, wherein the anti-Sortilin antibody increases the level of Progranulin in the brain, blood, one or more peripheral organs, or any combination thereof.

12. The anti-Sortilin antibody of any one of claims 1 to 9, wherein the anti-Sortilin antibody reduces cellular levels of Sortilin in vivo.

13. 13. The anti-Sortilin antibody of claim 12, wherein the anti-Sortilin antibody reduces cellular levels of Sortilin in the brain, one or more peripheral organs, or any combination thereof.

14. The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and does not reduce cellular levels of Sortilin.

15. The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody increases cellular levels of Progranulin and does not decrease cellular levels of Sortilin.

16. The anti-Sortilin antibody of any one of claims 1 to 15, wherein the anti-Sortilin antibody further inhibits the interaction between Sortilin and nerve growth factor precursor (pro-NGF).

17. 17. The anti-Sortilin antibody of claim 16, wherein 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.

18. The anti-Sortilin antibody of any one of claims 1 to 17, wherein the anti-Sortilin antibody specifically binds to human Sortilin, mouse Sortilin, or both.

19. The anti-Sortilin antibody of any one of claims 1 to 18, wherein 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.

20. The anti-Sortilin antibody according to any one of claims 1 to 19, wherein the anti-Sortilin antibody is a bispecific antibody that recognizes a first antigen and a second antigen.

21. 21. The anti-Sortilin antibody of claim 20, wherein the first antigen is Sortilin and the second antigen is an antigen that promotes transport across the blood-brain barrier.

22. 22. The anti-Sortilin antibody of claim 21, wherein 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, CD98hc, and ANG1005.

23. The anti-Sortilin antibody of any one of claims 1 to 22, wherein the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on a human Sortilin or mammalian Sortilin protein.

24. 24. The anti-Sortilin antibody of claim 23, wherein the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv or scFv fragment.

25. The anti-sortilin antibody, (a) inducing one or more progranulin activities; (b) decreasing endosomal internalization of Progranulin or a fragment thereof; and (c) increasing the effective concentration of Progranulin. The anti-Sortilin antibody of any one of claims 1 to 24, further comprising one or more activities selected from the group consisting of:

26. The anti-Sortilin antibody of any one of claims 1 to 25, wherein the anti-Sortilin antibody binds to a discontinuous Sortilin epitope.

27. 27. The anti-Sortilin antibody of claim 26, wherein 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.

28. each of said peptides comprises 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 of the amino acid sequence of SEQ ID NO:1; 28. The anti-Sortilin antibody of claim 27, comprising 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:

29. The anti-Sortilin antibody of any one of claims 1 to 25, wherein the anti-Sortilin antibody binds to a conformational epitope of Sortilin.

30. The anti-sortilin antibody, 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 367-391 of SEQ ID NO:1; v. amino acid residues 314-338 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 314-338 of SEQ ID NO:1; vi. amino acid residues 297-317 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 297-317 of SEQ ID NO:1; vii. amino acid residues 237-260 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-260 of SEQ ID NO:1; viii. 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; ix. amino acid residues 237-247 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-247 of SEQ ID NO:1; x. amino acid residues 237-247 and 314-338 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-247 and 314-338 of SEQ ID NO:1; xi. amino acid residues 233-243 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 233-243 of SEQ ID NO:1; xii. amino acid residues 212-221 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 212-221 of SEQ ID NO:1; xiii. amino acid residues 207-227 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207-227 of SEQ ID NO:1; xiv. 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; xv. amino acid residues 207-231 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207-231 of SEQ ID NO:1; xvi. 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 The anti-Sortilin antibody of any one of claims 1 to 25, which binds to one or more amino acids within the amino acid residues selected from the group consisting of:

31. The anti-Sortilin antibody is 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 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, 26. The anti-Sortilin antibody of any one of claims 1 to 25, which binds to one or more amino acid residues on a mammalian Sortilin protein that correspond to amino acid residues selected from the group consisting of: 134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386 and S595.

32. 32. The anti-Sortilin antibody of any one of claims 1 to 31, 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, S-6, S-8, S-45, S-49, S-60, S-63, S-64, S-65, S-72, and S-83.

33. 32. The anti-Sortilin antibody of any one of claims 1 to 31, 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-14, S-15, S-18, S-19, S-20, S-21, S-22, S-29, S-51, S-57, S-61, and S-82.

34. 32. The anti-Sortilin antibody of any one of claims 1 to 31, 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, S-30, and S-60.

35. 32. The anti-Sortilin antibody of any one of claims 1 to 31, wherein 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.

36. 32. The anti-Sortilin antibody of any one of claims 1 to 31, wherein 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.

37. 32. The anti-Sortilin antibody of any one of claims 1 to 31, wherein 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.

38. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody being 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-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 9, 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.

39. The anti-sortilin antibody, (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; (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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149; (e) HVR-H2 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249, and 252-256.

39. The anti-Sortilin antibody of claim 38, comprising:

40. The anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (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% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; (b) an HVR-L2 comprising 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; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, 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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, 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, 129-130, 133-140, 142, 144-145, and 147-149; (b) HVR-H2 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 an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178; (c) 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, or SEQ ID NOs: 179-186, 188, 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 190-191, 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.

39. The anti-sortilin antibody of claim 38.

41. 1. An isolated 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.

42. 1. An isolated 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.

43. 1. An isolated 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-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.

44. 1. An isolated 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-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.

45. 1. An isolated 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-8, S-49, S-50, and any combination thereof.

46. 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.

47. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (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% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; (b) an HVR-L2 comprising 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; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, 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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; and / or the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, 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, 129-130, 133-140, 142, 144-145, and 147-149; (b) HVR-H2 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 an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178; (c) 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, or SEQ ID NOs: 179-186, 188, 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 190-191, 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. The isolated anti-Sortilin antibody.

48. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) HVR-L1 comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO: 7); (b) 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 (a) YTFX １ X ２ YX ３ M.X. ４ (In the sequence, X １ is T, G, V, P, L, F, A or R, and X ２ is G, A or S, and X ３ is Y, M or L; X ４ is H or W) (SEQ ID NO: 480), and (b) X １ X ２ X ３ P.X. ４ X ５ GX ６ T.X. ７ YAQKFQG (in the sequence, X １ is W, I or G; X ２ is I, V or T, and X ３ is N, G or L; X ４ is N, S, V or M, and X ５ is S, G, W or Q; X ６ is G, F, A, Y, S, N or R, and X ７ is N, R, S or M) (SEQ ID NO: 481); and (c) HVR-H3 comprising the amino acid sequence of ARGKRSSGWYEGYGMDV (SEQ ID NO: 180); The isolated anti-Sortilin antibody.

49. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) RASQSX １ X ２ SNLA (in the sequence, X １ is V or I, X ２ is S or G) (SEQ ID NO: 508), and (b) 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 the heavy chain variable domain (a) YTX １ X ２ X ３ X ４ X ５ X ６ S (in the sequence, X １ is F or L, and X ２ is T or A, and X ３ is S or K, and X ４ is Y, T, R, L, T, G, Q or H; ５ is Y, T or L; X ６ HVR-H1 comprising the amino acid sequence of (SEQ ID NO:509): (b) X １ INPx ２ G.G.X. ３ X ４ SYA ５ X ６ Forex ７ G (in the sequence, X １ is I or V, and X ２ is S, W, Y, V, F, L or I; X ３ is S or T, and X ４ is T or A, and X ５ is Q or R, and X ６ is K or R, and X ７ is Q or R) (SEQ ID NO:510); and (c) X １ RDPX ２ GX ３ X ４ X ５ X ６ X ７ P.X. ８ X ９ R.X. １０ X １１ X １２ GX １３ DV (in the sequence, X １ is A, V or T, and X ２ is S, F or G, and X ３ is I or A, and X ４ is A or G, and X ５ is A, L or V; X ６ is A, L or P; X ７ is G, F or Y, and X ８ is A, G or F, and X ９ is S, G or A, and X １０ is Y, G, P, H or S; X １１ is Y or N, and X １２ is Y, L, Q or R; X １３ and HVR-H3 comprising the amino acid sequence of (SEQ ID NO:511): The isolated anti-Sortilin antibody.

50. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) HVR-L1 comprising the amino acid sequence of RASQSISSWLA (SEQ ID NO: 8); (b) 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 (a) X １ TFX ２ X ３ YAX ４ X ５ (In the sequence, X １ is G or Y, and X ２ is S, R, G or T, and X ３ is S, G or N, and X ４ is I or M, and X ５ is S or A) (SEQ ID NO: 565), and (b) GIX １ P.X. ２ X ３ GX ４ AX ５ YAQKFQG (in the sequence, X １ is I or V, and X ２ is I, R, G, A, S, T or Q, and X ３ is F or G, and X ４ is T, R or W, and X ５ is S, N, Q or W) (SEQ ID NO:566), and (c) HVR-H3 comprising the amino acid sequence of ARQGRKTGYYYYYGMDV (SEQ ID NO: 197); The isolated anti-Sortilin antibody.

51. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) RSSQX １ LLX ２ SNGYNYLD (in the sequence, X １ is S or G, and X ２ is H or R) (SEQ ID NO:580), (b) HVR-L2 comprising the amino acid sequence of LGSNRXS, wherein X is A or V (SEQ ID NO: 581); (c) an HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 100); and / or the heavy chain variable domain (a) YSISSX １ X ２ YWG (in the sequence, X １ is G or V, and X ２ is Y or R) (SEQ ID NO: 582); and (b) X １ IYX ２ SGSTYYNPSLKS (in the formula, X １ is T, S or A, and X ２ is H or P) (SEQ ID NO: 583), and (c) HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 233); The isolated anti-Sortilin antibody.

52. 1. An isolated anti-Sortilin antibody, the anti-Sortilin antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) HVR-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14); (b) HVR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26); and (c) HVR-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122); and / or the heavy chain variable domain (a) X １ SIX ２ S.X. ３ X ４ YYWG (in the sequence, X １ is G or Y, and X ２ is S, V, Y, K or P, and X ３ is S or R, and X ４ is D or E) (SEQ ID NO: 589), and (b) X １ IYX ２ X ３ GST ４ YNPSLKS (sequence, X １ is S, G, Q or L; X ２ is Y, W or R; X ３ is S, R, K or A, and X ４ is Y or V) (SEQ ID NO: 590); and (c) HVR-H3 comprising the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253); The isolated anti-Sortilin antibody.

53. The anti-Sortilin antibody of any one of claims 1 to 52, wherein the anti-Sortilin antibody has an IgG1, IgG2, IgG3 or IgG4 isotype.

54. (a) the anti-Sortilin antibody has a human or murine 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, 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, where 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 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 or Kabat numbering. The anti-sortilin antibody of claim 53.

55. (a) the 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 or Kabat numbering; (b) the 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 or Kabat numbering; or (c) the Fc region further comprises an amino acid substitution of S228P according to EU or Kabat numbering; 55. The anti-sortilin antibody of claim 54.

56. 10. The anti-Sortilin antibody of any one of the preceding claims, wherein 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.

57. The anti-Sortilin antibody has a dissociation constant (K) ranging from about 100 nM to about 0.005 nM, or less than 0.005 nM, for human Sortilin, mouse Sortilin, or both. Ｄ ) The anti-Sortilin antibody of any one of the preceding claims.

58. The anti-Sortilin antibody has a dissociation constant (K) for human Sortilin in the range of about 70.4 nM to about 0.005 nM, or less than 0.005 nM. Ｄ ) The anti-Sortilin antibody of any one of the preceding claims.

59. The anti-Sortilin antibody has a dissociation constant (K) for mouse Sortilin in the range of about 40.3 nM to about 0.07 nM, or less than 0.07 nM. Ｄ ) The anti-Sortilin antibody of any one of the preceding claims.

60. 13. An isolated nucleic acid comprising a nucleic acid sequence encoding an anti-Sortilin antibody according to any one of the preceding claims.

61. A vector comprising the nucleic acid of claim 60.

62. 62. An isolated host cell comprising the vector of claim 61.

63. 63. A method for producing an anti-Sortilin antibody, comprising culturing the host cell of claim 62 so that the anti-Sortilin antibody is produced.

64. 64. The method of claim 63, further comprising recovering the anti-Sortilin antibody produced by the host cell.

65. 65. An isolated anti-Sortilin antibody produced by the method of claim 63 or 64.

66. A pharmaceutical composition comprising the anti-Sortilin antibody of any one of claims 1 to 59 and a pharma- ceutically acceptable carrier.

67. 1. A method of increasing progranulin levels in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody.

68. 68. The method of claim 67, wherein the level of progranulin is increased in the brain, blood and / or one or more peripheral organs of the individual.

69. 1. A method for increasing extracellular levels of Progranulin from one or more cells, the method comprising contacting the one or more cells with an anti-Sortilin antibody.

70. 70. The method of any one of claims 67 to 69, wherein the level of Progranulin is increased without decreasing the cellular level of Sortilin.

71. A method of reducing cellular levels of Sortilin in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody.

72. 72. The method of claim 71, wherein the level of sortilin is decreased in the brain and / or one or more peripheral organs of the individual.

73. 1. A method for decreasing a cellular level of sortilin in one or more cells, the method comprising contacting the one or more cells with an anti-sortilin antibody.

74. (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; (b) the anti-Sortilin antibody reduces cell surface levels of Sortilin, reduces intracellular levels of Sortilin, reduces total levels of Sortilin, or 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 reduces the cellular level of Sortilin and does not inhibit the interaction between Sortilin and Progranulin; (e) the anti-Sortilin antibody reduces 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; (g) the anti-Sortilin antibody increases the cellular level of Progranulin and does not inhibit the interaction between Sortilin and Progranulin; (h) the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and increases the cellular level of Progranulin; (i) the anti-Sortilin antibody inhibits the interaction between Sortilin and Progranulin and does not reduce the cellular level of Sortilin; (j) the anti-Sortilin antibody increases the cellular level of Progranulin and does not decrease the cellular level of Sortilin; (k) the anti-sortilin antibody further inhibits the interaction between sortilin and nerve growth factor precursor (pro-NGF); (l) the anti-Sortilin antibody further inhibits the interaction between Sortilin and nerve growth factor precursor (pro-NGF) by a) reducing the effective level of Sortilin available for interaction with one or more proteins, b) inducing degradation of Sortilin, or both; (m) the anti-sortilin antibody induces one or more progranulin activities; (n) the anti-Sortilin antibody reduces endosomal internalization of Progranulin or a fragment thereof; and / or (o) the anti-sortilin antibody increases the effective concentration of progranulin; 74. The method according to any one of claims 67 to 73.

75. (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 recognizing a first antigen and a second antigen, wherein the first antigen is a Sortilin protein and the second antigen is an antigen that promotes transport across the blood-brain barrier, and optionally 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, CD98hc, and ANG1005; (g) the anti-sortilin antibody is a multivalent antibody; (h) the anti-sortilin antibody is a conjugated antibody; (i) the anti-sortilin antibody is a chimeric antibody; (j) the anti-sortilin antibody is a monoclonal antibody; (k) 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; or (l) 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, and optionally, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment; 75. The method according to any one of claims 67 to 74.

76. 76. The method of any one of claims 67-75, wherein the anti-Sortilin antibody binds to a discontinuous Sortilin epitope.

77. 77. The method of claim 76, wherein 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.

78. 78. The method of claim 77, wherein each of the peptides comprises 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 of the amino acid sequence of SEQ ID NO:1, 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.

79. 76. The method of any one of claims 67-75, wherein the anti-Sortilin antibody binds to a conformational epitope of Sortilin.

80. The anti-sortilin antibody, 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 367-391 of SEQ ID NO:1; v. amino acid residues 314-338 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 314-338 of SEQ ID NO:1; vi. amino acid residues 297-317 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 297-317 of SEQ ID NO:1; vii. amino acid residues 237-260 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-260 of SEQ ID NO:1; viii. 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; ix. amino acid residues 237-247 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-247 of SEQ ID NO:1; x. amino acid residues 237-247 and 314-338 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 237-247 and 314-338 of SEQ ID NO:1; xi. amino acid residues 233-243 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 233-243 of SEQ ID NO:1; xii. amino acid residues 212-221 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 212-221 of SEQ ID NO:1; xiii. amino acid residues 207-227 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207-227 of SEQ ID NO:1; xiv. 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; xv. amino acid residues 207-231 of SEQ ID NO:1, or amino acid residues on a mammalian sortilin protein corresponding to amino acid residues 207-231 of SEQ ID NO:1; xvi. 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 The method of any one of claims 67 to 75, wherein the binding is to one or more amino acids within the amino acid residues selected from the group consisting of:

81. The anti-Sortilin antibody is characterized in that the anti-Sortilin antibody is a nucleotide sequence 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 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, 76. The method of any one of claims 67-75, wherein the mammalian Sortilin protein binds to one or more amino acid residues on the mammalian Sortilin protein corresponding to amino acid residues selected from the group consisting of: 3, L134, V135, I136, M137, T138, T210, T218, Y222, S223, S227, S242, K243, K248, K254, S305, R311, S316, R325, S379, R382, Y386 and S595.

82. 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-48, S-49, S-50, S-51, 82. The method of any one of claims 67-81, comprising at least one, two, three, four, five or six HVRs of 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.

83. The anti-sortilin antibody, (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; (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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; (d) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149; (e) HVR-H2 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) the method of claim 82, comprising an 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249, and 252-256.

84. The anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (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% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-16, 20-22, and 24-25; (b) an HVR-L2 comprising 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; (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125, 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: 41-50, 52, 54-56, 58-62, 64-66, 68-70, 72, 74, 79-80, 82-85, 88-91, 95, 97-101, 103-107, 109, 111-116, 118, and 121-125; the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126-127, 129-130, 133-140, 142, 144-145, and 147-149, 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, 129-130, 133-140, 142, 144-145, and 147-149; (b) HVR-H2 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 an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-153, 155-158, 160-166, 169-175, and 177-178; (c) 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, 222-225, 229, 231-234, 236-239, 241, 243-247, 249 and 252-256, or SEQ ID NOs: 179-186, 188, 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 190-191, 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.

82. The method according to any one of claims 67 to 81.

85. the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain; (a) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO: 7), an HVR-L2 comprising the amino acid sequence of AASSLQS (SEQ ID NO: 27), and an HVR-L3 comprising the amino acid sequence of QQSDVSPIT (SEQ ID NO: 42); and / or the heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of YTFX １ X ２ YX ３ M.X. ４ (In the sequence, X １ is T, G, V, P, L, F, A or R, and X ２ is G, A or S, and X ３ is Y, M or L; X ４ HVR-H1 comprising the amino acid sequence of (SEQ ID NO: 480), １ X ２ X ３ P.X. ４ X ５ GX ６ T.X. ７ YAQKFQG (in the sequence, X １ is W, I or G; X ２ is I, V or T, and X ３ is N, G or L; X ４ is N, S, V or M, and X ５ is S, G, W or Q; X ６ is G, F, A, Y, S, N or R, and X ７ is N, R, S, or M) (SEQ ID NO:481), and HVR-H3 comprising the amino acid sequence of ARGKRSSGWYEGYGMDV (SEQ ID NO:180); (b) the light chain variable domain is RASQSX １ X ２ SNLA (in the sequence, X １ is V or I, X ２ 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 QQRLGPWT (SEQ ID NO:55), and / or said heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of YTX １ X ２ X ３ X ４ X ５ X ６ S (in the sequence, X １ is F or L, and X ２ is T or A, and X ３ is S or K, and X ４ is Y, T, R, L, T, G, Q or H; ５ is Y, T or L; X ６ HVR-H1 comprising the amino acid sequence of (SEQ ID NO:509), １ INPx ２ G.G.X. ３ X ４ SYA ５ X ６ Forex ７ G (in the sequence, X １ is I or V, and X ２ is S, W, Y, V, F, L or I; X ３ is S or T, and X ４ is T or A, and X ５ is Q or R, and X ６ is K or R, and X ７ HVR-H2 comprising the amino acid sequence of (SEQ ID NO:510), １ RDPX ２ GX ３ X ４ X ５ X ６ X ７ P.X. ８ X ９ R.X. １０ X １１ X １２ GX １３ DV (in the sequence, X １ is A, V or T, and X ２ is S, F or G, and X ３ is I or A, and X ４ is A or G, and X ５ is A, L or V; X ６ is A, L or P; X ７ is G, F or Y, and X ８ is A, G or F, and X ９ is S, G or A, and X １０ is Y, G, P, H or S; X １１ is Y or N, and X １２ is Y, L, Q or R; X １３ and HVR-H3 comprising the amino acid sequence of (SEQ ID NO:511), (c) the 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 the heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of X １ TFX ２ X ３ YAX ４ X ５ (In the sequence, X １ is G or Y, and X ２ is S, R, G or T, and X ３ is S, G or N, and X ４ is I or M, and X ５ is S or A) (SEQ ID NO: 565), and HVR-H1 comprising the amino acid sequence of GIX １ P.X. ２ X ３ GX ４ AX ５ YAQKFQG (in the sequence, X １ is I or V, and X ２ is I, R, G, A, S, T or Q, and X ３ is F or G, and X ４ is T, R or W, and X ５ 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); (d) the light chain variable domain is １ LLX ２ SNGYNYLD (in the sequence, X １ is S or G, and X ２ and / or said heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of LGSNRXS (wherein X 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 said heavy chain variable domain comprises the amino acid sequence of YSISSX １ X ２ YWG (in the sequence, X １ is G or V, and X ２ HVR-H1 comprising the amino acid sequence of (SEQ ID NO:582): １ IYX ２ SGSTYYNPSLKS (in the formula, X １ is T, S or A, and X ２ is H or P) (SEQ ID NO:583), and an HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO:233); or (e) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 14), an HVR-L2 comprising the amino acid sequence of GASSRAT (SEQ ID NO: 26), and an HVR-L3 comprising the amino acid sequence of QQSHVSPWT (SEQ ID NO: 122); and / or the heavy chain variable domain comprises an HVR-L1 comprising the amino acid sequence of X １ SIX ２ S.X. ３ X ４ YYWG (in the sequence, X １ is G or Y, and X ２ is S, V, Y, K or P, and X ３ is S or R, and X ４ HVR-H1 comprising the amino acid sequence of (SEQ ID NO:589), １ IYX ２ X ３ GST ４ YNPSLKS (sequence, X １ is S, G, Q or L; X ２ is Y, W or R; X ３ is S, R, K or A, and X ４ 82. The method of any one of claims 67 to 81, comprising an HVR-H2 comprising the amino acid sequence of ARGVGSGYSYGYRYFDY (SEQ ID NO: 253), wherein ARGVGSGYSYGYRYFDY is Y or V (SEQ ID NO: 590).

86. (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; (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-29, S-82, and any combination thereof; (e) the anti-Sortilin antibody competes 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; (f) 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; (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 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-48, S-49, and 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.

87. 82. The method of any one of claims 67-81, 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.

88. (a) the anti-sortilin antibody is of the IgG class, the IgM class, or the IgA class; (b) the anti-Sortilin antibody has an IgG1, IgG2, IgG3, or IgG4 isotype; (c) the anti-Sortilin antibody has a human or murine 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, wherein the numbering of the residues is according to EU or Kabat numbering; (d) 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, where the numbering of the residues is according to EU or Kabat numbering; or (e) The method of any one of claims 67-87, wherein 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, wherein the numbering of the residues is according to EU or Kabat numbering.

89. (c), (d), and (e) (a) one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, wherein the numbering of said residues is according to EU or Kabat numbering; (b) one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of said residues is according to EU or Kabat numbering; or 89. The method of claim 88, further comprising (c) an amino acid substitution of S228P according to EU or Kabat numbering.

90. (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 ) (b) the anti-Sortilin antibody has a dissociation constant (K) for human Sortilin in the range of about 70.4 nM to about 0.005 nM, or less than 0.005 nM. 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, for mouse Sortilin; Ｄ 90. The method of any one of claims 67 to 89, comprising the steps of:

91. 60. 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 one of claims 1-59.

92. 60. A method of inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal outgrowth and abnormal branching, microglial activation and inflammatory responses, comprising administering to an individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1-59.

93. 60. A method of promoting one or more of wound healing, autophagy and clearance of aggregated proteins, comprising administering to an individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 59.

94. 60. A method of preventing, reducing the risk of, or treating an individual having arthritis, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1-59.

95. 60. A method of reducing expression of one or more pro-inflammatory mediators, comprising administering to an individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1-59.

96. 96. The method of claim 95, 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.

97. 97. The method of any one of claims 67-96, wherein the anti-Sortilin antibodies comprise two or more anti-Sortilin antibodies.

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