Anti-sortin antibodies and methods of use thereof

Abstract

The present disclosure relates generally to compositions comprising antibodies, such as monoclonal antibodies, chimeric antibodies, affinity matured antibodies, humanized antibodies, antibody fragments, etc., that specifically bind to sorters, such as human sorters or mammalian sorters, and have improved and / or enhanced functional characteristics; and uses of such compositions in preventing, reducing risk, or treating an individual in need thereof.

Description

[0001] This application is a divisional application of a patent application filed on July 12, 2019, with application number 201980002132.9 and titled “Anti-sortilin antibodies and methods of use thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 698,007, filed on July 13, 2018, U.S. Provisional Application No. 62 / 860,184, filed on June 11, 2019, and U.S. Application No. 62 / 868,849, filed on June 28, 2019, each of which is incorporated herein by reference in its entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under Grant No. R44AG050363 from the National Institutes of Health. The U.S. Government has certain rights in this invention.

[0006] Submit sequence listings as ASCII text files

[0007] The following content, submitted as an ASCII text document, is incorporated herein by reference in its entirety: Sequence Listing in Computer Readable Form (CRF) (File Name: 735022001940SEQLIST.TXT, Record Date: July 10, 2019, Size: 153KB). Technical Field

[0008] The present disclosure relates to anti-sortilin antibodies and therapeutic uses of such antibodies. Background Art

[0009] Sortilin is a type I transmembrane protein that serves as a receptor for several ligands and is used to sort selected cargoes from the trans-Golgi network (TGN) to secondary endosomes and lysosomes for degradation. Sortilin carries a large extracellular domain that is homologous to yeast VPS10P and is part of the VPS10 family, and contains 10 bladed β-propeller structures and a cysteine-rich 10CC module (Nykjaer, A et al., (2012) Trends Neurosci 35:261-270; and Zheng, Y et al., (2011) PLoS One 6:e21023). A small portion of sortilin may be masked by the activity of ADAM10 or γ-secretase (<5%) (Nykjaer, A et al. (2012) Trends Neurosci 35:261-270; and Willnow, TE et al. (2011) Curr Opin Lipidol 22:79-85).

[0010] Sortilin binds to the secreted protein progranulin (PGRN) and targets it for lysosomal degradation, thereby negatively regulating the extracellular levels of PGRN (Hu, F et al. (2010) Neuron 68, 654-667). Consistent with this, the deficiency of sortilin significantly increases plasma PGRN levels in mouse models in vivo and in human cells in vitro (Carrasquillo, MM et al. (2010) Am J Hum Genet 87, 890-897; Lee, WC et al. (2014) Hum Mol Genet 23, 1467-1478). In addition, polymorphisms in sortilin have been shown to be significantly associated with serum levels of PGRN in humans (Carrasquillo MM et al. (2010), Am J Hum Genet. 10; 87(6): 890-7).

[0011] Progranulin (PGRN) is a secreted growth factor-like, nutritional anti-inflammatory 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 hereditary frontotemporal dementia (FTD; an early-onset neurodegenerative disease). In patients with heterozygous loss-of-function mutations in PGRN, extracellular levels of the protein are reduced by approximately 50%, and these patients are invariably diagnosed with FTD, making PGRN a causative gene for the 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, a PGRN mutant allele has been identified in patients with Alzheimer's disease (Seelaar, H et al. (2011). Journal of neurology, neurosurgery, and psychiatry 82, 476-486). Importantly, PGRN plays a protective role in several disease models in which PGRN levels are increased, thereby accelerating behavioral recovery from ischemia (Tao, J et al. (2012) Brain Res 1436, 130-136; Egashira, Y. et al. (2013). J Neuroinflammation 10, 105); inhibiting motor deficits in a Parkinson's disease model (Van Kampen, JM et al. (2014). PLoS One 9, e97032); reducing lesions in models of amyotrophic lateral sclerosis (Laird, AS et al. (2010). PLoS One 5, e13368.) and arthritis (Tang, W et al. (2011). Science 332, 478-484); and preventing memory deficits in an Alzheimer's disease model (Minami, SS et al. (2014). Nat Med 20, 1157-1164).

[0012] Sortilin also directly binds to pro-neurotrophins, such as pro-nerve growth factor (pro-NGF), pro-BDNF, pro-neurotrophin-3, etc., which have a propeptide domain and are typically pro-apoptotic. Such pro-neurotrophin precursors are released during stress, and sortilin is involved in regulating their release and stimulating apoptosis by binding to and associating with p75NTR on receiving cells (Willnow, TE et al. (2008) Nat Rev Neurosci 9:899-909; Nykjaer, A et al., Trends Neurosci 35:261-270; and Nykjaer, A et al. (2004) Nature 427:843-848; Hiroko Yano et al. (2009) J Neurosci.; 29:14790-14802; Teng H.K. et al., J. Neurosci. 25:5455-5463 (2005)). Sortilin also directly binds to p75NTR (Skeldal S et al. (2012) J Biol Chem.; 287: 43798). Sortilin also binds to a region of neurotensin 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 Trk receptors NTRK1, NTRK2, and NTRK3; and can regulate their anterograde axonal transport and signaling (Vaegter, CB et al. (2011) Nat. Neurosci. 14: 54-61). Sortilin also interacts with amyloid precursor protein and regulates the processing and trafficking of the protein and the resulting production of pathogenic amyloid-β peptide (Gustafsen C et al. (2013). J Neurosci. 2; 33 (1): 64-71).

[0013] Additionally, sortilin has been shown to bind to apolipoproteins and lipoprotein lipase; therefore, its deficiency results in decreased VLDL release and decreased cholesterol in the liver (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 direct binding 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), Aβ peptide (Carlo, AS et al. (2013) J. Neurosc, 33: 358-370) and PCSK9 (Gustafsen et al. (2014) Cell Metab, 19: 310-318). Sortilin has also been shown to bind to and regulate the extracellular levels of PCSK9, which directs the low-density lipoprotein receptor for degradation in lysosomes, leading to increased LDL cholesterol levels (Gustafsen C et al. (2014). Cell Metab. 2014 Feb 4;19(2):310-8).

[0014] When sortilin is present in intracellular vesicles such as endosomes, its amino-terminal extracellular domain is directed towards the lumen, where the cargo in the vesicle is located. However, the carboxyl-terminal intracellular / cytoplasmic domain of sortilin is bound to a series of adaptor proteins that regulate the transport of sortilin from the surface and within the intracellular compartment. These adaptor proteins include AP2 (a clathrin adaptor that regulates phagocytosis from the cell surface) and the retromer complex / AP1, which regulates movement from the primary endosome to the Golgi apparatus for recycling; and interacts with GGA (ADP-ribosylation factor binding with γ-adapter protein ears localized to the Golgi apparatus) family proteins to move directly from the Golgi apparatus to the primary endosome, usually followed by lysosomal degradation. Therefore, sortilin can bind to ligands at its lumenal domain while engaging cytoplasmic adaptors, thereby determining the destination of the sortilin to determine its intracellular fate, such as degradation of progranulin and other factors.

[0015] Sortilin and its various ligands have been shown to be involved in a variety of diseases, disorders, and conditions, such as frontotemporal dementia, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis-frontotemporal dementia phenotype, Alzheimer's disease, Parkinson's disease, depression, neuropsychiatric disorders, vascular dementia, seizures, retinal dystrophies, age-related macular degeneration, glaucoma, traumatic brain injury, aging, epileptic seizures, wound healing, stroke, arthritis, and atherosclerotic vascular disease, through various interactions of sortilin with proteins such as progranulins.

[0016] Therefore, there is a need for therapeutic antibodies that specifically bind to sortilin and block the binding of sortilin to its ligand, such as progranulin, or otherwise modulate the effective concentration of the ligand, in order to treat one or more diseases, disorders, and conditions associated with sortilin activity.

[0017] All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0018] The present disclosure generally relates to compositions comprising antibodies, e.g., monoclonal antibodies, chimeric antibodies, humanized antibodies, antibody fragments, etc., that specifically bind human Sortilin and methods of using such compositions.

[0019] In some aspects, the disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises 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 one 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.

[0020] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0021] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0022] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLES (SEQ ID NO: 3), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0023] In some aspects, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0024] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0025] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 10), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0026] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 21), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0027] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0028] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLHSNGYNYLD (SEQ ID NO: 26), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0029] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0030] In some aspects, the disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0031] In some aspects, the disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises a heavy chain variable region having HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0032] In some embodiments of any of the above aspects, the anti-sortilin antibody: (a) reduces cell surface sortilin levels to a greater extent than the 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 progranulin levels to a greater extent than the 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 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 sortilin levels to a greater extent than the 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) increases extracellular progranulin levels to a greater extent than the increase caused by an anti-sortilin antibody selected from the group consisting of (c) inhibits the interaction between sortilin and progranulin to a degree greater 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) any combination of (a)-(c).

[0033] Certain aspects of the present disclosure provide an anti-sortilin antibody having a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-56; 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, or 80.

[0034] In some embodiments, an anti-sortilin antibody of the present 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.

[0035] In some embodiments, an anti-sortilin antibody of the present 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.

[0036] In some embodiments, an anti-sortilin antibody of the present 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.

[0037] In some embodiments, an anti-sortilin antibody of the present 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.

[0038] In some embodiments, an anti-sortilin antibody of the present 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.

[0039] In some embodiments, an anti-sortilin antibody of the present 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.

[0040] In some embodiments, an anti-sortilin antibody of the present 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.

[0041] In some embodiments, an anti-sortilin antibody of the present 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.

[0042] In some embodiments, an anti-sortilin antibody of the present 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.

[0043] In some embodiments, an anti-sortilin antibody of the present 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.

[0044] In some aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0045] In certain aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60.

[0046] In certain aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:61.

[0047] In certain aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:72.

[0048] In some embodiments that may be combined with any of the preceding aspects, the anti-sortilin antibodies of the present disclosure are of the IgG class, the IgM class, or the IgA class. In certain specific embodiments, the anti-sortilin antibodies are of the IgG class and have an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments of the present disclosure, an anti-sortilin antibody of the IgG1, IgG2, IgG3, or IgG4 isotype is provided, wherein (a) the antibody is of the IgG1 or IgG2 isotype and the Fc region comprises an amino acid substitution at position P331S, wherein the numbering of the residue positions is according to EU numbering; (b) the antibody is of the IgG1 isotype and the Fc region comprises an amino acid substitution at positions L234A, L235A, and P331S, wherein the numbering of the residue positions is according to EU numbering; (c) the antibody is of the IgG1, IgG2, or IgG4 isotype and the Fc region comprises an amino acid substitution at position N297A, wherein the numbering of the residue positions is according to EU numbering; or (d) the Fc region comprises an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue positions is according to EU numbering. In some embodiments, the antibody is of the IgG1 isotype and the Fc region comprises an amino acid substitution at positions L234A, L235A, and P331S, wherein the numbering of the residue positions is according to EU numbering.

[0049] In some aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises 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.

[0050] In some aspects, the present disclosure provides an antibody that binds to Sortilin, wherein the antibody comprises 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.

[0051] 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 antibodies of the present disclosure specifically bind to human Sortilin. 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 antibodies of the present disclosure are monoclonal antibodies.

[0052] 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 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, transmembrane peptide, polyarginine peptide, angiopeppeptide, basic immunoglobulin (basigin), Glut1, CD98hc or ANG1005.

[0053] In certain embodiments of the present disclosure, the anti-sortilin antibody is an antibody fragment that binds to human sortilin. 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.

[0054] In certain embodiments, the disclosure provides an anti-sortilin antibody, wherein (a) the anti-sortilin antibody increases extracellular progranulin levels, decreases cellular sortilin levels, inhibits the interaction between sortilin and progranulin, or any combination thereof; (b) the anti-sortilin antibody decreases cell surface sortilin levels, increases extracellular progranulin levels, inhibits the interaction between sortilin and progranulin, or any combination thereof; (c) the anti-sortilin antibody decreases cell surface sortilin levels, decreases intracellular sortilin levels, decreases total sortilin levels, or any combination thereof; (d) the anti-sortilin antibody induces sortilin degradation, sortilin cleavage, sortilin internalization, sortilin downregulation, or any combination thereof; (e) the anti-sortilin antibody decreases cellular sortilin levels and inhibits the interaction between sortilin and progranulin; (f) the anti-sortilin antibody decreases cellular sortilin levels and increases cellular progranulin levels; and / or (g) the anti-sortilin antibody increases the effective concentration of progranulin.

[0055] In certain embodiments, the present disclosure provides an anti-sortilin antibody, wherein the anti-sortilin antibody reduces cell surface sortilin levels, increases extracellular progranulin levels, inhibits 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. D ) 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, wherein the K D is determined by FACS (see, e.g., Example 1). In some embodiments, the dissociation constant (K) of the antibody for human sortilin is D ) is more 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, wherein the K D is determined by FACS. In some embodiments, the dissociation constant (K) of the anti-sortilin antibody for human sortilin D ) is in the range of about 1.10E-8M to about 4.68E-10M, wherein the K D is determined by FACS (see, e.g., Example 1); or in the range of about 270 pM to about 2910 pM, wherein the K D is determined by biolayer interferometry (see, e.g., Example 4). In some embodiments, the dissociation constant (K) of the antibody for human sortilin is D ) is in the range of about 5.0E-10M to about 1.0E-9M, wherein the K D is determined by FACS; or in the range of about 250-500 pM, wherein the K D It was determined by biolayer interferometry.

[0056] In some embodiments that may be combined with any of the preceding embodiments, the anti-sortilin antibody (a) of the present disclosure reduces cell surface sortilin levels, wherein its half maximal effective concentration (EC) is less than 10%. 50) is less than 150 pM; (b) reduces cell surface sortilin levels 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 relative to a control as measured by flow cytometry; increases progranulin secretion by more than about 1.13-fold relative to a control at 0.63 nM IgG, or more than about 1.22-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; blocks the binding of progranulin to sortilin, wherein the half maximal effective concentration (EC) is greater than 1.0 fold relative to a control as measured by flow cytometry. 50 ) is less than 0.325 nM; (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.

[0057] In some embodiments, an anti-sortilin antibody (a) of the present disclosure reduces cell surface sortilin levels, wherein its half maximal effective concentration (EC 50 ) is less than 681 pM; (b) reduces cell surface sortilin levels 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 a control, as measured by flow cytometry; (c) increases progranulin secretion by more than about 1.11-fold relative to a control at 0.63 nM IgG, or more than about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; (d) blocks the binding of progranulin to sortilin, wherein the half maximal effective concentration (EC) is greater than 1.11-fold relative to a control at 0.63 nM IgG, or about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; 50 ) is less than 0.751 nM; (e) blocks the binding of progranulin to sortilin by greater than about 90% at 50 nM IgG relative to a control, or by greater than about 95% at 150 nM IgG, as measured by flow cytometry; or (f) any combination thereof.

[0058] In some embodiments, an anti-Sortilin antibody of the present disclosure competes for binding to Sortilin with an antibody comprising a heavy chain variable region domain and a 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 antibodies of the present disclosure bind to substantially the same epitope of sortilin 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.

[0059] 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 an anti-sortilin antibody of any of the aforementioned aspects and embodiments. Accordingly, some aspects provide a vector containing a nucleic acid encoding an anti-sortilin antibody, and some aspects provide an isolated host cell containing such a vector. In certain aspects, the present disclosure provides a method for producing an anti-sortilin antibody that binds to sortilin, the method comprising culturing such isolated host cells to produce the anti-sortilin antibody. 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 method of the present disclosure.

[0060] In another aspect, the present disclosure relates to a pharmaceutical composition comprising any of the anti-sortilin antibodies described herein and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure relates to the use of any of the antibodies or compositions described herein for the preparation or manufacture of a medicament. In some embodiments, the present disclosure relates to the use of any of the antibodies or compositions described herein for the preparation or manufacture of a medicament for the treatment of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, epileptic 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 antibodies or compositions described herein for use in methods of treatment. Some embodiments provide an antibody or composition described herein for use in a method of 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.

[0061] In certain aspects, provided herein is a method of preventing, reducing the risk of, or treating a disease, disorder, or injury in a subject, the method comprising administering to a subject 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.

[0062] In certain aspects, provided herein is a method of inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal overgrowth and abnormal branching, microglial activation, and an inflammatory response, the method comprising administering to an individual a therapeutically effective amount of an anti-sortilin antibody of the present disclosure.

[0063] In certain aspects, provided herein is a method of promoting one or more of wound healing, autophagy, and clearance of aggregated proteins, the method comprising administering to an individual a therapeutically effective amount of an anti-sortilin antibody of the present disclosure.

[0064] In certain aspects, provided herein is a method of preventing, reducing the risk of, or treating arthritis in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-sortilin antibody of the present disclosure.

[0065] In certain aspects, provided herein is a method of reducing the expression of one or more proinflammatory mediators, the method comprising administering to a subject a therapeutically effective amount of an anti-sortilin antibody of the present disclosure. In some embodiments, 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.

[0066] In some aspects, provided herein is a method of inhibiting the interaction between sortilin and progranulin, the method 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, the level of extracellular progranulin is increased.

[0067] In some aspects, provided herein is a method for increasing progranulin levels in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody or pharmaceutical composition of the present disclosure. In some embodiments, progranulin levels are increased in plasma. In some embodiments, progranulin levels are increased in cerebrospinal fluid. In some aspects, provided herein is a method for decreasing sortilin levels in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody or pharmaceutical composition of the present disclosure. In some embodiments, sortilin levels are decreased in peripheral blood leukocytes. In some embodiments, the individual has one or more mutations in a gene encoding a progranulin protein. In some embodiments, the individual is heterozygous for one or more loss-of-function mutations in the gene encoding a progranulin protein. In some embodiments, the individual has a c9orf72 hexanucleotide repeat expansion. The individual has or is at risk for frontotemporal dementia, Alzheimer's disease, or amyotrophic lateral sclerosis.

[0068] In some embodiments that may be combined with any of the preceding aspects or embodiments, the present disclosure provides a method, wherein the anti-sortilin antibody comprises two or more anti-sortilin antibodies. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1A-Figure 1C Provided are pharmacokinetic and pharmacodynamic studies in non-human primates administered a single dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS (S-60-15.1[N33T] plus huIgG1 containing L234A / L235A / P331S mutations). Figure 1A The percentage of SORT1 levels in peripheral blood leukocytes at the indicated time (hours) after treatment with the indicated anti-sortilin antibody doses relative to baseline is provided. SORT1 expression was reduced at all anti-sortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in earlier and more prolonged reductions in SORT1 levels compared to lower anti-sortilin antibody doses (5 mg / kg, 20 mg / kg). Figure 1B The percentage of PGRN levels in plasma at the indicated time (hours) after treatment with the indicated anti-sortilin antibody doses relative to baseline is provided. PGRN levels increased in a time- and dose-dependent manner. Specifically, for all anti-sortilin antibody doses tested, plasma PGRN levels increased at C max The levels of TNF-α and TNF-α decreased to 3 to 4 times the baseline level and remained elevated for a longer period of time at higher antibody doses. Figure 1C The percentage of PGRN levels in CSF relative to baseline at the indicated time (hours) after treatment with the indicated anti-sortilin antibody doses is provided. CSF PGRN levels were 2 to 3 times the baseline in animals administered 20 mg / kg, 60 mg / kg, or 200 mg / kg. As measured by plasma PGRN levels ( Figure 1B ), CSF PGRN levels remained elevated over time in the higher antibody dose groups. Figures 1A-1C , n = 3 animals / dose.

[0070] Figure 2A-2C A pharmacokinetic and pharmacodynamic study of non-human primates administered repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS is provided. Animals (2 males and 2 females) were administered a 60 mg / kg dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS once weekly for four weeks. Dosing days are indicated by vertical dashed lines. Figure 2AMean values ​​(+ / - standard deviation) of the percentage of SORT1 concentration in peripheral blood white blood cells (WBCs) relative to baseline at the indicated time (day) are presented.SORT1 levels in peripheral blood leukocytes remained reduced throughout the duration of the study. Figure 2B Mean values ​​(+ / - standard deviations) of the percentage (normalized) of PGRN concentrations in plasma relative to baseline at the specified time (day) are provided. Plasma PGRN levels increased to 5 to 6 times the baseline at peak levels. A decrease in plasma PGRN was observed after the fourth and final administration of anti-sortilin antibody; however, plasma PGRN levels remained at 2 times the baseline. Prevention 2C Mean values ​​(+ / - standard deviations) of the percentage (normalized) of PGRN concentrations in CSF relative to baseline at the specified time (day) are provided. CSF PGRN levels were 3 to 4 times the baseline ( Figure 2C ). DETAILED DESCRIPTION

[0071] Certainly

[0072] As used herein, the term "preventing" includes providing protection against the occurrence or recurrence of a particular disease, disorder, or condition in an individual. An individual may be susceptible to, susceptible to, or at risk of developing a particular disease, disorder, or condition but has not yet been diagnosed with the disease, disorder, or condition.

[0073] As used herein, an individual who is "at risk" of developing a particular disease, disorder, or condition may or may not have detectable symptoms of the disease or disease, and may or may not have exhibited detectable symptoms of the disease or disease prior to the treatment methods described herein. "At risk" means that the individual has one or more risk factors, as known in the art, which are measurable parameters associated with developing a particular disease, disorder, or condition. An individual who has one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition than an individual who does not have one or more of these risk factors.

[0074] As used herein, the term "treatment" refers to a clinical intervention intended to alter the natural course of the individual being treated during the course of clinical pathology. Desirable therapeutic effects include reducing the rate of progression of a particular disease, disorder, or condition, ameliorating or lessening its pathology, and alleviating or improving its prognosis. For example, a subject is successfully "treated" if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0075] "Effective amount" refers to at least the amount required to effectively achieve the desired therapeutic or preventive result in terms of dosage and over the desired time period. The effective amount can be provided in one or more administrations. The effective amount herein can vary according to a variety of factors, such as the disease state; the age, sex and weight of the individual; and the ability of the treatment to elicit the desired response in the individual. An effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the treatment. For preventive applications, beneficial or desired results include results such as eliminating or reducing risk, reducing severity or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presented during the course of the disease. For therapeutic applications, beneficial or desired results include clinical results such as reducing one or more symptoms caused by the disease, increasing the quality of life of individuals suffering from the disease, reducing the dose of other drug treatments required to treat the disease, enhancing the effect of another drug treatment (such as drug treatment via targeted therapy), delaying the progression of the disease and / or prolonging survival. The effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a preventive or therapeutic treatment. As will be understood in a clinical setting, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if it can achieve or realize a desired result when combined with one or more other agents.

[0076] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Administration in conjunction also encompasses administration with a co-formulation, or administration with separate compositions, including administration with different dosing frequencies or time intervals, and administration using the same route of administration or different routes of administration.

[0077] "Subject" for purposes of treatment, prevention, or risk reduction refers to any animal classified as a mammal, including humans, domestic and farm animals, as well as zoo animals, sport animals, or pets, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. Preferably, the subject is a human.

[0078] Unless otherwise indicated, the terms "sortilin" or "sortilin polypeptide" are used interchangeably herein to refer to any native sortilin from any mammalian source, including from primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). In some embodiments, the terms encompass wild-type sequences and naturally occurring variant sequences, such as splice variants or allelic variants. In some embodiments, the terms encompass "full-length," unprocessed sortilin as well as any form of sortilin that results from processing in a cell. In some embodiments, the sortilin protein is human sortilin. In some embodiments, the amino acid sequence of an exemplary human sortilin protein is SEQ ID NO: 81.

[0079] The terms "anti-sortilin antibody," "antibody that binds to sortilin," and "antibody that specifically binds to sortilin" refer to antibodies that are capable of binding to sortilin with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting sortilin. In one embodiment, the extent 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, the antibody binds to sortilin with 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., 10-8 M or lower, e.g., 10-8 M to 10-13 M, e.g., 10-9 M to 10-13 M). In certain embodiments, the anti-sortilin antibody binds to an epitope of sortilin that is conserved between sortilin proteins from different species.

[0080] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody." The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) (including multispecific antibodies formed from at least two intact antibodies), and antibody fragments, so long as the antibodies exhibit the desired biological activity.

[0081] "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, but the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V) at one end. H ), followed by multiple constant domains. Each light chain has a variable domain at one end (V L) and has a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the heavy chain variable domain. It is believed that specific amino acid residues form an interface between the light chain and heavy chain variable domains.

[0082] 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, p. 71 and Chapter 6.

[0083] The 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. Immunoglobulins can be divided into different classes, or isotypes, based on the amino acid sequence of their heavy chain constant domains (CH). There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains called 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 and generally described in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (WB Saunders Co., 2000).

[0084] The "variable region" or "variable domain" of an antibody, such as the anti-sortilin antibodies of the present disclosure, refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains may be 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 site.

[0085] The term "variable" refers to the fact that the sequences of certain segments of the variable domain vary widely between antibodies (such as the anti-sortilin antibodies of the present disclosure). The variable domain mediates antigen binding and determines the specificity of a particular antibody for its specific antigen. However, variability is not evenly distributed throughout the variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in the light and heavy chain variable domains. The relatively highly conserved portions of the variable domain are called framework regions (FRs). The variable domains of native heavy and light chains each contain four FR regions connected by three HVRs, primarily in a β-sheet configuration, which form loops connecting the β-sheet structure and, in some cases, forming part of the β-sheet structure. The HVRs in each chain are held together tightly by the FR regions and, together with the HVRs from the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not directly involved in binding an antibody to an antigen, but exhibit various effector functions, such as enabling the antibody to participate in antibody-dependent cellular toxicity.

[0086] An "isolated" antibody, such as an anti-sortilin antibody of the present disclosure, is one that has been identified, separated, and / or recovered from components of its production environment (e.g., naturally or recombinantly). Preferably, an isolated polypeptide is free from association with all other contaminating components of its production environment. Contaminating components of its production environment, such as components produced by recombinantly transfected cells, are substances that typically interfere with research, diagnostic, or therapeutic applications of 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, as determined by, for example, the Lowry method; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator; or (3) to homogeneity as determined by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibodies include antibodies produced in situ within recombinant T cells because at least one component of the antibody's natural environment will be absent. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step.

[0087] As used herein, the term "monoclonal antibody" refers to an antibody 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 trace amounts, such as the anti-sortilin antibodies of the present disclosure. Monoclonal antibodies are highly specific for a single antigenic site. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to specificity, monoclonal antibodies have the advantage that they are synthesized by hybridoma cultures and are not contaminated by other immunoglobulins. The modifier "monoclonal" indicates the property of the antibody being obtained from a population of substantially homogeneous antibodies and should not 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 can be prepared by a variety of techniques, including, but not limited to, one or more of the following methods: immunization of animals, including but not limited to rats, mice, rabbits, guinea pigs, hamsters, and / or chickens, with one or more of DNA, virus-like particles, polypeptides, and / or cells; hybridoma methods; B-cell cloning methods; recombinant DNA methods; and techniques for producing human or human-like antibodies in animals that have partial or complete human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0088] The terms "full-length antibody," "intact antibody," or "whole antibody" are used interchangeably to refer to an antibody, such as the anti-sortilin antibodies of the present disclosure, in substantially intact form, as opposed to an antibody fragment. In particular, whole 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, an intact antibody may have one or more effector functions.

[0089] "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen-binding and / or variable regions of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; bifunctional antibodies; linear antibodies (see U.S. Patent 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0090] Papain digestion of antibodies, such as the anti-sortilin antibodies of the present disclosure, produces two identical antigen-binding fragments, termed "Fab" fragments, and a residual "Fc" fragment, a name reflecting the ability to crystallize readily. The Fab fragment consists of an intact L chain together with the variable region domain (V) of the H chain. H ) and the first constant domain of a heavy chain (C H1) Composition. Each Fab fragment is monovalent with respect to antigen binding, i.e., the Fab fragment 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 antigens. The Fab' fragment differs from the Fab fragment in that the F(ab') fragment has a C H The carboxyl terminus of the constant domain contains several additional residues, including one or more cysteines in the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0091] The Fc fragment comprises the carboxyl-terminal portions of two H chains held together by disulfide bonds.The effector functions of antibodies are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcR) found on certain cell types.

[0092] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. The fragment is composed of a dimer consisting of a heavy chain variable domain and a light chain variable domain in tight non-covalent association. These two domains fold to form six hypervariable loops (3 loops each from the H and L chains), which provide the amino acid residues for antigen binding and give the antibody antigen-binding specificity. However, even a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) can still recognize and bind to an antigen, but with lower affinity than the complete binding site.

[0093] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising the VH and VL antibody domains linked into a single polypeptide chain. Preferably, the sFv polypeptide also comprises a V H With V L A polypeptide linker between the domains that enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0094] "Functional fragments" of antibodies, such as the anti-sortilin antibodies of the present disclosure, comprise a portion of an intact antibody that retains or has altered FcR binding ability, and generally include the antigen-binding or variable region of the intact antibody, or the F region of the antibody. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0095] The term "bifunctional antibody" refers to a H With V L Small antibody fragments are prepared by constructing sFv fragments (see previous paragraph) with short linkers (about 5-10 residues) between the domains to achieve interchain rather than intrachain pairing of the variable domains, thereby generating bivalent fragments (i.e., fragments with two antigen-binding sites). Bispecific diabodies are heterodimers of two "crossover" sFv fragments, in which the V domains of the two antibodies are bound to each other. H and V L Domains are present on different polypeptide chains.

[0096] As used herein, "chimeric antibody" refers to an antibody (immunoglobulin) in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the one or more chains is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, such as the chimeric anti-sortilin antibodies of the present disclosure, as well as fragments of such antibodies, as long as they exhibit the desired biological activity. The chimeric antibodies of interest herein include The antibody, wherein the antigen binding region of the antibody is derived from an antibody generated by, for example, immunizing macaques with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0097] "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 HVRs (e.g., CDRs) correspond to HVRs of a non-human antibody and all or substantially all FRs correspond to FRs of a human antibody. A humanized antibody optionally may 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 undergone humanization.

[0098] A "human antibody" is an antibody whose amino acid sequence corresponds to that of an antibody produced by a human and / or prepared using any of the techniques for making human antibodies as disclosed herein, such as the anti-sortilin antibodies of the present disclosure. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues. Human antibodies can be made using various techniques known in the art, including phage display libraries and yeast-based platform technologies. Human antibodies can be made by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci are disabled, for example, by immunization with a xenomouse; and by production via human B-cell fusion tumor technology.

[0099] The terms "hypervariable region," "HVR," or "HV," when used herein, refer to the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops, such as those of the anti-sortilin antibodies of the present disclosure. Generally, antibodies comprise six HVRs: three in V and three in HVR. H (H1, H2, H3), and three in V L Among them are (L1, L2, L3). In natural antibodies, H3 and L3 display the highest diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. Naturally occurring camelid antibodies composed only of heavy chains are functional and stable in the absence of light chains.

[0100] A variety of HVR descriptions are in use and encompassed herein. In some embodiments, HVRs may be the most commonly used Kabat complementarity determining regions (CDRs) based on sequence variability (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Chothia refers to the position 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. The residues of each of these HVRs are as follows.

[0101]

[0102] HVRs may comprise "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL; and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102 or 95-102 (H3) in VH. For each of these extended HVR definitions, variable domain residues are numbered according to Kabat et al. (supra).

[0103] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0104] As used herein, an "acceptor human framework" is a construct comprising a V derived from a human immunoglobulin framework or a human common framework. L or V H The acceptor human framework "derived from" a human immunoglobulin framework or a human common framework may comprise the same amino acid sequence thereof, or it 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 VH, preferably the changes occur only at three, two or one of positions 71H, 73H and 78H; for example, the amino acid residues at said positions may be 71A, 73T and / or 78A. In one embodiment, the sequence of the VL acceptor human framework is identical to that of the VH. L The framework sequences are identical to those of human immunoglobulins or human consensus framework sequences.

[0105] "Human Common Framework" refers to the selected human immunoglobulin V L or V H The framework of the most frequently occurring amino acid residues in the framework sequence. L or V H The sequence is selected from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for V L , the subgroup may be subgroup κI, κII, κIII or κIV according to Kabat et al. (supra).H , the subgroup may be subgroup I, subgroup II or subgroup III according to Kabat et al. (supra).

[0106] An "amino acid modification" at a specified position of, for example, an anti-sortilin antibody of the present disclosure refers to a substitution or deletion of the specified residue, or an insertion of at least one amino acid residue adjacent to the specified residue. An insertion "adjacent" to a specified residue means an insertion within one to two residues thereof. The insertion may be at the N-terminus or C-terminus of the specified residue. Preferred amino acid modifications herein are substitutions.

[0107] "Affinity matured" antibodies, such as the anti-sortilin antibodies of the present disclosure, are antibodies that have one or more alterations in one or more of their HVRs that result in an improvement in the affinity of the antibody for the antigen compared to a parent antibody that does not have the alteration. In one embodiment, affinity matured antibodies have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies are produced using 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 is described in, e.g., 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).

[0108] As used herein, the term "specific recognition" or "specific binding" refers 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 biomolecules. 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 one that binds to that target or epitope with greater affinity, avidity, more readily, and / or for a longer duration of time than it binds to other targets or other epitopes of the target. By reading this definition, it should also be understood that, for example, an antibody (or moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (but can include) exclusive binding. An antibody that specifically binds to a target may have an association constant of at least about 103 M -1 or 10 4 M -1 , sometimes 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 to 10 9 M -1 , or about 10 10 M -1 to 10 11 M -1 or higher. A variety of immunoassay formats can be used to select antibodies that specifically immunoreact with a particular protein. For example, solid-phase ELISA immunoassays are commonly used to select monoclonal antibodies that specifically immunoreact with a protein. For a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0109] As used herein, an "interaction" between sortilin and a second protein encompasses, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, binding, covalent binding, and ionic binding. As used herein, an antibody "inhibits an interaction between two proteins" when it disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody or fragment thereof of the present disclosure "inhibits an interaction between the two proteins" when it binds to one of the two proteins.

[0110] An "agonist" antibody or "activating" antibody is an antibody that, after the antibody binds to the antigen, induces (e.g., increases) one or more activities or functions of the antigen, such as the agonist anti-sortilin antibodies of the disclosure.

[0111] "Blocking" antibodies, "antagonist" antibodies, or "inhibitory" antibodies are antibodies that inhibit or reduce (e.g., decrease) the binding of an antigen to one or more ligands after the antibody binds to the antigen, and / or inhibit or reduce (e.g., decrease) one or more activities or functions of the antigen after the antibody binds to the antigen, such as the anti-sortilin antibodies of the present disclosure. In some embodiments, a blocking antibody, antagonist antibody, or inhibitory antibody substantially or completely inhibits the binding of an antigen to one or more ligands and / or one or more activities or functions of the antigen.

[0112] Antibody "effector functions" refer to the 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.

[0113] 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 immunoglobulin heavy chain Fc region may be different, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. During, for example, antibody manufacture or purification, or by recombinant engineering of nucleic acids encoding antibody heavy chains, the C-terminal lysine (residue 447 according to the EU numbering system) in the Fc region may be removed. Therefore, the composition of a complete antibody may include antibody groups that have all K447 residues removed, antibody groups that have not had the K447 residue removed, and antibody groups with a mixture of antibodies containing and not containing the K447 residue. Suitable native sequence Fc regions for use in antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0114] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A allotype and A allotype); 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.

[0115] A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution in a native sequence Fc region or in a parent polypeptide Fc region, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions, compared to the native sequence Fc region or the parent polypeptide Fc region. The variant Fc region herein preferably has at least about 80% homology to the native sequence Fc region and / or the parent polypeptide Fc region, and most preferably has at least about 90% homology thereto, and more preferably has at least about 95% homology thereto.

[0116] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. In addition, preferred FcRs are receptors that bind to IgG antibodies (gamma receptors) and include receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including variants and alternative splicing forms of these receptors, FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibitory receptors"), which have similar amino acid sequences, the main difference being their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. Other FcRs, including those that will be identified in the future, are encompassed within the term "FcR" herein. FcRs can also extend the serum half-life of antibodies. As used herein, "percentage (%) of amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence refers to the percentage of amino acid residues in the candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the candidate sequence with the specific peptide or polypeptide sequence and introducing gaps, if necessary, to achieve the maximum percentage of sequence identity, and not considering any conservative substitutions as part of the sequence identity. Quantification can be performed in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN. TM (DNASTAR) software is used to perform the alignment to determine the percent amino acid sequence identity. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm known in the art that achieves maximum alignment over the full length of the compared sequences.

[0117] An "isolated" cell is a molecule or cell that has been identified and separated from at least one contaminating cell with which it is normally associated in the environment in which it was produced. In some embodiments, an isolated cell is free from all components associated with the environment in which it was produced. The isolated cell is in a form that is different from the form or environment in which it is found in nature. An isolated cell is distinct from a cell naturally present in a tissue, organ, or individual. In some embodiments, an isolated cell is a host cell of the present disclosure.

[0118] An "isolated" nucleic acid molecule encoding an antibody, such as an anti-sortilin antibody of the present disclosure, is one that has been identified and separated from at least one contaminating 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 all components associated with the environment in which it was produced. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are present in a form that is different from the form or environment 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 cells.

[0119] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it is connected. One type of vector is a "plasmid", which means a circular double-stranded DNA to which another DNA segment can be connected. Another type of vector is a phage vector. Another type of vector is a viral vector, in which another DNA segment can be connected to the viral genome. Certain vectors are capable of autonomous replication in the host cell into which the vector is introduced (e.g., bacterial vectors and episomal mammalian vectors having a bacterial origin of replication). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the host cell genome after being introduced into the host cell, and thus replicated together with the host genome. In addition, certain vectors can guide the expression of the gene to which it is operably connected. Such vectors are referred to herein as "recombinant expression vectors", or simply "expression vectors". In general, the expression vectors utilized in recombinant DNA technology are typically in the form of plasmids. In this specification, since plasmids are the most commonly used vector forms, "plasmids" and "vectors" are used interchangeably.

[0120] "Polynucleotide" or "nucleic acid" are used interchangeably herein to refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction.

[0121] "Host cell" includes an individual cell or cell culture that can serve as or has served as a recipient of a vector for incorporating a polynucleotide insert. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with a polynucleotide of the disclosure.

[0122] As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed.

[0123] As used herein, the term "about" refers to the typical error range for the corresponding value that is readily understood by those skilled in the art. Reference to "about" a value or parameter herein includes (and describes) embodiments for that value or parameter itself.

[0124] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, a reference to an "antibody" is a reference to one or more antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0125] It should be understood that aspects and embodiments of the present disclosure described herein include "comprising" aspects and embodiments, "consisting of" and "consisting essentially of" aspects and embodiments.

[0126] Comprehensive traces

[0127] The present disclosure relates in part to anti-sortilin antibodies that exhibit one or more improved and / or enhanced functional characteristics relative to the anti-sortilin antibody S-60 having a heavy chain variable region and a light chain variable region as described in WO2016164637. Non-limiting improved and / or enhanced functional characteristics include, for example, the ability of the antibody to bind to sortilin with higher affinity; reduce cell surface sortilin levels; reduce half maximal effective concentration (EC 50 ) to reduce cell surface Sortilin levels; improve the maximum reduction of cell surface Sortilin levels; increase the extracellular secretion of Sortilin ligands, such as progranulin (PGRN); reduce the half maximal effective concentration (EC 50 ) to block the binding of PGRN to Sortilin; Improve the maximum blocking of the binding of PGRN to Sortilin; Or any combination thereof. Also contemplated herein are anti-sortilin antibodies with different Fc variants that exhibit one or more improved and / or enhanced functional characteristics, including a reduction in the half maximal effective concentration (EC 50 ) to reduce cell surface Sortilin levels; improve the maximum reduction of cell surface Sortilin levels; increase the extracellular secretion of Sortilin ligands, such as progranulin (PGRN); reduce the half maximal effective concentration (EC 50 ) to block the binding of PGRN to Sortilin; and improving the maximum blockade of the binding of PGRN to Sortilin.

[0128] In some embodiments, the anti-sortilin antibodies of the present disclosure are more potent in reducing cell surface Sortilin levels than anti-sortilin antibodies having heavy chain variable regions and light chain variable regions corresponding to S-60. In some embodiments, efficacy is measured by a half maximal effective concentration (EC) for reducing cell surface cellular SORT1 levels. 50 ) to measure.

[0129] The present disclosure also relates to methods of making and using the 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.

[0130] In some embodiments, the anti-sortilin antibodies of the present disclosure may have one or more activities that are attributable, at least in part, to the ability of the antibodies to reduce sortilin levels (e.g., cell surface levels) by inducing sortilin degradation, downregulation, cleavage, receptor desensitization, and / or lysosomal targeting. In some embodiments, the anti-sortilin antibodies exhibit one or more of the following properties: a. a dissociation constant (K) for human sortilin. D ) is lower than the K of an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60 D b. at a concentration lower than the half-maximal effective concentration (EC) of an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60; 50 ) reduce cell surface Sortilin levels (e.g., reduce cell surface Sortilin levels on cells engineered to express human Sortilin in vitro); c. when the dissociation constant (K D ) for human sortilin D can be in the range of about 0.560 nM to about 1.63 nM; d. When the dissociation constant (K D ) for human sortilin D can be in the range of about 0.270 nM to about 2.910 nM; e. When the half maximal effective concentration (EC 50 ), with an EC ranging from about 72.58 pM to about 103.6 pM 50f. reducing cell surface Sortilin levels (e.g., reducing cell surface Sortilin levels on cells engineered to express human Sortilin in vitro); g. increasing extracellular PGRN secretion above that caused by an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60; h. blocking the binding of PGRN to Sortilin (e.g., blocking the binding of PGRN to Sortilin on cells engineered to express human Sortilin in vitro), when the half maximal effective concentration (EC) is determined, for example, by FACS in vitro. 50 ), its EC 50 can be in the range of about 0.325 nM to about 2.27 nM; and / or i. improves the maximal blockade of PGRN binding to Sortilin above that of an anti-Sortilin antibody having heavy and light chain variable regions corresponding to S-60.

[0131] Advantageously, the anti-sortilin antibodies of the present disclosure more effectively reduce (e.g., by up to about 3.02-fold) cell surface Sortilin levels (e.g., having a lower EC 50 ) (See, e.g., Example 2). In some embodiments, the anti-sortilin antibodies of the present disclosure have a lower EC compared to a control anti-sortilin antibody (e.g., a control anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 The anti-sortilin antibodies of the present disclosure more effectively reduce the binding of PGRN to Sortilin (e.g., up to about 5.36-fold) (see, e.g., Example 3). Furthermore, the anti-sortilin antibodies of the present disclosure have a higher affinity (e.g., up to about 2.79-fold higher affinity) for Sortilin compared to a control anti-sortilin antibody (e.g., a control anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) (e.g., a lower K as measured by FACS or biolayer interferometry). D values) (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 Sortilin levels (see, e.g., Examples 2 and 4), nor does it necessarily correlate with increased ability or efficacy to block PGRN binding to Sortilin (see, e.g., Examples 3 and 4).

[0132] The present disclosure also relates to anti-sortilin antibodies with improved stability during manufacture, 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).

[0133] Sortilin

[0134] In one aspect, the present disclosure provides antibodies, such as isolated (e.g., monoclonal) antibodies, that interact or otherwise bind to a region, such as an epitope, within the Sortilin protein of the present disclosure. In some embodiments, the antibodies interact or otherwise bind to a region, such as an epitope, within the Sortilin protein of the present disclosure with improved / enhanced kinetics (e.g., relative to an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the antibodies bind to the Sortilin protein of the present disclosure at a half-maximal effective concentration (EC) that is lower than that of a control antibody (e.g., relative to an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 ) interacts with or otherwise binds to a region, such as an epitope, within human Sortilin. In some embodiments, the anti-Sortilin antibodies of the present disclosure bind to Sortilin and, upon binding to Sortilin, modulate one or more Sortilin activities, such as an activity associated with Sortilin expression on a cell. Sortilin proteins of the present disclosure include, but are not limited to, mammalian Sortilin, human Sortilin, mouse Sortilin, and rat Sortilin. Exemplary Sortilin sequences are shown in Table 32.

[0135] Sortilin is known by various names, such 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 set forth below as SEQ ID NO:81 (wherein the key amino acid residues predicted to be involved in progranulin binding are depicted in bold and the predicted pro-NGF binding region is underlined):

[0136]

[0137] The amino acid sequence of mouse sortilin is set forth in SEQ ID NO:82:

[0138]

[0139] The amino acid sequence of rat sortilin is set forth in SEQ ID NO:83:

[0140]

[0141] In some embodiments, Sortilin is a precursor protein that includes a signal sequence. In some embodiments, Sortilin is a mature protein. In some embodiments, mature Sortilin does not include a signal sequence. In some embodiments, mature Sortilin is expressed on a cell.

[0142] The Sortilin proteins of the present disclosure include several domains, including but not limited to a signal sequence, a precursor peptide, a lumenal domain, a Vps10p domain, an 10CC domain, a transmembrane domain, and a cytoplasmic domain. In addition, the proteins of the present disclosure are expressed at high levels in a variety of tissues, including but not limited to the brain, spinal cord, heart and skeletal muscle, thyroid, placenta, and testis.

[0143] Thus, as used herein, "sortilin" of the present disclosure includes, but is not limited to, mammalian sortilin, human sortilin, primate sortilin, mouse sortilin, and rat sortilin. Additionally, the anti-sortilin antibodies of the present disclosure may bind to an epitope within one or more of mammalian sortilin, human sortilin, primate sortilin, mouse sortilin, and rat sortilin.

[0144] sortilin domain

[0145] The sortilins of the present disclosure contain several domains, such as the Vps10p domain containing an Asp box motif, a ten-bladed β-propeller structure, and a hydrophobic loop; and the IOCC domain.

[0146] As disclosed herein, the interaction between the Sortilin proteins of the present disclosure and pro-neurotrophins or neurotrophins is mediated by a Vps10p domain comprising a ten-bladed β-propeller structure and an Asp box motif. In certain embodiments, the Sortilin proteins of the present disclosure contain a Vps10p domain comprising a ten-bladed β-propeller structure and located within amino acid residues 78-611 of human Sortilin (SEQ ID NO: 81) or amino acid residues of a mammalian Sortilin corresponding 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 corresponding to amino acid residues 190-220 of SEQ ID NO: 81 are located within the Vps10p domain.

[0147] The Vps10p domains of the present disclosure may 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 of mammalian Sortilin corresponding to amino acid residues 200-207 of SEQ ID NO: 81.

[0148] As disclosed herein, the interaction between Sortilin of the present disclosure and p75 is mediated by the 10CC domain of the hydrophobic loop of the Vps10p domain.

[0149] In certain embodiments, the Sortilin proteins of the present disclosure contain an 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.

[0150] In other embodiments, the Sortilin proteins of the present disclosure contain 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 mammalian Sortilin corresponding to amino acid residues 130-141 of SEQ ID NO:81.

[0151] It will be understood by those skilled in the art that the starting and ending residues of the domains of the present disclosure may vary depending on the computer modeling program used or the method used to determine the domains.

[0152] Sortilin binding partner

[0153] The sortilins of the present disclosure can interact with (e.g., bind to) one or more proteins including, but not limited to, progranulin (PGRN); neurotrophins, such as proneurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-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, Aβ peptide, PCSK9, p75NTR, and receptor-associated protein (RAP).

[0154] Progranulin (PGRN)

[0155] It has been shown that the sortilins of the present disclosure directly interact with (eg, bind to) progranulin and mediate the degradation of progranulin (eg, Zheng, Y et al. (2011) PLoS ONE 6(6):e21023).

[0156] Progranulin is known by various names such 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 kDa secreted glycoprotein with 7.5 repeats of the smaller granulin (epithelin) motif, ranging from 6-25 kDa, which is 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.

[0157] Thus, anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease cell surface sortilin levels, and / or block the interaction (e.g., binding) between sortilin and progranulin will be useful in preventing, reducing the risk of, or treating the following conditions and / or diseases associated with decreased levels of progranulin expression and / or activity, cell death (e.g., neuronal cell death): frontotemporal dementia, Alzheimer's disease, vascular dementia, epileptic seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, unwanted symptoms of normal aging dementia, mixed dementia, Creutzfeldt-Jakob disease, normal-pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies The invention also includes but is not limited to: lewybodies, multiple system atrophy, intervertebral disc degeneration, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal degeneration, acute disseminated encephalomyelitis, granulomatous diseases, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disorders, arthritis, multiple sclerosis, metabolic disorders, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, injury and / or one or more unwanted symptoms of normal aging. In addition, anti-sortilin antibodies of the present disclosure that increase progranulin levels, decrease cell surface sortilin levels, and / or block the interaction (e.g., binding) between sortilin and progranulin can inhibit the interaction between sortilin and progranulin, can induce one or more progranulin activities, can reduce the endosomal internalization of progranulin or its fragments, and / or can increase the effective concentration of progranulin.

[0158] In some embodiments, an anti-sortilin antibody of the present disclosure that increases progranulin levels, decreases cell surface sortilin levels, and / or blocks the interaction (e.g., binding) between sortilin and progranulin binds to one or more amino acids within amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632, and / or 740-749 of human sortilin (SEQ ID NO: 81); or amino acid residues corresponding to SEQ ID NO: 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.In other embodiments, an anti-sortilin antibody of the present disclosure that increases progranulin levels, decreases cell surface sortilin levels, and / or blocks the interaction (e.g., binding) between sortilin and progranulin may bind to one or more of the following amino acids: amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys247, and Ser249 of human sortilin (SEQ ID NO: 81). s248, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or Glu700; or corresponding to SEQ ID 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, 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 mammalian sortilin.

[0159] Other sortilin ligands

[0160] It has been shown that Sortilin of the present disclosure can directly interact (e.g., bind) with pro-neurotrophins (e.g., pro-NGF), which bear a prodomain and typically promote apoptosis. The binding can be mediated via a linear epitope on Sortilin corresponding to amino acid residues 163-174 of SEQ ID NO: 81. Sortilin of the present disclosure has also been shown to interact (e.g., bind) with neurotensin within the β-propeller structure of Sortilin, and a key contact has been shown to be at Serine 283 of human Sortilin.

[0161] It has also been shown that the Sortilin proteins of the present disclosure interact (e.g., bind) with 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 can act with p75 as co-receptors for pro-neurotrophins that induce apoptotic signaling. Additionally, it has been shown that the Sortilin proteins of the present disclosure interact (e.g., bind) with the amyloid precursor protein (APP).

[0162] 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 the degradation of LpL. Sortilin proteins of the present disclosure have been shown to interact with (e.g., bind to) apolipoprotein A (APOA5). As disclosed herein, Sortilin proteins of the present disclosure bind to APOA5 and alter the degradation of APOA5.

[0163] It has been shown that the Sortilin of the present disclosure interacts (e.g., binds) with apolipoprotein E (APOE, APOE2, APOE3, APOE4). As disclosed herein, the Sortilin of the present disclosure binds to APOE and agents carried by APOE, such as Aβ peptide, and alters their degradation and transport. Furthermore, it has been shown that the Sortilin of the present disclosure interacts (e.g., binds) with receptor-associated protein (RAP). Additionally, it has been shown that the Sortilin of the present disclosure interacts (e.g., binds) with proprotein convertase subtilisin / kexin type 9 (PCSK9) and secretes it into the circulation.

[0164] In some embodiments of any of the anti-sortilin antibodies, the anti-sortilin antibodies of the present disclosure may also 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 the following: proneurotrophin, 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 9. Such antibodies may be useful in preventing, reducing the risk of, or treating conditions and / or diseases associated with decreased expression and / or activity of one or more other sortilin ligands, cell death (e.g., neuronal cell death). In some embodiments, the one or more additional ligands are one or more of: proneurotrophin, 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 9.

[0165] Anti-sortilin antibodies of the present disclosure that inhibit (e.g., block) the interaction between sortilin and one or more other sortilin ligands of the present disclosure can also prevent cell death (e.g., apoptosis) induced by one or more other sortilin ligands. In some embodiments, the one or more other ligands are one or more of the following: proneurotrophin, 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 9.

[0166] In some embodiments of any of the anti-sortilin antibodies, an anti-sortilin antibody of the disclosure that inhibits (e.g., blocks) the interaction between sortilin and one or more sortilin ligands of the disclosure binds to one or more amino acids within the following amino acid residues: amino acid residues 131-138, 175-181, 190-220, 199-220, 190-211, 196-207, 196-199, 200-207, 203-207, 207-231, 207-227, 212-221, 233-243, 237-247, 237-260, 297-317, 314-338, 367-391, 429-443, 623-632, and / or 740-749 of human sortilin (SEQ ID NO: 81); or amino acid residues corresponding to SEQ ID NO: 82; 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. In some embodiments, the one or more additional ligands are one or more of: proneurotrophin, 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 9.

[0167] In other embodiments of any of the anti-sortilin antibodies, an anti-sortilin antibody of the disclosure that inhibits (e.g., blocks) the interaction between sortilin and one or more sortilin ligands of the disclosure binds to one or more of the following amino acid residues: amino acid residues His131, Val132, Pro133, Leu134, Val135, Ile136, Met137, Thr138, Arg196, Phe198, Arg199, Phe203, Lys205, Phe207, Thr210, Thr218, Tyr222, Ser223, Ser227, Ser242, Lys243, Lys254, and Ser256 of human sortilin (SEQ ID NO: 81). s248, Lys254, Lys260, Ser305, Phe306, Gly307, Arg311, Phe314, Ser316, Arg325, Arg326, Ile327, Phe350, Tyr351, Ser352, Ile353, Asn373, Ser379, Arg382, Tyr386, Ser595 and / or Glu700; or corresponding to SEQ 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, Lys In some embodiments, the one or more additional ligands are selected from the group consisting of amino acid residues 150, 151, 152, 153, 160, 165, 169, 180, 181, 182, 183, 184, 186, 188, 189, 200, 210, 211, 212, 213, 214, 215, 216, 188, 189, 217, 220, 221, 222, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 248, 254, 254, 260, 305, 306, 307, 311, 314, 247, 256, 257, 268, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 290, 391, 392, 393, 394, 395

[0168] Sortilin antibodies

[0169] Certain aspects of the present disclosure relate to anti-sortilin antibodies comprising one or more improved and / or enhanced functional characteristics. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise one or more improved and / or enhanced functional characteristics relative to the anti-sortilin antibody S-60, which has a heavy chain variable region and a light chain variable region as described in WO2016164637. In some embodiments, the anti-sortilin antibodies of the present disclosure have an affinity for sortilin (e.g., human sortilin) ​​that is higher than the affinity of a control anti-sortilin antibody (e.g., a control anti-sortilin antibody 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 sortilin levels (cell surface levels) to a greater extent and at a lower half-maximal effective concentration (EC50) relative to a 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). In some embodiments, the anti-sortilin antibodies of the present disclosure improve the maximum reduction of cell surface sortilin levels relative to an 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 increase secretion of extracellular progranulin (PGRN) relative to an 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 block the binding of PGRN to Sortilin to a greater extent and at a lower half-maximal effective concentration (EC50) relative to a 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). In some embodiments, the anti-sortilin antibodies of the present disclosure improve the maximum blockade of PGRN binding to Sortilin relative to an anti-sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60.

[0170] Also encompassed herein are anti-sortilin antibodies with different Fc variants that exhibit one or more improved and / or enhanced functional characteristics relative to an anti-sortilin antibody comprising a heavy chain variable region and a light chain variable region corresponding to S-60, including reduced half maximal effective concentration (EC50) for reducing cell surface sortilin levels; improved maximal reduction in cell surface sortilin levels; increased extracellular secretion of PGRN; reduced half maximal effective concentration (EC50) for blocking binding of PGRN to Sortilin; and improved maximal blocking of binding of PGRN to Sortilin.

[0171] In some embodiments, the anti-sortilin antibodies of the present disclosure are human antibodies, bispecific antibodies, monoclonal antibodies, multivalent antibodies, conjugated antibodies, or chimeric antibodies.

[0172] In a preferred embodiment, the anti-sortilin antibodies of the present disclosure are monoclonal antibodies.

[0173] Anti-sortilin antibody binding epitope

[0174] In some embodiments, the anti-sortilin antibodies of the present disclosure bind to Sortilin and / or naturally occurring variants of the present disclosure. In some embodiments, the anti-sortilin antibodies of the present disclosure bind to Sortilin, wherein the Sortilin is a human protein. In some embodiments, the anti-sortilin antibodies of the present disclosure bind to Sortilin, wherein the Sortilin is a wild-type protein. In some embodiments, the anti-sortilin antibodies of the present disclosure bind to Sortilin, wherein the Sortilin is a naturally occurring variant.

[0175] In certain preferred embodiments, the anti-Sortilin antibodies of the present disclosure specifically bind to human Sortilin.

[0176] Certain aspects of the present disclosure provide anti-sortilin antibodies that bind to a discontinuous sortilin epitope. In some embodiments, the discontinuous sortilin epitope comprises two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or ten or more peptides. In some embodiments, the peptides each comprise five or more, six or more, seven or more, eight or more, nine 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 corresponding to the amino acid sequence of SEQ ID NO: 8 or more, five or more, six or more, seven or more, eight or more, nine 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 mammalian sortilin of NO: 81. Other aspects of the present disclosure provide anti-sortilin antibodies that bind to a conformational epitope of sortilin.

[0177] 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 amino acid residues on mammalian Sortilin corresponding to amino acid residues 207-231 of SEQ ID NO: 81. In some embodiments, the anti-sortilin antibody binds to one or more amino acids of the following amino acid residues: amino acid residues Thr218, Tyr222, Ser223, and / or Ser227 of human Sortilin (SEQ ID NO: 81), or amino acid residues on mammalian Sortilin corresponding 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 of the following amino acid residues: amino acid residues F105, L108, R109, G110, I537, F569, E590, F592, L593, S595, and / or W597 of human sortilin (SEQ ID NO: 81), or amino acid residues on mammalian sortilin corresponding to amino acid residues F105, L108, R109, G110, I537, F569, E590, F592, L593, S595, and / or W597 of SEQ ID NO: 81. Other aspects of the present disclosure provide anti-sortilin antibodies that bind to an epitope having amino acid residues (S / T)-X-(D / N)-XXXX-(W / F / Y), wherein X represents any amino acid (SEQ ID NO: 84).

[0178] In some embodiments, the anti-sortilin antibodies of the present disclosure bind to the sortilin of the present disclosure expressed on the surface of a cell and the naked antibody inhibits the interaction (e.g., binding) between the sortilin and a protein selected from the group consisting of progranulin (PGRN), proneurotrophin, neurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-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), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP). In some embodiments, the anti-sortilin antibodies of the present disclosure bind to the sortilin of the present disclosure expressed on the surface of a cell and the naked antibody inhibits the interaction (e.g., binding) between sortilin and PGRN.

[0179] In some embodiments, an anti-sortilin antibody of the disclosure that binds to a Sortilin of the disclosure inhibits the interaction (e.g., binding) between the Sortilin and progranulin, proneurotrophin, neurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-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), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP) on the cell surface or inside the cell.

[0180] In some embodiments, an anti-sortilin antibody of the disclosure that binds to a sortilin of the disclosure inhibits the interaction (e.g., binding) between the sortilin and progranulin, proneurotrophin, neurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-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), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), PCSK9, and receptor-associated protein (RAP) by inducing degradation of sortilin.

[0181] In some embodiments, the anti-sortilin antibodies of the present disclosure bind to human sortilin or a homolog thereof, including but not limited to mammalian sortilin or sortilin of a non-human primate. In some embodiments, the anti-sortilin antibodies of the present disclosure bind specifically to human sortilin. In some embodiments, the anti-sortilin antibodies of the present disclosure bind to human sortilin and do not cross-react with orthologs or homologs of sortilin from other species.

[0182] Competitive binding of anti-sortilin antibodies

[0183] In some embodiments, an anti-Sortilin antibody of the present 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 present disclosure competitively inhibit the binding of at least one antibody selected from the group consisting of S-60, S-60-1, S-60-2, S-60-3, S-60-4, S-60-5, S-60-6, S-60-7, S-60-8, and S-60-9 (as 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-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[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24; and any combination thereof.

[0184] In some embodiments, when an anti-sortilin antibody of the present disclosure reduces 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 (as 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[N33 D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N 33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-1 5.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], and any combination thereof, wherein the anti-sortilin antibody competes for binding to sortilin with one or more anti-sortilin 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 (as 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-60-15.11[N33W], S-60-15.12[N33 F], 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.

[0185] In some embodiments, when an anti-sortilin antibody of the present disclosure reduces 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 (as 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-60-30, S-60-40, S-60-50 ... , S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N 33S], 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, said anti-sortilin antibody competes for binding to sortilin with one or more anti-sortilin 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 (as 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[N33 Y], 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.

[0186] In some embodiments, one or more of the compounds 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 (as 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[N33D], S-60-15.7[N33E], S-60-15.8[N33F], S-60-15.9[N33F], S-60-15.10[N33F], S-60-15.11[N33F], S-60-15.12[N33S], S-60-15.13[N33G], S-60-15.14[N33R], S-60-15.15[N33D], S-60-15. -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 An anti-sortilin antibody of the present disclosure that reduces the binding of sortilin by 100% indicates that the anti-sortilin antibody substantially completely blocks the binding of one or more anti-sortilin 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 (as 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[N33(wt)], 33S], 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, the anti-sortilin antibody and the one or more 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 (as 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[N3 3R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-1 5.8[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-60-1 5.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-1 and any combination thereof, wherein the antibodies are present in an amount corresponding to a 10:1 ratio, a 9:1 ratio, an 8:1 ratio, a 7:1 ratio, a 6:1 ratio, a 5:1 ratio, a 4:1 ratio, a 3:1 ratio, a 2:1 ratio, a 1:1 ratio, a 0.75:1 ratio, a 0.5:1 ratio, a 0.25:1 ratio, a 0.1:1 ratio, a 0.075:1 ratio, a 0.050:1 ratio, a 0.025:1 ratio, a 0.01:1 ratio, a 0.0075:1 ratio, a 0.0050:1 ratio, a 0.0025:1 ratio, a 0.001:1 ratio, a 0.00075:1 ratio, a 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 ratio, 1:0.075 ratio, 1:0.050 ratio, 1:0.025 ratio, 1:0.01 ratio, 1:0.0075 ratio, 1:0.0050 ratio, 1:0.0025 ratio, 1:0.001 ratio, 1:0.00075 ratio, 1:0.00050 ratio, 1:0.00025 ratio, or 1:0.0001 ratio of anti-sortilin antibodies to 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 (as 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[ -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, the anti-sortilin antibody is present in an amount ranging from about 1.5-fold to 100-fold excess or more 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 (as 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[N 33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15 .10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I] , S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24; and any combination thereof. In some embodiments, the anti-sortilin antibody is present in an amount that is about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold greater than 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 (as 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[N3 3H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15 .11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24; and any combination thereof.

[0187] In some embodiments, an anti-Sortilin antibody of the present disclosure binds to an epitope of human Sortilin that is the same as or overlaps with an epitope of Sortilin 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 present disclosure bind to an epitope of human sortilin that is the same as or overlaps with an epitope of sortilin bound by at least one antibody 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 (as 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[N 33Q], 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, the anti-sortilin antibodies of the present disclosure bind to substantially the same epitope of sortilin as that 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 present disclosure bind to substantially the same sortilin epitope as bound by at least one antibody 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 (as 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-60-15.11[N33W], S-60-15.12[N3 3F], 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. Detailed exemplary methods for mapping epitopes to which antibodies bind are provided in Morris (1996) "Epitope Mapping Protocols," Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).

[0188] Any suitable competition assay or Sortilin binding assay known in the art, such as a BIAcor assay, an ELISA assay, or flow cytometry, can be used to determine whether an anti-Sortilin antibody competes for binding to Sortilin with 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 (as 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 -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, fixed sortilin or cells expressing sortilin on the cell surface are incubated in a solution containing a first labeled antibody (e.g., human or non-human primate) that binds to sortilin and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to sortilin. The second antibody can be present in the hybridoma supernatant. As a control, fixed sortilin or cells expressing sortilin are incubated in a solution containing the first labeled antibody but without the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to sortilin, excess unbound antibody is removed, and the amount of label associated with the fixed sortilin or cells expressing sortilin is measured. If the amount of label associated with the fixed sortilin or cells expressing sortilin in the test sample is substantially reduced relative to the control sample, this indicates that the second antibody competes with the first antibody for binding to sortilin. See Harlow and Lane (1988) Antibodies: A Laboratory Manual, Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0189] In some embodiments, an anti-Sortilin antibody of the present 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.

[0190] In some embodiments, an anti-sortilin antibody of the present disclosure binds to substantially the same epitope of sortilin 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.

[0191] Additional anti-sortilin antibodies, e.g., antibodies that specifically bind to the sortilins of the present disclosure, can be identified, screened, and / or characterized for their physical / chemical properties and / or biological activities by various assays known in the art.

[0192] Anti-sortilin antibody heavy and light chain variable regions

[0193] A. Heavy chain HVR

[0194] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 14-16). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 14-16).

[0195] In some embodiments, HVR-H1 comprises the sequence YSISSGYYWG (SEQ ID NO: 1). In some embodiments, HVR-H2 comprises the sequence according to Formula I: TIYHSGSTYYNPSLX1S (SEQ ID NO: 4), wherein 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 the 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.

[0196] In some embodiments, HVR-H1 comprises an amino acid sequence that is 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% identical 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 that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H2 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: 2-3) but retains the ability to bind to Sortilin. In certain embodiments, no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 amino acids are substituted, inserted, and / or deleted in an HVR-H2 amino acid sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises an amino acid sequence that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 5-6. In some embodiments, HVR-H3 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: 5-6) but retains the ability to bind to Sortilin. In certain embodiments, no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 amino acids are substituted, inserted, and / or deleted in an HVR-H3 amino acid sequence selected from SEQ ID NOs: 5-6.

[0197] In some embodiments, the heavy chain variable region includes HVR-H1 comprising the sequence YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising a sequence according to Formula I, and HVR-H3 comprising a sequence according to Formula II.

[0198] In some embodiments, the heavy chain variable region comprises an HVR-H1 comprising the sequence of SEQ ID NO: 1, an HVR-H2 comprising a sequence selected from SEQ ID NOs: 2-3, and an HVR-H3 comprising a sequence selected from SEQ ID NOs: 5-6.

[0199] In some embodiments, the heavy chain variable region comprises 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, S-60-24, or any combination thereof (as shown in Tables 14-16).

[0200] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region, wherein the heavy chain variable region comprises one or more of the following: (a) a heavy chain variable region comprising the same heavy chain variable region as 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-60-15.1 4[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24, or 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%, or at least 96% of the HVR-H1 amino acid sequence of 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. %, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an HVR-H1; (b) an HVR-H2 comprising an amino acid sequence that is at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an antibody 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[N33L], S-60-16, S-60-18, S-60-19 or S-60-24, an HVR-H2 that is 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% identical to an HVR-H2 amino acid sequence of S-17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24; and (c ) containing 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. An HVR-H3 that is 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% identical to an HVR-H3 amino acid sequence of S-17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24.

[0201] In some embodiments, an anti-sortilin antibody of the present disclosure comprises an HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0202] B. Light Chain HVR

[0203] In some embodiments, the anti-sortilin antibodies of the present disclosure include a light chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 17-19). In some embodiments, the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 17-19).

[0204] In some embodiments, HVR-L1 comprises a sequence according to Formula III: RSSQX1LLX2SX3GYNYLD (SEQ ID NO: 28), wherein 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 comprises the following sequences: RSSQSLLRSNGYNYLD (SEQ ID NO:8), RSSQSLLRSTGYNYLD (SEQ ID NO:9), RSSQSLLRSSGYNYLD (SEQ ID NO:10), RSSQSLLRSGGYNYLD (SEQ ID NO:11), RSSQSLLRSRGYNYLD (SEQ ID NO:11) 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 In some embodiments, HVR-L1 comprises the sequence RSSQSLLRSNGYNYLD (SEQ ID NO: 8). In another specific embodiment, HVR-L1 comprises the sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9) (as shown in Table 19).

[0205] In some embodiments, HVR-L2 comprises a sequence according to Formula IV: LGSNRX1S (SEQ ID NO: 31), wherein X1 is A or V. In some embodiments, HVR-L2 comprises a sequence selected from SEQ ID NOs: 29-30.

[0206] In some embodiments, HVR-L3 comprises a sequence according to Formula V: MQQQEX1PLT (SEQ ID NO: 34), wherein X1 is A or T. In some embodiments, HVR-L3 comprises a sequence selected from SEQ ID NOs: 32-33.

[0207] In some embodiments, HVR-L1 comprises an amino acid sequence that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L1 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: 8-27) but retains the ability to bind to Sortilin. In certain embodiments, no more than one, no more than two, no more than three, no more than four, or no more than five amino acids are substituted, inserted, and / or deleted in an HVR-L1 amino acid sequence selected from SEQ ID NOs: 8-27. In some embodiments, HVR-L2 comprises an amino acid sequence that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L2 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: 29-30) but retains the ability to bind to Sortilin. In certain embodiments, no more than one, no more than two, no more than three, no more than four, or no more than five amino acids are substituted, inserted, and / or deleted in an HVR-L2 amino acid sequence selected from SEQ ID NOs: 29-30. In some embodiments, HVR-L3 comprises an amino acid sequence that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 32-33. In some embodiments, HVR-L3 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: 32-33) but retains the ability to bind to Sortilin. In certain embodiments, no more than one, no more than two, no more than three, no more than four, or no more than five amino acids are substituted, inserted, and / or deleted in an HVR-L3 amino acid sequence selected from SEQ ID NOs: 32-33.

[0208] In some embodiments, the light chain variable region comprises an HVR-L1 comprising a sequence according to Formula III, an HVR-L2 comprising a sequence according to Formula IV, and an HVR-L3 comprising a sequence according to Formula V. In some embodiments, the light chain variable region comprises an HVR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 8-27, an HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 29-30, and an HVR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 32-33.

[0209] In some embodiments, the light chain variable region comprises 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 17-19).

[0210] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable region, wherein the light chain variable region comprises one or more of the following: (a) a light chain variable region comprising the same light chain variable region as 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, or at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 100% of the HVR-L1 amino acid sequence of S-60-16, S-60-18, S-60-19, or S-60-24. 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 an HVR-L1; (b) comprising an HVR-L1 having an amino acid sequence that is 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 an antibody 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, or 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 more of the HVR-L2 amino acid sequence of S-17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24. and (c) HVR-L2 having an amino acid sequence that is 100% identical to that 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, or S-60-24, an HVR-L3 that is 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% identical to an HVR-L3 amino acid sequence of S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24.

[0211] In some embodiments, an anti-sortilin antibody of the present disclosure comprises an HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO:8), an HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:29), and an HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO:32).

[0212] In some embodiments, an anti-sortilin antibody of the present disclosure comprises an HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO:9), an HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:29), and an HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO:32).

[0213] C. Heavy Chain HVR and Light Chain HVR

[0214] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region comprising one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 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 shown in Tables 17-19). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 14-16), and the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 17-19).

[0215] In some embodiments, the heavy chain variable region comprises an HVR-H1 comprising the sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising a sequence according to Formula I, and an HVR-H3 comprising a sequence according to Formula II, and the light chain variable region comprises an HVR-L1 comprising a sequence according to Formula III, an HVR-L2 comprising a sequence according to Formula IV, and an HVR-L3 comprising a sequence according to Formula V. In some embodiments, the heavy chain variable region comprises an HVR-H1 comprising the sequence of SEQ ID NO: 1, an HVR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 2-3, and an HVR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 5-6, and the light chain variable region comprises an HVR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 8-27, an HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 29-30, and an HVR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 32-33.

[0216] In some aspects, the heavy chain variable region includes 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 includes 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 of SEQ ID NO: 32.

[0217] In some embodiments, the anti-sortilin antibodies of the present disclosure include antibodies comprising 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], 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) and 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-60-15.9[N33Y], The light chain variable regions of HVR-L1, HVR-L2 and HVR-L3 (as shown in Tables 17-19) of S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24, or any combination thereof.

[0218] In some embodiments, an anti-sortilin antibody of the present 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 comprises 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 Tables 14-19).

[0219] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one or more of the following: (a) a light chain variable region comprising a heavy chain variable region and a light chain variable region comprising the same heavy chain variable region as 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-60-2 4; (b) an HVR-H1 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 amino acid sequence of HVR-H1 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-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[N33L], S-60-16, S-60-18, S-60-19 or S-60-24; and (c) an HVR-H2 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 amino acid sequence of HVR-H2 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-60-15.1 4[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 wherein the light chain variable region comprises one or more of the following: (a) an HVR-H3 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 amino acid sequence of HVR-H3 of antibody S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N 33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15 .10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I] , S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24; (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 amino acid sequence of HVR-L1 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-60-1 5.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], and (c) an HVR-L2 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 amino acid sequence of HVR-L2 of antibody S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24; 0-11, 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[N3 3F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24, or an HVR-L3 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 an HVR-L3 amino acid sequence of S-17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24.

[0220] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0221] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRVS (SEQ ID NO: 30), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0222] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLES (SEQ ID NO: 3), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0223] In some aspects, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0224] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO: 9), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0225] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO: 8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0226] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIQQGYYGMDV (SEQ ID NO: 5); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLHSNGYNYLD (SEQ ID NO: 26), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQETPLT (SEQ ID NO: 33).

[0227] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6); and a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQGLLRSNGYNYLD (SEQ ID NO: 27), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO: 29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO: 32).

[0228] D. Heavy chain variable region

[0229] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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 that is 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% identical 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 retains 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 are substituted, inserted, and / or deleted in a heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56.

[0230] In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:56.

[0231] In some embodiments, the anti-sortilin antibodies of the present 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[N33 33Q], 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).

[0232] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 comprising the amino acid sequence of YSISSGYYWG (SEQ ID NO: 1), HVR-H2 comprising the amino acid sequence of TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and HVR-H3 comprising the amino acid sequence of ARQGSIKQGYYGMDV (SEQ ID NO: 6).

[0233] E. Light chain variable region

[0234] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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 that is 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% identical 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 retains 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 are substituted, inserted, and / or deleted in a light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0235] 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.

[0236] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33 33Q], 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).

[0237] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO:32).

[0238] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable region comprising HVR-L1 comprising the amino acid sequence of RSSQSLLRSTGYNYLD (SEQ ID NO:9), HVR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence of MQQQEAPLT (SEQ ID NO:32).

[0239] F heavy chain variable region and light chain variable region

[0240] In some aspects, the anti-sortilin antibodies of the present disclosure include 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 that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 54-56, and the light chain variable region comprises an amino acid sequence that is 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% identical to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region containing an amino acid sequence that comprises a substitution (e.g., a conservative substitution, insertion, or deletion relative to an amino acid sequence selected from SEQ ID NOs: 54-56) but retains the ability to bind to Sortilin, and a light chain variable region containing an amino acid sequence that comprises a substitution (e.g., a conservative substitution, insertion, or deletion relative to an amino acid sequence selected from SEQ ID NOs: 57-80) but retains 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 are substituted, inserted, and / or deleted in a heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56; and 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 are substituted, inserted, and / or deleted in a light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0241] In some aspects, the anti-sortilin antibodies of the present disclosure comprise 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.

[0242] In some embodiments, an anti-sortilin antibody of the present disclosure binds to sortilin, 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: 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: 77 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.

[0243] In one aspect, an anti-sortilin antibody of the present 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.

[0244] In one aspect, an anti-sortilin antibody of the present 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.

[0245] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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-60-1 The heavy chain variable region of S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 (as shown in Table 30); 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], The light chain variable region of S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 (as shown in Table 31).

[0246] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 56 and 60. In some embodiments, the antibodies comprise 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 antibodies comprise 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).

[0247] Exemplary anti-sortilin antibodies

[0248] In some embodiments, the anti-sortilin antibody is an anti-sortilin monoclonal antibody comprising a heavy chain variable region and a light chain variable region 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-60-15.2[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. In some embodiments, the anti-sortilin antibody is an anti-sortilin monoclonal antibody comprising the heavy and light chains 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-60-15.2[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[N33I], S-60-15.8[N33V], S-60-15.9[N33V], S-60-15.10[N33I], S-60-15.11[N33I], S-60-15.12[N33I], S-60-15.13[N33I], S-60-15.14[N33I], S-60-15.15[N33I], S-60-15.16[N33I], S-60-15.17[N33I], S-60-15.18[N33I], S-60-15.19[N33I], S-60-15.21[N33I], S-60-15.22[N33I], S-60-15.23[N33I], S-60-15.24[N33I], S-60-15.25[N33I], S-60-15.26[N33I], S 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[N3 3I], 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.

[0249] (1)S-60-10

[0250] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-10, or to the amino acid sequence of SEQ ID NO: 54; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-10, or to the amino acid sequence of SEQ ID NO: 57. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-10, or to the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain comprises the amino acid sequences of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-10. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-10, or to the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-10. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, the VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-10 or SEQ ID NO: 57, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVR sequences selected from the following: (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.

[0251] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0252] (2)S-60-11

[0253] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-11, or to the amino acid sequence of SEQ ID NO: 54; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-11, or to the amino acid sequence of SEQ ID NO: 58. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-11, or to 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 present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-11, or to the amino acid sequence of SEQ ID NO:58, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-11. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-11 or SEQ ID NO: 58, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0254] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 140. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0255] (3)S-60-12

[0256] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-12, or to the amino acid sequence of SEQ ID NO: 54; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-12, or to the amino acid sequence of SEQ ID NO: 59. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-12, or to the amino acid sequence of SEQ ID NO:54, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-12. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-12, or to the amino acid sequence of SEQ ID NO:59, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-12. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-12 or SEQ ID NO: 59, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0257] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 141. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0258] (4)S-60-13

[0259] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-13, or to the amino acid sequence of SEQ ID NO: 55; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-13, or to the amino acid sequence of SEQ ID NO: 57. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-13, or to the amino acid sequence of SEQ ID NO:55, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-13. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-13, or to the amino acid sequence of SEQ ID NO: 57, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-13. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-13 or SEQ ID NO: 57, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0260] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0261] (5)S-60-14

[0262] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-14, or to the amino acid sequence of SEQ ID NO: 55; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-14, or to the amino acid sequence of SEQ ID NO: 58. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-14, or to the amino acid sequence of SEQ ID NO:55, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-14. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-14, or to the amino acid sequence of SEQ ID NO:58, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-14. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-14 or SEQ ID NO: 58, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0263] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 135 or SEQ ID NO: 136. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 140. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0264] (6)S-60-15

[0265] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-15, or to the amino acid sequence of SEQ ID NO: 56; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-15, or to the amino acid sequence of SEQ ID NO: 57. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-15, or to the amino acid sequence of SEQ ID NO:56, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-15. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-15, or to the amino acid sequence of SEQ ID NO:57, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-15. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, the VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-15 or SEQ ID NO: 57, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0266] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0267] (7)S-60-15.1

[0268] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-15.1, or to the amino acid sequence of SEQ ID NO: 56; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-15.1, or to the amino acid sequence of SEQ ID NO: 60. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-15.1, or to the amino acid sequence of SEQ ID NO:56, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-15.1. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-15.1, or to the amino acid sequence of SEQ ID NO: 60, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-15.1. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. 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 a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0269] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 142. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0270] (8)S-60-16

[0271] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-16, or to the amino acid sequence of SEQ ID NO: 56; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-16, or to the amino acid sequence of SEQ ID NO: 77. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-16, or to the amino acid sequence of SEQ ID NO:56, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-16. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-16, or to the amino acid sequence of SEQ ID NO:77, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-16. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-16 or SEQ ID NO: 77, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0272] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 131. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0273] (9)S-60-18

[0274] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-18, or to the amino acid sequence of SEQ ID NO: 56; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-18, or to the amino acid sequence of SEQ ID NO: 78. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-18, or to 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 present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-18, or to the amino acid sequence of SEQ ID NO:78, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-18. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 light chain variable domain amino acid sequence of antibody S-60-18 or to 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-18 or SEQ ID NO: 78, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0275] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0276] (10)S-60-19

[0277] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-19, or to the amino acid sequence of SEQ ID NO: 54; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-19, or to the amino acid sequence of SEQ ID NO: 79. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-19, or to 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 present disclosure comprises a light chain variable domain 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 light chain variable domain amino acid sequence of antibody S-60-19, or to 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, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-19 or SEQ ID NO: 79, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0278] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 105 or SEQ ID NO: 106. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0279] (11)S-60-24

[0280] In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises 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 amino acid sequence of the heavy chain variable domain of antibody S-60-24, or to the amino acid sequence of SEQ ID NO: 56; and / or the light chain variable domain comprises 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 amino acid sequence of the light chain variable domain of antibody S-60-24, or to the amino acid sequence of SEQ ID NO: 80. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable domain 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 amino acid sequence of the heavy chain variable domain of antibody S-60-24, or to the amino acid sequence of SEQ ID NO:56, wherein the heavy chain variable domain comprises the amino acid sequence of HVR-H1, HVR-H2, and HVR-H3 of antibody S-60-24. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a light chain variable domain 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 amino acid sequence of the light chain variable domain of antibody S-60-24, or to the amino acid sequence of SEQ ID NO:80, wherein the light chain variable domain comprises the amino acid sequence of HVR-L1, HVR-L2, and HVR-L3 of antibody S-60-24. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) 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 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 the anti-sortilin antibody comprising the sequence retains the ability to bind to sortilin. In certain embodiments, a total of 1 to 10 amino acids are 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 are 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 substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion, or deletion occurs in the FR region. 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 a specific embodiment, VH comprises one, two, or three HVRs selected from the following: (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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) 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 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 the anti-sortilin antibodies comprising said sequence retain the ability to bind to sortilin. In certain embodiments, there are a total of 1 to 10 amino acid substitutions, insertions, and / or deletions 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, there are a total of 1 to 5 amino acid substitutions, insertions, and / or deletions 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 substitution, insertion or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-24 or SEQ ID NO: 80, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two or three HVRs selected from the following: (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.

[0281] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 or SEQ ID NO: 138. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 134. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise 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.

[0282] In some embodiments, an anti-Sortilin antibody of the present disclosure binds to substantially the same epitope of Sortilin 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.

[0283] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-10. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-10. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-10. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-10. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-10.

[0284] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-11. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-11. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-11. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-11. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-11.

[0285] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-12. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-12. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-12. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-12. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-12.

[0286] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-13. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-13. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-13. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-13. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-13.

[0287] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-14. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin 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 the light chain variable region of monoclonal antibody S-60-14.

[0288] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-15. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin 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 the light chain variable region of monoclonal antibody S-60-15.

[0289] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-15.1.

[0290] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-16.

[0291] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-18. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin 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 the light chain variable region of monoclonal antibody S-60-18.

[0292] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-19.

[0293] In some embodiments, the anti-sortilin antibody is the anti-sortilin monoclonal antibody S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody that binds to substantially the same epitope of sortilin as S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the monoclonal antibody S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-24.

[0294] 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 antibodies of the present disclosure are of the IgG class, the IgM class, or the IgA class. In some embodiments, the anti-sortilin antibodies of the present disclosure are of the IgG class and have an IgG1, IgG2, IgG3, or IgG4 isotype.

[0295] Additional anti-sortilin antibodies, e.g., antibodies that specifically bind to the sortilins of the present disclosure, can be identified, screened, and / or characterized for physical / chemical properties and / or biological activity by various assays known in the art.

[0296] 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 as compared to the use of the corresponding single anti-sortilin antibody.

[0297] In some embodiments, the anti-Sortilin antibodies of the present disclosure are antibody fragments that bind to human Sortilin.

[0298] 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.

[0299] In some embodiments, an anti-sortilin antibody of the present disclosure is an antibody fragment, wherein the antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0300] Antibody framework

[0301] In some embodiments, the anti-sortilin antibodies of the present disclosure include 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). ​​In some embodiments, VH FR1 comprises the sequence QVQLQESGPGLVKPSETLSLTCAVSG (SEQ ID NO: 35). In some embodiments, VH FR2 comprises the sequence WIRQPPGKGLEWIG (SEQ ID NO: 36). In some embodiments, VH FR3 comprises the sequence according to Formula VI: X1VTISVDTSKNQFSLX2LSSVTAADTAVYYC (SEQ ID NO: 39), wherein 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 VHFR1 comprising the sequence of SEQ ID NO:35, VHFR2 comprising the sequence of SEQ ID NO:36, VHFR3 according to Formula VI, and VHFR4 comprising the sequence of SEQ ID NO:40.

[0302] In some embodiments, the antibody comprises a heavy chain variable region comprising a VH FR1 comprising the sequence of SEQ ID NO:35, a VHFR2 comprising the sequence of SEQ ID NO:36, a VHFR3 comprising a sequence selected from SEQ ID NOs:37-38, and a VHFR4 comprising the sequence of SEQ ID NO:40.

[0303] In some embodiments, the anti-sortilin antibodies of the present disclosure include antibodies containing S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15. 33L], S-60-16, S-60-18, S-60-19 or S-60-24 (as shown in Tables 20-23).

[0304] In some embodiments, the anti-sortilin antibodies of the present disclosure include 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 VLFR1, VLFR2, VLFR3, and VLFR4 (as shown in Tables 24-27). In some embodiments, VLFR1 comprises a sequence according to Formula VII: DIVMTQSPLSLPVTPGX1X2ASISC (SEQ ID NO: 44), wherein X1 is E or G, and X2 is P or S. In some embodiments, VLFR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 41-43. In some embodiments, VLFR2 comprises a sequence according to Formula VIII: WYLQKPGQX1PQLLIY (SEQ ID NO: 47), wherein X1 is S or P. In some embodiments, VLFR2 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: GVPDRX1SGSGSGTDFTLKISRX2EAEDVGX3YYC (SEQ ID NO: 52), wherein X1 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, the anti-sortilin antibodies of the present disclosure comprise 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.

[0305] 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 the group consisting of SEQ ID NOs: 41-43, a VL FR2 comprising a sequence selected from the group consisting of SEQ ID NOs: 45-46, a VL FR3 comprising a sequence selected from the group consisting of SEQ ID NOs: 48-51, and a VL FR4 comprising a sequence of SEQ ID NO: 53.

[0306] In some embodiments, the anti-sortilin antibodies of the present disclosure include antibodies comprising 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 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 VL FR1, VL FR2, VL FR3 and VLFR4 (as shown in Tables 24-27).

[0307] In some embodiments, the anti-sortilin antibodies of the present disclosure include 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, VHFR2, VHFR3, and VHFR4 (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 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 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 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. In some embodiments, an anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising a VHFR1 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 the group consisting of 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 the group consisting of SEQ ID NOs: 41-43, a VL FR2 comprising a sequence selected from the group consisting of SEQ ID NOs: 45-46, a VL FR3 comprising a sequence selected from the group consisting of SEQ ID NOs: 48-51, and a VL FR4 comprising the sequence of SEQ ID NO: 53.

[0308] In some embodiments, the anti-sortilin antibodies of the present disclosure include antibodies comprising 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-6 VH of 0-15.14[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 FR1, VH FR2, VH FR3 and VHFR4 (as shown in Tables 20-23); and heavy chain variable regions containing 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 VL FR1, VL FR2, VL FR3 and VL FR4 (as shown in Tables 24-27).

[0309] Anti-sortilin antibody activity

[0310] In certain aspects of any of the described anti-sortilin antibodies, the anti-sortilin antibodies of the present disclosure can inhibit one or more activities of sortilin, including, but not limited to, reducing cellular sortilin levels (e.g., cell surface sortilin levels, intracellular sortilin levels, and / or total sortilin levels); increasing progranulin levels (e.g., extracellular progranulin levels 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 can inhibit additional activities of sortilin, including, but not limited to, inhibiting interaction (e.g., binding) with one or more of the following: proneurotrophins of the present disclosure (proneurotrophin-3, proneurotrophin 4 / 5, pro-NGF, pro-BDNF, etc.), neurotrophins of the present disclosure (neurotrophin-3, neurotrophin 4 / 5, NGF, BDNF, etc.), neurotensin, p75, sortilin propeptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), and receptor-associated protein (RAP); reducing the secretion of PCSK9; and reducing the production of beta-amyloid peptide.

[0311] In certain embodiments, the disclosure provides an anti-sortilin antibody, wherein (a) the anti-sortilin antibody increases extracellular progranulin levels, decreases cellular sortilin levels, inhibits the interaction between sortilin and progranulin, or any combination thereof; (b) the anti-sortilin antibody decreases cell surface sortilin levels, increases extracellular progranulin levels, inhibits the interaction between sortilin and progranulin, or any combination thereof; (c) the anti-sortilin antibody decreases cell surface sortilin levels, decreases intracellular sortilin levels, decreases total sortilin levels, or any combination thereof; (d) the anti-sortilin antibody induces sortilin degradation, sortilin cleavage, sortilin internalization, sortilin downregulation, or any combination thereof; (e) the anti-sortilin antibody decreases cellular sortilin levels and inhibits the interaction between sortilin and progranulin; (f) the anti-sortilin antibody decreases cellular sortilin levels and increases cellular progranulin levels; and / or (g) the anti-sortilin antibody increases the effective concentration of progranulin.

[0312] In certain embodiments, the disclosure provides an anti-sortilin antibody, wherein the anti-sortilin antibody reduces cell surface sortilin levels, increases extracellular progranulin levels, inhibits the interaction between sortilin and progranulin, or any combination thereof.

[0313] In some embodiments, an anti-sortilin antibody (a) of the present disclosure reduces cell surface sortilin levels, wherein its half maximal effective concentration (EC 50 ) is less than 150 pM; (b) reduces cell surface sortilin levels 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 relative to a control as measured by flow cytometry; increases progranulin secretion by more than about 1.13-fold relative to a control at 0.63 nM IgG, or more than about 1.22-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; blocks the binding of progranulin to sortilin, wherein the half maximal effective concentration (EC) is greater than 1.0 fold relative to a control as measured by flow cytometry. 50 ) is less than 0.325 nM; (e) blocks the binding of progranulin to sortilin by greater than about 88% relative to a control at 50 nM IgG or greater than about 27.5% at 150 nM IgG, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0314] In some embodiments, an anti-sortilin antibody (a) of the present disclosure reduces cell surface sortilin levels, wherein its half maximal effective concentration (EC 50 ) is less than 681 pM; (b) reduces cell surface sortilin levels 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 a control, as measured by flow cytometry; (c) increases progranulin secretion by more than about 1.11-fold relative to a control at 0.63 nM IgG, or more than about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; (d) blocks the binding of progranulin to sortilin, wherein the half maximal effective concentration (EC) is greater than 1.11-fold relative to a control at 0.63 nM IgG, or about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; 50 ) is less than 0.751 nM; (e) blocks the binding of progranulin to sortilin by greater than about 90% relative to a control at 50 nM IgG or greater than about 95% at 150 nM IgG, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0315] Reduce sortilin levels

[0316] In some embodiments, an anti-Sortilin antibody of the present disclosure binds to a Sortilin of the present disclosure expressed on the surface of a cell and, upon binding to said surface-expressed Sortilin, modulates (e.g., induces or inhibits) one or more Sortilin activities of the present disclosure.

[0317] In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface sortilin levels in vitro. In some embodiments, the anti-sortilin antibodies of the present disclosure can reduce cell surface sortilin levels in vivo (e.g., in the brain and / or peripheral organs of an individual). In some embodiments, the reduction in cell surface sortilin levels comprises a reduction in cell surface sortilin levels. As used herein, an anti-sortilin antibody reduces cell surface sortilin levels if it induces a reduction in cell surface sortilin levels at saturating antibody concentrations (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) as measured by any in vitro cell-based assay or suitable in vivo model described herein or known in the art. In some embodiments, the reduction in cell surface sortilin levels comprises a reduction in intracellular sortilin levels. As contemplated herein, an anti-sortilin antibody reduces intracellular Sortilin levels if it induces a decrease in intracellular Sortilin levels at saturating antibody concentrations and / or relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) as measured by any in vitro cell-based assay or suitable in vivo model described herein or known in the art. In some embodiments, the decrease in cellular Sortilin levels comprises a decrease in total Sortilin levels. As contemplated herein, an anti-sortilin antibody reduces total Sortilin levels if it induces a decrease in total Sortilin levels at saturating antibody concentrations and / or relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) as measured by any in vitro cell-based assay or suitable in vivo model described herein or known in the art.

[0318] As used herein, sortilin levels can refer to the expression level of a gene encoding sortilin; the expression level of one or more transcripts encoding sortilin; the expression level of sortilin; and / or the amount of sortilin present within a cell and / or on the cell surface. Any method known in the art for measuring gene expression, transcription, translation, and / or protein abundance levels or localization can be used to determine sortilin levels.

[0319] Cellular Sortilin levels may refer to, but are not limited to, cell surface Sortilin levels, intracellular Sortilin levels, and total Sortilin levels. In some embodiments, reduced cell Sortilin levels include reduced cell surface Sortilin levels. In some embodiments, anti-Sortilin antibodies of the present disclosure that reduce cell Sortilin levels (e.g., cell surface Sortilin levels) have one or more of the following characteristics: (1) inhibit or reduce one or more Sortilin activities; (2) are capable of inhibiting or reducing the binding of Sortilin to one or more of its ligands; (3) are capable of reducing Sortilin expression in cells expressing Sortilin; (4) are capable of interacting with, binding to, or recognizing Sortilin; (5) are capable of specifically interacting with or binding to Sortilin; and (6) are capable of treating, ameliorating, or preventing any aspect of a disease or condition described or contemplated herein.

[0320] 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 ligand mimics to transiently activate sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce a decrease in cellular sortilin levels and / or inhibition of the interaction (e.g., binding) between sortilin and one or more sortilin ligands after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce degradation of sortilin after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce sortilin cleavage after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce sortilin internalization after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce sortilin shedding after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce downregulation of sortilin expression after transient activation of sortilin. In some embodiments, the isolated anti-sortilin antibodies of the present disclosure act as ligand mimics and induce desensitization of sortilin after transient activation of sortilin.

[0321] In certain embodiments, the anti-sortilin antibodies of the present disclosure can reduce cellular sortilin levels (e.g., cell surface sortilin levels, intracellular sortilin levels, and / or total sortilin levels) by inducing sortilin degradation. Thus, in some embodiments, the anti-sortilin antibodies of the present disclosure induce sortilin degradation.

[0322] The anti-sortilin antibodies of the present disclosure can be used at half maximal effective concentrations (EC 50 In certain embodiments, the EC of the antibody is 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 about 72.58 pM to about 680.9 nM. 50 In certain embodiments, the EC of the antibody is about 103.6 pM to about 680.9 nM. 50 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.

[0323] In some embodiments, the EC of the antibody 50 Less than about or equal to about 675pM, 650pM, 625pM, 600pM, 575pM, 550pM, 525pM, 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.

[0324] In some embodiments, the EC of the antibody 50 Less than about 680.9 pM. In some embodiments, the EC of the antibody 50greater than or equal to 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. That is, the EC of the antibody 50 The present invention can have an upper limit of about 675pM, 650nM, 650pM, 625pM, 600pM, 575pM, 550pM, 525pM, 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, 1pM or 0.5pM and an upper limit of about 0.1pM, 0.5 In some embodiments, the EC of the antibody is within the range of an independently selected lower limit of 1 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 or 675 pM, wherein the lower limit is less than the upper limit. 50 is about 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, 1 any of 100 pM, 105 pM, 110 pM, 115 pM, 120 pM, 125 pM, 130 pM, 135 pM, 140 pM, 145 pM, 150 pM, 155 pM, 160 pM, 165 pM, 170 pM, 175 pM, 180 pM, 185 pM, 190 pM, 195 pM or 200 pM.

[0325] In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface sortilin levels as measured by flow cytometry at a half maximal effective concentration (EC 50 ) is less than 150 pM. In some embodiments, the EC of the anti-sortilin antibodies of the present disclosure is 50 is about 103.6 pM. In some embodiments, the EC of the anti-sortilin antibodies of the present disclosure is 50 It is about 72.58pM.

[0326] In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface Sortilin levels by more than 40% at 1.25 nM IgG or by more than about 80% at 0.63 nM IgG as measured by flow cytometry. In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface Sortilin levels by about 60.92% at 1.25 nM IgG as measured by flow cytometry. In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface Sortilin levels by about 69.3% at 150 nM IgG as measured by flow cytometry. In some embodiments, the anti-sortilin antibodies of the present disclosure reduce cell surface Sortilin levels by about 70.3% at 150 nM IgG as measured by flow cytometry.

[0327] Various methods are known in the art for measuring antibody EC. 50 In some embodiments, EC 50 is measured using cells engineered to express human sortilin. In some embodiments, EC 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 full-length antibody in a monovalent form. In some embodiments, EC 50 is determined using antibodies containing constant regions that exhibit enhanced Fc receptor binding. 50 This was determined using antibodies containing constant regions that exhibited reduced Fc receptor binding.

[0328] In some embodiments, the anti-sortilin antibodies of the present disclosure are more effective at reducing cell surface sortilin levels than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the anti-sortilin antibodies of the present disclosure are more effective at reducing cell surface sortilin levels than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 In some embodiments, the anti-sortilin antibodies of the present disclosure reduce the levels of sortilin (e.g., cell surface levels) compared to the EC values ​​of a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 The EC of 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% is lower. 50 Reduction of cell Sortilin levels (e.g., cell surface levels). In some embodiments, the anti-Sortilin antibodies of the present disclosure have an EC of 100% or less compared to a control antibody (e.g., an anti-Sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 An EC 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. 50 Reducing cell sorting protein levels (e.g., cell surface levels).

[0329] In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 1.5-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 1.1-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60).

[0330] In some embodiments, an anti-sortilin antibody (a) of the present disclosure reduces cell surface sortilin levels, wherein its half maximal effective concentration (EC 50) is less than 681 pM; (b) reduces cell surface sortilin levels 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 a control, as measured by flow cytometry; (c) increases progranulin secretion by more than about 1.11-fold relative to a control at 0.63 nM IgG, or more than about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; (d) blocks the binding of progranulin to sortilin, wherein the half maximal effective concentration (EC) is greater than 1.11-fold relative to a control at 0.63 nM IgG, or about 1.75-fold relative to a control at 50 nM IgG, as measured by a standard ELISA; 50 ) is less than 0.751 nM; (e) blocks the binding of progranulin to sortilin by greater than about 90% relative to a control at 50 nM IgG or greater than about 95% at 150 nM IgG, as measured by flow cytometry; or (f) any combination thereof (see, e.g., Examples 2-4).

[0331] Increased progranulin levels

[0332] In some embodiments, the anti-sortilin antibodies of the present disclosure increase extracellular progranulin levels in vitro. In some embodiments, the anti-sortilin antibodies of the present disclosure may increase or increase cellular progranulin levels in vivo (e.g., in the brain, blood, and / or peripheral organs of a subject). As used herein, an anti-sortilin antibody increases extracellular progranulin levels if it induces an increase in extracellular progranulin at a saturating antibody concentration (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) as measured by any in vitro cell-based assay or tissue-based assay described herein or known in the art (such as a brain tissue-based assay). As contemplated herein, an anti-sortilin antibody increases cellular progranulin levels if it induces an increase in cellular progranulin at saturating antibody concentration (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) and / or relative 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-based assay or tissue-based assay described herein or known in the art (such as a brain tissue-based assay).

[0333] As used herein, progranulin levels can refer to the expression level of a gene encoding a progranulin; the expression level of one or more transcripts encoding a progranulin; the expression level of a progranulin; and / or the amount of a progranulin secreted by a cell and / or present in a cell. Any method known in the art for measuring gene expression, transcription, translation, protein abundance, protein secretion levels, and / or protein localization can be used to determine progranulin levels.

[0334] As used herein, progranulin levels may refer to, but are not limited to, extracellular progranulin levels, intracellular progranulin levels, and total progranulin levels. In some embodiments, increased progranulin levels comprise increased extracellular progranulin levels.

[0335] In some embodiments, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin by more than about 1.11-fold compared to a control at 0.63 nM IgG as measured by a standard ELISA. In some embodiments, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin by about 1.42-fold compared to a control at 0.63 nM IgG as measured by a standard ELISA. In some embodiments, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin by more than about 1.75-fold compared to a control at 50 nM IgG as measured by a standard ELISA. In some embodiments, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin by about 1.97-fold compared to a control at 50 nM IgG as measured by a standard ELISA. In some embodiments, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin by about 2.29-fold compared to a control at 50 nM IgG as measured by a standard ELISA.

[0336] Various methods for measuring progranulin secretion are known in the art, including, for example, ELISA (see, for example, Examples 2 and 4). 50 Progranulin secretion 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 full-length antibody in a monovalent form. 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.

[0337] In some embodiments, the anti-sortilin antibodies of the present disclosure are more effective at increasing progranulin levels than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the anti-sortilin antibodies of the present disclosure increase progranulin levels at a lower EC than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 In some embodiments, an anti-sortilin antibody of the present disclosure increases progranulin levels (e.g., extracellular levels) relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) 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%. In some embodiments, an anti-sortilin antibody of the disclosure increases the level of progranulin (e.g., extracellular level) by 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 compared to a control antibody (e.g., an anti-sortilin antibody having heavy and light chain variable regions corresponding to S-60).

[0338] In some embodiments, the anti-sortilin antibodies of the present disclosure increase progranulin levels by about 1.1-fold compared to 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 by about 1.3-fold compared to a control antibody (e.g., an anti-sortilin antibody having heavy and light chain variable regions corresponding to S-60).

[0339] In some embodiments, the anti-sortilin antibodies of the present disclosure increase 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 an increase of more than 1.5-fold. In some embodiments, the increase in the effective concentration of progranulin is maintained for 7-28 days.

[0340] Reduces interactions between sortilin and its binding partners

[0341] In certain embodiments, the anti-sortilin antibodies inhibit the interaction (e.g., binding) between the Sortilin proteins of the present disclosure and one or more proteins selected from the group consisting of progranulin, proneurotrophin, neurotrophin, proneurotrophin-3, neurotrophin-3, proneurotrophin-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), Aβ 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, the anti-sortilin antibodies of the present disclosure inhibit the interaction (e.g., binding) between the Sortilin proteins of the present disclosure and progranulin.

[0342] In some embodiments, the anti-sortilin antibodies may inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and the neurotrophins of the present disclosure, such as proneurotrophin, proneurotrophin-3, proneurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, and BDNF. In other embodiments, the anti-sortilin antibodies may inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and neurotensin. In other embodiments, the anti-sortilin antibodies may inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and p75. In other embodiments, the anti-sortilin antibodies may inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and Sort-pro. In other embodiments, the anti-sortilin antibodies may inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and APP. In other embodiments, the anti-sortilin antibodies may inhibit the production of Aβ peptides. In other embodiments, the anti-sortilin antibodies may inhibit the transport and secretion of PCSK9. In other embodiments, the anti-sortilin antibodies can inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and LpL. In other embodiments, the anti-sortilin antibodies can inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and APOA5. In other embodiments, the anti-sortilin antibodies can inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and APOE. In other embodiments, the anti-sortilin antibodies can inhibit the interaction (e.g., binding) between Sortilin of the present disclosure and RAP.

[0343] In some embodiments, the anti-sortilin antibodies of the present disclosure bind to sortilin of the present disclosure expressed on the surface of a cell and the naked antibody inhibits the interaction (e.g., binding) between sortilin and one or more sortilin ligands. In some embodiments, the anti-sortilin antibodies of the present disclosure that bind to sortilin of the present disclosure inhibit the interaction (e.g., binding) between the sortilin and one or more sortilin ligands on the cell surface or inside the cell by reducing the effective level of sortilin that can interact with these proteins. In some embodiments, the anti-sortilin antibodies of the present disclosure that bind to sortilin of the present disclosure inhibit the interaction (e.g., binding) between the sortilin and one or more sortilin ligands by inducing degradation of sortilin.

[0344] A. Reduces the interaction between sortilin and progranulin

[0345] In some embodiments, the anti-sortilin antibodies of the present disclosure increase progranulin levels and / or decrease cellular sortilin levels while blocking (e.g., inhibiting) the interaction (e.g., binding) between sortilin and progranulin. Thus, in some embodiments, the 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 the binding of progranulin to sortilin at a saturating antibody concentration (e.g., 0.6 nM, 0.63 nM, 1.25 nM, 50 nM, or 150 nM) relative to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60) in any in vitro assay or cell-based culture assay described herein or known in the art.

[0346] The anti-sortilin antibodies of the present disclosure can be used at half maximal effective concentrations (EC 50 In certain embodiments, the EC of the antibody is 50 In certain embodiments, the EC of the antibody is less than about 2.2 nM. 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 about 325 pM to about 751 nM. 50 In certain embodiments, the EC of the antibody is about 405 pM to about 751 nM. 50In certain embodiments, the EC of the antibody is about 588 pM to about 751 nM. 50 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.

[0347] In some embodiments, the antibody is effective for reducing the binding of progranulin to sortilin. 50 Less than or equal to 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, 475 pM, 450 pM, 425 pM, 400 pM, 375 pM, 350 pM pM, 2pM, 1pM, or 0.5pM.

[0348] In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 is about 1.22 nM. In some embodiments, the EC of the anti-sortilin antibodies of the present disclosure is 50 is about 588 pM. In some embodiments, the EC of the anti-sortilin antibodies of the present disclosure is 50 is about 405 pM. In some embodiments, the EC of the anti-sortilin antibodies of the present disclosure is 50 It is about 325pM.

[0349] Various methods are known in the art for measuring antibody EC. 50 Methods for determining the value of the protein include, for example, flow cytometry (see, for example, Example 3). In some embodiments, the protein associated with the EC that reduces the binding of progranulin to sortilin is 50 is measured in vitro using cells expressing human sortilin. In some embodiments, EC 50 is measured at a temperature of about 4°C. In some embodiments, EC 50is 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 for reducing the binding of progranulin to sortilin 50 is determined using a monovalent antibody (e.g., Fab) or a full-length antibody in a monovalent form. In some embodiments, EC 50 is determined using antibodies containing constant regions that exhibit enhanced Fc receptor binding. In some embodiments, the ECs for reducing progranulin binding to sortilin 50 This was determined using antibodies containing constant regions that exhibited reduced Fc receptor binding.

[0350] In some embodiments, the anti-sortilin antibodies of the present disclosure are more effective at reducing the binding of progranulin to sortilin than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the anti-sortilin antibodies of the present disclosure are more effective at reducing the binding of progranulin to sortilin than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 Reduction of progranulin binding to sortilin (e.g., as measured in vitro). In some embodiments, the anti-sortilin antibodies of the present disclosure have an EC greater than that of a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 The EC of 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% is lower. 50 Reduce the binding of progranulin to sortilin. In some embodiments, the anti-sortilin antibodies of the present disclosure have an EC of 0.0400 / 0.0500 compared to a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). 50 An EC 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. 50 Reduces the binding of progranulin to sortilin.

[0351] In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 1.3-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 1.8-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 1.9-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60). In some embodiments, the EC of an anti-sortilin antibody of the present disclosure is 50 At least 2.3-fold lower than a control antibody (e.g., an anti-sortilin antibody having a heavy chain variable region and a light chain variable region corresponding to S-60).

[0352] Any in vitro cell-based 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 reducing Sortilin expression (e.g., by reducing cell surface Sortilin levels). 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 at least about 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%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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 %, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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 more. In some embodiments, the anti-sortilin antibodies of the present disclosure block the binding of progranulin to Sortilin by greater than 90% at 50 nM IgG or greater than about 96% at 150 nM IgG as measured by flow cytometry. In some embodiments, the anti-sortilin antibodies of the present disclosure block the binding of progranulin to Sortilin by about 90.74% at 50 nM IgG as measured by flow cytometry. In some embodiments, the anti-sortilin antibodies of the present disclosure block the binding of progranulin to Sortilin by about 96.5% at 150 nM IgG as measured by flow cytometry.In some embodiments, an anti-sortilin antibody of the present disclosure blocks the binding of progranulin to sortilin by about 96.9% at 150 nM IgG as measured by flow cytometry.

[0353] Reduce the expression of pro-inflammatory mediators

[0354] In some embodiments, the anti-sortilin antibodies of the present disclosure, upon binding to sortilin ex...

Claims

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

2. The antibody of claim 1, wherein the anti-sortilin antibody: (a) reduces the level of Sortilin on the cell surface to an extent greater than the 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 level of extracellular progranulin beyond the level 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 an extent exceeding 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) to (c).

3. The antibody of claim 1 or claim 2, wherein the dissociation constant (K) of the antibody for human sortilin is D ) is more 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, wherein the K D was determined by FACS.

4. The antibody of any one of claims 1-3, wherein the dissociation constant (K) of the antibody for human sortilin is D ) is in the range of about 5.0E-10M to about 1.0E-9M, wherein the K D is determined by FACS; or in the range of about 250-500 pM, wherein the K D It was determined by biolayer interferometry.

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

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

7. An antibody that binds to Sortilin, wherein the antibody comprises: (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.

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

60.

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

57.

10. An antibody that binds to sortilin, wherein the antibody comprises 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 sortilin, wherein the antibody comprises 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 of any one of claims 1-9, wherein the antibody belongs to the IgG class, the IgM class or the IgA class.

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

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

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

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

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

81.

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

19. The antibody of any one of claims 1-18, wherein the antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.

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

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. 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, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetrant peptide, polyarginine peptide, vascular peptide, basic immunoglobulin, Glut1, CD98hc and ANG1005.

23. The antibody of any one of claims 1-9 and claims 12-22, wherein the antibody is an antibody fragment that binds to human Sortilin.

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 1-24.

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

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

28. A method for producing an antibody that binds to Sortilin, the method comprising culturing the host cell of claim 27, thereby producing the antibody.

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

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

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

32. A method of preventing, reducing the risk of, or treating a subject suffering from a disease, disorder, or injury, the method comprising administering to the subject a therapeutically effective amount of an antibody as described in any one of claims 1-24 and claim 30 or a pharmaceutical composition as described in claim 31.

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 and osteoarthritis.

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. A method of inhibiting one or more of neuroinflammation, axonopathy characterized by short axonal overgrowth and abnormal branching, microglial activation, and inflammatory response in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an anti-sortilin antibody as described in any one of claims 1-24 and claim 30 or a pharmaceutical composition as described in claim 31.

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

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

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

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 of inhibiting the interaction between sortilin and progranulin, the method comprising exposing a cell expressing sortilin to an anti-sortilin antibody as described in any one of claims 1-24 and claim 30 or a pharmaceutical composition as described in claim 31.

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

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

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

44. The method of any one of claims 40-43, wherein extracellular progranulin levels are increased.

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

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

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

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

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

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

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

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

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

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