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 disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, affinity-matured, humanized antibodies, antibody fragments, etc., that specifically bind a Sortilin protein, e.g., human Sortilin or mammalian Sortilin, and have improved and / or enhanced functional characteristics, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 698,007, filed July 13, 2018, U.S. Provisional Patent Application No. 62 / 860,184, filed June 11, 2019, and U.S. Provisional Patent Application No. 62 / 868,849, filed June 28, 2019, each of which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. R44AG050363 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 735022001940SEQLIST.TXT, Recorded: July 10, 2019, Size: 153KB).

[0004] Field The present disclosure relates to anti-Sortilin antibodies and therapeutic uses of such antibodies. [Background technology]

[0005] background Sortilin is a type I transmembrane protein that acts as a receptor for several ligands and also functions in sorting select cargo from the trans-Golgi network (TGN) to late endosomes and lysosomes for degradation. Sortilin has a large extracellular domain that is homologous to yeast VPS10P and is part of the VPS10 family, containing a 10-bladed beta-propeller structure and a cysteine-rich 10CC module (Nykjaer, A et al., (2012) Trends Neurosci 35:261-270; and Zheng, Y et al., (2011) PLoS One 6:e21023). A small fraction of sortilin can be released by the activity of ADAM10 or gamma secretase (<5%) (Nykjaer, A et al., (2012) Trends Neurosci 35:261-270; and Willnow, TE et al., (2011) Curr Opin Lipidol 22:79-85).

[0006] Sortilin binds to the secreted protein progranulin (PGRN) and targets it for lysosomal degradation, thus negatively regulating the extracellular levels of PGRN (Hu, F et al. (2010) Neuron 68, 654-667). Accordingly, sortilin deficiency significantly increases plasma PGRN levels in both in vivo mouse models and in vitro human cells (Carrasquillo, MM et al. (2010) Am J Hum Genet 87, 890-897; Lee, WC et al. (2014) Hum Mol Genet 23, 1467-1478). Furthermore, sortilin polymorphisms have been shown to be strongly associated with PGRN serum levels in humans (Carrasquillo MM et al. (2010) Am J Hum Genet. 10;87(6):890-7).

[0007] Progranulin (PGRN) is a growth factor-like trophic and anti-inflammatory secretory protein that also acts as an adipokine involved in diet-induced obesity and insulin resistance (Nguyen DA et al., (2013). Trends in Endocrinology and Metabolism, 24, 597-606). Progranulin deficiency accounts for approximately 25% of all inherited forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of-function mutations in PGRN have approximately 50% reduced extracellular levels of this protein and invariably develop FTD, making PGRN the causative gene for this disease (Baker, M et al., (2006) Nature 442, 916-919; Carecchio M et al., (2011) J Alzheimers Dis 27, 781-790; Cruts, M et al., (2008) Trends Genet 24, 186-194; Galimberti, D et al., (2010) J Alzheimers Dis 19, 171-177). In addition, mutant PGRN alleles have been identified in patients with Alzheimer's disease (Seelaar, H et al., (2011) Journal of neurology, neurosurgery, and psychiatry 82, 476-486).Importantly, elevated PGRN levels are protective in multiple disease models, 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 impairment in Parkinson's disease models (Van Kampen, JM et al. (2014). PLoS One 9, e97032), alleviating pathology in models of amyotrophic lateral sclerosis (Laird, A. S. et al., (2010). PLoS One 5, e13368) and arthritis (Tang, W. et al., (2011). Science 332, 478-484), and preventing memory impairment in Alzheimer's disease models (Minami, S. S. et al. al.,(2014).Nat Med 20,1157-1164).

[0008] Sortilin also contains a prodomain and directly binds to proneurotrophins such as pro-nerve growth factor (pro-NGF), pro-BDNF, and proneurotrophin-3, which are typically pro-apoptotic. Such proneurotrophin precursors are released under stress, and sortilin is involved in regulating their release, as well as binding to recipient cells and stimulating apoptosis in conjunction with p75NTR (Willnow, TE et al., (2008) Nat Rev Neurosci 9:899-909; Nykjaer, A et al., Trends Neurosci 35:261-270; and Nykjaer, A et al., (2004) Nature 427:843-848; Hiroko Yano et al., (2009) J Neurosci.;29:14790-14802. Teng HK, et al., J. Neurosci. 25:5455-5463 (2005)). Sortilin also directly binds to p75NTR (Skeldal S et al., (2012) J Biol Chem.; 287:43798). Sortilin also binds to neurotensin in a region that partially overlaps with progranulin binding (Quistgaard, EM et al., (2009) Nat Struct Mol Biol 16:96-98; and Zheng, Y et al., PLoS One 6:e21023). Sortilin also interacts with the Trk receptors NTRK1, NTRK2, and NTRK3; it may regulate their anterograde axonal transport and signaling (Vaegter, CB et al., (2011) Nat. Neurosci. 14:54-61). Sortilin also interacts with and regulates the processing and transport of amyloid precursor protein and the resulting production of abnormal beta-amyloid peptides (Gustafsen C et al., (2013). J Neurosci. 2; 33(1): 64-71).

[0009] Sortilin has also been shown to bind to apolipoprotein and lipoprotein lipase; therefore, deficiency results in decreased VLDL release from the liver and decreased cholesterol (Willnow, TE et al., (2011) Curr Opin Lipidol 22:79-85; Kjolby, M et al., (2010) Cell Metab 12:213-223; Nilsson, SK et al., (2007) Biochemistry 46:3896-3904; Nilsson, SK et al., (2008) J Biol Chem 283:25920-25927; and Klinger, SC et al., (2011) J Cell Sci 124:1095-1105). Recently, sortilin has also been implicated in binding directly to APP (Gustafsen, C et al., (2013) J. Neurosc. 33:64-71) and to the APP-processing enzyme BACE1 (Gustafsen, C et al., (2013) J. Neurosc. 33:64-71; and Finan, GM et al., J Biol Chem 286:12602-12616). Sortilin also binds to apolipoprotein E (APOE), Abeta peptide (Carlo, AS et al., (2013) J. Neurosc, 33:358-370), and PCSK9 (Gustafsen et al., (2014) Cell Metab, 19:310-318). Sortilin has also been shown to bind to PCSK9, which directs the low-density lipoprotein receptor for degradation in lysosomes, regulating its extracellular levels and increasing LDL cholesterol levels (Gustafsen C et al., (2014). Cell Metab. 2014 Feb 4;19(2):310-8).

[0010] When present in intracellular vesicles such as endosomes, sortilin's amino-terminal extracellular domain faces the lumen, where the vesicle's cargo resides. However, its carboxy-terminal intracellular / cytoplasmic domain binds to a series of adaptor proteins that regulate its transport from the surface and within intracellular compartments. These include AP2 (a clathrin adaptor for regulating endocytosis from the cell surface) and the retromer complex / AP1 (which regulates recycling from early endosomes to the Golgi apparatus); and interacts with GGA (Golgi-localized γ-ear-containing ADP-ribosylation factor-binding) family proteins, which direct sortilin from the Golgi apparatus to early endosomes, usually for subsequent degradation via lysosomes. Thus, while sortilin can bind ligands via its luminal domain, it also binds to cytoplasmic adaptors that determine its destination and intracellular fate, such as degradation of progranulin and other factors.

[0011] Due to its various interactions with proteins such as progranulin, sortilin and its many ligands have been implicated in a variety of diseases, disorders, and conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis-frontotemporal dementia phenotype, Alzheimer's disease, Parkinson's disease, depression, neuropsychiatric disorders, vascular dementia, seizures, retinal dystrophies, age-related macular degeneration, glaucoma, traumatic brain injury, aging, seizures, wound healing, stroke, arthritis, and atherosclerotic vascular disease.

[0012] Thus, there is a need for therapeutic antibodies that specifically bind to the Sortilin protein and block the binding of Sortilin to its ligands, such as Progranulin, or otherwise modulate the effective concentration of the ligand, to treat one or more diseases, disorders, and conditions associated with Sortilin activity.

[0013] All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0014] The present disclosure is generally directed to compositions comprising antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind to human sortilin, and methods of using such compositions.

[0015] In some aspects, the disclosure provides antibodies that bind to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising SEQ ID NO:1, HVR-H2 comprising SEQ ID NO:2 or SEQ ID NO:3, and HVR-H3 comprising SEQ ID NO:5 or SEQ ID NO:6; and the light chain variable region comprises HVR-L1 comprising any of SEQ ID NOs:8-27, HVR-L2 comprising SEQ ID NO:29 or SEQ ID NO:30, and HVR-L3 comprising SEQ ID NO:32.

[0016] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0017] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0018] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0019] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0020] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0021] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 10), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0022] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 21), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0023] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0024] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0025] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0026]

[0014] In some aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0027]

[0014] In some aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, the antibody comprising a heavy chain variable region having HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0028] In some embodiments of any of the above aspects, the anti-Sortilin antibody (a) reduces cell surface levels of Sortilin to a greater extent than the level of reduction caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79; (b) increases extracellular levels of Progranulin to a greater extent than the level of increase caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79; (c) inhibits the interaction between Sortilin and Progranulin to a greater extent than the level of inhibition caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79; or (d) any combination of (a)-(c). In some embodiments of any of the above aspects, the anti-Sortilin antibody (a) reduces cell surface levels of Sortilin to a greater extent than the level of reduction caused by an anti-Sortilin antibody selected from the group consisting of S-60-1, S-60-2, S-60-3, S-60-4, S-60-7, or S-60-8; (b) reduces extracellular levels of Progranulin to a greater extent than the level of reduction caused by an anti-Sortilin antibody selected from the group consisting of S-60-1, S-60-2, S-60-3, S-60-4, S-60-7, or S-60-8. or S-60-8; (c) inhibiting the interaction between Sortilin and Progranulin to a greater extent than the level of inhibition caused by an anti-Sortilin antibody selected from the group consisting of S-60-1, S-60-2, S-60-3, S-60-4, S-60-7, or S-60-8; or (d) performing any combination of (a)-(c).

[0029] A specific embodiment of the present disclosure provides an anti-Sortilin antibody having a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54 to 56; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 57 to 58, 60 to 78, or 80.

[0030] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0031] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58.

[0032] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:59.

[0033] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0034] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58.

[0035] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0036] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:77.

[0037] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:78.

[0038] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:79.

[0039] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:80.

[0040] In some aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0041] In certain aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60.

[0042] In certain aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:61.

[0043] In certain aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:72.

[0044] In some embodiments that may be combined with any of the preceding aspects, the anti-Sortilin antibody of the present disclosure is of the IgG class, IgM class, or IgA class. In certain specific embodiments, the anti-Sortilin antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. Some embodiments of the present disclosure provide anti-Sortilin antibodies of the IgG1, IgG2, IgG3, or IgG4 isotype, wherein (a) the antibody is an IgG1 or IgG2 isotype and the Fc region comprises an amino acid substitution at position P331S (residue positions are numbered according to EU numbering); (b) the antibody is an IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S (residue positions are numbered according to EU numbering); (c) the antibody is an IgG1, IgG2, or IgG4 isotype and the Fc region comprises an amino acid substitution at position N297A (residue positions are numbered according to EU numbering); or (d) the Fc region comprises amino acid substitutions at positions S267E and L328F (residue positions are numbered according to EU numbering). In some embodiments, the antibody is of the IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S (numbering of residue positions is according to EU numbering).

[0045] In some aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.

[0046] In some aspects, the disclosure provides an antibody that binds to a sortilin protein, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.

[0047] In certain embodiments of the present disclosure, the Sortilin protein is a human protein. In some embodiments, the Sortilin protein is a wild-type protein. In certain embodiments, the Sortilin protein is a naturally occurring variant. In some embodiments, the anti-Sortilin antibody of the present disclosure specifically binds to a human Sortilin protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In certain embodiments, the anti-Sortilin antibody of the present disclosure is a monoclonal antibody.

[0048] In some embodiments, the anti-Sortilin antibodies of the present disclosure are bispecific antibodies that recognize a first antigen and a second antigen. In certain embodiments, the bispecific antibodies of the present disclosure recognize both Sortilin and an antigen that promotes transport across the blood-brain barrier. In some specific embodiments, the first antigen is Sortilin, and the second antigen is 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, Poly-Arginine Peptide, Angiopep Peptide, Basigin, Glut1, CD98hc, or ANG1005.

[0049] In certain embodiments of the present disclosure, the anti-Sortilin antibody is an antibody fragment that binds to human Sortilin protein. In some embodiments, the anti-Sortilin antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human Sortilin, naturally occurring variants of human Sortilin, and disease variants of human Sortilin. In certain embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0050] In certain embodiments, the disclosure provides anti-Sortilin antibodies that (a) increase extracellular levels of Progranulin, decrease cellular levels of Sortilin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof; (b) decrease cell surface levels of Sortilin, increase extracellular levels of Progranulin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof; (c) decrease cell surface levels of Sortilin, decrease intracellular levels of Sortilin, decrease total levels of Sortilin, or any combination thereof; (d) induce Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof; (e) decrease cellular levels of Sortilin and inhibit the interaction between Sortilin and Progranulin; (f) decrease cellular levels of Sortilin and increase cellular levels of Progranulin; and / or (g) increase the effective concentration of Progranulin.

[0051] In certain embodiments, the present disclosure provides anti-Sortilin antibodies that reduce cell surface levels of Sortilin, increase extracellular levels of Progranulin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof. In some embodiments, the anti-Sortilin antibody has a dissociation constant (K) for human Sortilin that is up to 2.5-fold lower than an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79. D ) (in this case, K D as determined by FACS. See, e.g., Example 1. In some embodiments, the antibody has a dissociation constant (K) for human Sortilin that is greater than 1-fold and up to about 2.1-fold lower than an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79. D ) (in this case, K DIn some embodiments, the anti-Sortilin antibody has a K of about 1.10E-8M to about 4.68E-10M for human Sortilin (where K is D is determined by FACS. See, e.g., Example 1), or about 270 to about 2910 pM (in this case, K D is determined by biolayer interferometry. See, e.g., Example 4. D In some embodiments, the antibody has a K of about 5.0E-10 M to about 1.0E-9 M for human sortilin (where K D determined by FACS), or approximately 250-500 pM (in this case, K D is the dissociation constant (K) in the range of D )

[0052] In some embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody of the present disclosure (a) inhibits cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 150 pM, as measured by flow cytometry. 50 (b) reduce cell surface levels of Sortilin by more than about 50% at 1.25 nM IgG, more than about 80% at 0.63 nM IgG, or more than about 69% at 150 nM IgG compared to the control, as measured by flow cytometry; increase Progranulin secretion by more than about 1.13-fold at 0.63 nM IgG or more than about 1.22-fold at 50 nM IgG compared to the control, as measured by standard ELISA; increase Progranulin binding to Sortilin by a median effective concentration (EC ) of less than 0.325 nM, as measured by flow cytometry. 50 (e) blocks the binding of Progranulin to Sortilin by greater than about 88% at 50 nM IgG or greater than about 27.5% at 150 nM IgG relative to a control, as measured by flow cytometry; or (f) any combination thereof.

[0053] In some embodiments, the anti-Sortilin antibodies of the disclosure (a) inhibit cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 681 pM, as measured by flow cytometry. 50 (b) reduces cell surface levels of Sortilin by more than about 40% at 1.25 nM IgG, more than about 29% at 0.6 nM IgG, or more than about 62% at 150 nM IgG relative to the control, as measured by flow cytometry; (c) increases Progranulin secretion by more than about 1.11-fold relative to the control at 0.63 nM IgG, or more than about 1.75-fold relative to the control at 50 nM IgG, as measured by standard ELISA; (d) reduces Progranulin binding to Sortilin by a median effective concentration (EC) of less than 0.751 nM, as measured by flow cytometry. 50 (e) blocks the binding of Progranulin to Sortilin by greater than about 90% at 50 nM IgG or greater than about 95% at 150 nM IgG relative to a control, as measured by flow cytometry; or (f) any combination thereof.

[0054] In some embodiments, an anti-Sortilin antibody of the disclosure competes for binding to Sortilin with an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, S-60-24, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-Sortilin antibody of the present disclosure binds to essentially the same Sortilin epitope as an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, and S-60-24.

[0055] In another aspect, the present disclosure relates to an antibody produced by any of the methods described herein. In some aspects, the present disclosure provides an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-Sortilin antibody of any one of the preceding aspects and embodiments. Accordingly, some aspects provide a vector comprising a nucleic acid encoding the anti-Sortilin antibody, and some aspects provide an isolated host cell containing such a vector. In certain aspects, the present disclosure provides a method of producing an anti-Sortilin antibody that binds to Sortilin, comprising culturing such an isolated host cell such that the anti-Sortilin antibody is produced. In certain embodiments, the method further comprises recovering the antibody produced by the cell. In some aspects, provided herein is an isolated antibody that binds to Sortilin and is produced by the methods of the present disclosure.

[0056] In another aspect, the disclosure relates to a pharmaceutical composition comprising any of the anti-Sortilin antibodies described herein and a pharmaceutically acceptable carrier. In some embodiments, the disclosure relates to the use of any of the antibodies or compositions described herein for preparing or manufacturing a medicament. In some embodiments, the disclosure relates to the use of any of the antibodies or compositions described herein for preparing or manufacturing a medicament for treating frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, neuropathic pain, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, or osteoarthritis. Some embodiments provide an antibody or composition described herein for use in a method of treatment. Some embodiments provide an antibody or composition described herein for use in a method for treating frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, neuropathic pain, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, or osteoarthritis.

[0057] In certain aspects, provided herein are methods of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury, comprising administering to an individual in need thereof a therapeutically effective amount of an anti-Sortilin antibody of the present disclosure. In some embodiments, the disease, disorder, or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, neuropathic pain, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis. In some embodiments, the disease, disorder, or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, and amyotrophic lateral sclerosis.

[0058] In certain aspects, provided herein are methods of inhibiting one or more of neuroinflammation, axonal degeneration 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 the present disclosure.

[0059] In certain aspects, provided herein are methods 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 the present disclosure.

[0060] In certain aspects, provided herein are methods of preventing, reducing the risk of, or treating an individual with arthritis, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of the present disclosure.

[0061] In certain aspects, provided herein are methods 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 the present disclosure. In some 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.

[0062] In some aspects, provided herein are methods for inhibiting the interaction between Sortilin and Progranulin, comprising exposing a cell expressing Sortilin to an anti-Sortilin antibody or pharmaceutical composition of the present disclosure. In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo. In some embodiments, the method further comprises reducing the level of Sortilin expressed on the cell surface. In some embodiments, increasing the extracellular level of Progranulin.

[0063] In some aspects, provided herein are methods for increasing the level of Progranulin in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody or pharmaceutical composition of the present disclosure. In some embodiments, the level of Progranulin is increased in plasma. In some embodiments, the level of Progranulin is increased in cerebrospinal fluid. In some aspects, provided herein are methods for decreasing the level of Sortilin in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody or pharmaceutical composition of the present disclosure. In some embodiments, the level of Sortilin is decreased in peripheral leukocytes. In some embodiments, the individual has one or more mutations in the gene encoding Progranulin. In some embodiments, the individual is heterozygous for one or more loss-of-function mutations in the gene encoding Progranulin. In some embodiments, the individual has a c9orf72 hexanucleotide repeat expansion. The individual has or is at risk of frontotemporal dementia, Alzheimer's disease, or amyotrophic lateral sclerosis.

[0064] In some embodiments that may be combined with any of the preceding aspects or embodiments, the present disclosure provides methods, wherein the anti-Sortilin antibodies comprise two or more anti-Sortilin antibodies. [Brief explanation of the drawings]

[0065] [Figure 1A]Pharmacokinetic and pharmacodynamic studies are shown in non-human primates administered a single dose of the anti-Sortilin antibody S-60-15.1[N33T]LALAPS (S-60-15.1[N33T] with huIgG1 harboring the L234A / L235A / P331S mutations). Figure 1A shows the levels of SORT1 in peripheral leukocytes at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. SORT1 expression was reduced with all anti-Sortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in both an earlier and more prolonged decrease in SORT1 levels compared with lower anti-Sortilin antibody doses (5 mg / kg, 20 mg / kg). Figure 1B shows the levels of PGRN in plasma at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. PGRN levels increased in a time- and dose-dependent manner. Notably, plasma PGRN levels increased 3- to 4-fold at Cmax compared to baseline levels for all anti-sortilin antibody doses tested and remained elevated for extended periods at higher antibody doses. Figure 1C shows CSF PGRN levels as a percentage of baseline at the indicated time points (hours) after treatment, along with the indicated anti-sortilin antibody dose. CSF PGRN levels increased 2- to 3-fold relative to baseline in animals administered either 20 mg / kg, 60 mg / kg, or 200 mg / kg. As observed with plasma PGRN levels (Figure 1B), CSF PGRN levels remained elevated for extended periods in the higher antibody dose groups. For Figures 1A-1C, n = 3 animals per dose. [Figure 1B]Pharmacokinetic and pharmacodynamic studies are shown in non-human primates administered a single dose of the anti-Sortilin antibody S-60-15.1[N33T]LALAPS (S-60-15.1[N33T] with huIgG1 harboring the L234A / L235A / P331S mutations). Figure 1A shows the levels of SORT1 in peripheral leukocytes at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. SORT1 expression was reduced with all anti-Sortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in both an earlier and more prolonged decrease in SORT1 levels compared with lower anti-Sortilin antibody doses (5 mg / kg, 20 mg / kg). Figure 1B shows the levels of PGRN in plasma at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. PGRN levels increased in a time- and dose-dependent manner. Notably, plasma PGRN levels increased 3- to 4-fold at Cmax compared to baseline levels for all anti-sortilin antibody doses tested and remained elevated for extended periods at higher antibody doses. Figure 1C shows CSF PGRN levels as a percentage of baseline at the indicated time points (hours) after treatment, along with the indicated anti-sortilin antibody dose. CSF PGRN levels increased 2- to 3-fold relative to baseline in animals administered either 20 mg / kg, 60 mg / kg, or 200 mg / kg. As observed with plasma PGRN levels (Figure 1B), CSF PGRN levels remained elevated for extended periods in the higher antibody dose groups. For Figures 1A-1C, n = 3 animals per dose. [Figure 1C]Pharmacokinetic and pharmacodynamic studies are shown in non-human primates administered a single dose of the anti-Sortilin antibody S-60-15.1[N33T]LALAPS (S-60-15.1[N33T] with huIgG1 harboring the L234A / L235A / P331S mutations). Figure 1A shows the levels of SORT1 in peripheral leukocytes at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. SORT1 expression was reduced with all anti-Sortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in both an earlier and more prolonged decrease in SORT1 levels compared with lower anti-Sortilin antibody doses (5 mg / kg, 20 mg / kg). Figure 1B shows the levels of PGRN in plasma at the indicated time points (hours) after treatment, as a percentage of baseline, along with the indicated anti-Sortilin antibody dose. PGRN levels increased in a time- and dose-dependent manner. Notably, plasma PGRN levels increased 3- to 4-fold at Cmax compared to baseline levels for all anti-sortilin antibody doses tested and remained elevated for extended periods at higher antibody doses. Figure 1C shows CSF PGRN levels as a percentage of baseline at the indicated time points (hours) after treatment, along with the indicated anti-sortilin antibody dose. CSF PGRN levels increased 2- to 3-fold relative to baseline in animals administered either 20 mg / kg, 60 mg / kg, or 200 mg / kg. As observed with plasma PGRN levels (Figure 1B), CSF PGRN levels remained elevated for extended periods in the higher antibody dose groups. For Figures 1A-1C, n = 3 animals per dose. [Figure 2A]Figures 2A–2C show pharmacokinetic and pharmacodynamic studies in nonhuman primates administered repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Animals (two males and two females) received the anti-sortilin antibody S-60-15.1[N33T]LALAPS at a dose of 60 mg / kg once weekly for four weeks. Days of administration are indicated by vertical dashed lines. Figure 2A shows the mean (+ / - standard deviation) concentrations of SORT1 in peripheral white blood cells (WBCs) at the indicated time points (days) as a percentage of baseline. SORT1 levels in peripheral WBCs remained reduced throughout the study period. Figure 2B shows the mean (+ / - standard deviation) concentrations of PGRN in plasma at the indicated time points (days) as a percentage of baseline (normalized). Plasma PGRN levels were elevated 5–6-fold above baseline at peak levels. A decrease in plasma PGRN was observed after the fourth and final dose of anti-sortilin antibody; however, plasma PGRN levels remained elevated twofold over baseline. Figure 2C shows the mean (+ / - standard deviation) CSF PGRN concentrations at the indicated time points (days) as a percentage of baseline (normalized). CSF PGRN levels were elevated three to four times over baseline (Figure 2C). [Figure 2B]Figures 2A–2C show pharmacokinetic and pharmacodynamic studies in nonhuman primates administered repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Animals (two males and two females) received the anti-sortilin antibody S-60-15.1[N33T]LALAPS at a dose of 60 mg / kg once weekly for four weeks. Days of administration are indicated by vertical dashed lines. Figure 2A shows the mean (+ / - standard deviation) concentrations of SORT1 in peripheral white blood cells (WBCs) at the indicated time points (days) as a percentage of baseline. SORT1 levels in peripheral WBCs remained reduced throughout the study period. Figure 2B shows the mean (+ / - standard deviation) concentrations of PGRN in plasma at the indicated time points (days) as a percentage of baseline (normalized). Plasma PGRN levels were elevated 5–6-fold above baseline at peak levels. A decrease in plasma PGRN was observed after the fourth and final dose of anti-sortilin antibody; however, plasma PGRN levels remained elevated twofold over baseline. Figure 2C shows the mean (+ / - standard deviation) CSF PGRN concentrations at the indicated time points (days) as a percentage of baseline (normalized). CSF PGRN levels were elevated three to four times over baseline (Figure 2C). [Figure 2C]Figures 2A–2C show pharmacokinetic and pharmacodynamic studies in nonhuman primates administered repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Animals (two males and two females) received the anti-sortilin antibody S-60-15.1[N33T]LALAPS at a dose of 60 mg / kg once weekly for four weeks. Days of administration are indicated by vertical dashed lines. Figure 2A shows the mean (+ / - standard deviation) concentrations of SORT1 in peripheral white blood cells (WBCs) at the indicated time points (days) as a percentage of baseline. SORT1 levels in peripheral WBCs remained reduced throughout the study period. Figure 2B shows the mean (+ / - standard deviation) concentrations of PGRN in plasma at the indicated time points (days) as a percentage of baseline (normalized). Plasma PGRN levels were elevated 5–6-fold above baseline at peak levels. A decrease in plasma PGRN was observed after the fourth and final dose of anti-sortilin antibody; however, plasma PGRN levels remained elevated twofold over baseline. Figure 2C shows the mean (+ / - standard deviation) CSF PGRN concentrations at the indicated time points (days) as a percentage of baseline (normalized). CSF PGRN levels were elevated three to four times over baseline (Figure 2C). DETAILED DESCRIPTION OF THE INVENTION

[0066] definition As used herein, the term "preventing" includes providing prophylaxis against the occurrence or recurrence of a particular disease, disorder, or condition in an individual who may be susceptible to, predisposed to, or at risk of developing a particular disease, disorder, or condition, but who has not yet been diagnosed with the disease, disorder, or condition.

[0067] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms prior to the treatment methods described herein. "At risk" indicates that an individual has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition, as known in the art. Individuals with one or more of these risk factors have a higher probability of developing a particular disease, disorder, or condition than individuals without one or more of these risk factors.

[0068] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual's clinical pathology. Desirable therapeutic effects include reducing the rate of progression, ameliorating or alleviating morbidity, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully "treated," for example, if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0069] An "effective amount" refers to at least an amount that is effective, at a dosage and for a period of time necessary to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. The effective amount herein can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the treatment to induce a desired response in the individual. An effective amount is also one in which the therapeutic beneficial effects outweigh any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desired results include results such as elimination or reduction of the risk, reduction in severity, or delay in onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes observed during the course of disease development. For therapeutic use, beneficial or desired results include clinical results, such as reduction in one or more symptoms caused by the disease, improvement in the quality of life of those suffering from the disease, reduction in the dose of other drugs required to treat the disease, enhancing the effect of another drug, for example, via targeting, delay in disease progression, and / or prolonged survival. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment.As understood in clinical situations, the effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.Therefore, "effective amount" can be determined in light of the administration of one or more therapeutic agents, and a single agent can be considered to be given in an effective amount when it can or does achieve the desired result in conjunction with one or more other agents.

[0070] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Administering in conjunction also encompasses administration as a co-formulation or as separate compositions, including at different dosing frequencies or intervals, and using the same or different routes of administration.

[0071] An "individual" for purposes of treating, preventing, or reducing risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual is a human.

[0072] The terms "Sortilin" or "Sortilin polypeptide" are used interchangeably herein and refer herein to any naturally occurring Sortilin from any mammalian source, including primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences, e.g., splice variants or allelic variants. In some embodiments, the term encompasses "full-length," unprocessed Sortilin, as well as any form of Sortilin that results from processing in the cell. In some embodiments, the Sortilin is human Sortilin. In some embodiments, the amino acid sequence of an exemplary human Sortilin is SEQ ID NO: 81.

[0073] The terms "anti-Sortilin antibody," "antibody that binds to Sortilin," and "antibody that specifically binds to Sortilin" refer to an antibody that can bind to Sortilin with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting Sortilin. In one embodiment, the magnitude of binding of an anti-Sortilin antibody to an unrelated, non-Sortilin polypeptide is less than about 10% of the binding of the antibody to Sortilin, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to Sortilin has a dissociation constant (KD) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 M or less, e.g., 10 M to 10 M, e.g., 10 M to 10 M). In certain embodiments, the anti-Sortilin antibody binds to an epitope of Sortilin that is conserved among Sortilins from different species.

[0074] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0075] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V) followed by a number of constant domains. H Each light chain has a variable domain (V L ) at its other end, with the light-chain constant domain aligned with the first heavy-chain constant domain and the light-chain variable domain aligned with the heavy-chain variable domain. Particular amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain.

[0076] For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0077] Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of 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, which have heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known; see, e.g., Abbas et al., Cellular and Molecular Immunology, 4 th It is generally described in Saunders Co., ed. (WBSaunders Co., 2000).

[0078] A "variable region" or "variable domain" of an antibody, such as an anti-Sortilin antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding sites.

[0079] The term "variable" refers to the fact that certain segments of variable domains differ extensively in sequence among antibodies, such as the anti-sortilin antibodies of the present disclosure. Variable domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the variable domains. Instead, variability is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more highly conserved portions of variable domains are called framework regions (FRs). Naturally occurring heavy and light-chain variable domains each contain four FR regions connected by three HVRs that primarily adopt a beta-sheet configuration and form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0080] An "isolated" antibody, such as an anti-Sortilin antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, an isolated polypeptide is free from association with all other contaminating components from the production environment. Contaminating components from the production environment, such as those arising from recombinantly transfected cells, are typically materials that would interfere with research, diagnostic, or therapeutic uses for the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to greater than 95% by weight, and in some embodiments, greater than 99% by weight, of the antibody, as determined, for example, by the Lowry method; (2) to at least 15 residues from the N-terminus, or sufficient to obtain internal amino acid sequence by use of a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining. Isolated antibodies include antibodies in situ within recombinant T cells. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step since at least one component of the antibody's natural environment will not be present.

[0081] As used herein, the term "monoclonal antibody" refers to an antibody, such as a monoclonal anti-Sortilin antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by a hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to, immunization of animals, including but not limited to, rats, mice, rabbits, guinea pigs, hamsters, and / or chickens, with one or more of the following methods: DNA(s), virus-like particles, polypeptide(s), and / or cell(s); hybridoma methods; B-cell cloning methods; recombinant DNA methods; and techniques for producing human or human-like antibodies in animals that possess some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0082] The terms "full length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to antibodies, such as the anti-Sortilin antibodies of the present disclosure, in a substantially intact form, as opposed to antibody fragments. Specifically, complete antibodies include antibodies having heavy and light chains, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, intact antibodies may have one or more effector functions.

[0083] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see Example 2 of U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0084] Papain digestion of antibodies, such as the anti-Sortilin antibodies of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments, and a residual "Fc" fragment (the name reflects its ability to crystallize readily). The Fab fragment contains the variable region domain of the heavy chain (V H ) and the first constant domain of one heavy chain (C H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment that roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still capable of cross-linking antigen. The Fab' fragment is a C fragment containing one or more cysteines from the antibody hinge region. H F(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0085] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of the antibody are determined by the sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain types of cells.

[0086] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable region domain in tight, non-covalent association. The folding of these two domains leaves six hypervariable loops (three loops from each H and L chain) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) still has the ability to recognize and bind antigen, albeit with lower affinity than the entire binding site.

[0087] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains linked in a single polypeptide chain. Preferably, the sFv polypeptide contains a VH domain that enables the sFv to form the desired structure for antigen binding. H Domain and V L The sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0088] A "functional fragment" of an antibody, such as an anti-Sortilin antibody of the present disclosure, includes a portion of an intact antibody that generally includes the antigen-binding or variable region of the intact antibody, or the F region of the antibody that retains or modifies FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0089] The term "diabody" refers to a V diabody in which inter-chain, rather than intra-chain, pairing of variable domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domain and V L This refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with a short linker (approximately 5-10 residues) between the domains. Bispecific diabodies are small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with a short linker (approximately 5-10 residues) between the domains. H and V L It is a heterodimer of two "crossover" sFv fragments in which the domains are present on different polypeptide chains.

[0090] As used herein, a "chimeric antibody" refers to an antibody (immunoglobulin), such as a chimeric anti-Sortilin antibody of the present disclosure, in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, so long as the desired biological activity is exhibited. Chimeric antibodies of interest herein include PRIMATIZED® antibodies in which the antigen-binding region of the antibody is derived from, for example, an antibody produced by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0091] "Humanized" forms of non-human (e.g., murine) antibodies, such as humanized forms of the anti-Sortilin antibodies of the present disclosure, are chimeric antibodies comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been subjected to humanization.

[0092] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody, such as an anti-Sortilin antibody of the present disclosure, that is produced by a human and / or that has been generated using any of the techniques for making human antibodies as disclosed herein. This definition of 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 and yeast-based platform technologies. Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xeno-mouse, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous genetic loci have been disabled. Additionally, human antibodies can be generated by human B-cell hybridoma technology.

[0093] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to regions of an antibody variable domain, such as those of an anti-Sortilin antibody of the present disclosure, that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs; H Three of these (H1, H2, H3) and V LIn natural antibodies, H3 and L3 show the greatest diversity among the six HVRs, and H3 in particular is thought to play a unique role in conferring fine specificity to antibodies. Naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains.

[0094] Several HVR delineations are in use and are encompassed herein. In some embodiments, HVRs may be Kabat complementarity-determining regions (CDRs), which are based on sequence variability and are the most commonly used (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, HVRs may be AbM HVRs. AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. In some embodiments, HVRs may be "contact" HVRs. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. TIFF2025004050000001.tif44170

[0095] HVRs may also include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) of the VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) of the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0096] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0097] As used herein, an "acceptor human framework" refers to a V-type nucleotide sequence derived from a human immunoglobulin framework or a human consensus framework. L or V H The acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When pre-existing amino acid changes are present in the VH, preferably these changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is a framework having the sequence: L It is identical to a human immunoglobulin framework sequence or a human consensus framework sequence.

[0098] The "human consensus framework" is based on human immunoglobulin V L or V H In selecting framework sequences, the framework represents the most commonly occurring amino acid residues. L or V H The selection of sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). For example, V L In the present invention, the subgroup may be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al., supra. HIn this case, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0099] For example, an "amino acid modification" at a particular position of an anti-Sortilin antibody of the present disclosure refers to a substitution or deletion of the particular residue, or an insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue means an insertion within 1 to 2 residues thereof. The insertion may be at the N-terminus or C-terminus of the particular residue. A preferred amino acid modification herein is a substitution.

[0100] An "affinity matured" antibody, such as an anti-Sortilin antibody of the present disclosure, is an antibody with one or more modifications in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody without those modification(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described, for example, by 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).

[0101] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction, such as attraction or binding, between a target and an antibody, such as an anti-Sortilin antibody of the present disclosure, that determines the presence of a target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody, such as an anti-Sortilin antibody of the present disclosure, that specifically or preferentially binds to a target or epitope is an antibody that binds to this target or epitope with higher affinity, antibody avidity, more readily, and / or for a longer duration than it binds to other targets or other epitopes of targets. For example, it is also understood by reading this definition that an antibody (or moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds to a target has at least about 10 3 M -1 Or 10 4 M -1 , depending on the time, about 10 5 M -1 Or 10 6 M -1 , in other cases, about 10 6 M -1 Or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 , or about 10 10 M -1 ~10 11 M -1The binding constant of an antibody may be greater than or equal to 100 kJ / mL. A variety of immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0102] As used herein, an "interaction" between a sortilin protein and a second protein includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. As used herein, an antibody "inhibits the interaction" between two proteins when the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody or fragment thereof of the present disclosure "inhibits the interaction" between two proteins when the antibody or fragment thereof binds to one of the two proteins.

[0103] An "agonist" or "activating" antibody is an antibody, such as an agonist anti-Sortilin antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0104] A "blocking," "antagonist," or "inhibitory" antibody is an antibody, such as an anti-Sortilin antibody of the present disclosure, that inhibits or diminishes (e.g., reduces) antigen binding to one or more ligands and / or inhibits or diminishes (e.g., reduces) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, a blocking, antagonist, or inhibitory antibody substantially or completely inhibits antigen binding to one or more ligands and / or one or more activities or functions of the antigen.

[0105] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.

[0106] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or Pro230 to its carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population having all K447 residues removed, an antibody population having no K447 residues 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.

[0107] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A allotypes and A allotypes), native-sequence human IgG2 Fc regions, native-sequence human IgG3 Fc regions, and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0108] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein will preferably have at least about 80% homology with the native-sequence Fc region and / or the Fc region of the parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto.

[0109] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibiting receptors"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies. As used herein, "percent amino acid sequence identity" and "homology" with respect to peptide, polypeptide, or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to those in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for alignment comparisons, including any algorithms known in the art necessary to achieve maximal alignment over the full length of the sequences being compared.

[0110] An "isolated" cell is a molecule or cell that has been identified and separated from at least one contaminating cell that is normally associated with it in the environment in which it was produced. In some embodiments, an isolated cell is free from all components associated with the production environment. An isolated cell is in a form other than the form or setting in which it is found in nature. An isolated cell is distinguished from cells that naturally occur in a tissue, organ, or individual. In some embodiments, an isolated cell is a host cell of the present disclosure.

[0111] An "isolated" nucleic acid molecule encoding an antibody, such as an anti-Sortilin antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is normally associated in the environment in which it is produced. Preferably, the isolated nucleic acid is free from association with all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are in a form other than in the form or setting in which they are found in nature. Thus, isolated nucleic acid molecules are distinguished from nucleic acids encoding the polypeptides and antibodies herein that are naturally present in a cell.

[0112] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby be replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably, as the plasmid is the most commonly used form of vector.

[0113] "Polynucleotide" or "nucleic acid," used interchangeably herein, refer to a polymer of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.

[0114] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporation of a polynucleotide insert. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (morphologically or in terms of genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the present disclosure.

[0115] As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed.

[0116] The term "about" as used herein refers to a normal range of error for the respective value, which is readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter itself.

[0117] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, reference to an "antibody" is a reference to one antibody to many antibodies, such as molar amounts, including equivalents thereof known to those skilled in the art, and so forth.

[0118] It is understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0119] overview The present disclosure relates, in part, to anti-Sortilin antibodies that exhibit one or more improved and / or enhanced functional characteristics compared to S-60, an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region described in WO2016164637. Non-limiting improved and / or enhanced functional characteristics include, for example, binding to Sortilin with higher affinity, reducing cell surface levels of Sortilin, and / or increasing the 50% effective concentration (EC) for reducing cell surface levels of Sortilin. 50 ), improves the maximum reduction in cell surface levels of sortilin, sortilin ligands: for example, increases the extracellular secretion of progranulin (PGRN), and increases the 50% effective concentration (EC ) for blocking PGRN binding to sortilin. 50 ), improve maximal blockade of PGRN binding to sortilin, or any combination thereof. 50 ), improving the maximum reduction in cell surface levels of sortilin, increasing extracellular secretion of sortilin ligands, such as progranulin (PGRN), and increasing the 50% effective concentration (EC ) for blocking PGRN binding to sortilin. 50 Also contemplated herein are anti-Sortilin antibodies with various Fc variants that exhibit one or more improved and / or enhanced functional characteristics, including reduced Fc expression and improved maximal blockade of PGRN binding to Sortilin.

[0120] In some embodiments, the anti-Sortilin antibodies of the present disclosure have greater efficacy in reducing cell surface levels of Sortilin than anti-Sortilin antibodies having heavy chain variable regions and light chain variable regions corresponding to S-60. In some embodiments, efficacy is measured using a median effective concentration (EC) for reducing cell surface cellular levels of SORT1. 50 ) is measured by

[0121] The disclosure further relates to methods of making and using anti-Sortilin antibodies as described herein; pharmaceutical compositions containing such antibodies; nucleic acids encoding such antibodies; and host cells containing nucleic acids encoding such antibodies.

[0122] In some embodiments, anti-Sortilin antibodies of the present disclosure may have one or more activities due, at least in part, to the antibody's ability to reduce levels of Sortilin (e.g., cell surface levels) by inducing degradation, down-regulation, cleavage, receptor desensitization, and / or lysosomal targeting of Sortilin. In some embodiments, the anti-Sortilin antibody exhibits one or more of the following properties: a. A dissociation constant (K) for human Sortilin that is lower than that of an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60. D ) that has a 50% effective concentration (EC ) lower than that of an anti-Sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to bS-60; 50 ) to reduce cell surface levels of sortilin (e.g., to reduce cell surface levels of sortilin on genetically engineered cells expressing human sortilin in vitro); c. For example, K D The dissociation constant (K) for human sortilin, as determined by fluorescence-activated cell sorting (FACS), can range from about 0.560 nM to about 1.63 nM. D ) ; d. For example, K D As determined by biolayer interferometry, the dissociation constant (K) for human sortilin can range from about 0.270 nM to about 2.910 nM. D ) have; e. For example, EC 50 The 50% effective concentration (EC), as determined by in vitro FACS, can range from about 72.58 pM to about 103.6 pM. 50) to reduce the cell surface levels of sortilin (e.g., reduce the cell surface levels of sortilin on genetically engineered cells expressing human sortilin in vitro); f. to reduce the cell surface levels of sortilin, with a maximum reduction that may range from approximately 51.33% to 88.76%; higher than that of an anti-sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to gS-60, and increase the extracellular secretion of PGRN; h. to, for example, reduce the cell surface levels of PGRN on EC 50 The 50% effective concentration (EC), as determined by FACS in vitro, can range from about 0.325 nM to about 2.27 nM. 50 ) that blocks PGRN binding to sortilin (e.g., blocks PGRN binding to sortilin on genetically engineered cells expressing human sortilin in vitro); and / or improves maximal blockade of PGRN binding to sortilin, higher than that of an anti-sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to iS-60.

[0123] Advantageously, the anti-Sortilin antibodies of the present disclosure exhibit more potent (e.g., lower EC 50 ) and reduce cell surface levels of Sortilin (e.g., by up to about 3.02-fold) (see, e.g., Example 2). In some embodiments, the anti-Sortilin antibodies of the disclosure have a more potent and lower EC2 than a control anti-Sortilin antibody (e.g., a control anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 (up to about 5.36-fold) (see, e.g., Example 3). Additionally, advantageously, the anti-Sortilin antibodies of the present disclosure exhibit higher affinity (e.g., up to about 2.79-fold higher affinity) for Sortilin (e.g., lower K as measured by FACS or biolayer interferometry) compared to a control anti-Sortilin antibody (e.g., a control anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). Dvalues) (see, e.g., Examples 1 and 4). Surprisingly, higher affinity for sortilin does not necessarily correlate with increased ability or efficacy to reduce cell surface levels of sortilin (see, e.g., Examples 2 and 4), or increased ability or efficacy to block binding of PGRN to sortilin (see, e.g., Examples 3 and 4).

[0124] The present disclosure further relates to anti-Sortilin antibodies that have improved stability during manufacturing, storage, and in vivo administration. In some embodiments, the anti-Sortilin antibodies of the present disclosure have improved stability under various stress conditions (see, e.g., Example 4).

[0125] Sortilin protein In one aspect, the disclosure provides antibodies, such as isolated (e.g., monoclonal) antibodies, that interact with or otherwise bind to a region, such as an epitope, within a Sortilin protein of the disclosure. In some embodiments, the antibody interacts with or otherwise binds to a region, such as an epitope, within a Sortilin protein of the disclosure with improved / enhanced kinetics (e.g., relative to an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). In some embodiments, the antibody has a lower 50% effective concentration (EC 50 ), which interacts with or otherwise binds to a region, such as an epitope, within the human Sortilin protein. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein and, after binding to the Sortilin protein, modulate one or more Sortilin activities, e.g., activities associated with Sortilin expression on a cell. 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. Exemplary Sortilin protein sequences are shown in Table 32.

[0126] Sortilin is variously referred to as sortilin 1, SORT1, 100 kDa NT receptor, glycoprotein 95 (GP95), progranulin receptor (PGRN-R), and neurotensin receptor 3 (NT-3 or NTR-3). Sortilin is an 831 amino acid protein that 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: 81 (key amino acid residues predicted to be involved in progranulin binding are shown in bold, and the predicted pro-NGF binding region is underlined): TIFF2025004050000002.tif178170

[0127] The amino acid sequence of mouse sortilin is shown in SEQ ID NO:82: TIFF2025004050000003.tif105170

[0128] The amino acid sequence of rat sortilin is shown in SEQ ID NO:83: TIFF2025004050000004.tif105170

[0129] In some embodiments, the Sortilin is a preprotein that includes a signal sequence. In some embodiments, the Sortilin is a mature protein. In some embodiments, the mature Sortilin protein does not include a signal sequence. In some embodiments, the mature Sortilin protein is expressed on a cell.

[0130] The sortilin proteins of the present disclosure comprise multiple 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. In addition, the proteins of the present disclosure are expressed at high levels in several tissues, including, but not limited to, the brain, spinal cord, heart and skeletal muscle, thyroid, placenta, and testis.

[0131] Thus, as used herein, the "Sortilin" proteins of the present disclosure include, but are not limited to, mammalian Sortilin proteins, human Sortilin proteins, primate Sortilin proteins, mouse Sortilin proteins, and rat Sortilin proteins. Additionally, anti-Sortilin antibodies of the present disclosure may bind to epitopes within one or more of mammalian Sortilin proteins, human Sortilin proteins, primate Sortilin proteins, mouse Sortilin proteins, and rat Sortilin proteins.

[0132] Sortilin protein domain The sortilin proteins of the present disclosure contain several domains, including a Vps10p domain, which contains an Asp-box motif, a ten-bladed beta-propeller structure, and a hydrophobic loop; and a 10CC domain.

[0133] As disclosed herein, the interaction between a Sortilin protein of the disclosure and a proneurotrophin or neurotrophin is mediated by a Vps10p domain containing a ten-bladed beta-propeller structure and an Asp-box motif. In certain embodiments, a Sortilin protein of the disclosure comprises a Vps10p domain that comprises a ten-bladed beta-propeller structure and is located within amino acid residues 78-611 of human Sortilin (SEQ ID NO: 81) or amino acid residues of a mammalian Sortilin that correspond to amino acid residues 78-611 of SEQ ID NO: 81. In certain embodiments, amino acid residues 190-220 of human Sortilin (SEQ ID NO: 81) or amino acid residues of a mammalian Sortilin that correspond to amino acid residues 190-220 of SEQ ID NO: 81 are located within the Vps10p domain.

[0134] The Vps10p domain of the present disclosure can include an Asp-box motif. As used herein, the Asp-box motif has the following sequence: (S / T)-X-(D / N)-XXXX-(W / F / Y) (SEQ ID NO: 84), or XX-(S / T)-X-(D / N)-XGX-(T / S)-(W / F / Y)-X (SEQ ID NO: 85), where X represents any amino acid. In human sortilin, the Asp-box motif is SSDFAKNF (SEQ ID NO: 86), located at amino acid residues 200-207 of human sortilin. Thus, in certain embodiments, the Asp-box motif is located at amino acid residues 200-207 of human sortilin (SEQ ID NO: 81) or at amino acid residues in a mammalian sortilin corresponding to amino acid residues 200-207 of SEQ ID NO: 81.

[0135] As disclosed herein, the interaction between the sortilin proteins of the present disclosure and p75 is mediated by the 10CC domain of the hydrophobic loop of the Vps10p domain.

[0136] In certain embodiments, a Sortilin protein of the present disclosure contains a 10CC domain located within amino acid residues 610-757 of human Sortilin (SEQ ID NO: 81) or amino acid residues of a mammalian Sortilin corresponding to amino acid residues 610-757 of SEQ ID NO: 81. In preferred embodiments, amino acid residues 592-593, 610-660, and / or 667-749 of human Sortilin (SEQ ID NO: 81) or amino acid residues of a mammalian Sortilin corresponding to amino acid residues 592-593, 610-660, and / or 667-749 of SEQ ID NO: 81 are located within the 10CC domain of Sortilin.

[0137] In other embodiments, a sortilin protein of the disclosure contains a hydrophobic loop within the Vps10p domain located within amino acid residues 130-141 of human sortilin (SEQ ID NO:81) or amino acid residues of a mammalian sortilin corresponding to amino acid residues 130-141 of SEQ ID NO:81.

[0138] As one of skill in the art will appreciate, the starting and ending residues of a domain of the present disclosure may vary depending on the computer modeling program used or the method used to determine the domain.

[0139] Sortilin binding partners Sortilin proteins of the present disclosure can interact with (e.g., bind to) one or more proteins including, but not limited to, progranulin (PGRN) protein; neurotrophins, such as pro-neurotrophin, 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); neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), amyloid precursor protein, Abeta peptide, PCSK9, p75NTR, and receptor-associated protein (RAP).

[0140] Progranulin (PGRN) The sortilin proteins of the present disclosure have been shown to directly interact with (e.g., bind to) progranulin and mediate the degradation of progranulin (e.g., Zheng, Y et al., (2011) PLoS ONE 6(6):e21023).

[0141] Progranulin is variously referred to as PGRN, proepithelin, granulin-epithelin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a 593-amino acid protein encoding a 68.5 kD secreted glycoprotein with 7.5 repeats of small granulin (epithelin) motifs ranging from 6 to 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.

[0142] Thus, anti-Sortilin antibodies of the disclosure that increase progranulin levels, decrease cell surface levels of sortilin, and / or block the interaction (e.g., binding) of sortilin with progranulin may be used to treat conditions such as decreased expression and / or activity levels of progranulin, cell death (e.g., neuronal cell death), frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophies, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, undesirable symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease , inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, inflammatory diseases, arthritis, multiple sclerosis, metabolic disorders, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, trauma, and / or conditions and / or diseases associated with one or more undesirable symptoms of normal aging. Additionally, anti-Sortilin antibodies of the disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin may inhibit the interaction between Sortilin and Progranulin, may induce one or more Progranulin activities, may decrease endosomal internalization of Progranulin or a fragment thereof, and / or may increase the effective concentration of Progranulin.

[0143] In some embodiments, anti-Sortilin antibodies of the disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin are antibodies that bind to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-369, 370-371, 372-373, 374-375, 376-377, 378-379, 380-381, 382-383, 384-385, 386-387, 388-389, 390-401, 401-402, 402-403, 403-404, 404-405, 405-410, 411-412, 413-414, 415-416, 417-418, 420-421, 422-423, 424-425, 426-427, 428-430, 429-431, 430-432, 431-433, 432-434, 433-435, 434-436, 435-44 or 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 a mammalian sortilin corresponding to amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632, and / or 740-749 of SEQ ID NO:81.In other embodiments, anti-Sortilin antibodies of the disclosure that increase Progranulin levels, decrease cell surface levels of Sortilin, and / or block the interaction (e.g., binding) between Sortilin and Progranulin bind to amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe198, Phe19 ... he203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, Lys254, Lys260, Ser305, Phe 306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382 , Tyr386, Ser595, and / or Glu700; or 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, L and / or Glu700.

[0144] Other sortilin ligands Sortilin proteins of the present disclosure include a pro-domain and have been shown to directly interact with (e.g., bind to) pro-neurotrophins (e.g., pro-NGF), which are typically pro-apoptotic. This binding can be mediated through a linear epitope on Sortilin corresponding to amino acid residues 163-174 of SEQ ID NO: 81. Sortilin proteins of the present disclosure have also been shown to interact with (e.g., bind to) neurotensin within the beta-propeller structure of Sortilin, with a critical contact shown to be at serine 283 of human Sortilin.

[0145] The Sortilin proteins of the present disclosure have also been shown to interact with (e.g., bind to) the low-affinity nerve growth factor (NGF) receptor (p75) within the hydrophobic loop of the 10CC domain of Sortilin or the Vps10p domain of Sortilin. As disclosed herein, the Sortilin proteins of the present disclosure, together with p75, can function as coreceptors for pro-neurotrophins that induce apoptotic signaling. The Sortilin proteins of the present disclosure have further been shown to interact with (e.g., bind to) the amyloid precursor protein (APP).

[0146] Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) lipoprotein lipase (LpL). As disclosed herein, Sortilin proteins of the present disclosure bind to LpL and alter its degradation. Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) apolipoprotein AV (APOA5). As disclosed herein, Sortilin proteins of the present disclosure bind to APOA5 and alter its degradation.

[0147] Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) apolipoprotein E (APOE, APOE2, APOE3, APOE4). As disclosed herein, Sortilin proteins of the present disclosure bind to and alter the degradation and trafficking of APOE, as well as APOE-carried agents, such as Abeta peptide. In addition, Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) receptor-associated protein (RAP). Furthermore, Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) proprotein convertase subtilisin / kexin type 9 (PCSK9) and secrete it into the circulation.

[0148] In some embodiments of any of the anti-Sortilin antibodies, the anti-Sortilin antibodies of the present disclosure may inhibit (e.g., block) the interaction between Sortilin and one or more other Sortilin ligands of the present disclosure. In some embodiments, the one or more other ligands are one or more of pro-neurotrophin, neurotensin, low-affinity nerve growth factor (NGF) receptor (p75), amyloid precursor protein, lipoprotein lipase, apolipoprotein AV, apolipoprotein, receptor-associated protein, and / or proprotein convertase subtilisin / kexin type 9. Such antibodies may be beneficial for preventing, reducing the risk of, or treating conditions and / or diseases associated with reduced levels of one or more other Sortilin ligand expression and / or activity, cell death (e.g., neuronal cell death). In some embodiments, the one or more other ligands are one or more of a pro-neurotrophin, neurotensin, low-affinity nerve growth factor (NGF) receptor (p75), amyloid precursor protein, lipoprotein lipase, apolipoprotein AV, apolipoprotein, receptor-associated protein, and / or proprotein convertase subtilisin / kexin type 9.

[0149] Anti-Sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction of Sortilin with one or more other Sortilin ligands of the present disclosure may also prevent cell death (e.g., apoptosis) induced by the one or more other Sortilin ligands. In some embodiments, the one or more other ligands are one or more of pro-neurotrophin, neurotensin, low-affinity nerve growth factor (NGF) receptor (p75), amyloid precursor protein, lipoprotein lipase, apolipoprotein AV, apolipoprotein, receptor-associated protein, and / or proprotein convertase subtilisin / kexin type 9.

[0150] In some embodiments of any of the anti-Sortilin antibodies, the anti-Sortilin antibodies of the disclosure that inhibit (e.g., block) the interaction of Sortilin with one or more Sortilin ligands of the disclosure are selected from the group consisting of amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 446-450, 452-454, 456-460, 462-463, 464-470, 466-471, 468-472, 469-480, 470-473, 471-474, 472-475, 473-476, 474-477, 475-480, 476-481, 477-482, 478-483, 479-484, 485-486, 487-488, 489-490, 491-500, 501-502, 502-503, 503-504, 504-505, 505-506, 507-510, 512-513, 514-515, 51 or 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 SEQ ID NO:81. In some embodiments, the one or more other ligands are one or more of a pro-neurotrophin, neurotensin, low-affinity nerve growth factor (NGF) receptor (p75), amyloid precursor protein, lipoprotein lipase, apolipoprotein AV, apolipoprotein, receptor-associated protein, and / or proprotein convertase subtilisin / kexin type 9.

[0151] In other embodiments of any of the anti-Sortilin antibodies, the anti-Sortilin antibodies of the disclosure that inhibit (e.g., block) the interaction of Sortilin with one or more Sortilin ligands of the disclosure comprise amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys20 of human Sortilin (SEQ ID NO: 81). 5, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys248, Lys254, Lys260, Ser305, Phe306, Gly30 7, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386 , Ser595, and / or Glu700; or 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, Lys244, Lys245, Lys246, Lys247, Lys248, Lys249, Lys250, Lys251, Lys252, Lys253, Lys254, Lys255, Lys256, Lys257, Lys258, Lys259, Lys260, Lys261, Lys262, Lys263, Lys264, Lys265, Lys266, Lys267, Lys268, Lys269, Lys270, Lys271, Lys272, Lys273, Lys274, Lys275, Lys276, Lys277, Lys278, Lys279, Lys280, Lys281, Lys282, Lys283, Lys284, Lys285, Lys286, Lys287, Lys288, Lys289, Lys290, Lys291, Lys292, Lys293, Lys294, Lys295, Lys296, Lys297, Lys298, Lys299, Lys299, Lys299, Lys290, Lys291, Lys292, Lys 48, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595, and / or Glu700 of a mammalian sortilin. In some embodiments, the one or more other ligands are one or more of pro-neurotrophin, neurotensin, low-affinity nerve growth factor (NGF) receptor (p75), amyloid precursor protein, lipoprotein lipase, apolipoprotein AV, apolipoprotein, receptor-associated protein, and / or proprotein convertase subtilisin / kexin type 9.

[0152] Sortilin antibodies Certain aspects of the present disclosure relate to anti-Sortilin antibodies comprising one or more improved and / or enhanced functional properties. In some embodiments, the anti-Sortilin antibodies of the present disclosure comprise one or more improved and / or enhanced functional properties relative to S-60, an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region as described in WO2016164637. In some embodiments, the anti-Sortilin antibodies of the present disclosure have a higher affinity for Sortilin (e.g., human Sortilin) ​​than that of a control anti-Sortilin antibody (e.g., a control anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the present disclosure reduce cellular levels (e.g., cell surface levels) of Sortilin to a greater extent than that of the control antibody (e.g., a control anti-Sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60), and have a 50% effective concentration (EC50) lower than that of the control antibody. In some embodiments, anti-Sortilin antibodies of the present disclosure improve maximal reduction of cell surface levels of Sortilin compared to anti-Sortilin antibodies comprising heavy chain variable regions and light chain variable regions corresponding to S-60. In some embodiments, anti-Sortilin antibodies of the present disclosure increase secretion of extracellular Progranulin (PGRN) compared to anti-Sortilin antibodies comprising heavy chain variable regions and light chain variable regions corresponding to S-60. In some embodiments, anti-Sortilin antibodies of the present disclosure block PGRN binding to Sortilin to a greater extent than a control antibody (e.g., a control anti-Sortilin antibody comprising heavy chain variable regions and light chain variable regions corresponding to S-60), and have a lower 50% effective concentration (EC50) than that of the control antibody. In some embodiments, anti-Sortilin antibodies of the present disclosure improve maximal blockade of PGRN binding to Sortilin compared to anti-Sortilin antibodies comprising heavy chain variable regions and light chain variable regions corresponding to S-60.

[0153] Also contemplated herein are anti-Sortilin antibodies with various Fc variants that exhibit one or more improved and / or enhanced functional properties compared to anti-Sortilin antibodies comprising heavy chain and light chain variable regions corresponding to S-60, including a reduced 50% effective concentration (EC50) for reducing cell surface levels of Sortilin, an improved maximal reduction in cell surface levels of Sortilin, an increased extracellular secretion of PGRN, a reduced 50% effective concentration (EC50) for blocking PGRN binding to Sortilin, and an improved maximal blocking of PGRN binding to Sortilin.

[0154] In some embodiments, an anti-Sortilin antibody of the disclosure is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

[0155] In a preferred embodiment, the anti-Sortilin antibodies of the present disclosure are monoclonal antibodies.

[0156] Anti-sortilin antibody binding epitope In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein and / or a naturally occurring variant of the present disclosure. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein that is a human protein. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein that is a wild-type protein. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein that is a naturally occurring variant.

[0157] In certain preferred embodiments, the anti-Sortilin antibodies of the present disclosure specifically bind to human Sortilin protein.

[0158] Certain aspects of the present disclosure provide anti-Sortilin antibodies that bind to discontinuous Sortilin epitopes. In some embodiments, the discontinuous Sortilin epitopes include two or more epitopes, three or more epitopes, four or more epitopes, five or more epitopes, six or more epitopes, seven or more peptides, eight or more epitopes, nine or more epitopes, or ten or more epitopes. In some embodiments, the peptides each comprise 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: 81; 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: 81. Another aspect of the disclosure provides anti-Sortilin antibodies that bind to a conformational epitope of Sortilin.

[0159] Certain aspects of the present disclosure provide anti-Sortilin antibodies that bind to one or more amino acids within amino acid residues 207-231 of human Sortilin (SEQ ID NO: 81); or within amino acid residues on a mammalian Sortilin that correspond to amino acid residues 207-231 of SEQ ID NO: 81. In some embodiments, the anti-Sortilin antibodies bind to one or more amino acids within amino acid residues Thr218, Tyr222, Ser223, and / or Ser227 of human Sortilin (SEQ ID NO: 81); or within amino acid residues on a mammalian Sortilin that correspond to amino acid residues Thr218, Tyr222, Ser223, and / or Ser227 of SEQ ID NO: 81. In some embodiments, the anti-Sortilin antibody binds to one or more amino acid residues F105, L108, R109, G110, 1537, F569, E590, F592, L593, S595, and / or W597 of human Sortilin (SEQ ID NO: 81); or amino acid residues on a mammalian Sortilin corresponding to amino acid residues F105, L108, R109, G110, 1537, F569, E590, F592, L593, S595, and / or W597 of SEQ ID NO: 81. Another aspect of the disclosure provides an anti-Sortilin antibody that binds to an epitope having amino acid residues (S / T)-X-(D / N)-XXXX-(W / F / Y), where X represents any amino acid (SEQ ID NO: 84).

[0160] In some embodiments, an anti-Sortilin antibody of the disclosure binds to a Sortilin protein of the disclosure expressed on the surface of a cell, and the naked antibody inhibits an interaction (e.g., binding) between a Sortilin protein and a protein selected from progranulin (PGRN), pro-neurotrophin, neurotrophin, 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), brain-derived neurotrophic factor (BDNF), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Abeta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP). In some embodiments, an anti-Sortilin antibody of the disclosure binds to a Sortilin protein of the disclosure expressed on the surface of a cell, and the naked antibody inhibits the interaction (e.g., binding) between a Sortilin protein and PGRN.

[0161] In some embodiments, anti-Sortilin antibodies of the disclosure that bind to a Sortilin protein of the disclosure inhibit the interaction (e.g., binding) between Sortilin protein and progranulin, pro-neurotrophin, neurotrophin, 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), brain-derived neurotrophic factor (BDNF), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Abeta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP) by reducing the effective level of Sortilin available to interact with these proteins either on the cell surface or inside the cell.

[0162] In some embodiments, anti-Sortilin antibodies of the disclosure that bind to a Sortilin protein of the disclosure inhibit the interaction (e.g., binding) between Sortilin protein and progranulin, pro-neurotrophin, neurotrophin, 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), brain-derived neurotrophic factor (BDNF), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Abeta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP) by inducing degradation of Sortilin.

[0163] In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to human Sortilin or a homolog thereof, including but not limited to, a mammalian Sortilin protein or a non-human primate Sortilin protein. In some embodiments, the anti-Sortilin antibodies of the present disclosure specifically bind to human Sortilin. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to human Sortilin and do not cross-react with Sortilin orthologs or homologs from other species.

[0164] Anti-Sortilin antibody competitive binding In some embodiments, an anti-Sortilin antibody of the disclosure competitively inhibits the binding of at least one other anti-Sortilin antibody selected from any of the antibodies listed in Tables 1-29. In some embodiments, the anti-Sortilin antibodies of the disclosure are 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33G], S-60-15.7[N33R], S-60-15.8[N33D], S-60-15.9[N33G], S-60-15.10[N33G], S-60-15.11[N33G], S-60-15.12[N33G], S-60-15.13[N33G], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15.16[N33G], S-60-15.17[N33G], S-60-15.18[N33G], S-60-15.19[N33G], S-60-15.19[N33G], S-60-15.19[N33G], S-60-1 3H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24; and any combination thereof.

[0165] In some embodiments, the anti-Sortilin antibodies of the disclosure, for binding to Sortilin, are characterized in that the anti-Sortilin antibody is 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N 33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7 [N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-1 5.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-6 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and any combination thereof, when the binding of one or more 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and any combination thereof, when the binding of one or more 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 (described in WO2016164637); 5[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-6 0-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S -60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33 W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.S-60-15, S-60-16, S-60-18, S-60-19, S-60-24, and any combination thereof.

[0166] In some embodiments, the anti-Sortilin antibodies of the disclosure, for binding to Sortilin, are characterized in that the anti-Sortilin antibody is 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N 33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15. 7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60- 15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V] , S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S- 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, S-60-9, S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and any combination thereof, when the binding of one or more antibodies selected from 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, S-60-9, S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and any combination thereof is reduced by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% compared to binding to Sortilin in the absence of the anti-Sortilin antibody. 7, S-60-8, and S-60-9 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16;S-60-18, S-60-19, S-60-24, and any combination thereof.

[0167] In some embodiments, 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D] to Sortilin. ], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, S-60-24, and any of them The anti-Sortilin antibodies of the present disclosure that reduce by 100% the binding of one or more antibodies selected from the combinations 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N3 3S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15. 6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60- 15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I ], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24, and any combination thereof. In some embodiments, an anti-Sortilin antibody and one or more 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60- 15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-6 0-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N3 3L], S-60-16; S-60-18, S-60-19, S-60-24, and any combination thereof, are used in combination with an anti-Sortilin antibody and one or more antibodies selected from 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt )], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N3 3K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, S-60-24, and any combination thereof, at a 10:1 ratio, a 9:1 ratio, or an 8:1 ratio; 7:1 ratio, 6:1 ratio, 5:1 ratio, 4:1 ratio, 3:1 ratio, 2:1 ratio, 1:1 ratio, 0.75:1 ratio, 0.5:1 ratio, 0.25:1 ratio, 0.1:1 ratio, 0.075:1 ratio, 0.050:1 ratio, 0.025:1 ratio, 0.01:1 ratio, 0.0075: ratio, 0.0050:1 ratio, 0.0025:1 ratio Ratio, 0.001:Ratio, 0.00075:1 Ratio, 0.00050:1 Ratio, 0.00025:1 Ratio, 0.0001:Ratio, 1:10 Ratio, 1:9 Ratio, 1:8 Ratio, 1:7 Ratio, 1:6 Ratio, 1:5 Ratio, 1:4 Ratio, 1:3 Ratio, 1:2 Ratio, 1:0.75 Ratio, 1:0.5 Ratio, 1:0.25 Ratio, 1:0.1 The compound is present in an amount corresponding to the ratio 1:0.075, 1:0.050, 1:0.025, 1:0.01, 1:0.0075, 1:0.0050, 1:0.0025, 1:0.001, 1:0.00075, 1:0.00050, 1:0.00025, or 1:0.0001. In some embodiments, the anti-Sortilin antibody is 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N 33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60 -15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.In some embodiments, the anti-Sortilin antibody is present in an excess ranging from about 1.5-fold to 100-fold, or greater than 100-fold, compared to the amount of one or more antibodies selected from 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[ N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-1 5.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60- 15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V] , S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-6 The antibody or antibodies may be present in an amount that is about 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 15x, 20x, 25x, 30x, 35x, 40x, 45x, 50x, 55x, 60x, 65x, 70x, 75x, 80x, 85x, 90x, 95x, or 100x excess relative to the amount of one or more antibodies selected from the group consisting of 0-24, and any combination thereof.

[0168] In some embodiments, the anti-Sortilin antibodies of the disclosure bind to an epitope on human Sortilin that is the same as or overlaps with a Sortilin epitope bound by at least one antibody selected from any of the antibodies listed in Tables 1-29. In some embodiments, the anti-Sortilin antibodies of the disclosure are 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-20, S-60-21, S-60-22, S-60-23, S-60-24, S-60-25, S-60-26, S-60-27, S-60-28, S-60-29, S-60-30, S-60-31, S-60-32, S-60-33, S-60-34, S-60-35, S-60-36, S-60-37, S-60-38, S-60-39, S-60-40, S-60-41, S-60-42, S-60-43, S-60-44, S-60-45, S-60-46, S-60-47, S-60-48, S-60-49, S-60-50, S-60-51, S-60-52, 60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15 .3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33 S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24; and any combination thereof. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to essentially the same Sortilin epitope as at least one antibody selected from any of the antibodies listed in Tables 1-29.In some embodiments, the anti-Sortilin antibodies of the disclosure are 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 (described in WO2016164637); or S-60-10, S-60-11, S-60- 12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60 and any combination thereof. Detailed exemplary methods for mapping antibody-binding epitopes are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ).

[0169] Anti-Sortilin antibodies can be assayed for binding to Sortilin using any suitable competition or sortilin binding assay known in the art, such as BIAcore analysis, ELISA assay, or flow cytometry, to detect 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 (described in WO2016164637); or S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[ N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-1 5.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I] The assay can determine whether a hybridoma competes with one or more antibodies selected from S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24; and any combination thereof. In an exemplary competition assay, immobilized sortilin or cells expressing sortilin on their cell surface are incubated in a solution containing a first, labeled antibody that binds to sortilin (e.g., human or non-human primate) and a second, unlabeled antibody being tested for its ability to compete with the first antibody for binding to sortilin. The second antibody may be present in a hybridoma supernatant. As a control, immobilized sortilin or cells expressing sortilin are incubated in a solution containing the first, labeled antibody but not the second, unlabeled antibody. After incubation under conditions that allow binding of the first antibody to sortilin, excess unbound antibody is removed and the amount of label associated with the immobilized sortilin or cells expressing sortilin is measured.If the amount of label associated with immobilized sortilin or cells expressing sortilin is substantially reduced in the test sample compared to the control sample, it indicates that the second antibody competes with the first antibody for binding to sortilin. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0170] In some embodiments, an anti-Sortilin antibody of the disclosure competes for binding to Sortilin with an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, S-60-24, and any combination thereof.

[0171] In some embodiments, an anti-Sortilin antibody of the disclosure binds to essentially the same Sortilin epitope as an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, and S-60-24.

[0172] Additional anti-Sortilin antibodies, e.g., antibodies that specifically bind to a Sortilin protein of the present disclosure, can be identified, screened, and / or characterized for their physical / chemical properties and / or biological activity by a variety of assays known in the art.

[0173] Anti-Sortilin antibody heavy and light chain variable regions A. Heavy chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as set forth in Tables 14-16). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as set forth in Tables 14-16).

[0174] In some embodiments, HVR-H1 comprises the sequence YSISSGYYWG (SEQ ID NO: 1). In some embodiments, HVR-H2 comprises a sequence according to Formula I: TIYHSGSTYYNPSLX1S (SEQ ID NO: 4), where X1 is K or E. In some embodiments, HVR-H2 comprises a sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises a sequence according to Formula II: ARQGSIX1QGYYGMDV (SEQ ID NO: 7). In some embodiments, HVR-H3 comprises a sequence selected from SEQ ID NOs: 5-6.

[0175] In some embodiments, HVR-H1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 1. In some embodiments, HVR-H1 comprises an amino acid sequence that contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NO: 1), but retains the ability to bind to sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids are substituted, inserted, and / or deleted in the HVR-H1 amino acid sequence of SEQ ID NO: 1. In some embodiments, HVR-H2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NOs: 2-3), while retaining the ability to bind to sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids are substituted, inserted, and / or deleted in the HVR-H2 amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 5-6. In some embodiments, HVR-H3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NOs: 5-6), yet retains the ability to bind to sortilin.In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids are substituted, inserted, and / or deleted in an HVR-H3 amino acid sequence selected from SEQ ID NOs: 5-6.

[0176] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the sequence according to Formula I, and HVR-H3 comprising the sequence according to Formula II.

[0177] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6.

[0178] In some embodiments, the heavy chain variable region is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33H], S-60-15.11[N33K], S-60-15.12[N33Q], S-60-15.13[N33Y], S-60-15.14[N33R], S-60-15.15[N33R], S-60-15.16[N33T], S-60-15.17[N33S], S-60-15.18[N33S], S-60-15.19[N33G], S-60-15.20[N33R], S-60-15.21[N33R], S-60-15.22[N33R], S-60-15.23[N33R], S-60-15.24[N33R], S-60-15.25[N33R], S-60-15.26[N33R], S-60- S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof (as shown in Tables 14-16), including HVR-H1, HVR-H2, and HVR-H3.

[0179] In some embodiments, the anti-Sortilin antibodies of the disclosure include (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33Y], S-60-15.11[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.12[N33Y], S-60-15.13[N33Y], S-60-15.14[N33Y], S-60-15.15[N33Y], S-60-15.16[N33Y], S-60-15.17[N33Y], S-60-15.18[N33Y], S-60-15.19 ], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24; (b) HVR-H1 comprising an amino acid sequence having 9%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[ N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N 33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. and (c) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33 (wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H], S-60-15.7 [N33K], S-60-15.8 [N33K], S-60-15.9 [N33R], S-60-15.10 [N33T], S-60-15.11 [N33S], S-60-15.12 [N33G], S-60-15.13 [N33R], S-60-15.14 [N33D], S-60-15.15 [N33D], S-60-15.16 [N33H], S-60-15.17 [N33K], S-60-15.18 [N33R], S-60-15.19 [N33D], S-60-15.20 [N33H], S-60-15.21 [N33S], S-60-15.22 [N33S], S-60-15.23 [N33G], S-60-15.24 [N33R], S-60-15.25 [N33D], S-60-15.26 [N33H], S-60-15.27 [N33K], 0-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-6 0-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; H of S-60-18, S-60-19, or S-60-24 and a heavy chain variable region comprising one or more of HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a VR-H3 amino acid sequence.

[0180] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0181] B. Light chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (as set forth in Tables 17-19). In some embodiments, the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as set forth in Tables 17-19).

[0182] In some embodiments, HVR-L1 comprises a sequence according to Formula III: RSSQX1LLX2SX3GYNYLD (SEQ ID NO: 28), where X1 is S or G, X2 is R or H, and X3 is N, T, S, G, R, D, H, K, Q, Y, E, W, F, I, V, A, M, or L. In some embodiments, HVR-L1 comprises a sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 is selected from the group consisting of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), RSSQSLLRSTGYNYLD (SEQ ID NO: 9), RSSQSLLRSSGYNYLD (SEQ ID NO: 10), RSSQSLLRSGGYNYLD (SEQ ID NO: 11), RSSQSLLRSRG YNYLD (SEQ ID NO: 12), RSSQSLLRSDGYNYLD (SEQ ID NO: 13), RSSQSLLRSHGYNYLD (SEQ ID NO: 14), RSSQSLLRSKGYNYLD (SEQ ID NO: 15), RSSQSLLRSQGYNYLD (SEQ ID NO: 16), RSSQSLLRSYGYNYLD (SEQ ID NO: 17), RSSQSLLRSEGYNYLD (SEQ ID NO: 18), RSSQSLLRSWGYNYLD (SEQ ID NO: 19), RSSQSLLRSFGYNYLD (SEQ ID NO: 20), RSSQSL In one specific embodiment, HVR-L1 comprises the sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8). In another specific embodiment, HVR-L1 comprises the sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 9) (as shown in Table 19).

[0183] In some embodiments, HVR-L2 comprises a sequence according to Formula IV:LGSNRX1S (SEQ ID NO: 31), where X1 is A or V. In some embodiments, HVR-L2 comprises a sequence selected from SEQ ID NOs: 29-30.

[0184] In some embodiments, HVR-L3 comprises a sequence according to formula V:MQQQEX1PLT (SEQ ID NO: 34), where X1 is A or T. In some embodiments, HVR-L3 comprises a sequence selected from SEQ ID NOs: 32-33.

[0185] In some embodiments, HVR-L1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 8-27), but retains the ability to bind to sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids are substituted, inserted, and / or deleted in the HVR-L1 amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NOs: 29-30), but retains the ability to bind to sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, or at most 5 amino acids are substituted, inserted, and / or deleted in the HVR-L2 amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 32-33. In some embodiments, HVR-L3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence of SEQ ID NOs: 32-33), yet retains the ability to bind to sortilin.In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids are substituted, inserted, and / or deleted in an HVR-L3 amino acid sequence selected from SEQ ID NOs: 32-33.

[0186] In some embodiments, the light chain variable region comprises HVR-L1 comprising a sequence according to Formula III, HVR-L2 comprising a sequence according to Formula IV, and HVR-L3 comprising a sequence according to Formula V. In some embodiments, the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8-27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29-30, and HVR-L3 comprising a sequence selected from SEQ ID NOs: 32-33.

[0187] In some embodiments, the light chain variable region is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33H], S-60-15.11[N33K], S-60-15.12[N33Q], S-60-15.13[N33Y], S-60-15.14[N33R], S-60-15.15[N33T], S-60-15.16[N33S], S-60-15.17[N33R], S-60-15.18[N33Q], S-60-15.19[N33Y], S-60-15.20[N33R], S-60-15.21[N33R], S-60-15.22[N33R], S-60-15.23[N33R], S-60-15.24[N33R], S-60-15.25[N33R], S-60-15.26[N33R], S-60- S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof (as shown in Tables 17-19).

[0188] In some embodiments, the anti-Sortilin antibodies of the disclosure include (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33Y], S-60-15.11[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.12[N33Y], S-60-15.13[N33Y], S-60-15.14[N33Y], S-60-15.15[N33Y], S-60-15.16[N33Y], S-60-15.17[N33Y], S-60-15.18[N33Y], S-60-15.19 ], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24; (b) an HVR-L1 comprising an amino acid sequence having 9%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[ N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N 33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. and (c) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33 (wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G], S-60-15.4 [N33R], S-60-15.5 [N33D], S-60-15.6 [N33H], S-60-15.7 [N33K], S-60-15.8 [N33K], S-60-15.9 [N33R], S-60-15.10 [N33T], S-60-15.11 [N33S], S-60-15.12 [N33G], S-60-15.13 [N33R], S-60-15.14 [N33D], S-60-15.15 [N33D], S-60-15.16 [N33H], S-60-15.17 [N33K], S-60-15.18 [N33R], S-60-15.19 [N33D], S-60-15.20 [N33H], S-60-15.21 [N33S], S-60-15.22 [N33S], S-60-15.23 [N33G], S-60-15.24 [N33R], S-60-15.25 [N33D], S-60-15.26 [N33H], S-60-15.27 [N33K], 0-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-6 0-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; H of S-60-18, S-60-19, or S-60-24 and a light chain variable region comprising one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a VR-L3 amino acid sequence.

[0189] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0190] In some embodiments, an anti-Sortilin antibody of the disclosure comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0191] C. Heavy Chain HVR and Light Chain HVR In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as set forth in Tables 14-16), and a light chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (as set forth in Tables 17-19). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as set forth in Tables 14-16), and the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as set forth in Tables 17-19).

[0192] In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the sequence according to Formula I, and HVR-H3 comprising the sequence according to Formula II, and the light chain variable region comprises HVR-L1 comprising the sequence according to Formula III, HVR-L2 comprising the sequence according to Formula IV, and HVR-L3 comprising the sequence according to Formula V. In some embodiments, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6, and the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8-27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29-30, and HVR-L3 comprising a sequence selected from SEQ ID NOs: 32-33.

[0193] In some aspects, the heavy chain variable region comprises HVR-H1 comprising the sequence of SEQ ID NO: 1, HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6, and the light chain variable region comprises HVR-L1 comprising a sequence selected from SEQ ID NOs: 8-27, HVR-L2 comprising a sequence selected from SEQ ID NOs: 29-30, and HVR-L3 comprising the sequence of SEQ ID NO: 32.

[0194] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y] , S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof (as shown in Tables 14-16), HVR-H1, HVR-H2, and HVR-H3. and antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10 [N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16; S-60-18, S-60-19, S-60-24, or any combination thereof (as set forth in Tables 17-19).

[0195] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3 and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the antibody is selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33 K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W ], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A ], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Tables 14-19), including HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3.

[0196] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is selected from the group consisting of: (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33 3K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (b) an HVR-H1 comprising an amino acid sequence having 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1 [N33T], S-60-15.2 [N33S], S-60-15.3 [N33G] ], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33 E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.and (c) an HVR-H2 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H2 amino acid sequence of S-60-17[N33L], S-60-16; S-60-18, S-60-19, or S-60-24; and (d) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15 .1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60- 15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-6 0-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F ], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16 and the light chain variable region comprises one or more of: (a) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and (b) antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15, S-60-16, S-60-17, S-60-18, S-60-19, S-60-24; and 0-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H] , S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N3 3E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.(b) an HVR-L1 comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the HVR-L1 amino acid sequence of S-60-14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24; 11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S- 60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y ], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.1 an HVR-L2 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L2 amino acid sequence of S-60-15.3[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24; and (c) Antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15 [N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R ], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N3 3Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.and one or more of the HVR-L3s comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L3 amino acid sequence of S-60-12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24.

[0197] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0198] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0199] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0200] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0201] In some aspects, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0202] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0203] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33).

[0204] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0205] D. Heavy Chain Variable Region In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence that contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 54-56), but maintains the ability to bind to Sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56.

[0206] In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:56.

[0207] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], and S-60-15.9 [N33Y], S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Table 30).

[0208] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0209] E. Light Chain Variable Region In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence that contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 57-80), but maintains the ability to bind to Sortilin. In certain embodiments, at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0210] In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 60.

[0211] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], and S-60-15.9 [N33Y], S-60-15.10 [N33E], S-60-15.11 [N33W], S-60-15.12 [N33F], S-60-15.13 [N33I], S-60-15.14 [N33V], S-60-15.15 [N33A], S-60-15.16 [N33M], S-60-15.17 [N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Table 31).

[0212] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0213] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

[0214] F. Heavy Chain Variable Region and Light Chain Variable Region In some aspects, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-56; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 57-80. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56, and the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence that contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 54-56), and a light chain variable region comprising an amino acid sequence that contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 57-80), while maintaining the ability to bind to Sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56; and up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0215] In some aspects, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-56; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 57-58, 60-78, and 80.

[0216] In some embodiments, the anti-Sortilin antibodies of the disclosure bind to a Sortilin protein, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59 a light chain variable region comprising the amino acid sequence of SEQ ID NO: 58; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 78; a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79; or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80.

[0217] In one embodiment, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:56 and a light chain variable region having the amino acid sequence of SEQ ID NO:57.

[0218] In one embodiment, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:56 and a light chain variable region having the amino acid sequence of SEQ ID NO:60.

[0219] In some embodiments, the anti-Sortilin antibodies of the disclosure include antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[ N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Table 30) and the heavy chain variable regions of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-1 and S-60-15.16;S-60-18, S-60-19, or S-60-24 (as shown in Table 31).

[0220] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 56 and 60. In some embodiments, the antibody comprises the heavy chain variable region of S-60-15[N33(wt)] (as shown in Table 30), and the light chain variable region of antibody S-60-15[N33(wt)] (as shown in Table 31). In some embodiments, the antibody comprises the heavy chain variable region of S-60-15.1[N33T] (as shown in Table 30), and the light chain variable region of antibody S-60-15.1[N33T] (as shown in Table 31).

[0221] Exemplary Anti-Sortilin Antibodies In some embodiments, the anti-Sortilin antibody is S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33 and an anti-Sortilin monoclonal antibody comprising the heavy chain variable region and the light chain variable region of an antibody selected from S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24. In some embodiments, the anti-Sortilin antibody is S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9 [N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24.

[0222] (1) S-60-10 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-10. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-10.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-10 or SEQ ID NO: 54, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-10, (b) the HVR-H2 amino acid sequence of antibody S-60-10, and (c) the HVR-H3 amino acid sequence of antibody S-60-10. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-10 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-10 or SEQ ID NO: 57, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-10, (b) the HVR-L2 amino acid sequence of antibody S-60-10, and (c) the HVR-L3 amino acid sequence of antibody S-60-10.

[0223] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 139.

[0224] (2)S-60-11 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO:58. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-11. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-11.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-11 or SEQ ID NO: 54, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-11, (b) the HVR-H2 amino acid sequence of antibody S-60-11, and (c) the HVR-H3 amino acid sequence of antibody S-60-11. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-11 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-11 or SEQ ID NO: 58, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-11, (b) the HVR-L2 amino acid sequence of antibody S-60-11, and (c) the HVR-L3 amino acid sequence of antibody S-60-11.

[0225] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 140. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 140.

[0226] (3) S-60-12 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO:59. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-12. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-12.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-12 or SEQ ID NO: 54, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-12, (b) the HVR-H2 amino acid sequence of antibody S-60-12, and (c) the HVR-H3 amino acid sequence of antibody S-60-12. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-12 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-12 or SEQ ID NO: 59, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-12, (b) the HVR-L2 amino acid sequence of antibody S-60-12, and (c) the HVR-L3 amino acid sequence of antibody S-60-12.

[0227] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 141. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 141.

[0228] (4)S-60-13 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO:55; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-13. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-13.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-13 or SEQ ID NO: 55, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-13, (b) the HVR-H2 amino acid sequence of antibody S-60-13, and (c) the HVR-H3 amino acid sequence of antibody S-60-13. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-13 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-13 or SEQ ID NO: 57, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-13, (b) the HVR-L2 amino acid sequence of antibody S-60-13, and (c) the HVR-L3 amino acid sequence of antibody S-60-13.

[0229] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136 and a light chain comprising the amino acid sequence of SEQ ID NO: 139.

[0230] (5)S-60-14 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO:55; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO:58. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-14. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-14.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-14 or SEQ ID NO: 55, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-14, (b) the HVR-H2 amino acid sequence of antibody S-60-14, and (c) the HVR-H3 amino acid sequence of antibody S-60-14. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-14 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-14 or SEQ ID NO: 58, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-14, (b) the HVR-L2 amino acid sequence of antibody S-60-14, and (c) the HVR-L3 amino acid sequence of antibody S-60-14.

[0231] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 140. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136 and a light chain comprising the amino acid sequence of SEQ ID NO: 140.

[0232] (6)S-60-15 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO:57. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-15 or SEQ ID NO: 56, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-15, (b) the HVR-H2 amino acid sequence of antibody S-60-15, and (c) the HVR-H3 amino acid sequence of antibody S-60-15. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15 or the amino acid sequence of SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-15 or SEQ ID NO: 57, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-15, (b) the HVR-L2 amino acid sequence of antibody S-60-15, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.

[0233] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 139.

[0234] (7) S-60-15.1 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO:60. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15.1. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15.1.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-15.1 or SEQ ID NO: 56, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-15.1, (b) the HVR-H2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-H3 amino acid sequence of antibody S-60-15.1. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-15.1 or the amino acid sequence of SEQ ID NO: 60. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-15.1 or SEQ ID NO: 60, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-15.1, (b) the HVR-L2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.1.

[0235] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 142. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.

[0236] (8)S-60-16 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO:77. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-16. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-16.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-16 or SEQ ID NO: 56, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-16, (b) the HVR-H2 amino acid sequence of antibody S-60-16, and (c) the HVR-H3 amino acid sequence of antibody S-60-16. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-16 or the amino acid sequence of SEQ ID NO: 77. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-16 or SEQ ID NO: 77, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-16, (b) the HVR-L2 amino acid sequence of antibody S-60-16, and (c) the HVR-L3 amino acid sequence of antibody S-60-16.

[0237] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 131. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 131.

[0238] (9)S-60-18 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO:78. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-18. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-18.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-18 or SEQ ID NO: 56, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-18, (b) the HVR-H2 amino acid sequence of antibody S-60-18, and (c) the HVR-H3 amino acid sequence of antibody S-60-18. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-18 or the amino acid sequence of SEQ ID NO: 78. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-18 or SEQ ID NO: 78, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-18, (b) the HVR-L2 amino acid sequence of antibody S-60-18, and (c) the HVR-L3 amino acid sequence of antibody S-60-18.

[0239] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 132.

[0240] (10)S-60-19 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO:54; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO:79. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-19. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-19.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-19 or SEQ ID NO: 54, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-19, (b) the HVR-H2 amino acid sequence of antibody S-60-19, and (c) the HVR-H3 amino acid sequence of antibody S-60-19. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-19 or the amino acid sequence of SEQ ID NO: 79. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-19 or SEQ ID NO: 79, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-19, (b) the HVR-L2 amino acid sequence of antibody S-60-19, and (c) the HVR-L3 amino acid sequence of antibody S-60-19.

[0241] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106 and a light chain comprising the amino acid sequence of SEQ ID NO: 133.

[0242] (11)S-60-24 In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO:56; and / or the light chain variable domain comprises an amino acid sequence at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO:80. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-24. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-24.In some embodiments, an anti-Sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VH sequence of antibody S-60-24 or SEQ ID NO: 56, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody S-60-24, (b) the HVR-H2 amino acid sequence of antibody S-60-24, and (c) the HVR-H3 amino acid sequence of antibody S-60-24. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but wherein the anti-Sortilin antibody comprising that sequence retains the ability to bind to Sortilin.In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody S-60-24 or the amino acid sequence of SEQ ID NO: 80. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-Sortilin antibody comprises the VL sequence of antibody S-60-24 or SEQ ID NO: 80, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody S-60-24, (b) the HVR-L2 amino acid sequence of antibody S-60-24, and (c) the HVR-L3 amino acid sequence of antibody S-60-24.

[0243] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain comprising the amino acid sequence of SEQ ID NO: 134. In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 134.

[0244] In some embodiments, an anti-Sortilin antibody of the disclosure binds to essentially the same Sortilin epitope as an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, and S-60-24.

[0245] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-10. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-10.

[0246] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-11. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-11.

[0247] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-12. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-12.

[0248] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-13. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-13.

[0249] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-14. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-14.

[0250] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-15. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-15.

[0251] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-15.1. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-15.1.

[0252] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-16. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-16.

[0253] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-18. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-18.

[0254] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-19. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-19.

[0255] In some embodiments, the anti-Sortilin antibody is anti-Sortilin monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody that binds to essentially the same Sortilin epitope as S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region of monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the light chain variable region of monoclonal antibody S-60-24. In some embodiments, the anti-Sortilin antibody is an isolated antibody comprising the heavy chain variable region and light chain variable region of monoclonal antibody S-60-24.

[0256] In certain embodiments, the anti-Sortilin antibody is an antagonist antibody. In certain embodiments, the anti-Sortilin antibody is an agonist antibody. In some embodiments, the anti-Sortilin antibody of the present disclosure is of the IgG class, the IgM class, or the IgA class. In some embodiments, the anti-Sortilin antibody of the present disclosure is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

[0257] Additional anti-Sortilin antibodies, e.g., antibodies that specifically bind to a Sortilin protein of the present disclosure, can be identified, screened, and / or characterized for their physical / chemical properties and / or biological activity by a variety of assays known in the art.

[0258] Certain aspects of the present disclosure relate to the use of two or more anti-Sortilin antibodies that exhibit additive or synergistic effects when used together compared to the use of a corresponding single anti-Sortilin antibody.

[0259] In some embodiments, the anti-Sortilin antibodies of the present disclosure are antibody fragments that bind to human Sortilin protein.

[0260] In some embodiments, the anti-Sortilin antibodies of the present disclosure are antibody fragments that bind to one or more human proteins selected from the group consisting of human Sortilin, naturally occurring variants of human Sortilin, and disease variants of human Sortilin.

[0261] In some embodiments, the anti-Sortilin antibodies of the disclosure are antibody fragments that are Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragments.

[0262] Antibody Framework In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, three or more, or all four) framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4 (as set forth in Tables 20-23). ​​In some embodiments, VH FR1 comprises the sequence QVQLQESGPGLVKPSETLSL TCAVSG (SEQ ID NO: 35). In some embodiments, VH FR2 comprises the sequence WIRQPPGKGLEWIG (SEQ ID NO: 36). In some embodiments, VH FR3 comprises a sequence according to Formula VI: X1VTISVDTSKNQFSLX2LSSVTAADTAVYYC (SEQ ID NO: 39), where X1 is Q or R and X2 is E or K. In some embodiments, VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 37-38. In some embodiments, VH FR4 comprises the sequence WGQGTTVTVSS (SEQ ID NO: 40). In some embodiments, the antibody comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 according to Formula VI, and a VH FR4 comprising the sequence of SEQ ID NO: 40.

[0263] In some embodiments, the antibody comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 comprising a sequence selected from SEQ ID NOs: 37-38, and a VH FR4 comprising the sequence of SEQ ID NO: 40.

[0264] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33H], S-60-15.10[N33R], S-60-15.11[N33R], S-60-15.12[N33H], S-60-15.13[N33K], S-60-15.14[N33Q], S-60-15.15[N33Q], S-60-15.16[N33Q], S-60-15.17[N33Q], S-60-15.18[N33Q], S-60-15.19[N33Q], S-60-15.20[N33Q], S-60-15.21[N33Q], S-60-15.22[N33Q], S-60-15.23[N33Q], S-60-15.24[N33Q], S-60-15.25[N33Q], S-60-15.26[N33Q] ], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Tables 20-23).

[0265] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising one or more (e.g., one or more, two or more, three or more, or all four) framework regions selected from VL FR1, VL FR2, VL FR3, and VL FR4 (as set forth in Tables 24-27). In some embodiments, VL FR1 comprises a sequence according to Formula VII: DIVMTQSPLSLPVTPGX1X2ASISC (SEQ ID NO: 44) where X1 is E or G and X2 is P or S. In some embodiments, VL FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 41-43. In some embodiments, VL FR2 comprises a sequence according to Formula VIII: WYLQKPGQX1PQLLIY (SEQ ID NO: 47) where X1 is S or P. In some embodiments, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 45-46. In some embodiments, VL FR3 comprises a sequence according to Formula IX: GVPDRX1SGSGSGT DFTLKISRX2EAEDVGX3YYC (SEQ ID NO: 52), where Xi is F or L, X2 is A or V, and X3 is V or A. In some embodiments, VL FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 48-51. In some embodiments, VL FR4 comprises the sequence FGGGTKVEIK (SEQ ID NO: 53). In some embodiments, an anti-Sortilin antibody of the disclosure comprises a light chain variable region comprising a VL FR1 comprising a sequence according to Formula VII, a VL FR2 comprising a sequence according to Formula VIII, a VL FR3 comprising a sequence according to Formula IX, and a VL FR4 comprising the sequence of SEQ ID NO: 53.

[0266] In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a light chain variable region comprising a VL FR1 comprising a sequence selected from SEQ ID NOs: 41-43, a VL FR2 comprising a sequence selected from SEQ ID NOs: 45-46, a VL FR3 comprising a sequence selected from SEQ ID NOs: 48-51, and a VL FR4 comprising the sequence of SEQ ID NO: 53.

[0267] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33H], S-60-15.10[N33R], S-60-15.11[N33R], S-60-15.12[N33H], S-60-15.13[N33K], S-60-15.14[N33Q], S-60-15.15[N33Q], S-60-15.16[N33Q], S-60-15.17[N33Q], S-60-15.18[N33Q], S-60-15.19[N33Q], S-60-15.20[N33Q], S-60-15.21[N33Q], S-60-15.22[N33Q], S-60-15.23[N33Q], S-60-15.24[N33Q], S-60-15.25[N33Q], S-60-15.26[N33Q] ], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Tables 24-27).

[0268] In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising one or more (e.g., one or more, two or more, three or more, or all four) framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4 (as shown in Tables 20-23), and a light chain variable region comprising one or more (e.g., one or more, two or more, three or more, or all four) framework regions selected from VL FR1, VL FR2, VL FR3, and VL FR4 (as shown in Tables 24-27). In some embodiments, an anti-Sortilin antibody of the disclosure comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 according to Formula VI, and a VH FR4 comprising the sequence of SEQ ID NO: 40; and a light chain variable region comprising a VL FR1 comprising the sequence according to Formula VII, a VL FR2 comprising the sequence according to Formula VIII, a VL FR3 comprising the sequence according to Formula IX, and a VL FR4 comprising the sequence of SEQ ID NO: 53. In some embodiments, an anti-Sortilin antibody of the present disclosure comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO: 35, a VH FR2 comprising the sequence of SEQ ID NO: 36, a VH FR3 comprising a sequence selected from SEQ ID NOs: 37-38, and a VH FR4 comprising the sequence of SEQ ID NO: 40; and a light chain variable region comprising a VL FR1 comprising a sequence selected from SEQ ID NOs: 41-43, a VL FR2 comprising a sequence selected from SEQ ID NOs: 45-46, a VL FR3 comprising a sequence selected from SEQ ID NOs: 48-51, and a VL FR4 comprising the sequence of SEQ ID NO: 53.

[0269] In some embodiments, the anti-Sortilin antibodies of the disclosure are selected from the group consisting of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33H], S-60-15.10[N33R], S-60-15.11[N33R], S-60-15.12[N33H], S-60-15.13[N33K], S-60-15.14[N33Q], S-60-15.15[N33Q], S-60-15.16[N33Q], S-60-15.17[N33Q], S-60-15.18[N33Q], S-60-15.19[N33Q], S-60-15.20[N33Q], S-60-15.21[N33Q], S-60-15.22[N33Q], S-60-15.23[N33Q], S-60-15.24[N33Q], S-60-15.25[N33Q], S-60-15.26[N33Q] ], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Tables 20-23). The heavy chain variable region containing FR4, and antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33H], S-60-15.10[N33H], S-60-15.11[N33K], S-60-15.12[N33K], S-60-15.13[N33K], S-60-15.14[N33K], S-60-15.15[N33K], S-60-15.16[N33K], S-60-15.17[N33K], S-60-15.18[N33K], S-60-15.19[N33K], S-60-15.20[N33K], S-60-15.21[N33K], S-60-15.22[N33K], S-60-15.23[N33K], S-60-15.24[N33K], S-60-15.25[N33K], S-60-15.26[N33K], S-60-15.27 and a light chain variable region comprising VL FR1, VL FR2, VL FR3, and VL FR4 of S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16;S-60-18, S-60-19, or S-60-24 (as shown in Tables 24-27).

[0270] Anti-sortilin antibody activity In certain aspects of any of the anti-Sortilin antibodies, the anti-Sortilin antibodies of the present disclosure can inhibit one or more activities of a Sortilin protein, including, but not limited to, decreasing cellular levels of Sortilin (e.g., cell surface levels of Sortilin, intracellular levels of Sortilin, and / or total levels of Sortilin); increasing Progranulin levels (e.g., extracellular levels of Progranulin and / or cellular Progranulin levels); and inhibiting the interaction (e.g., binding) between Progranulin and Sortilin. As contemplated herein, the anti-Sortilin antibodies of the present disclosure may inhibit additional activities of Sortilin protein, including, but not limited to, inhibiting interaction with (e.g., binding to) one or more of the pro-neurotrophins of the present disclosure (such as pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro-BDNF), the neurotrophins of the present disclosure (such as neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Abeta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), and receptor-associated protein (RAP); reducing the secretion of PCSK9; reducing the production of beta-amyloid peptide.

[0271] In certain embodiments, the disclosure provides anti-Sortilin antibodies that (a) increase extracellular levels of Progranulin, decrease cellular levels of Sortilin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof; (b) decrease cell surface levels of Sortilin, increase extracellular levels of Progranulin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof; (c) decrease cell surface levels of Sortilin, decrease intracellular levels of Sortilin, decrease total levels of Sortilin, or any combination thereof; (d) induce Sortilin degradation, Sortilin cleavage, Sortilin internalization, Sortilin downregulation, or any combination thereof; (e) decrease cellular levels of Sortilin and inhibit the interaction between Sortilin and Progranulin; (f) decrease cellular levels of Sortilin and increase cellular levels of Progranulin; and / or (g) increase the effective concentration of Progranulin.

[0272] In certain embodiments, the present disclosure provides anti-Sortilin antibodies that reduce cell surface levels of Sortilin, increase extracellular levels of Progranulin, inhibit the interaction between Sortilin and Progranulin, or any combination thereof.

[0273] In some embodiments, the anti-Sortilin antibodies of the disclosure (a) inhibit cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 150 pM, as measured by flow cytometry. 50(b) reduce cell surface levels of Sortilin by more than about 50% at 1.25 nM IgG, more than about 80% at 0.63 nM IgG, or more than about 69% at 150 nM IgG compared to a control, as measured by flow cytometry; increase Progranulin secretion by more than about 1.13-fold over a control at 0.63 nM IgG, or more than about 1.22-fold over a control at 50 nM IgG, as measured by standard ELISA; increase Progranulin binding to Sortilin by a median effective concentration (EC ) of less than 0.325 nM, as measured by flow cytometry. 50 ) blocks the binding of Progranulin to Sortilin by greater than about 88% at 50 nM IgG or greater than about 27.5% at 150 nM IgG compared to a control, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0274] In some embodiments, the anti-Sortilin antibodies of the disclosure (a) inhibit cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 681 pM, as measured by flow cytometry. 50 (b) reduce cell surface levels of Sortilin by more than about 40% at 1.25 nM IgG, more than about 29% at 0.6 nM IgG, or more than about 62% at 150 nM IgG compared to control, as measured by flow cytometry; (c) increase Progranulin secretion by more than about 1.11-fold over control at 0.63 nM IgG or more than about 1.75-fold over control at 50 nM IgG, as measured by standard ELISA; (d) increase Progranulin binding to Sortilin by a median effective concentration (EC) of less than 0.751 nM, as measured by flow cytometry. 50 (e) blocks the binding of Progranulin to Sortilin by greater than about 90% at 50 nM IgG or greater than about 95% at 150 nM IgG compared to a control, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0275] Decreased sortilin levels In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to a Sortilin protein of the present disclosure that is expressed on the surface of a cell and modulate (e.g., induce or inhibit) one or more Sortilin activities of the present disclosure after binding to the surface-expressed Sortilin protein.

[0276] In some embodiments, anti-Sortilin antibodies of the present disclosure reduce cellular levels of Sortilin in vitro. In some embodiments, anti-Sortilin antibodies of the present disclosure may reduce cellular levels of Sortilin in vivo (e.g., in the brain and / or peripheral organs of an individual). In some embodiments, reducing cellular levels of Sortilin comprises reducing cell surface levels of Sortilin. As used herein, an anti-Sortilin antibody reduces cell surface levels of Sortilin if it induces a reduction in cell surface levels of Sortilin at saturating antibody concentrations (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or compared to a control antibody (e.g., an anti-Sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to S-60), as measured by any in vitro cellular assay or suitable in vivo model described herein or known in the art. In some embodiments, reducing cellular levels of Sortilin comprises reducing intracellular levels of Sortilin. As contemplated herein, an anti-Sortilin antibody reduces intracellular levels of Sortilin when it induces a decrease in intracellular levels of Sortilin at saturating antibody concentrations and / or compared to a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60) as measured by any in vitro cellular assay or suitable in vivo model described herein or known in the art. In some embodiments, a decrease in cellular levels of Sortilin comprises a decrease in total levels of Sortilin. As contemplated herein, an anti-Sortilin antibody reduces total levels of Sortilin when it induces a decrease in total levels of Sortilin at saturating antibody concentrations and / or compared to a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60) as measured by any in vitro cellular assay or suitable in vivo model described herein or known in the art.

[0277] As used herein, the level of sortilin may refer to the expression level of the gene encoding sortilin; the expression level of one or more transcripts encoding sortilin; the expression level of sortilin protein; and / or the amount of sortilin protein present in the cell and / or on the cell surface. Any method known in the art for measuring the levels of gene expression, transcription, translation, and / or protein amount or localization can be used to determine the level of sortilin.

[0278] Cellular levels of Sortilin can refer to, but are not limited to, cell surface levels of Sortilin, intracellular levels of Sortilin, and total levels of Sortilin. In some embodiments, reducing cellular levels of Sortilin includes reducing cell surface levels of Sortilin. In some embodiments, anti-Sortilin antibodies of the present disclosure that reduce cellular levels of Sortilin (e.g., cell surface levels of Sortilin) ​​have one or more of the following characteristics: (1) inhibiting or reducing one or more Sortilin activities; (2) the ability to inhibit or reduce binding of Sortilin to one or more of its ligands; (3) the ability to reduce Sortilin expression in Sortilin-expressing cells; (4) the ability to interact with, bind to, or recognize Sortilin protein; (5) the ability to specifically interact with and bind to Sortilin protein; and (6) the ability to treat, ameliorate, or prevent any aspect of a disease or disorder described or contemplated herein.

[0279] In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce downregulation of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce cleavage of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce internalization of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce shedding of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce degradation of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure induce desensitization of Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure act as a ligand mimetic that transiently activates Sortilin. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure act as a ligand mimetic to transiently activate Sortilin and subsequently induce a decrease in cellular levels of Sortilin and / or inhibition of the interaction (e.g., binding) between Sortilin and one or more Sortilin ligands. In some embodiments, an isolated anti-Sortilin antibody of the present disclosure acts as a ligand mimetic to transiently activate Sortilin and subsequently induce Sortilin degradation. In some embodiments, an isolated anti-Sortilin antibody of the present disclosure acts as a ligand mimetic to transiently activate Sortilin and subsequently induce Sortilin cleavage. In some embodiments, an isolated anti-Sortilin antibody of the present disclosure acts as a ligand mimetic to transiently activate Sortilin and subsequently induce Sortilin internalization. In some embodiments, an isolated anti-Sortilin antibody of the present disclosure acts as a ligand mimetic to transiently activate Sortilin and subsequently induce Sortilin shedding. In some embodiments, an isolated anti-Sortilin antibody of the present disclosure acts as a ligand mimetic to transiently activate Sortilin and subsequently induce downregulation of Sortilin expression. In some embodiments, the isolated anti-Sortilin antibodies of the present disclosure act as ligand mimetics to transiently activate Sortilin and subsequently induce desensitization of Sortilin.

[0280] In certain embodiments, the anti-Sortilin antibodies of the present disclosure may reduce cellular levels of Sortilin (e.g., cell surface levels of Sortilin, intracellular levels of Sortilin, and / or total levels of Sortilin) ​​by inducing Sortilin degradation. Thus, in some embodiments, the anti-Sortilin antibodies of the present disclosure induce Sortilin degradation.

[0281] The anti-Sortilin antibodies of the present disclosure have median effective concentrations (EC 50 ) (e.g., as measured in vitro) may reduce cellular levels (e.g., cell surface levels) of sortilin. In certain embodiments, the EC 50 In certain embodiments, the EC of the antibody is less than about 680.9 pM. 50 In certain embodiments, the EC of the antibody is between about 72.58 pM and about 680.9 nM. 50 In certain embodiments, the EC of the antibody is from about 103.6 pM to about 680.9 nM. 50 is less than about 600 pM, 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 1 pM, or 0.5 pM.

[0282] In some embodiments, the EC 50 is about 675 pM, 650 pM, 625 pM, 600 pM, 575 pM, 550 pM, 525 pM, 500 pM, 475 pM, 450 pM, 425 pM, 400 pM, 375 pM, 350 pM, 325 pM, 300 pM, 275 pM, 250 pM, 225 pM, 200 pM, 175 pM, 150 pM, 125 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, or 0.5 pM or less.

[0283] In some embodiments, the EC 50 In some embodiments, the EC50 of the antibody is less than about 680.9 pM. 50is about 0.1 pM, 0.5 pM, 1 pM, 10 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 125 pM, 150 pM, 175 pM, 200 pM, 225 pM, 250 pM, 275 pM, 300 pM, 325 pM, 350 pM, 375 pM, 400 pM, 425 pM, 450 pM, 475 pM, 500 pM, 525 pM, 550 pM, 575 pM, 600 pM, 625 pM, 650 pM, 675 pM or more. 50 are upper limits of about 675 pM, 650 nM, 650 pM, 625 pM, 600 pM, 575 pM, 550 pM, 525 pM, 500 pM, 475 pM, 450 pM, 425 pM, 400 pM, 375 pM, 350 pM, 325 pM, 300 pM, 275 pM, 250 pM, 225 pM, 200 pM, 175 pM, 150 pM, 125 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 1 pM, or 0.5 pM, and upper limits of about 0.1 pM, 0.5 pM, 1 pM, 10 In some embodiments, the EC of the antibody may be any of a range having a lower limit independently selected from 20 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 125 pM, 150 pM, 175 pM, 200 pM, 225 pM, 250 pM, 275 pM, 300 pM, 325 pM, 350 pM, 375 pM, 400 pM, 425 pM, 450 pM, 475 pM, 500 pM, 525 pM, 550 pM, 575 pM, 600 pM, 625 pM, 650 pM, or 675 pM, where the lower limit is less than the upper limit. 50is approximately 1pM, 2pM, 3pM, 4pM, 5pM, 6pM, 7pM, 8pM, 9pM, 10pM, 15pM, 20pM, 25pM, 30pM, 35pM, 40pM, 45pM, 50pM, 55pM, 60pM, 65pM, 70pM, 75pM, 80pM, 85pM, 90pM, 95pM, 100pM , 105pM, 110pM, 115pM, 120pM, 125pM, 130pM, 135pM, 140pM, 145pM, 150pM, 155pM, 160pM, 165pM, 170pM, 175pM, 180pM, 185pM, 190pM, 195pM, or 200pM.

[0284] In some embodiments, the anti-Sortilin antibodies of the disclosure inhibit cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 150 pM, as measured by flow cytometry. 50 In some embodiments, the EC 50 In some embodiments, the EC of the anti-Sortilin antibodies of the disclosure is about 103.6 pM. 50 is approximately 72.58 pM.

[0285] In some embodiments, anti-Sortilin antibodies of the present disclosure reduce cell surface levels of Sortilin by more than about 40% at 1.25 nM IgG or more than about 80% at 0.63 nM IgG as measured by flow cytometry. In some embodiments, anti-Sortilin antibodies of the present disclosure reduce cell surface levels of Sortilin by about 60.92% at 1.25 nM IgG as measured by flow cytometry. In some embodiments, anti-Sortilin antibodies of the present disclosure reduce cell surface levels of Sortilin by about 69.3% at 150 nM IgG as measured by flow cytometry. In some embodiments, anti-Sortilin antibodies of the present disclosure reduce cell surface levels of Sortilin by about 70.3% at 150 nM IgG as measured by flow cytometry.

[0286] For example, antibody ECs, including by flow cytometry (see, e.g., Example 2) 50Various methods for measuring EC values ​​are known in the art. 50 is measured in vitro using cells genetically engineered to express human sortilin. 50 is measured at a temperature of about 4° C. In some embodiments, EC 50 is measured at a temperature of about 25° C. In some embodiments, EC 50 is measured at a temperature of about 35° C. In some embodiments, EC 50 is measured at a temperature of about 37° C. In some embodiments, EC 50 is determined using a monovalent antibody (e.g., Fab) or a monovalent form of a full-length antibody. In some embodiments, EC 50 is determined using an antibody containing a constant region that exhibits enhanced Fc receptor binding. 50 is determined using antibodies containing constant regions that exhibit reduced Fc receptor binding.

[0287] In some embodiments, the anti-Sortilin antibodies of the present disclosure have greater efficacy in reducing cell surface levels of Sortilin than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the present disclosure have a lower EC 50 In some embodiments, an anti-Sortilin antibody of the disclosure reduces the cellular levels (e.g., cell surface levels) of Sortilin (e.g., as measured in vitro). In some embodiments, an anti-Sortilin antibody of the disclosure reduces the cellular levels (e.g., cell surface levels) of Sortilin by more than the EC50 of a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% lower than 50 In some embodiments, the anti-Sortilin antibodies of the disclosure reduce cellular levels (e.g., cell surface levels) of Sortilin at an EC20 level greater than that of a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 at least about 1 fold, at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 12.5 fold, at least about 15 fold, at least about 17.5 fold, at least about 20 fold, at least about 22.5 fold, at least about 25 fold, at least about 27.5 fold, at least about 30 fold, at least about 50 fold, or at least about 100 fold lower EC 50 Decreases by.

[0288] In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 1.5-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 1.1-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 It has.

[0289] In some embodiments, the anti-Sortilin antibodies of the disclosure (a) inhibit cell surface levels of Sortilin at a 50% effective concentration (EC) of less than 681 pM, as measured by flow cytometry. 50(b) reduce cell surface levels of Sortilin by more than about 40% at 1.25 nM IgG, more than about 29% at 0.6 nM IgG, or more than about 62% at 150 nM IgG compared to control, as measured by flow cytometry; (c) increase Progranulin secretion by more than about 1.11-fold over control at 0.63 nM IgG or more than about 1.75-fold over control at 50 nM IgG, as measured by standard ELISA; (d) increase Progranulin binding to Sortilin by a median effective concentration (EC) of less than 0.751 nM, as measured by flow cytometry. 50 (e) blocks the binding of Progranulin to Sortilin by greater than about 90% at 50 nM IgG or greater than about 95% at 150 nM IgG compared to a control, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0290] Increased progranulin levels In some embodiments, anti-Sortilin antibodies of the present disclosure increase extracellular levels of Progranulin in vitro. In some embodiments, anti-Sortilin antibodies of the present disclosure may increase cellular levels of Progranulin in vivo (e.g., in the brain, blood, and / or peripheral organs of an individual). As used herein, an anti-Sortilin antibody increases extracellular levels of Progranulin when it induces an increase in extracellular levels of Progranulin at saturating antibody concentrations (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or compared to a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60), as measured by any in vitro cell or tissue (such as brain tissue) assay described herein or known in the art. As contemplated herein, an anti-Sortilin antibody increases cellular levels of Progranulin when the anti-Sortilin antibody induces an increase in the level of cellular Progranulin at saturating antibody concentrations (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or compared to a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60) as measured by any in vitro cell or tissue (such as brain tissue) assay described herein or known in the art.

[0291] As used herein, the level of Progranulin may refer to the expression level of the gene encoding Progranulin; the expression level of one or more transcripts encoding Progranulin; the expression level of Progranulin protein; and / or the amount of Progranulin protein secreted from a cell and / or present in the cell. The level of Progranulin can be determined using any method known in the art for measuring the levels of gene expression, transcription, translation, protein amount, protein secretion, and / or localization.

[0292] As used herein, progranulin levels may refer to, but are not limited to, extracellular levels of progranulin, intracellular levels of progranulin, and total levels of progranulin. In some embodiments, increased levels of progranulin include increased extracellular levels of progranulin.

[0293] In some embodiments, an anti-Sortilin antibody of the present disclosure increases progranulin secretion by more than about 1.11-fold over a control at 0.63 nM IgG as measured by standard ELISA. In some embodiments, an anti-Sortilin antibody of the present disclosure increases progranulin secretion by more than about 1.42-fold over a control at 0.63 nM IgG as measured by standard ELISA. In some embodiments, an anti-Sortilin antibody of the present disclosure increases progranulin secretion by more than about 1.75-fold over a control at 50 nM IgG as measured by standard ELISA. In some embodiments, an anti-Sortilin antibody of the present disclosure increases progranulin secretion by about 1.97-fold over a control at 50 nM IgG as measured by standard ELISA. In some embodiments, an anti-Sortilin antibody of the present disclosure increases progranulin secretion by about 2.29-fold over a control at 50 nM IgG as measured by standard ELISA.

[0294] Various methods for measuring progranulin secretion are known in the art, including, for example, by ELISA (see, e.g., Examples 2 and 4). 50 is measured in vitro using cells expressing human sortilin. In some embodiments, progranulin secretion is determined using a monovalent antibody (e.g., Fab) or a monovalent form of a full-length antibody. In some embodiments, progranulin secretion is determined using an antibody containing a constant region that exhibits enhanced Fc receptor binding. In some embodiments, progranulin secretion is determined using an antibody containing a constant region that exhibits reduced Fc receptor binding.

[0295] In some embodiments, the anti-Sortilin antibodies of the present disclosure have greater efficacy in increasing Progranulin levels than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the present disclosure increase Progranulin levels (e.g., extracellular levels) with a lower EC 50 In some embodiments, an anti-Sortilin antibody of the disclosure increases levels (e.g., extracellular levels) of Progranulin by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% compared to a control antibody (e.g., an anti-Sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the disclosure increase levels of Progranulin (e.g., extracellular levels) by about 1-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 12.5-fold, at least about 15-fold, at least about 17.5-fold, at least about 20-fold, at least about 22.5-fold, at least about 25-fold, at least about 27.5-fold, at least about 30-fold, at least about 50-fold, or at least about 100-fold greater than a control antibody (e.g., an anti-Sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to S-60).

[0296] In some embodiments, the anti-Sortilin antibodies of the present disclosure elevate Progranulin levels by about 1.1-fold more than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the present disclosure elevate Progranulin levels by about 1.3-fold more than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60).

[0297] In some embodiments, the anti-Sortilin antibody of the present disclosure increases the effective concentration of Progranulin. The effective concentration of Progranulin refers to the concentration of Progranulin in plasma or cerebrospinal fluid. In some embodiments, the increase in the effective concentration of Progranulin is greater than 1.5-fold. In some embodiments, the effective concentration of Progranulin is increased over a period of 7 to 28 days.

[0298] Decreased interaction between sortilin and binding partners In certain embodiments, an anti-Sortilin antibody inhibits interaction (e.g., binding) between a Sortilin protein of the present disclosure and one or more proteins selected from progranulin, pro-neurotrophin, neurotrophin, 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), brain-derived neurotrophic factor (BDNF), neurotensin, p75, Sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Abeta peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP), and / or naturally occurring variants. In a specific embodiment, an anti-Sortilin antibody of the present disclosure inhibits the interaction (e.g., binding) between a Sortilin protein of the present disclosure and Progranulin.

[0299] In some embodiments, an anti-Sortilin antibody may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and a neurotrophin of the present disclosure, such as pro-neurotrophin, pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, and BDNF. In other embodiments, an anti-Sortilin antibody may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and neurotensin. In other embodiments, an anti-Sortilin antibody may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and p75. In other embodiments, an anti-Sortilin antibody may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and Sort-pro. In other embodiments, an anti-Sortilin antibody may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and APP. In other embodiments, an anti-Sortilin antibody may inhibit the production of Abeta peptide. In other embodiments, anti-Sortilin antibodies may inhibit the trafficking and secretion of PCSK9. In other embodiments, anti-Sortilin antibodies may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and LpL. In other embodiments, anti-Sortilin antibodies may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and APOA5. In other embodiments, anti-Sortilin antibodies may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and APOA5. In other embodiments, anti-Sortilin antibodies may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and APOE. In other embodiments, anti-Sortilin antibodies may inhibit the interaction (e.g., binding) between a Sortilin protein of the present disclosure and RAP.

[0300] In some embodiments, an anti-Sortilin antibody of the present disclosure binds to a Sortilin protein of the present disclosure expressed on the surface of a cell, and the naked antibody inhibits the interaction (e.g., binding) between the Sortilin protein and one or more Sortilin ligands. In some embodiments, an anti-Sortilin antibody of the present disclosure that binds to the Sortilin protein inhibits the interaction (e.g., binding) between the Sortilin protein and one or more Sortilin ligands by reducing the effective level of Sortilin available to interact with these proteins on the cell surface or inside the cell. In some embodiments, an anti-Sortilin antibody of the present disclosure that binds to the Sortilin protein inhibits the interaction (e.g., binding) between the Sortilin protein and one or more Sortilin ligands by inducing degradation of Sortilin.

[0301] A. Decreased interaction between sortilin and progranulin In some embodiments, anti-Sortilin antibodies of the present disclosure increase Progranulin levels and / or decrease cellular levels of Sortilin while blocking (e.g., inhibiting) the interaction (e.g., binding) between Sortilin and Progranulin. Thus, in some embodiments, anti-Sortilin antibodies of the present disclosure block the interaction (e.g., binding) between Sortilin and Progranulin. As used herein, an anti-Sortilin antibody blocks the interaction (e.g., binding) between Sortilin and Progranulin if it reduces Progranulin binding to Sortilin compared to a control antibody (e.g., an anti-Sortilin antibody having heavy chain variable regions and light chain variable regions corresponding to S-60) at a saturating antibody concentration (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) in any in vitro or cell culture assay described herein or known in the art.

[0302] The anti-Sortilin antibodies of the present disclosure inhibit Progranulin binding to Sortilin at a median effective concentration (EC 50) (e.g., as measured in vitro). In certain embodiments, the EC 50 In certain embodiments, the EC 50 In certain embodiments, the EC of the antibody is less than about 1.22 nM. 50 In certain embodiments, the EC of the antibody is less than about 751 pM. 50 In certain embodiments, the EC of the antibody is between about 325 pM and about 751 nM. 50 In certain embodiments, the EC of the antibody is between about 405 pM and about 751 nM. 50 In certain embodiments, the EC of the antibody is between about 588 pM and about 751 nM. 50 is less than about 2.2 nM, 2.1 nM, 2.0 nM, 1.9 nM, 1.8 nM, 1.7 nM, 1.6 nM, 1.5 nM, 1.4 nM, 1.3 nM, 1.2 nM, 1.1 nM, 1.0 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 1 pM, or 0.5 pM.

[0303] In some embodiments, the EC of an antibody to reduce Progranulin binding to Sortilin 50 are approximately 2.2nM, 2.1nM, 2.0nM, 1.9nM, 1.8nM, 1.7nM, 1.6nM, 1.5nM, 1.4nM, 1.3nM, 1.2nM, 1.1nM, 1.0nM, 900pM, 800pM, 700pM, 600pM, 500pM, 475pM, 450pM, 425pM, 400pM, 375pM, 350pM, 325pM 300pM, 275pM, 250pM, 225pM, 200pM, 175pM, 150pM, 125pM, 100pM, 90pM, 80pM, 70pM, 60pM, 50pM, 40pM, 30pM, 20pM, 10pM, 9pM, 8pM, 7pM, 6pM, 5pM, 4pM, 3pM, 2pM, 1pM, or 0.5pM or less.

[0304] In some embodiments, the EC of the anti-Sortilin antibody of the disclosure 50In some embodiments, the EC50 of the anti-Sortilin antibodies of the disclosure is about 1.22 nM. 50 In some embodiments, the EC of the anti-Sortilin antibodies of the disclosure is about 588 pM. 50 In some embodiments, the EC of the anti-Sortilin antibodies of the disclosure is about 405 pM. 50 is approximately 325 pM.

[0305] For example, antibody ECs, including by flow cytometry (see, e.g., Example 3) 50 Various methods for measuring EC values ​​are known in the art. In some embodiments, the EC values ​​for reducing Progranulin binding to Sortilin are 50 is measured in vitro using cells expressing human sortilin. 50 is measured at a temperature of about 4° C. In some embodiments, EC 50 is measured at a temperature of about 25° C. In some embodiments, EC 50 is measured at a temperature of about 35° C. In some embodiments, EC 50 is measured at a temperature of about 37° C. In some embodiments, the EC 50 is determined using a monovalent antibody (e.g., Fab) or a monovalent form of a full-length antibody. In some embodiments, EC 50 is determined using an antibody containing a constant region that exhibits enhanced Fc receptor binding. In some embodiments, the EC 50 is determined using antibodies containing constant regions that exhibit reduced Fc receptor binding.

[0306] In some embodiments, the anti-Sortilin antibodies of the disclosure have greater efficacy in reducing Progranulin binding to Sortilin than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). In some embodiments, the anti-Sortilin antibodies of the disclosure reduce Progranulin binding to Sortilin with a lower EC 50 In some embodiments, the anti-Sortilin antibodies of the disclosure reduce Progranulin binding to Sortilin by less than the EC2 of a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% lower than 50 In some embodiments, the anti-Sortilin antibodies of the disclosure reduce Progranulin binding to Sortilin by less than the EC2 of a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 at least about 1 fold, at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold, at least about 12.5 fold, at least about 15 fold, at least about 17.5 fold, at least about 20 fold, at least about 22.5 fold, at least about 25 fold, at least about 27.5 fold, at least about 30 fold, at least about 50 fold, or at least about 100 fold lower EC 50 Decrease by.

[0307] In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 1.3-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 1.8-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 1.9-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 In some embodiments, the anti-Sortilin antibodies of the disclosure have an EC that is at least 2.3-fold lower than a control antibody (e.g., an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60). 50 It has.

[0308] Any in vitro cellular assay or suitable in vivo model described herein or known in the art can be used to measure inhibition or reduction of the interaction (e.g., binding) between Sortilin and one or more Sortilin ligands. In some embodiments, the anti-Sortilin antibodies of the present disclosure inhibit or reduce the interaction (e.g., binding) between Sortilin and one or more Sortilin ligands by decreasing Sortilin expression (e.g., by reducing cell surface levels of Sortilin).In some embodiments, the anti-Sortilin antibodies of the disclosure inhibit the interaction (e.g., binding) between Sortilin and one or more Sortilin ligands by at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, ...

Claims

1. An antibody that binds to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, (a) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); (b) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRVS (SEQ ID NO: 30), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33); (c) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO: 3), an HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); (d) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); (e) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); (f) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33); (g) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO: 5); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO: 26), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO: 33); (h) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); (i) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 10), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); or (j) The antibody, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 21), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

2. The anti-sortilin antibody: (a) reduces cell surface levels of Sortilin to a greater extent than the level of reduction caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:56 and a light chain variable region comprising the sequence of SEQ ID NO:79; (b) increasing the extracellular level of Progranulin to a level greater than that caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:56 and a light chain variable region comprising the sequence of SEQ ID NO:79; (c) inhibits the interaction between Sortilin and Progranulin to a greater extent than the level of inhibition caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:56 and a light chain variable region comprising the sequence of SEQ ID NO:79; or (d) The antibody according to claim 1, which performs any combination of (a) to (c).

3. For human Sortilin, the dissociation constant (K) is greater than 1-fold to up to about 2.1-fold lower than an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:56 and a light chain variable region comprising the sequence of SEQ ID NO:

79. Ｄ ) wherein K Ｄ The antibody of claim 1 or claim 2, wherein the antibody is determined by FACS.

4. For human sortilin, the dissociation constant (K Ｄ ) wherein K Ｄ is determined by FACS, or in the range of about 250-500 pM Ｄ wherein K Ｄ The antibody according to any one of claims 1 to 3, wherein said antibody is determined by biolayer interferometry.

5. 1. An antibody that binds to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

6. 1. An antibody that binds to a sortilin protein, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).

7. An antibody that binds to a sortilin protein, (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:59; (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57; (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:58; (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57; (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:77; (h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:78; (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:54, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:79; (j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:80; (k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60; (l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:61; or (m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

72. The antibody comprising:

8. An antibody that binds to a sortilin protein, the antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

60.

9. An antibody that binds to a sortilin protein, the antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

57.

10. An antibody that binds to a sortilin protein, the antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 and a light chain comprising the amino acid sequence of SEQ ID NO:

142.

11. An antibody that binds to a sortilin protein, the antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO:

142.

12. The antibody according to any one of claims 1 to 9, which is of the IgG, IgM or IgA class.

13. 13. The antibody of claim 12, which is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

14. (a) is an IgG1 or IgG2 isotype and the Fc region comprises an amino acid substitution at position P331S, where the numbering of residue positions is according to EU numbering; (b) an IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, where the numbering of residue positions is according to EU numbering; (c) is an IgG1, IgG2, or IgG4 isotype and the Fc region comprises an amino acid substitution at position N297A, where the numbering of residue positions is according to EU numbering; or (d) the antibody of claim 13, wherein the Fc region comprises amino acid substitutions at positions S267E and L328F, the numbering of residue positions being according to EU numbering.

15. 15. The antibody of claim 14, which is of the IgG1 isotype and wherein the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, the numbering of residue positions being according to EU numbering.

16. The antibody of any one of claims 1 to 15, wherein the sortilin protein is a human sortilin protein.

17. The antibody of claim 16, wherein the human sortilin protein comprises the amino acid sequence of SEQ ID NO:

81.

18. The antibody of any one of claims 1 to 16, wherein the sortilin protein is a wild-type protein, a naturally occurring variant, or a disease variant.

19. The antibody of any one of claims 1 to 18, which is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.

20. The antibody of claim 19, which is a bispecific antibody that recognizes a first antigen and a second antigen.

21. 21. The 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 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, poly-arginine peptide, angiopep peptide, basigin, Glut1, CD98hc, and ANG1005.

23. The antibody according to any one of claims 1 to 9 and 12 to 22, which is an antibody fragment that binds to human sortilin protein.

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

25. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of any one of claims 1 to 24.

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

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

28. 30. A method for producing an antibody that binds to sortilin, comprising culturing the host cell of claim 27 so that the antibody is produced.

29. 30. The method of claim 28, further comprising recovering the antibody produced by the host cell.

30. 30. An isolated antibody that binds to Sortilin produced by the method of claim 28 or 29.

31. A pharmaceutical composition comprising the antibody of any one of claims 1 to 24 and claim 30 and a pharma- ceutically acceptable carrier.

32. A method of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury, comprising administering to said individual a therapeutically effective amount of an antibody according to any one of claims 1 to 24 and claim 30 or a pharmaceutical composition according to claim 31.

33. 33. The method of claim 32, wherein the disease, disorder, or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, or osteoarthritis.

34. 34. The method of claim 33, wherein the disease, disorder, or injury is selected from frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, and amyotrophic lateral sclerosis.

35. 32. A method of inhibiting one or more of neuroinflammation, axonal degeneration characterized by short axonal outgrowth and abnormal branching, microglial activation, and inflammatory response in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

36. 32. A method of promoting one or more of wound healing, autophagy, and clearance of aggregated proteins in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

37. 32. A method of preventing, reducing the risk of, or treating arthritis in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

38. 32. A method of reducing expression of one or more proinflammatory mediators in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

39. 39. The method of claim 38, wherein the one or more proinflammatory mediators are selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, and CCL5.

40. A method for inhibiting the interaction between Sortilin and Progranulin, the method comprising exposing a cell expressing Sortilin to an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

41. 41. The method of claim 40, wherein the cell is in vitro.

42. 41. The method of claim 40, wherein the cell is in vivo.

43. 43. The method of any one of claims 40-42, further comprising reducing the level of sortilin expressed at the cell surface.

44. The method according to any one of claims 40 to 43, wherein the extracellular level of progranulin is increased.

45. 32. A method of increasing the level of Progranulin in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

46. 46. ​​The method of claim 45, wherein the level of progranulin is increased in plasma.

47. 46. ​​The method of claim 45, wherein the level of progranulin is increased in cerebrospinal fluid.

48. 32. A method of lowering levels of Sortilin in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-Sortilin antibody of any one of claims 1 to 24 and claim 30 or a pharmaceutical composition of claim 31.

49. 49. The method of claim 48, wherein the level of sortilin is reduced in peripheral white blood cells.

50. 50. The method of any one of claims 32 to 34 and 45 to 49, wherein the individual has one or more mutations in the gene encoding progranulin.

51. 51. The method of claim 50, wherein the individual is heterozygous for one or more loss-of-function mutations in the gene encoding progranulin.

52. 52. The method of claim 50 or claim 51, wherein the individual has or is at risk for frontotemporal dementia, Alzheimer's disease, or amyotrophic lateral sclerosis.

53. The method of any one of claims 32 to 52, wherein the anti-Sortilin antibodies comprise two or more anti-Sortilin antibodies.

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