An anti-syntenin antibody for use in therapy

Abstract

The present disclosure generally relates to the use of compositions of antibodies such as monoclonal antibodies, chimeric antibodies, affinity matured antibodies, humanized antibodies, antibody fragments, etc., that specifically bind to one or more epitopes within sorting proteins such as human sorting proteins or mammalian sorting proteins and have improved and / or enhanced functional characteristics, in treating diseases or injuries and / or delaying the progression of said diseases or injuries in an individual in need thereof.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 860,207, filed on June 11, 2019; U.S. Provisional Application No. 62 / 868,850, filed on June 28, 2019; U.S. Provisional Application No. 62 / 874,475, filed on July 15, 2019; U.S. Provisional Application No. 62 / 947,503, filed on December 12, 2019; and U.S. Provisional Application No. 62 / 961,591, filed on January 15, 2020, each of which is hereby incorporated by reference in its entirety.

[0003] Submission of a Sequence Listing as an ASCII text file

[0004] The content of the following submission file in ASCII text file format is hereby incorporated by reference in its entirety: computer - readable form (CRF) of the sequence listing (file name: 735022003040SEQLIST.TXT, date of record: June 9, 2020, size: 135 KB). Technical field

[0005] The present disclosure relates to the therapeutic use of anti - Sortilin antibodies. Background art

[0006] Sortilin is a type I transmembrane protein that serves as a receptor for several ligands and plays a role in sorting selected cargos from the trans - Golgi network (TGN) to late endosomes and lysosomes for degradation. Sortilin binds the secreted protein progranulin (PGRN) and targets it for lysosomal degradation, thus negatively regulating the extracellular levels of PGRN (Hu, F. et al. (2010) Neuron 68, 654 - 667). Accordingly, in both in vivo mouse models and in vitro human cells, the lack of Sortilin significantly increases plasma PGRN levels (Carrasquillo, M.M. et al., (2010) Am J Hum Genet 87, 890 - 897; Lee, W.C. et al., (2014) Hum Mol Genet 23, 1467 - 1478). In addition, polymorphisms in Sortilin have been shown to be strongly associated with PGRN serum levels in humans (Carrasquillo MM et al., (2010), Am J Hum Genet. 10; 87(6):890 - 7).

[0007] Progranulin (PGRN) is a secreted growth factor-like trophic and anti-inflammatory protein that also functions as an adipokine involved in diet-induced obesity and insulin resistance (Nguyen DA et al., (2013). Trends in Endocrinology and Metabolism, 24, 597-606). Lack of progranulin causes approximately 25% of all heritable forms of frontotemporal dementia (FTD), an early-onset neurodegenerative disease. Patients with heterozygous loss-of-function mutations in PGRN have extracellular protein levels reduced by approximately 50%, and they will invariably develop 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, PGRN mutant alleles have been identified in patients with Alzheimer’s disease (Seelaar, H et al., (2011). Journal of neurology, neurosurgery, and psychiatry 82, 476-486). Importantly, PGRN plays a protective role in several disease models, where increased PGRN levels accelerate behavioral recovery from ischemia (Tao, J et al., (2012) Brain Res 1436, 130-136; Egashira, Y. et al., (2013) JNeuroinflammation10, 105), suppress motor deficits in a Parkinson’s disease model (Van Kampen, J.M et al (2014). PLoS One 9, e97032), attenuate lesions in models of amyotrophic lateral sclerosis (Laird, A.S et al., (2010). PLoSOne 5, e13368.) and arthritis (Tang, W et al., (2011). Science 332, 478-484), and prevent memory deficits in an Alzheimer’s disease model (Minami, S.S et al., (2014). Nat Med 20, 1157-1164).

[0008] Through its various interactions with proteins such as progranulin, sortilin and its multiple ligands have been shown to be involved in various diseases, disorders and afflictions, such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), the ALS-FTD phenotype, Alzheimer's disease, Parkinson's disease, depression, neuropsychiatric disorders, vascular dementia, seizures, retinal dystrophy, age-related macular degeneration, glaucoma, traumatic brain injury, aging, seizures, wound healing, stroke, arthritis and atherosclerotic vascular disease.

[0009] Novel therapeutic antibodies targeting sortilin are a solution for treating diseases associated with sortilin activity. Monoclonal antibodies administered systemically typically exhibit a biphasic pharmacokinetic profile, i.e., first distributing relatively rapidly and then being eliminated more slowly (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). The circulation of systemically administered antibodies is typically limited to the vasculature and interstitial space (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). This is due to their size, polarity, recycling and clearance kinetics, as well as their generally relatively long half-lives, which are often 11-30 days in humans (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552).

[0010] The administration of monoclonal antibodies presents challenges for therapeutic use. Monoclonal antibodies have limited oral bioavailability, so they are typically administered intravenously, subcutaneously or intramuscularly (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552). Among those options, subcutaneous administration is the most convenient because it can be done at home and often by the patient themselves, but intravenous administration delivers higher systemic exposure. Delivery to the cerebrospinal fluid (CSF) requires a higher systemic dose. Thus, when treatment requires affecting the CSF, intravenous administration is usually needed because subcutaneous administration cannot deliver a high enough dose.

[0011] However, for patients with neurodegenerative diseases such as FTD and ALS, intravenous administration is particularly challenging. These diseases affect patients over a long period, so regular treatment is required over the course of many years. Since intravenous administration cannot be done at home, patients must be transported regularly to infusion centers, which becomes a burden for both the patient and the caregiver. Finally, memory loss, mood swings, aggressive behavior and other behavioral symptoms of these diseases make it difficult to achieve patient compliance.

[0012] Accordingly, there is a need for therapeutic antibodies that specifically bind to sorting proteins and block the binding of sorting proteins to their ligands such as progranulin, or otherwise modulate the effective concentration of the ligand to treat one or more diseases, disorders, and afflictions associated with sorting protein activity. In addition, due to limitations in the mode of administration and dosing, there is a further need to identify methods of treating patients with an appropriate dose and administering the dose in a manner that readily achieves patient compliance. All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety. SUMMARY OF THE INVENTION

[0013] The present disclosure generally relates to methods of using compositions comprising antibodies that specifically bind to human sorting proteins, such as monoclonal antibodies, chimeric antibodies, humanized antibodies, antibody fragments, and the like.

[0014] In certain aspects, the present disclosure provides a method of treating a disease or injury in an individual and / or delaying the progression of the disease or injury, the method comprising administering an anti-sortilin antibody intravenously to the individual at a dose of at least about 30 mg / kg once every four weeks or more frequently, wherein the antibody comprises: (i) a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32); (ii) a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRVS (SEQ ID NO:30), and HVR-L3 having the amino acid sequence MQQQETPLT (SEQ ID NO:33); (iii) a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO:3), and HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).(iv) A heavy chain variable region, said heavy chain variable region comprising HVR-H1 containing the amino acid sequence YYSISSGYYWG (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 a light chain variable region, said light chain variable region comprising 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 (SEQ ID NO:32); (v) A heavy chain variable region, said heavy chain variable region comprising HVR-H1 containing the amino acid sequence YYSISSGYYWG (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 a light chain variable region, said light chain variable region comprising 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 (SEQ ID NO:32); (vi) A heavy chain variable region, said heavy chain variable region comprising HVR-H1 containing the amino acid sequence YYSISSGYYWG (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 a light chain variable region, said light chain variable region comprising 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 MQQQETPLT (SEQ ID NO:33); (vii) A heavy chain variable region, said heavy chain variable region comprising HVR-H1 containing the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 containing the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 containing the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5);and a light chain variable region, the light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO:26), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence MQQQETPLT (SEQ ID NO:33); or (viii) a heavy chain variable region, the heavy chain variable region comprising HVR-H1 comprising the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region, the light chain variable region comprising HVR-L1 comprising the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO:27), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO:32).;

[0015] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0016] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region and a light chain variable region, wherein the antibody comprises a heavy chain variable region having HVR-H1 comprising the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO:9), HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0017] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:54 and a light chain variable region having the amino acid sequence of SEQ ID NO:57.

[0018] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:54 and a light chain variable region having the amino acid sequence of SEQ ID NO:58.

[0019] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:54 and a light chain variable region having the amino acid sequence of SEQ ID NO:59.

[0020] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:55 and a light chain variable region having the amino acid sequence of SEQ ID NO:57.

[0021] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:55 and a light chain variable region having the amino acid sequence of SEQ ID NO:58.

[0022] In some embodiments, the anti-sortilin antibody 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.

[0023] In some embodiments, the anti-sortilin antibody 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:77.

[0024] In some embodiments, the anti-sortilin antibody 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:78.

[0025] In some embodiments, the anti-sortilin antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:54 and a light chain variable region having the amino acid sequence of SEQ ID NO:79.

[0026] In some embodiments, the anti-sortilin antibody 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:80.

[0027] In some embodiments, the anti-sortilin antibody 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. In some embodiments, the anti-sortilin antibody 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.

[0028] In some embodiments, the antibody is of the IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A and P331S, wherein the residue positions are numbered according to EU numbering.

[0029] In some embodiments, the dose is at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg or at least about 60 mg / kg. In some embodiments, the dose is between about 30 mg / kg and about 60 mg / kg. In some embodiments, the dose is about 60 mg / kg.

[0030] In some embodiments, the anti-sortilin antibody is administered once every two weeks. In some embodiments, the anti-sortilin antibody is administered once every three weeks. In some embodiments, the anti-sortilin antibody is administered once every four weeks.

[0031] In some embodiments, the anti-sortilin antibody is administered at a dose of about 60 mg / kg once every four weeks.

[0032] In some embodiments, the disease or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis. In some embodiments, the disease or injury is frontotemporal dementia. In some embodiments, the disease or injury is amyotrophic lateral sclerosis.

[0033] In some embodiments, the individual is heterozygous for a mutation in GRN. In some embodiments, the mutation in GRN is a loss-of-function mutation. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion. In some embodiments, the individual displays symptoms of frontotemporal dementia. In some embodiments, the individual does not display symptoms of frontotemporal dementia.

[0034] In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least one-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least two-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the plasma of the individual at about five days after administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the plasma of the individual at about 42 days after administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the plasma of the individual at about 56 days after administration of the anti-sortilin antibody. In some embodiments, at about forty days after administration of the anti-sortilin antibody, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least 0.25-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody.

[0035] In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least two-fold, three-fold, or four-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the plasma of the individual at about five days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the plasma of the individual at about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of the anti-sortilin antibody.

[0036] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of the anti-sortilin antibody is at least 0.8-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of the anti-sortilin antibody is at least one-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about twelve days after administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 24 days after administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 56 days after administration of the anti-sortilin antibody. In some embodiments, at about 42 days after administration of the anti-sortilin antibody, the level of PGRN protein in the cerebrospinal fluid of the individual after administration of the anti-sortilin antibody is at least 0.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody.

[0037] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of the anti-sortilin antibody is at least two-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about twelve days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 24 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 28, 35, 42, 49 or 56 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 28 days, 35 days, 42 days, 49 days or 56 days after the last administration of the anti-sortilin antibody.

[0038] In some embodiments, the level of SORT1 protein on the peripheral white blood cells of an individual after administration of an anti-sortilin antibody is reduced by at least 50% compared to the level of SORT1 protein on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of SORT1 protein on the peripheral white blood cells of an individual after administration of an anti-sortilin antibody is reduced by at least 70% compared to the level of SORT1 protein on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about twelve days or more after administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about seventeen days or more after administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about forty days or more after administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about twelve days or more after the last administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about seventeen days or more after the last administration of the anti-sortilin antibody. In some embodiments, a reduction in the level of SORT1 expression is present in the peripheral white blood cells of an individual about forty days or more after the last administration of the anti-sortilin antibody.

[0039] In some embodiments, the half-life of the anti-sortilin antibody in plasma is about 5 days. In some embodiments, the half-life of the anti-sortilin antibody in plasma is about 8 days.

[0040] In some embodiments, an individual is treated for a treatment period of up to 48 weeks. In some embodiments, an individual is treated for a treatment period of 48 weeks. In some embodiments, administration of the anti-sortilin antibody occurs on the first day of the treatment period and every four weeks thereafter. In some embodiments, the anti-sortilin antibody is administered a total of 13 times during the treatment period.

[0041] In some embodiments, the disease or injury is frontotemporal dementia (FTD), and the plasma neurofilament light chain (NfL) level is reduced by at least 10%. In some embodiments, the disease or injury is frontotemporal dementia (FTD), and the plasma neurofilament light chain (NfL) level after administration of the anti-sortilin antibody is reduced by at least 10% compared to the plasma neurofilament light chain (NfL) level before administration of the anti-sortilin antibody.

[0042] In some embodiments, the protein level of CTSB in the CSF of an individual is increased by at least about 20% compared to the protein level of CTSB in the CSF of the individual before administration of the anti-sortilin antibody. In some embodiments, the protein level of SPP1 in the CSF of an individual is decreased by at least about 10% compared to the protein level of SPP1 in the CSF of the individual before administration of the anti-sortilin antibody. In some embodiments, the protein level of CTSB in the CSF of an individual is increased by at least about 20% after administration of the anti-sortilin antibody compared to the protein level of CTSB in the CSF of the individual before administration of the anti-sortilin antibody. In some embodiments, the protein level of SPP1 in the CSF of an individual is decreased by at least about 10% after administration of the anti-sortilin antibody compared to the protein level of SPP1 in the CSF of the individual before administration of the anti-sortilin antibody. In some embodiments, the protein level of N-acetylglucosamine kinase (NAGK) in the CSF of an individual is increased after administration of the anti-sortilin antibody compared to the protein level of NAGK in the CSF of the individual before administration of the anti-sortilin antibody. In some embodiments, the protein level of one or more inflammatory proteins in the CSF of an individual is decreased after administration of the anti-sortilin antibody compared to the protein level of the one or more inflammatory proteins in the CSF of the individual before administration of the anti-sortilin antibody, wherein the one or more inflammatory proteins are selected from the group consisting of 14-3-3 protein epsilon (YWHAE), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86.

[0043] In another aspect, provided herein is a method of monitoring the treatment of an individual being administered an anti-sortilin antibody, the method comprising measuring the level of one or more proteins in a sample from the individual before and after the individual has received one or more doses of the anti-sortilin antibody, wherein the one or more proteins are CTSB and / or SPP1. In some embodiments, the method of monitoring the treatment of an individual being administered an anti-sortilin antibody further comprises the step of assessing the activity of the anti-sortilin antibody in the individual based on the level of the one or more proteins in the sample. In some embodiments, the sample is from the cerebrospinal fluid or the blood of the individual. In some embodiments, the sample is from the cerebrospinal fluid of the individual.

[0044] On the other hand, the present disclosure provides a method for monitoring the treatment of an individual being administered an anti-sortilin antibody, the method comprising measuring the level of one or more proteins in a sample from the individual before and after the individual has received one or more doses of the anti-sortilin antibody, wherein the one or more proteins are selected from the group consisting of CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, and CD86. In some embodiments, the method further comprises evaluating the activity of the anti-sortilin antibody in the individual based on the level of one or more proteins in the sample. In some embodiments, the sample is from the cerebrospinal fluid of the individual. In some embodiments, the anti-sortilin antibody is determined to be active in the individual if the level of CTSB in the cerebrospinal fluid after the individual has received one or more doses of the anti-sortilin antibody is increased compared to the level of CTSB in the cerebrospinal fluid before the individual received one or more doses of the anti-sortilin antibody. In some embodiments, the anti-sortilin antibody is determined to be active in the individual if the level of CTSB in the cerebrospinal fluid after the individual has received one or more doses of the anti-sortilin antibody is increased by at least about 20% compared to the level of CTSB in the cerebrospinal fluid before the individual received one or more doses of the anti-sortilin antibody. In some embodiments, the anti-sortilin antibody is determined to be active in the individual if the level of SPP1 in the cerebrospinal fluid after the individual has received one or more doses of the anti-sortilin antibody is decreased compared to the level of SPP1 in the cerebrospinal fluid before the individual received one or more doses of the anti-sortilin antibody. In some embodiments, the anti-sortilin antibody is determined to be active in the individual if the level of SPP1 in the cerebrospinal fluid after the individual has received one or more doses of the anti-sortilin antibody is decreased by at least about 10% compared to the level of SPP1 in the cerebrospinal fluid before the individual received one or more doses of the anti-sortilin antibody. In some embodiments, the anti-sortilin antibody is determined to be active in the individual if the level of NAGK in the cerebrospinal fluid after the individual has received one or more doses of the anti-sortilin antibody is increased compared to the level of NAGK in the cerebrospinal fluid before the individual received one or more doses of the anti-sortilin antibody.In some embodiments, an antisortilin antibody is determined to be active in an individual if the level of one or more inflammatory proteins in cerebrospinal fluid is reduced in the individual after the individual has received one or more doses of the antisortilin antibody as compared to the level of the one or more inflammatory proteins in cerebrospinal fluid before the individual has received one or more doses of the antisortilin antibody, wherein the one or more inflammatory proteins are selected from the group consisting of 14-3-3 protein epsilon (YWHAE), allograft inflammatory factor 1 (AIF1), colony stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86. In some embodiments, the sample is from the blood of the individual. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figures 1A to 1C Provide pharmacokinetic and pharmacodynamic studies of non-human primates administered a single dose of the antisortilin antibody S-60-15.1 [N33T] LALAPS. Figure 1A Provide the level of SORT1 in peripheral white blood cells at the indicated time (hours) after treatment with the designated antisortilin antibody dose as a percentage relative to baseline. SORT1 expression was reduced at all antisortilin antibody doses tested. Higher antibody doses (60 mg / kg, 200 mg / kg) resulted in an earlier and more prolonged reduction in SORT1 levels as compared to lower antisortilin antibody doses (5 mg / kg, 20 mg / kg). Figure 1B Provide the level of PGRN in plasma at the indicated time (hours) after treatment with the designated antisortilin antibody dose as a percentage relative to baseline. The level of PGRN increased in a time- and dose-dependent manner. Specifically, for all antisortilin antibody doses tested, as compared to the baseline level, at 最大 C, the plasma PGRN level increased 3 to 4-fold and remained elevated for a longer period at higher antibody doses. Figure 1C Provide the level of PGRN in CSF at the indicated time (hours) after treatment with the designated antisortilin antibody dose as a percentage relative to baseline. In animals administered 20 mg / kg, 60 mg / kg, or 200 mg / kg, the CSF PGRN level increased 2 to 3-fold over baseline. As observed for the plasma PGRN level ( Figure 1B ), in the higher antibody dose groups, the CSF PGRN level remained elevated over time. For Figures 1A to 1C , n = 3 animals per dose.

[0046] Figures 2A to 2CProvide a pharmacokinetic and pharmacodynamic study of non-human primates administered repeated doses of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. The anti-sortilin antibody S-60-15.1[N33T]LALAPS was administered to animals (2 males and 2 females) once a week for four weeks at a dose of 60 mg / kg. The days of dosing are indicated by vertical dashed lines. Figure 2A Provide the mean (+ / - standard deviation) of the concentration of SORT1 in peripheral white blood cells (WBC) at the indicated time (days) as a percentage of baseline. Throughout the duration of the study, the SORT1 level in peripheral white blood cells remained decreased. Figure 2B Provide the mean (+ / - standard deviation) of the concentration of PGRN in plasma at the indicated time (days) as a percentage (normalized) of baseline. At peak levels, the plasma PGRN level increased to 5 to 6 times baseline. A decrease in plasma PGRN was observed after the fourth and final administration of the anti-sortilin antibody; however, the plasma PGRN level remained elevated to 2 times baseline. Figure 2C Provide the mean (+ / - standard deviation) of the concentration of PGRN in CSF at the indicated time (days) as a percentage (normalized) of baseline. The CSF PGRN level increased to 3 to 4 times baseline ( Figure 2C ).

[0047] Figures 3A to 3C Show the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on the SORT1 level in white blood cells and on the plasma PGRN level. In Figure 3A , the dashed lines represent the SORT1 expression levels on peripheral white blood cells (wbc) at the indicated time as a percentage change from baseline in 5 groups of healthy volunteers treated with the indicated dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS; the solid lines represent the plasma (PL) PGRN levels as a percentage change from baseline at the indicated time in 5 groups of healthy volunteers treated with the indicated dose of the anti-sortilin antibody S-60-15.1[N33T]LALAPS. Administration of the anti-sortilin antibody S-60-15.1[N33T]LALAPS to human subjects resulted in a decrease in the SORT1 expression level on peripheral white blood cells and an increase in the plasma PGRN level. Another analysis of the SORT1 level on peripheral white blood cells at the indicated time (days after dosing) in human subjects administered the anti-sortilin antibody S-60-15.1[N33T]LALAPS is provided in Figure 3BAnother analysis of progranulin (PGRN) levels relative to baseline at the indicated times (days post-dose) in human subjects administered the anti-sortilin antibody S-60-15.1[N33T]LALAPS provides the data in Figure 3C The horizontal dashed line indicates a two-fold increase relative to baseline.

[0048] Figures 4A to 4C Shows the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN levels in CSF. Pharmacodynamic data on CSF PGRN levels were obtained from cohorts of healthy volunteers dosed at 0 mg / kg (placebo), 15 mg / kg, 30 mg / kg, or 60 mg / kg. CSF samples were collected before dosing and then at approximately 30 hours, 12 days, 24 days, and 42 days after antibody administration. As Figure 4A shown, for all cohorts, a statistically significant increase in CSF PGRN levels was observed at 30 hours and 12 days (compared to the PGRN levels observed at baseline). In addition, administration of the antibody at 60 mg / kg resulted in an increase in the level of CSF PGRN that persisted for at least 24 days after a single IV dose of the anti-sortilin antibody. Figure 4B Shows the percent change from baseline in CSF PGRN levels in healthy volunteers dosed at 0 mg / kg (placebo), 15 mg / kg (cohort 3), 30 mg / kg ("cohort 4"), or 60 mg / kg ("cohort 5") on study day 13 (12 days post-dose). Asterisks indicate statistical significance. (****: P < 0.0001, adjusted for multiplicity.) Figure 4C Shows the percent change from baseline in CSF PGRN levels at the indicated days post-dose in healthy volunteers dosed at 60 mg / kg (combination of "cohort 5" and "cohort 6").

[0049] Figures 5A to 5C Shows the effect of the anti-sortilin antibody S-60-15.1[N33T]LALAPS on PGRN levels in plasma and CSF of aFTD-GRN and FTD-GRN subjects. Figure 5A Provides the mean percent change in plasma PGRN levels at the indicated days post-dose in one aFTD-GRN subject and three FTD-GRN subjects. Figure 5B Provides the mean percent change from baseline in CSF PGRN levels in one aFTD-GRN subject (study day 13) and three FTD-GRN patients (study day 57). Figure 5C Provides the concentration (ng / mL) of PGRN in CSF from normal healthy volunteers and from three FTD-GRN patients before dosing and on study day 57.

[0050] Figure 6 Provide a schematic description of the Phase 2 study described in Example 3. CSF = cerebrospinal fluid; GRN = granulin; IV = intravenous; MRI = magnetic resonance imaging; PD = pharmacodynamics; PET = positron emission tomography; q4w = every 4 weeks; TSPO = translocator protein.

[0051] Figure 7 Show the effect of the sortilin antibody S-60-15.1[N33T]LALAPS on the progranulin (PGRN) concentration (ng / mL) in the plasma of aFTD-GRN and FTD-GRN subjects at the indicated times after administration of the antibody. SD = single dose; MD = multiple doses. The median baseline concentration of PGRN in the plasma of healthy volunteers (HV) and FTD patients is indicated by the horizontal line.

[0052] Figure 8 Show the effect of the sortilin antibody S-60-15.1[N33T]LALAPS on the PGRN concentration (ng / mL) in the CSF of aFTD-GRN (asymptomatic) and FTD-GRN (symptomatic) subjects at the indicated times after administration of the antibody. The concentration of PGRN in the CSF of healthy volunteers (HV) is provided. One symptomatic subject did not have reportable CSF PGRN results at baseline.

[0053] Figure 9 Show the effect of the sortilin antibody S-60-15.1[N33T]LALAPS on the CSF protein signature in FTD-GRN patients according to SOMASCAN analysis of >1000 proteins as described in Example 5. The Y-axis provides the Z-score of the ratio of the level of each protein in FTD-GRN patients and healthy volunteers. The X-axis provides the Z-score of the ratio of the level of each protein in FTD-GRN patients at 57 days after administration of the sortilin antibody S-60-15.1[N33T]LALAPS and at baseline (before administration of the sortilin antibody S-60-15.1[N33T]LALAPS). Proteins that are upregulated in FTD-GRN patients and normalized after administration of the sortilin antibody S-60-15.1[N33T]LALAPS are shown in the upper left quadrant of the scatter plot. Proteins that are downregulated in FTD-GRN patients and restored after administration of the sortilin antibody S-60-15.1[N33T]LALAPS are shown in the lower right quadrant of the scatter plot.

[0054] Figures 10A to 10B Show the NfL plasma levels in FTD-GRN patients. At Figure 10AAmong them, the NfL plasma levels were measured using the Quinterix SIMOA Nf-Light Advantage assay. In Figure 10A Among them, the NfL plasma levels of each of the five patients at various time points were indicated as a ratio relative to the baseline level. Figure 10B Show Figure 10A The geometric mean of the data shown.

[0055] Figures 11A to 11B Show the effects of the antisortilin antibody S-60-15.1[N33T]LALAPS on the biomarker SPP1 upregulated in patients with FTD and the biomarker CTSB downregulated in patients with FTD. Figure 11A Show that, relative to healthy volunteers, the biomarker SPP1 is upregulated in patients with FTD, and treatment of patients with FTD with S-60-15.1[N33T]LALAPS reduces SPP1 to near-normal levels. In contrast, Figure 11B Show that, relative to healthy volunteers, the biomarker CTSB is downregulated in patients with FTD, and treatment of patients with FTD with S-60-15.1[N33T]LALAPS increases the CTSB level to near-normal levels. Detailed Description

[0056] Definitions

[0057] As used herein, the term "prevent" includes providing prevention of the occurrence or recurrence of a specific disease, disorder, or condition in an individual. The individual may be predisposed, susceptible to, or at risk of developing such a disease, disorder, or condition, but has not yet been diagnosed with the disease, disorder, or condition.

[0058] As used herein, an individual "at risk" of developing a specific disease, disorder, or condition may or may not have a detectable disease or symptom of the disease before the treatment methods described herein, and may or may not have shown a detectable disease or symptom of the disease. "At risk" means that the individual has one or more risk factors, which are measurable parameters known in the art to be associated with the development of a specific disease, disorder, or condition. An individual having one or more of these risk factors has a higher probability of developing a specific disease, disorder, or condition compared to an individual not having one or more of these risk factors.

[0059] As used herein, the term "treatment" refers to a clinical intervention that is intended to alter the natural course of an individual being treated during the course of a clinical condition. Desirable therapeutic effects include reducing the rate of progression of a specific disease, disorder, or condition, ameliorating or alleviating the pathological state of a specific disease, disorder, or condition, and relieving a specific disease, disorder, or condition or improving the prognosis of a specific disease, disorder, or condition. For example, an individual is successfully "treated" if one or more symptoms associated with a specific disease, disorder, or condition are alleviated or eliminated.

[0060] "Effective amount" means the amount that is at least required to effectively achieve the desired therapeutic or prophylactic result at the necessary dosage and for the necessary period of time. The effective amount can be administered in one or more doses. The effective amount herein can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the treatment to elicit the desired response in the individual. The effective amount is also the amount where the therapeutic beneficial effect outweighs any toxic or detrimental effect of the treatment. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk of a disease (including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presented during the development of the disease), alleviating the severity of the disease, or delaying the onset of the disease. For therapeutic use, beneficial or desired results include clinical outcomes such as alleviating one or more symptoms caused by the disease, increasing the quality of life of the diseased individual, reducing the dosage of other drug therapies required to treat the disease, enhancing the effect of another drug therapy such as by targeting, delaying the progression of the disease, and / or prolonging survival. The effective amount of a drug, compound, or pharmaceutical composition is the amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As is understood in the clinical situation, the effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and if a desired result is achieved or is achieved in combination with one or more other agents, a single agent can be considered to be administered in an effective amount.

[0061] As used herein, "administering in combination" with another compound or composition includes administering simultaneously and / or at different times. Administering in combination also encompasses administering in a co-formulation or in separate compositions, including at different dosing frequencies or intervals, and using the same administration route or different administration routes.

[0062] For purposes of treatment, prophylaxis, or risk reduction, an "individual" means any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. Preferably, the individual is a human.

[0063] Unless otherwise indicated, the terms "sorting protein" or "sorting protein polypeptide" are used interchangeably herein to refer to any native sorting protein from any mammalian source including primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences such as splice variants or allelic variants. In some embodiments, the term encompasses "full-length" unprocessed sorting proteins as well as any form of sorting protein produced by processing in cells. In some embodiments, the sorting protein is a human sorting protein. In some embodiments, the amino acid sequence of an exemplary human sorting protein is SEQ ID NO:81.

[0064] The terms "anti-sorting protein antibody", "antibody that binds sorting protein", and "antibody that specifically binds sorting protein" refer to antibodies that are capable of binding sorting protein with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent for targeting sorting protein. In one embodiment, the degree of binding of an anti-sorting protein antibody to an irrelevant non-sorting protein polypeptide is less than about 10% of the binding of the antibody to sorting protein, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds sorting protein has a dissociation constant (KD) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10-8 M or less, e.g., 10-8 M to 10-13 M, e.g., 10-9 M to 10-13 M). In certain embodiments, an anti-sorting protein antibody binds an epitope that is conserved among sorting proteins from different species.

[0065] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody". The term "antibody" is used in the broadest sense herein and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), including those formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0066] A "native antibody" is typically a heterotetrameric glycoprotein of about 150,000 daltons (Dalton), composed of two identical light ("L") chains and two identical heavy ("H") chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds 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 H ) at one end, followed by a number of constant domains. Each light chain has a variable domain (V L) and 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 variable domain of the light chain is aligned with the variable domain of the heavy chain. Certain amino acid residues are thought to form the interface between the variable domain of the light chain and the variable domain of the heavy chain.

[0067] For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, pages 71 and Chapter 6.

[0068] Light chains from any vertebrate species can be assigned to one of two distinct types called kappa (“κ”) and lambda (“λ”) based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of the constant domain (CH) of the heavy chain of the immunoglobulin, the immunoglobulin can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha (“α”), delta (“δ”), epsilon (“ε”), gamma (“γ”), and mu (“μ”), respectively. The γ and α classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structure and three-dimensional configuration of different classes of immunoglobulins are well known and are generally described, e.g., in Abbas et al., Cellular and Molecular Immunology, 4th Edition (W.B. Saunders Co., 2000).

[0069] 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 ”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen-binding site.

[0070] The term "variable" refers to the fact that among antibodies such as the anti-sortilin antibodies of the present disclosure, certain segments of the variable domains vary widely in sequence. The variable domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the entire span of the variable domains. Instead, in both the light chain variable domain and the heavy chain variable domain, it is concentrated in three segments called hypervariable regions (HVRs). The more highly conserved portions of the variable domains are called framework regions (FRs). The variable domains of native heavy and light chains each contain four FR regions that mainly adopt a β-sheet conformation and are connected by three HVRs, which form loops that connect the β-sheet structures and in some cases form part of the β-sheet structures. The HVRs in each chain are held tightly together 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, 5th ed., National Institute of Health, Bethesda, MD (1991)). The constant domains are not directly involved in the binding of the antibody to the antigen but exhibit various effector functions, such as the antibody's participation in antibody-dependent cytotoxicity.

[0071] An "isolated" antibody, such as the anti-sortilin antibodies of the present disclosure, is an antibody that has been identified, separated, and / or recovered away from the components of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free of all other contaminating components from its production environment. Contaminating components from its production environment, such as those produced by recombinant transfected cells, are substances that would typically interfere with the research, diagnostic, or therapeutic use of the antibody and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In a preferred embodiment, the polypeptide will be purified: (1) to obtain greater than 95% by weight of the antibody, as determined, for example, by the Lowry method, and in some embodiments, to achieve greater than 99% by weight; (2) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a spinning cup sequencer; or (3) to a homogeneity as determined by SDS-PAGE performed under non-reducing or reducing conditions using Coomassie Blue or preferably silver staining. Isolated antibodies include antibodies in situ within recombinant T cells, since there will be absent at least one component of the antibody's natural environment. However, generally, the isolated polypeptide or antibody will be prepared by at least one purification step.

[0072] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, such as the monoclonal anti-sortilin antibodies of the present disclosure, i.e., the individual antibodies that make up the population are identical, with the exception of possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific, targeting a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by hybridoma culture and are not contaminated with other immunoglobulins. The modifier "monoclonal" indicates the property of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring that the antibody be produced 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: immunizing an animal, including but not limited to a rat, mouse, rabbit, guinea pig, hamster, and / or chicken, with one or more of DNA, virus-like particles, one or more polypeptides, and / or one or more cells; the hybridoma method, the B-cell cloning method, the recombinant DNA method, and techniques for producing human antibodies or human-like antibodies in animals having a portion or all of the human immunoglobulin locus or genes encoding human immunoglobulin sequences.

[0073] The terms "full-length antibody", "intact antibody", or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as distinct from antibody fragments, such as the anti-sortilin antibodies of the present disclosure. Specifically, whole antibodies include those having heavy and light chains, including the Fc region. The constant domains may be the native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, intact antibodies may have one or more effector functions.

[0074] "Antibody fragment" includes a portion of an intact antibody, preferably the antigen-binding region and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see US 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.

[0075] Papain digestion of an antibody, such as the anti-sortilin antibody of the present disclosure, produces two identical antigen-binding fragments, called "Fab" fragments; and a residual "Fc" fragment, this name reflecting its ability to be readily crystallized. The Fab fragment consists of the entire L chain and the variable domain of the H chain (V H) and a first constant domain (C of a heavy chain H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody produces a single large F(ab')2 fragment that roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still able to cross-link antigens. The Fab' fragment differs from the Fab fragment in having a few extra residues at the carboxyl terminus of the C H 1 domain, which residues include one or more cysteines from the antibody hinge region. Fab'-SH is the name used herein for a Fab' in which one or more cysteine residues of the constant domain carry a free thiol group. F(ab')2 antibody fragments are initially produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical conjugations of antibody fragments are also known.

[0076] The Fc fragment contains the carboxyl-terminal portions of two H chains held together by disulfide bonds. The effector functions of an antibody are determined by sequences in the Fc region, which is also the region recognized by Fc receptors (FcRs) found on certain types of cells.

[0077] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of a heavy-chain variable domain and a light-chain variable domain in close non-covalent association. From the folding of these two domains, six hypervariable loops (3 loops each from the H chain and the L chain) diverge that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or a half-Fv containing only three HVRs specific for the antigen) can recognize and bind an antigen, but with lower affinity than the whole binding site.

[0078] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment that contains the VH antibody domain and the VL antibody domain joined into a single polypeptide chain. Preferably, the sFv polypeptide also contains a polypeptide linker between the V H domain and the V L domain that enables the sFv to form the structure required for antigen binding. For a review of sFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Volume 113, edited by Rosenberg and Moore, Springer-Verlag, New York, pages 269 - 315 (1994).

[0079] A "functional fragment" of an antibody, such as an anti-sortilin antibody of the present disclosure, comprises a portion of the intact antibody and generally includes the antigen-binding region or variable region of the intact antibody or the F region of the antibody that retains or has altered FcR-binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0080] The term "diabody" refers to a small antibody fragment prepared by constructing an sFv fragment (see the previous paragraph) in which there is a short linker (about 5-10 residues) between the V H domain and the V L domain such that intermolecular rather than intramolecular pairing of the variable domains is achieved, thereby generating a bivalent fragment, i.e., a fragment having two antigen-binding sites. A bispecific diabody is a heterodimer of two "swapped" sFv fragments, in which the V H domains and the V L domains of the two antibodies are present on different polypeptide chains.

[0081] As used herein, a "chimeric antibody" is an antibody (immunoglobulin) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequences in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical or homologous to the corresponding sequences in an antibody derived from another species or belonging to another antibody class or subclass, such as a chimeric anti-sortilin antibody of the present disclosure, and fragments of such antibodies, provided that they exhibit the desired biological activity. Target chimeric antibodies herein include antibodies in which the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing macaques with the target antigen. As used herein, "humanized antibody" is used as a subgroup of "chimeric antibody".

[0082] A "humanized" form of a non-human (e.g., murine) antibody, such as a humanized form of an anti-sortilin antibody of the present disclosure, is a chimeric antibody that contains 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 usually two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to those of the non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of the antibody constant region derived from a human antibody. An "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been humanized.

[0083] "Human antibody" refers to an antibody having an amino acid sequence corresponding to that of an antibody such as the anti-sortilin antibody of the present disclosure that is produced by a human and / or has been prepared using any technique for preparing human antibodies as disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. A variety of techniques known in the art can be used to generate human antibodies, including phage display libraries and yeast-based platform technologies. Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to respond to antigen stimulation by producing such antibodies, but whose endogenous loci have been disabled, e.g., immunized xenomice, and by human B cell hybridoma technology.

[0084] The terms "hypervariable region", "HVR", or "HV" when used herein refer to regions of an antibody variable domain that are highly variable in sequence and / or form structurally defined loops, such as those regions of the anti-sortilin antibody of the present disclosure. Generally, an antibody contains six HVRs; three in VH (H1, H2, H3), and three in VL (L1, L2, L3). In native antibodies, H3 and L3 exhibit the greatest diversity among the six HVRs, and in particular, H3 is thought to play a unique role in conferring fine specificity to the antibody. Naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. H H (H1, H2, H3), and three in VL L (L1, L2, L3). In native antibodies, H3 and L3 exhibit the greatest diversity among the six HVRs, and in particular, H3 is thought to play a unique role in conferring fine specificity to the antibody. Naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains.

[0085] A number of HVR depictions are in use and are covered herein. In some embodiments, the HVRs can be Kabat complementarity determining regions (CDRs) based on sequence variability and are the most commonly used (Kabat et al. (supra)). In some embodiments, the HVRs can be Chothia CDRs. Chothia refers instead to the positions of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, the HVRs can be AbM HVRs. AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by the AbM antibody modeling software of Oxford Molecular. In some embodiments, the HVRs can be "contact" HVRs. "Contact" HVRs are based on the analysis of available complex crystal structures. The residues from each of these HVRs are indicated below.

[0086]

[0087] HVRs may include "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 (a preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) in VH. For each of these extended HVR definitions, the variable domain residues are numbered according to Kabat et al. (supra).

[0088] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0089] As used herein, an "acceptor human framework" is a human immunoglobulin framework or a human consensus framework comprising a V L or V H The acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence 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 those changes are present only at three, two or one of positions 71H, 73H and 78H; for example, the amino acid residues at those positions may be 71A, 73T and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the V L The human immunoglobulin framework sequences or human consensus framework sequences are identical.

[0090] The "human consensus framework" represents the human immunoglobulin V L or V H The framework of the most commonly occurring amino acid residues in the framework sequence. L or V H The sequences are from a subset of variable domain sequences. Typically, the subset of sequences is as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for V L , the subgroup may be subgroup κI, κII, κIII or κIV as in Kabat et al. (supra). In addition, for V H, the subgroup can be Subgroup I, Subgroup II or Subgroup III as in Kabat et al. (supra).

[0091] "Amino acid modification" at a specified position of, for example, an anti-sortilin antibody of the present disclosure means substitution or deletion of the specified residue, or insertion of at least one amino acid residue adjacent to the specified residue. Insertion "adjacent" to the specified residue means insertion within one to two residues thereof. The insertion can be at the N-terminus or C-terminus of the specified residue. The preferred amino acid modification herein is substitution.

[0092] An "affinity matured" antibody, such as an anti-sortilin antibody of the present disclosure, is an antibody that has one or more alterations in one or more of its HV Rs, and the one or more alterations result in an improvement in the affinity of the antibody for the antigen as compared to a parental antibody that does not have the one or more alterations. In one embodiment, the affinity matured antibody has a nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe affinity maturation by shuffling of VH and VL domains. Random mutagenesis of HVRs and / or framework residues is described by, for example: 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).

[0093] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction such as attraction or binding between a target and an antibody such as an anti-sortilin antibody of the present disclosure, and the measurable and reproducible interaction determines the presence of the target in the presence of a heterogeneous population of molecules including biomolecules. For example, an antibody such as an anti-sortilin antibody that specifically or preferentially binds a target or epitope is an antibody that binds that target or epitope with greater affinity, avidity, more readily, and / or for a longer duration as compared to its binding to other targets or other epitopes of the target. It should also be understood by reading this definition that, for example, an antibody (or portion) that specifically or preferentially binds a first target may or may not specifically or preferentially bind a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds a target can have at least about 10 3M -1 or 10 4 M -1 and sometimes about 10 5 M -1 or 10 6 M -1 and in other cases about 10 6 M -1 or 10 7 M -1 or about 10 8 M -1 to 10 9 M -1 or about 10 10 M -1 to 10 11 M -1 or higher association constants. A variety of immunoassay formats can be used to select antibodies that are specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies that are specifically immunoreactive with a protein. For a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0094] As used herein, "interaction" between a sorting protein 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 the interaction between the two proteins" when the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins. When an antibody or fragment thereof of the present disclosure binds to one of the two proteins, the antibody or fragment thereof "inhibits the interaction between the two proteins."

[0095] An "agonist" antibody or "activating" antibody is an antibody that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen, such as an agonist anti-sorting protein antibody of the present disclosure.

[0096] A "blocking" antibody, "antagonist" antibody, or "inhibitory" antibody is an antibody that inhibits or reduces (e.g., decreases) the binding of an antigen to one or more ligands and / or inhibits or reduces (e.g., decreases) one or more activities or functions of an antigen after the antibody binds to the antigen, such as an anti-sorting protein antibody of the present disclosure. In some embodiments, the blocking antibody, antagonist antibody, or inhibitory antibody substantially or completely inhibits the binding of the antigen to one or more ligands and / or one or more activities or functions of the antigen.

[0097] Antibody "effector function" refers to those biological activities attributable to the Fc region of an antibody (natural sequence Fc region or amino acid sequence variant Fc region), and varies with antibody isotype.

[0098] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including the natural sequence Fc region and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, 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. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during the production or purification of an antibody, or by recombinant engineering of the nucleic acid encoding the heavy chain of the antibody. Thus, a composition of intact antibodies can include a population of antibodies in which all K447 residues have been removed, a population of antibodies in which the K447 residues have not been removed, and a population of antibodies having a mixture of antibodies containing the K447 residue and antibodies not containing the K447 residue. Natural sequence Fc regions in antibodies suitable for the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0099] "Natural sequence Fc region" contains an amino acid sequence identical to the amino acid sequence of the Fc region found in nature. Natural sequence human Fc regions include the natural sequence human IgG1 Fc region (non-A and A allotypes); the natural sequence human IgG2 Fc region; the natural sequence human IgG3 Fc region; and the natural sequence human IgG4 Fc region and their naturally occurring variants.

[0100] "Variant Fc region" contains an amino acid sequence that differs from the amino acid sequence of the natural sequence Fc region due to 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 compared to the natural sequence Fc region or the Fc region of the parental polypeptide, for example, about one to about ten amino acid substitutions in the natural sequence Fc region or in the Fc region of the parental polypeptide, and preferably about one to about five amino acid substitutions. A variant Fc region herein will preferably have at least about 80% homology with the natural sequence Fc region and / or with the Fc region of the parental polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.

[0101] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferably, the FcR is a native sequence human FcR. In addition, preferably the FcR is an FcR that binds an IgG antibody (gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. The FcγRII receptor includes FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor") that have similar amino acid sequences differing mainly in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif ("ITIM") in its cytoplasmic domain. Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of an antibody. As used herein, "percent amino acid sequence identity (%)" and "homology" with respect to a peptide, polypeptide, or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a specific peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN TM (DNASTAR) software. One of ordinary skill in the art can determine the parameters appropriate for measuring alignment, including any algorithms known in the art for achieving maximum alignment over the full length of the sequences being compared.

[0102] 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, the isolated cell is not accompanied by all of the components associated with the production environment. The isolated cell is in a form other than the form or arrangement in which it is found in nature. The isolated cell is different from a cell that naturally occurs in a tissue, organ, or individual. In some embodiments, the isolated cell is a host cell of the present disclosure.

[0103] An "isolated" nucleic acid molecule encoding an antibody such as an anti-sortilin antibody of the present disclosure is a nucleic acid molecule 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 was produced. Preferably, the isolated nucleic acid is not accompanied by all components associated with the production environment. The isolated nucleic acid molecules encoding the polypeptides and antibodies herein are in a form other than the form or arrangement in which they are found in nature. Thus, the isolated nucleic acid molecules are different from the nucleic acids encoding the polypeptides and antibodies herein that are naturally present in cells.

[0104] As used herein, the term "vector" means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double-stranded DNA to which an additional DNA segment can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which an additional DNA segment can be ligated into the viral genome. Certain vectors are capable of autonomous replication in the host cells into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can integrate into the genome of the host cell after being introduced into the host cell and, thereby, replicate along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors", or simply "expression vectors". Generally, expression vectors useful in recombinant DNA techniques often take the form of plasmids. In the present specification, "plasmid" and "vector" are used interchangeably because plasmids are the most commonly used form of vector.

[0105] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length and includes DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs or any substrate that can be incorporated into the polymer by DNA or RNA polymerase or by a synthetic reaction.

[0106] "Host cell" includes a single cell or cell culture that is or has been a recipient of one or more vectors for incorporation of a polynucleotide insert. Host cells include progeny of a single host cell, and the progeny may not be identical to the original parental cell (either in terms of morphology or in terms of genomic DNA complement) due to natural, accidental or deliberate mutations. Host cells include cells transfected in vivo with one or more polynucleotides of the present disclosure.

[0107] As used herein, "vector" includes a pharmaceutically acceptable carrier, excipient or stabilizer that is non-toxic to the cells or mammals to which it is exposed at the dosages and concentrations employed.

[0108] As used herein, the term "about" refers to the ordinary error range that is readily known to a person skilled in the art for the corresponding value. References herein to "about" a value or parameter include (and describe) embodiments that refer to the value or parameter itself.

[0109] Unless the context clearly indicates otherwise, as used herein and in the appended claims, the singular forms "a / an" and "the" include plural referents. For example, reference to "an antibody" refers to one to many antibodies, such as molar amounts, and includes equivalents known to those skilled in the art, and so forth.

[0110] It should be understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0111] Overview

[0112] The present disclosure relates to methods of treating a disease or injury in an individual and / or delaying the progression of the disease or injury in the individual by administering an anti-sortilin antibody to the individual. Non-limiting examples of diseases that can be treated or delayed include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As described below, the methods of the present disclosure meet the need in the art for methods of identifying a dose to treat a patient and administering the dose in a manner that readily achieves patient compliance.

[0113] Advantageously, administration of a single or repeated dose of the anti-sortilin antibody of the present disclosure intravenously to non-human primates (see, e.g., Example 1) results in a dose-dependent decrease in SORT1 protein on white blood cells and an increase in PGRN protein levels in plasma (e.g., a 2- to 6-fold increase) and cerebrospinal fluid (CSF) (e.g., a 2- to 4-fold increase). Additionally, although the half-life of the anti-sortilin antibody is relatively short (e.g., up to 73.6 hours), unexpectedly, the decrease in SORT1 protein on white blood cells and the increase in PGRN protein levels in plasma and CSF persist over time (e.g., up to 14 days after the last dose of the anti-sortilin antibody). Further, advantageously, the exposure increases over time (e.g., day 1 relative to day 22), indicating accumulation of the anti-sortilin antibody.

[0114] Similarly, intravenous administration of a single dose of the anti-sortilin antibodies of the present disclosure to healthy humans (see, e.g., Example 2) results in a dose-dependent decrease in SORT1 protein on white blood cells (e.g., a 50% or 70% decrease) and an increase in PGRN protein levels in plasma (e.g., a 1.29- to 2.14-fold increase) and CSF (e.g., a 0.57- to 1.13-fold increase). In addition, although the anti-sortilin antibodies have a relatively short half-life (e.g., up to 190 hours), unexpectedly, the decrease in SORT1 protein on white blood cells (e.g., for 40 days or longer) and the increase in PGRN protein levels in plasma (e.g., for 40 to 42 days or longer) and CSF (e.g., for at least 24 days) persist over time.

[0115] Patients with neurodegenerative diseases such as FTD and ALS are affected by the disease chronically and thus require regular treatment over the course of many years. Since intravenous administration of therapeutic agents cannot be performed at home, patients must be transported to an infusion center, which becomes a burden for both the patient and the caregiver. Finally, memory loss, mood swings, aggressive behavior, and other behavioral symptoms of these diseases make it difficult to achieve patient compliance.

[0116] Advantageously, although the anti-sortilin antibodies of the present disclosure exhibit a relatively short half-life and thus may not be expected to be therapeutically useful, when administered according to the methods provided herein, the antibodies unexpectedly exhibit a persistent pharmacodynamic (PD) effect (e.g., an increase in PGRN levels in plasma and CSF, and a decrease in SORT1 levels on WBCs and in CSF). Accordingly, the methods provided herein allow for relatively infrequent administration of anti-sortilin antibodies, which is particularly beneficial for patients with neurodegenerative diseases such as FTD and ALS.

[0117] Thus, in some embodiments, the present disclosure also relates to a method of treating FTD (see, e.g., Example 3) or ALS (see, e.g., Example 4) in an individual and / or delaying the progression of the FTD or ALS by administering an anti-sortilin antibody intravenously to the individual at a dose of at least about 30 mg / kg at least once every four weeks. In some embodiments, the anti-sortilin antibody is administered at a dose of about 60 mg / kg once every four weeks.

[0118] All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety.

[0119] Therapeutic Use

[0120] The present disclosure provides methods for treating a disease or injury in an individual and / or delaying the progression of the disease or injury, the methods comprising administering to the individual an antisortilin antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:2-3; and an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:5-6; and the light chain variable region comprises: an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:8-27; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:29-30; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:32.

[0121] As disclosed herein, the antisortilin antibodies of the present disclosure can be used to treat the following diseases and / or delay the progression of the diseases: frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, limbic-predominant age-related TDP43 encephalopathy (LATE), acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis or osteoarthritis. In some embodiments, the disease or injury is frontotemporal dementia or amyotrophic lateral sclerosis. In some embodiments, the antisortilin antibodies of the present disclosure can be used to treat or mitigate TDP43 lesions, including but not limited to TDP43 lesions associated with dementia, C9orf72-related diseases, FTD, Alzheimer's disease, ALS, LATE, and Parkinson's disease.

[0122] In some embodiments, the methods of the present disclosure comprise an antisortilin antibody comprising two or more antisortilin antibodies.

[0123] Dementia

[0124] Dementia is a nonspecific syndrome (i.e., a group of signs and symptoms) characterized by a severe loss of overall cognitive ability in a previously unimpaired individual, the severe loss exceeding that which might be expected from normal aging. Dementia can be static due to unique global brain injury. Alternatively, dementia can be progressive, resulting in long-term decline due to damage or disease in the body. Although dementia is more common in the elderly population, it can also occur before the age of 65. Cognitive areas affected by dementia include but are not limited to memory, attention span, language, and problem-solving. Typically, symptoms must be present for at least six months before an individual is diagnosed with dementia.

[0125] Exemplary forms of dementia include, but are not limited to, frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, and dementia with Lewy bodies.

[0126] Without wishing to be bound by theory, it is believed that administration of the anti-sortilin antibodies of the present disclosure can treat dementia and / or delay the progression of dementia. In some embodiments, administration of an anti-sortilin antibody can induce progranulin activity (e.g., neurotrophic and / or survival activity for neurons, and anti-inflammatory activity) in an individual with dementia.

[0127] Frontotemporal dementia

[0128] Frontotemporal dementia (FTD) is a disorder caused by the progressive decline of the frontal lobes of the brain. Over time, the degeneration can progress to the temporal lobes. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of cases of early-onset dementia. The clinical features of FTD include memory deficits, behavioral abnormalities, personality changes, and language deficits (Cruts, M. and Van Broeckhoven, C., Trends Genet. 24:186-194 (2008); Neary, D. et al., Neurology 51:1546-1554 (1998); Ratnavalli, E., Brayne, C., Dawson, K. and Hodges, J.R., Neurology 58:1615-1621 (2002)).

[0129] A large proportion of FTD cases are inherited in an autosomal dominant manner, but even within a family, the symptoms can range from FTD with behavioral disturbances, to primary progressive aphasia, to corticobasal ganglionic degeneration. Like most neurodegenerative diseases, FTD is characterized by the pathological presence of specific protein aggregates in the diseased brain. Historically, the initial descriptions of FTD identified the intracellular accumulation of hyperphosphorylated τ protein in neurofibrillary tangles or Pick bodies. The causative role of the microtubule-associated protein τ protein was supported by the identification of mutations in the gene encoding τ protein in several families (Hutton, M. et al., Nature 393:702-705 (1998)). However, most FTD brains do not show the accumulation of hyperphosphorylated τ protein, but do exhibit immunoreactivity to ubiquitin (Ub) and TAR DNA-binding protein (TDP43) (Neumann, M. et al., Arch. Neurol. 64:1388-1394 (2007)). Most of those FTD cases (FTD-U) that show Ub inclusions carry mutations in the progranulin gene.

[0130] Granulin precursor mutations result in haploinsufficiency, and the granulin precursor mutations are known to be present in nearly 50% of familial FTD cases, making the granulin precursor mutations a major genetic contributor to FTD. Without wishing to be bound by theory, it is believed that the loss-of-function heterozygosity of granulin precursor mutations indicates that in healthy individuals, granulin precursor expression plays a dose-dependent key role in protecting healthy individuals from developing FTD. Accordingly, increasing the level of granulin precursor by inhibiting the interaction between sortilin and granulin precursor can treat FTD and / or delay the progression of FTD.

[0131] In some embodiments, administration of an anti-sortilin antibody of the present disclosure can treat FTD and / or delay the progression of FTD. In some embodiments, administration of an anti-sortilin antibody can modulate the activity of one or more sortilins in an individual with FTD.

[0132] In some embodiments, treatment of FTD and / or delay of the progression of FTD is determined by change from baseline in a neurocognitive and / or functional test or assessment (i.e., clinical outcome assessment). Non-limiting examples of neurocognitive and functional tests that can be used to evaluate treatment of FTD and / or delay of the progression of FTD include the Frontotemporal Dementia Clinical Rating Scale (FCRS), Frontotemporal Dementia Rating Scale (FRS), Clinical Global Impression-Improvement (CGI-I) assessment, Neuropsychiatric Inventory (NPI) assessment, Color Trail Test (CTT) Part 2, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Delis-Kaplan Executive Function System Color-Word Interference Test, Interpersonal Reactivity Index, Winterlight Labs Speech Assessment (WLA), and Summerlight Labs Speech Assessment (SLA). In some embodiments, treatment of FTD and / or delay of the progression of FTD is determined by change from baseline in one neurocognitive and / or functional test or assessment. In some embodiments, treatment of FTD and / or delay of the progression of FTD is determined by change from baseline in more than one neurocognitive and / or functional test or assessment (such as 2, 3, 4, 5, 6, 7, 8, 9 or more neurocognitive and / or functional tests or assessments).

[0133] In some embodiments, treatment of FTD and / or delay of FTD progression is determined by changes from baseline in global and / or regional brain volume, volume of white matter hyperintensities, cerebral perfusion, fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity, and / or functional brain activity. In certain embodiments, cerebral perfusion is measured by arterial spin labeling MRI. In certain embodiments, radial diffusivity is measured by diffusion tensor imaging. In certain embodiments, functional brain activity is measured by functional MRI.

[0134] In some embodiments, treatment of FTD and / or delay of FTD progression is determined by changes from baseline in markers of neurodegeneration in whole blood, plasma, and CSF. Markers of neurodegeneration can include, but are not limited to, neurofilament light chain [NfL], tau protein, and / or phosphorylated tau protein (pTau). Neurofilament light chain can be measured by methods including, but not limited to, assays from Quanterix and / or Roche Diagnostics. In some embodiments, treatment with an anti-sortilin antibody of the present disclosure reduces NfL levels by at least 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, treatment of FTD and / or delay of FTD progression is determined by changes (e.g., increases) from baseline in markers of lysosomal function. Markers of lysosomal function can be, but are not limited to, cathepsins such as cathepsin B (CTSB). In some embodiments, treatment with an anti-sortilin antibody of the present disclosure increases the level of one or more lysosomal markers such as CTSB by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of one or more lysosomal markers such as CTSB. In some embodiments, treatment with an anti-sortilin antibody of the present disclosure increases the level of CTSB by at least about 20% compared to the baseline level of CTSB. Another non-limiting example of a lysosomal marker is N-acetylglucosamine kinase (NAGK). In some embodiments, treatment with an anti-sortilin antibody of the present disclosure increases the level of NAGK by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of NAGK.

[0135] In some embodiments, treatment of FTD and / or delay of FTD progression is determined by a change (e.g., decrease) from baseline in the level of an inflammatory marker such as osteopontin (SPP1). In some embodiments, treatment with an anti-sortilin antibody of the present disclosure reduces the level of one or more inflammatory markers such as SPP1 by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the baseline level of one or more inflammatory markers such as SPP1. In some embodiments, treatment with an anti-sortilin antibody of the present disclosure reduces the level of one or more inflammatory markers such as SPP1 by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, compared to the baseline level of one or more inflammatory markers such as SPP1. In some embodiments, treatment with an anti-sortilin antibody of the present disclosure reduces the level of SPP1 by at least about 10%, compared to the baseline level of SPP1. Other examples of inflammatory markers include, but are not limited to, YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), and CD86. In some embodiments, treatment with an anti-sortilin antibody of the present disclosure reduces the level of one or more inflammatory markers such as YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), or CD86 by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, compared to the baseline level of one or more inflammatory markers such as YWHAE (14-3-3 protein epsilon), allograft inflammatory factor 1 (AIF1), colony-stimulating factor 1 (CSF1), chitinase 1 (CHIT1), lymphocyte antigen 86 (LY86), or CD86.

[0136] In some embodiments, treatment of FTD and / or delay of FTD progression is determined by a change from baseline in a marker of microglial activity. Markers of microglial activity can be, but are not limited to, YKL-40 and / or interleukin-6. In some embodiments, treatment of FTD and / or delay of FTD progression is determined by a change from baseline in messenger ribonucleic acid (mRNA) expression in peripheral cells. In some embodiments, treatment of FTD and / or delay of FTD progression is determined by a change from baseline in an analyte related to FTD disease biology and / or response to progranulin antibodies.

[0137] In some embodiments, the levels of one or more proteins (e.g., one or more of YKL-40, IL-6, CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, or CD86) can be measured in a sample obtained from an individual, such as a sample of whole blood, plasma, and / or CSF. Non-limiting examples of methods that can be used to measure the levels of one or more proteins (e.g., one or more of YKL-40, IL-6, CTSB, SPP1, NAGK, YWHAE, AIF1, CSF1, CHIT1, LY86, or CD86) in a sample obtained from an individual include the SOMASCAN assay (see, e.g., Candia et al. (2017) Sci Rep 7,14248), western blotting, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA).

[0138] In some embodiments, treatment of FTD and / or delay of FTD progression is determined by a change from baseline in neuroinflammation and / or microglial activation. Neuroinflammation and / or microglial activation can be measured by any known method in the art. In certain embodiments, translocator protein - positron emission (TSPO-PET) imaging can be used to measure neuroinflammation and / or microglial activation. In certain embodiments, [18F]PBR06 and / or [11C]PBR28 PET are used as radiotracers in TSPO-PET imaging. In certain embodiments, [18F]PBR06 is used as a radiotracers in TSPO-PET imaging. In certain embodiments, [11C]PBR28 PET is used as a radiotracers in TSPO-PET imaging.

[0139] In some embodiments, the individual is heterozygous for a mutation in GRN (granulin gene). In some embodiments, the mutation in GRN is a loss-of-function mutation. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion. In some embodiments, the individual displays symptoms of FTD. In some embodiments, the individual does not display symptoms of FTD.

[0140] In some embodiments, the individual displays symptoms of FTD if the individual meets the diagnostic criteria for possible behavioral variant FTD (bvFTD) or probable bvFTD or primary progressive aphasia (PPA). In some embodiments, the individual has one or more of the behavioral / cognitive symptoms required for the diagnosis of possible bvFTD (Rascovsky et al., (2011) Brain 134(9):2456-2477). In some embodiments, the individual has mild complex symptoms (such as mild cognitive impairment, mild behavioral impairment) that do not significantly affect activities of daily living. In certain embodiments, the individual has bvFTD or PPa, with a motor neuron disease. In some embodiments, the individual has FTD of mild severity, as determined by a Clinical Dementia Rating Scale (CDR) global score of 1 or less and box scores of 1 or less for both the language domain and the behavior, movement, and personality domains of the Frontotemporal Dementia Clinical Rating Scale (FCRS).

[0141] Alzheimer's disease

[0142] Alzheimer's disease (AD) is the most common form of dementia. There is no cure for the disease, which worsens as it progresses and ultimately results in death. Most often, AD is diagnosed in people over 65 years of age. However, the occurrence of the less common early-onset Alzheimer's disease can be much earlier.

[0143] Common symptoms of Alzheimer's disease include behavioral symptoms such as difficulty remembering recent events; cognitive symptoms, confusion, irritability and aggression, mood swings, difficulty with language, and long-term memory loss. As the disease progresses, physical function is lost, ultimately resulting in death. Alzheimer's disease develops over an unknown and variable amount of time before becoming fully apparent, and it can progress for years without being diagnosed.

[0144] Sortilin has been shown to bind amyloid precursor protein (APP) and the APP-processing enzyme BACE1. Without wishing to be bound by theory, it is believed that these interactions are involved in Alzheimer's disease. Accordingly, and without wishing to be bound by theory, it is believed that the anti-sortilin antibodies of the present disclosure can be used to inhibit such interactions and prevent, reduce the risk of, or treat Alzheimer's disease in an individual in need thereof.

[0145] In some embodiments, and without wishing to be bound by theory, it is believed that the anti-sortilin antibodies of the present disclosure that inhibit the interaction between sortilin and a neurotrophin of the present disclosure (e.g., pro-neurotrophin, pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), p75, amyloid precursor protein (APP), and / or Aβ peptide, or inhibit one or more activities of sortilin can be used to treat Alzheimer's disease and / or delay the progression of Alzheimer's disease in an individual in need thereof.

[0146] In some embodiments, administration of the anti-sortilin antibodies of the present disclosure can treat Alzheimer's disease and / or delay the progression of Alzheimer's disease. In some embodiments, administration of the anti-sortilin antibodies can modulate one or more sortilin activities in an individual with Alzheimer's disease.

[0147] Vascular dementia

[0148] Vascular dementia (VaD) is a subtle, progressive deterioration of memory and other cognitive functions thought to be attributable to cerebrovascular disease (disease of the blood vessels within the brain). Cerebrovascular disease is a progressive change in our blood vessels (vasculature) within the brain (cerebrum). The most common age-related vascular change is the accumulation of cholesterol and other substances in the walls of the blood vessels. This results in thickening and hardening of the walls and narrowing of the blood vessels, which can lead to a reduced or even complete cessation of blood flow to brain regions supplied by the affected arteries. Patients with vascular dementia often present with symptoms similar to those of patients with Alzheimer's disease (AD). However, the associated changes in the brain are not attributable to AD lesions, but rather to chronically reduced blood flow in the brain, ultimately leading to dementia. VaD is considered to be one of the most common types of dementia in older adults. Symptoms of VaD include difficulty with memory, difficulty organizing and solving complex problems, slow thinking, distraction or "absent-mindedness," difficulty retrieving words from memory, changes in mood or behavior such as depression, irritability, or apathy, and hallucinations or delusions.

[0149] Without wishing to be bound by theory, it is believed that one or more activities of sortilin, or one or more interactions between sortilin and progranulin, the neurotensins disclosed herein (e.g., pro-neurotensin, pro-neurotensin-3, pro-neurotensin-4 / 5, pro-NGF, pro-BDNF, neurotensin-3, neurotensin-4 / 5, NGF, BDNF, etc.), neurotensin, lipoprotein lipase, apolipoprotein AV, and / or receptor-associated proteins are involved in vascular dementia. Thus, and without wishing to be bound by theory, it is believed that an anti-sortilin antibody of the present disclosure that inhibits one or more interactions between sortilin and the neurotensins disclosed herein (e.g., pro-neurotensin, pro-neurotensin-3, pro-neurotensin-4 / 5, pro-NGF, pro-BDNF, neurotensin-3, neurotensin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, sortilin leader peptide (Sort-pro), amyloid precursor protein (APP), Aβ peptide, lipoprotein lipase (LpL), apolipoprotein AV (APOA5), apolipoprotein E (APOE), and / or receptor-associated protein (RAP); or inhibits one or more activities of sortilin can be used to prevent vascular dementia in an individual in need thereof, reduce the risk of said vascular dementia, or treat said vascular dementia.

[0150] In some embodiments, administration of an anti-sortilin antibody of the present disclosure can treat VaD and / or delay the progression of VaD. In some embodiments, administration of an anti-sortilin antibody can modulate one or more sortilin activities in an individual with VaD.

[0151] Seizures, retinal dystrophy, traumatic brain injury, and spinal cord injury

[0152] As used herein, retinal dystrophy refers to any disease or disorder involving degeneration of the retina. Such diseases or disorders can lead to loss of vision or total blindness.

[0153] As used herein, seizure also includes epileptic seizure and refers to a transient symptom of abnormal excessive or synchronous neuronal activity in the brain. The external effects can be as severe as wild writhing movements or as mild as a brief loss of consciousness. Seizures can manifest as changes in mental state, tonic or clonic movements, convulsions, and various other mental symptoms.

[0154] Traumatic brain injury (TBI) may also be referred to as intracranial injury. Traumatic brain injury occurs when the brain is damaged by external force in a manner that causes trauma. Traumatic brain injury can be classified based on severity, mechanism (closed or penetrating head injury), or other characteristics (such as occurring in a specific location or over a wide area).

[0155] Spinal cord injury (SCI) includes any injury to the spinal cord caused by trauma rather than disease. Symptoms can vary widely from pain to paralysis to incontinence depending on the location of damage to the spinal cord and nerve roots. Spinal cord injury is described in various levels that can range from "incomplete" injuries that may have no impact on the patient to "complete" injuries that mean total loss of function.

[0156] It has been shown that neurotrophin precursors (such as neurotrophin precursor-4 / 5, neurotrophin-4 / 5, NGF precursor, BDNF precursor, etc.) play a role in seizures, retinal dystrophy, traumatic brain injury, and spinal cord injury.

[0157] Therefore, and without wishing to be bound by theory, it is believed that an anti-sorting protein antibody of the present disclosure that inhibits the interaction between a sorting protein and a neurotrophin of the present disclosure (such as a neurotrophin precursor, neurotrophin precursor-3, neurotrophin precursor-4 / 5, NGF precursor, BDNF precursor, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.); or inhibits one or more activities of a sorting protein can be used to prevent seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury in an individual in need, reduce the risk of said seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury, or treat said seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury.

[0158] In some embodiments, administering an anti-sorting protein antibody of the present disclosure can treat seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury, and / or delay the progression of seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury. In some embodiments, administering an anti-sorting protein antibody can modulate one or more sorting protein activities in an individual with seizures, retinal dystrophy, traumatic brain injury, and / or spinal cord injury.

[0159] Undesirable symptoms of aging

[0160] As used herein, undesirable symptoms of aging include, but are not limited to, memory loss, behavioral changes, dementia, Alzheimer's disease, retinal degeneration, atherosclerotic vascular disease, hearing loss, and cell breakdown.

[0161] In some embodiments, and without wishing to be bound by theory, it is believed that inhibiting the interaction between sortilin and progranulin, the neurotrophins of the present disclosure (such as pro-neurotrophins, pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein A-V (APOA-5), and / or receptor-associated protein (RAP); or an anti-sortilin antibody of the present disclosure that inhibits one or more activities of sortilin can be used to prevent one or more undesirable symptoms of aging, reduce the risk of one or more undesirable symptoms of aging, or treat one or more undesirable symptoms of aging.

[0162] In some embodiments, administering an anti-sortilin antibody of the present disclosure can treat one or more undesirable symptoms of aging and / or delay the progression of one or more undesirable symptoms of aging. In some embodiments, administering an anti-sortilin antibody can modulate one or more sortilin activities in an individual having one or more undesirable symptoms of aging.

[0163] Amyotrophic lateral sclerosis (ALS)

[0164] As used herein, amyotrophic lateral sclerosis (ALS), motor neuron disease, or Lou Gehrig's disease can be used interchangeably and refers to a debilitating disease with variable etiology characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle cramps, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (dyspnea).

[0165] Haploinsufficiency of PGRN due to heterozygous loss-of-function mutations in the GRN gene results in reduced CSF PGRN levels and is the cause of frontotemporal dementia (FTD) presenting with TDP-43 lesions (Sleegers et al., (2009) Ann Neurol 65:603; Smith et al., (2012) Am J Hum Genet 90:1102). TDP-43 has also been identified as the major pathological protein in ALS, thus indicating a similarity between ALS and FTD.

[0166] For example, over twenty dominant mutations in TDP-43 have been identified in sporadic and familial ALS patients (Lagier-Tourenne et al., (2009) Cell 136:1001), and TDP-43 positive aggregates are seen in approximately 95% of ALS cases (Prasad et al., (2019) Front Mol Neurosci 12:25). In addition, ALS risk genes such as MOBP, C9ORF72, MOBKL2B, NSF, and FUS can also cause FTD (Karch et al., (2018) JAMA Neurol 75:860). Moreover, both PGRN mutations and C9ORF72 mutations are associated with abnormal microglial activation, which appears to be another common pathology of FTD and ALS (Haukedal et al., (2019) J Mol Biol 431:1818). Other evidence also indicates that ALS and FTD are closely related disorders with overlapping genetic, neuropathological, and clinical features (Weishaupt et al., (2016) Trends MolMed 22:769; McCauley et al., (2018) Acta Neuropathol 137:715). Collectively, these results suggest that both diseases may benefit from shared therapies, and PGRN genetic variability acts as a modulator of the course of ALS.

[0167] In addition, in addition to demonstrating that loss of PGRN is detrimental in multiple models of acute and chronic neurodegeneration (Boddaert et al., (2018) Methods Mol Biol 1806:233), overexpression of PGRN has been found to be protective in many animal models of ALS (Laird et al., (2010) PLoS One 5:e13368; Tauffenberger et al., (2013) Hum Mol Genet 22:782; Beel et al., (2018) Mol Neurodegener 13:55; Chang et al., (2017) J Exp Med 214:2611). Moreover, common variants in GRN are significantly associated with a reduced age of onset and a shorter survival period after onset in ALS patients (Sleegers et al., (2008) Neurology 71:253).

[0168] Collectively, both human genetics and data from disease models support a protective function of PGRN in alleviating lesions in ALS patients associated with TDP-43 lesions.

[0169] In some embodiments, and without wishing to be bound by theory, it is believed that inhibiting the interaction between sortilin and progranulin, the neurotrophins of the present disclosure (such as pro-neurotrophins, pro-neurotrophin-3, pro-neurotrophin-4 / 5, pro-NGF, pro-BDNF, neurotrophin-3, neurotrophin-4 / 5, NGF, BDNF, etc.), neurotensin, p75, lipoprotein lipase (LpL), apolipoprotein A-V (APOA5), and / or receptor-associated protein (RAP); or an anti-sortilin antibody of the present disclosure that inhibits one or more activities of sortilin can be used to prevent or treat one or more undesirable symptoms of ALS.

[0170] In some embodiments, administering an anti-sortilin antibody of the present disclosure can treat ALS and / or delay the progression of ALS. In some embodiments, administering an anti-sortilin antibody can modulate one or more sortilin activities in an individual with ALS. In some embodiments, the individual is heterozygous for the C9orf72 hexanucleotide repeat expansion.

[0171] In some embodiments, the treatment of ALS and / or the delay of ALS progression is determined by changes from baseline in brain atrophy, brain connectivity, brain free water, and / or brain inflammation. Any method known in the art, including but not limited to MRI, can be used to measure brain atrophy, brain connectivity, brain free water, and / or brain inflammation. In certain embodiments, structural MRI is used to measure brain atrophy. In certain embodiments, diffusion tensor imaging (DTI) is used to measure brain free water and / or brain inflammation.

[0172] In some embodiments, the treatment of ALS and / or the delay of ALS progression is determined by changes from baseline in progranulin, markers of neurodegeneration, markers of glial activation, and / or markers of TDP-43 pathology. In certain embodiments, progranulin is measured using an Adipogen immunoassay. In certain embodiments, markers of neurodegeneration include but are not limited to neurofilament light chain. Neurofilament light chain can be measured by any known method in the art, including but not limited to assays from Quanterix and / or Roche Diagnostics. In certain embodiments, markers of glial activation include but are not limited to YKL-40 (CHI3L), IL-6, and / or GFAP. GFAP can be measured using any method known in the art, including but not limited to assays from Roche Diagnostics.

[0173] Parkinson's disease

[0174] Parkinson's disease, which may be referred to as idiopathic or primary parkinsonism, hypokinetic-rigid syndrome (HRS), or paralysis agitans, is a neurodegenerative brain disorder that affects the control of the motor system. Progressive death of dopamine-producing cells in the brain results in the main symptoms of Parkinson's disease. Most often, Parkinson's disease is diagnosed in people over the age of 50. In most people, Parkinson's disease is idiopathic (without a known cause). However, genetic factors also play a role in the disease.

[0175] The symptoms of Parkinson's disease include, but are not limited to, tremors in the hands, arms, legs, jaw, and face, muscle rigidity in the limbs and trunk, slowness of movement (bradykinesia), postural instability, difficulty walking, neuropsychiatric problems, changes in speech or behavior, depression, anxiety, pain, psychosis, dementia, hallucinations, and sleep problems.

[0176] In some embodiments, administration of an anti-sortilin antibody of the present disclosure can treat Parkinson's disease and / or delay the progression of Parkinson's disease. In some embodiments, administration of an anti-sortilin antibody can induce progranulin activity in an individual with Parkinson's disease. In some embodiments, administration of an anti-sortilin antibody can modulate sortilin activity in an individual with Parkinson's disease.

[0177] Multiple sclerosis

[0178] Multiple sclerosis (MS) may also be referred to as disseminated sclerosis or encephalomyelitis disseminata. MS is an inflammatory disease in which the fatty myelin sheath around the axons in the brain and spinal cord is damaged, resulting in demyelination and scar formation, as well as a wide range of signs and symptoms. See, for example, www.ninds.nih.gov / Disorders / Patient-Caregiver-Education / Hope-Through-Research / Multiple-Sclerosis-Hope-Through-Research.

[0179] The symptoms of MS include but are not limited to sensory changes such as loss of sensation or tingling; prickling or numbness such as hypoesthesia and paresthesia; muscle weakness; clonus; muscle spasm; difficulty moving; difficulty with coordination and balance such as ataxia; problems with speech such as dysarthria, or problems with swallowing such as dysphagia; visual problems such as nystagmus, optic neuritis including photopsia, and diplopia; fatigue; acute or chronic pain; and bladder and bowel difficulties; varying degrees of cognitive impairment; emotional symptoms of depression or lability; Uhthoff's phenomenon, which is the worsening of existing symptoms due to exposure to temperatures higher than the usual ambient temperature; and Lhermitte's sign, which is an electric shock sensation that travels down the back when the neck is flexed.

[0180] In some embodiments, administration of an anti-sortilin antibody of the present disclosure can treat multiple sclerosis and / or delay the progression of multiple sclerosis. In some embodiments, administration of an anti-sortilin antibody can induce the activity of one or more progranulin in an individual with multiple sclerosis. In some embodiments, administration of an anti-sortilin antibody can modulate the activity of one or more sortilin in an individual with multiple sclerosis.

[0181] Glaucoma and macular degeneration

[0182] Glaucoma describes a group of diseases characterized by, but not limited to, damage to the optic nerve, resulting in vision loss and blindness. Glaucoma is typically caused by an increase in the hydraulic pressure (= intraocular pressure) in the anterior chamber of the eye below the cornea. Glaucoma causes a successive loss of retinal ganglion cells that are important for vision. Age-related macular degeneration typically affects the elderly and mainly results in loss of vision in the macula, i.e., central vision. Macular degeneration results in, but is not limited to, drusen, pigment changes, metamorphopsia, eye bleeding, atrophy, reduced visual acuity, blurred vision, central scotoma, reduced color vision, and reduced contrast sensitivity.

[0183] Without wishing to be bound by theory, it is believed that administration of an anti-sortilin antibody of the present disclosure can treat glaucoma and macular degeneration, and / or delay the progression of glaucoma and macular degeneration. In some embodiments, administration of an anti-sortilin antibody can induce the activity of one or more progranulin in an individual with glaucoma or macular degeneration. In some embodiments, administration of an anti-sortilin antibody can modulate the activity of one or more sortilin in an individual with glaucoma or macular degeneration.

[0184] Progranulin mutations

[0185] In some embodiments, the individual is heterozygous for a mutation in GRN (granulin gene). In some embodiments, the mutation in GRN is a loss-of-function mutation.

[0186] In some embodiments, the presence of a mutation in GRN is determined by any known method in the art. Non-limiting examples of methods useful for determining the presence of a mutation in GRN include DNA sequencing, DNA hybridization, polymerase chain reaction (PCR), multiplex PCR, nested PCR, real-time PCR, quantitative PCR, semi-quantitative PCR, DNA microarray, multiplex ligation-dependent probe amplification, single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, heteroduplex analysis, Southern blotting, genetic linkage analysis (e.g., using short tandem repeats and / or variable number tandem repeats), fluorescence in situ hybridization, comparative genomic hybridization, allele-specific amplification, and / or restriction enzyme digestion methods (e.g., restriction fragment length polymorphism analysis) (Mahdieh et al., Iran J Pediatr (2013) 23(4):375-388).

[0187] In some embodiments, the presence of a mutation in GRN is determined by DNA sequencing (Chang et al., (2010) Arch Neurol 67(2):161-170). In some embodiments, the presence of a mutation in GRN is determined by DNA sequencing and genotyping (Chang et al., (2010) Arch Neurol 67(2):161-170).

[0188] In some embodiments, low serum progranulin predicts the presence of a mutation in GRN (Schofield et al., (2010) J Alzheimers Dis 22(3):981-4). The level of PGRN can be assayed as discussed in the "PGRN level" section below.

[0189] C9orf72 mutation

[0190] In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion.

[0191] In some embodiments, the presence of the C9orf72 hexanucleotide repeat expansion is determined by any known method in the art. Non-limiting examples of methods that can be used to determine the presence of the C9orf72 hexanucleotide repeat expansion include DNA sequencing, long-read DNA sequencing, DNA hybridization, polymerase chain reaction (PCR), multiplex PCR, nested PCR, real-time PCR, quantitative PCR, semi-quantitative PCR, DNA microarray, DNA blotting, multiplex ligation-dependent probe amplification, single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, heteroduplex analysis, genetic linkage analysis (e.g., using short tandem repeats and / or variable number tandem repeats), fluorescence in situ hybridization, comparative genomic hybridization, allele-specific amplification, and / or restriction enzyme digestion methods (e.g., restriction fragment length polymorphism analysis) (Mahdieh et al., Iran J Pediatr (2013) 23(4):375-388).

[0192] In some embodiments, the presence of C9orf72 hexanucleotide repeat expansions is determined by DNA sequencing (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, the presence of C9orf72 hexanucleotide repeat expansions is determined by long-read sequencing (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, the Pacific Biosciences sequencing platform or the Oxford Nanopore Technologies sequencing platform is used to determine the presence of C9orf72 hexanucleotide repeat expansions (Ebbert et al., Mol Neurodegener (2018) 13(1):46). In some embodiments, commercially available tests are used to determine the presence of C9orf72 hexanucleotide repeat expansions. Non-limiting examples of commercially available tests include those from GeneDx (available at the website www.genedx.com / wp-content / uploads / 2017 / 06 / info_sheet_C9orf72.pdf), Fulgent (available at the website www.fulgentgenetics.com / repeatexpansion-c9orf72), Prevention Genetics (available at the website www.preventiongenetics.com / testInfo.php?sel=test&val=C9orf72+Gene+Hexanucleotide+Repeat+Expansion) and / or Athena Diagnostics (available at the website www.athenadiagnostics.com / view-full-catalog / c / c9orf72-dna-test).

[0193] Drug dose

[0194] The antibodies provided herein (and any additional therapeutic agents) can be administered by any suitable means including parenteral, intralung, intranasal, intralesional, intrathecal, intracranial, intraspinal, intraarticular, intrathecal, oral, topical, or inhalation routes. Parenteral infusion includes intramuscular, intravenous administration (by bolus or by continuous infusion over a period of time), intraarterial, intraarticular, intraperitoneal, or subcutaneous administration. In some embodiments, the administration is intravenous administration. In some embodiments, the administration is subcutaneous. Administration can be effected by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, partly depending on whether the administration is short-term or long-term. A variety of dosing schedules are contemplated herein, including but not limited to single administration or multiple administrations at various time points, bolus dosing, and pulse infusion.

[0195] The antibodies provided herein will be formulated, dosed, and administered in a manner that is consistent with good medical practice. Considerations in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site to which the agent is to be delivered, the method of administration, the dosing schedule, and other factors known to the medical practitioner. The antibodies need not but optionally can be formulated with one or more agents currently used to prevent or treat the disorders discussed herein. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and the other factors discussed above. These agents are generally used at the same doses as described herein and by the same routes of administration as described herein, or at about 1 to 99% of the doses described herein, or at any dose and by any route that is determined empirically / clinically to be appropriate.

[0196] The dose of a particular anti-sortilin antibody in an individual to whom one or more administrations of the anti-sortilin antibody have been given can be determined empirically. An increasing dose of the anti-sortilin antibody is administered to the individual. To assess the efficacy of the anti-sortilin antibody, the clinical symptoms of any disease, disorder, or affliction of the present disclosure (e.g., frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, and the unwanted symptoms of normal aging) can be monitored.

[0197] For the prevention or treatment of a disease, the appropriate dose of the antibody of the present invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is suitably administered to the patient in a single dose or over a series of treatments.

[0198] Depending on the type and severity of the disease, an antibody in an amount of about 1 μg / kg to 15 mg / kg (such as 0.1 mg / kg - 10 mg / kg) can be an initial candidate dose for administration to an individual, whether by, for example, one or more separate administrations or by continuous infusion. Depending on the factors mentioned above, a typical daily dose can range from about 1 μg / kg to 100 mg / kg or more. For repeated administration over several days or longer, depending on the disorder, treatment will generally continue until the desired disease symptom suppression occurs. An exemplary dose of the antibody will be in the range of about 15 mg / kg to about 70 mg / kg. Thus, one or more doses of about 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg or 70 mg / kg (or any combination thereof) can be administered to the individual. Another exemplary dose of the antibody will be in the range of about 30 mg / kg to about 60 mg / kg. Thus, one or more doses of 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg or 60 mg / kg (or any combination thereof) can be administered to the individual.

[0199] In some aspects, the methods of the disclosure include administering an anti-sortilin antibody intravenously to an individual at a dose of at least about 30 mg / kg. In some embodiments, the dose is at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg or at least about 60 mg / kg. In some embodiments, the dose is between about 30 mg / kg and about 60 mg / kg. In some embodiments, the dose is about 60 mg / kg.

[0200] Such doses can be administered intermittently, such as weekly or every three weeks (such that the individual receives about two to about twenty times, or for example about six doses of the antibody). In certain embodiments, the dosing frequency is three times a day, twice a day, once a day, every other day, once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once a month, once every two months, once every three months, or longer. In some embodiments, the dose is administered about once a month. In some embodiments, the dosing frequency is equal to or greater than q2w (i.e., once every two weeks or a frequency less than once every two weeks for administering the dose), equal to or greater than q3w, equal to or greater than q4w, equal to or greater than q5w, equal to or greater than q6w, equal to or greater than q7w, or equal to or greater than q8w.

[0201] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 30 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 30 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 30 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 30 mg / kg once every four weeks.

[0202] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 35 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 35 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 35 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 35 mg / kg once every four weeks.

[0203] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 40 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 40 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 40 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 40 mg / kg once every four weeks.

[0204] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 45 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 45 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 45 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is administered intravenously to the individual at a dose of at least about 45 mg / kg once every four weeks.

[0205] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 50 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 50 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 50 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 50 mg / kg once every four weeks.

[0206] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least about 55 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 55 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 55 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least about 55 mg / kg once every four weeks.

[0207] In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of about 60 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of about 60 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of about 60 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of about 60 mg / kg once every four weeks.

[0208] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 30 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 30 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 30 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 30 mg / kg once every four weeks.

[0209] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 35 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 35 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 35 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 35 mg / kg once every four weeks.

[0210] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 40 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 40 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 40 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 40 mg / kg once every four weeks.

[0211] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 45 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 45 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 45 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 45 mg / kg once every four weeks.

[0212] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 50 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 50 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 50 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 50 mg / kg once every four weeks.

[0213] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual at a dose of at least 55 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 55 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 55 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of at least 55 mg / kg once every four weeks.

[0214] In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of 60 mg / kg once every four weeks or more frequently. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of 60 mg / kg once every two weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of 60 mg / kg once every three weeks. In some embodiments, the anti-sortilin antibody is intravenously administered to the individual at a dose of 60 mg / kg once every four weeks.

[0215] In certain embodiments, the anti-sortilin antibody is intravenously administered to the individual over a period of about 60 minutes.

[0216] In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 30 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 35 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 40 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 45 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 50 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least about 55 mg / kg in at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg in about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of about 60 mg / kg in at least 60 minutes.

[0217] In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 30 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 35 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 40 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 45 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 50 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of at least 55 mg / kg over at least 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg over about 60 minutes. In certain embodiments, the anti-sortilin antibody is administered intravenously to an individual at a dose of 60 mg / kg over at least 60 minutes.

[0218] In certain embodiments, at least 2 doses, at least 4 doses, at least 6 doses, at least 8 doses, at least 10 doses, at least 12 doses, at least 14 doses, at least 16 doses, at least 18 doses, or at least 20 doses of the anti-sortilin antibody are administered intravenously to an individual. In certain embodiments, a total of 13 doses of the anti-sortilin antibody are administered to an individual.

[0219] In some embodiments, the treatment of the individual lasts for a treatment period of up to 24 weeks, up to 25 weeks, up to 26 weeks, up to 27 weeks, up to 28 weeks, up to 29 weeks, up to 30 weeks, up to 31 weeks, up to 32 weeks, up to 33 weeks, up to 34 weeks, up to 35 weeks, up to 36 weeks, up to 37 weeks, up to 38 weeks, up to 39 weeks, up to 40 weeks, up to 41 weeks, up to 42 weeks, up to 43 weeks, up to 44 weeks, up to 45 weeks, up to 46 weeks, up to 47 weeks, or up to 48 weeks. In some embodiments, the treatment of the individual lasts for a treatment period of up to 48 weeks. In some embodiments, the treatment of the individual lasts for a treatment period of 48 weeks.

[0220] In some embodiments, the administration of the anti-sortilin antibody occurs on the first day of the treatment period and every four weeks thereafter.

[0221] In some embodiments, the anti-sortilin antibody is administered a total of 13 times during the treatment period.

[0222] An initial higher loading dose may be administered, followed by one or more lower doses. However, other dosing regimens may be useful. The progress of this therapy can be easily monitored by conventional techniques and assays.

[0223] PGRN level

[0224] In some aspects, the methods of the present disclosure include administering an anti-sortilin antibody intravenously to an individual, wherein the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, a 1-fold increase in the level of PGRN protein in the plasma of the individual corresponds to a 100% increase in the level of PGRN protein in the plasma of the individual. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least 1-fold higher, at least 1.25-fold higher, at least 1.5-fold higher, at least 1.75-fold higher, at least 2-fold higher, at least 2.25-fold higher, at least 2.5-fold higher, at least 2.75-fold higher, or at least 3-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least 1-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of the individual after administration of the anti-sortilin antibody is at least 2-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody.

[0225] In some embodiments, a two-fold increase in the level of PGRN protein in the plasma of an individual after administration of an anti-sortilin antibody corresponds to a 100% increase in the level of PGRN protein in the plasma of the individual compared to the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of an individual after administration of an anti-sortilin antibody is at least two-fold, at least three-fold, or at least four-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the plasma of an individual after administration of an anti-sortilin antibody is at least two-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody.

[0226] In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, or about 12 days after administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about five days after administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 42 days after administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 56 days after administration of the anti-sortilin antibody.

[0227] In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, or about 12 days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 28 days, 35 days, 42 days, 49 days, or 56 days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about five days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 28 days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 35 days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 42 days after the last administration of the anti-sortilin antibody. In some embodiments, a fold increase in the level of PGRN protein in the plasma of an individual is present at about 49 days after the last administration of the anti-sortilin antibody.

[0228] In some embodiments, there is a fold increase in the level of PGRN protein in the plasma of an individual at about 56 days after the last administration of the anti-sortilin antibody.

[0229] In some embodiments, at about forty days, about 41 days, or about 42 days after administration of the anti-sortilin antibody, the level of PGRN protein in the plasma of an individual after administration of the anti-sortilin antibody is at least 0.25-fold higher, at least 0.3-fold higher, at least 0.35-fold higher, at least 0.4-fold higher, at least 0.45-fold higher, at least 0.5-fold higher, at least 0.55-fold higher, at least 0.6-fold higher, at least 0.65-fold higher, at least 0.7-fold higher, at least 0.75-fold higher, at least 0.8-fold higher, at least 0.85-fold higher, at least 0.9-fold higher, at least 0.95-fold higher, at least 1-fold higher, or at least 1.5-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody. In some embodiments, at about forty days after administration of the anti-sortilin antibody, the level of PGRN protein in the plasma of an individual after administration of the anti-sortilin antibody is at least 0.25-fold higher than the level of PGRN protein in the plasma of the individual before administration of the anti-sortilin antibody.

[0230] In some embodiments, the level of PGRN protein in the plasma of an individual is determined by drawing blood at multiple time points. In certain embodiments, the level of PGRN protein in the plasma of an individual is determined by drawing blood 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-sortilin antibody and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 30, 42, 43, 57, 85, and / or 113 days after administration of the anti-sortilin antibody. In certain embodiments, the level of PGRN protein in the plasma of an individual is determined by drawing blood 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-sortilin antibody and 1, 2, 3, 6, 8, 13, 30, 43, 57, 85, and 113 days after administration of the anti-sortilin antibody. In certain embodiments, the level of PGRN protein in the plasma of an individual is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody, on the day of each administration of the anti-sortilin antibody, and 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, and / or 70 weeks after administration of the first dose of the anti-sortilin antibody. In certain embodiments, the level of PGRN protein in the plasma of an individual is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody, on the day of each administration of the anti-sortilin antibody, and 61 weeks after administration of the first dose of the anti-sortilin antibody.

[0231] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual, wherein the level of PGRN protein in the cerebrospinal fluid of the individual is higher after administering the anti-sortilin antibody than the level of PGRN protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, a 1-fold increase in the level of PGRN protein in the cerebrospinal fluid of the individual corresponds to a 100% increase in the level of PGRN protein in the cerebrospinal fluid of the individual. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is at least 0.8-fold higher, at least 0.85-fold higher, at least 0.9-fold higher, at least 0.95-fold higher, at least 1-fold higher, or at least 1.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is at least 0.8-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is at least 1-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody.

[0232] In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of the individual at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days after administering the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of the individual at about twelve days after administering the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of the individual at about 24 days after administering the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of the individual at about 56 days after administering the anti-sortilin antibody.

[0233] In some embodiments, a two-fold increase in the level of PGRN protein in the cerebrospinal fluid of an individual corresponds to a 100% increase in the level of PGRN protein in the cerebrospinal fluid of the individual. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of an anti-sortilin antibody is at least 2-fold higher, at least 2.5-fold higher, at least 3-fold higher, at least 3.5-fold higher, at least 4-fold higher, at least 4.5-fold higher, at least 5-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual after administration of an anti-sortilin antibody is at least two-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody.

[0234] In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days or about 42 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at any one of about 28 days, 35 days, 42 days, 49 days or 56 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about twelve days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 24 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 28 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 35 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 42 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 49 days after the last administration of the anti-sortilin antibody. In some embodiments, there is a multiplicative increase in the level of PGRN protein in the cerebrospinal fluid of an individual at about 56 days after the last administration of the anti-sortilin antibody.

[0235] In some embodiments, at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days or about 42 days after administration of the anti-sortilin antibody, the level of PGRN protein in the cerebrospinal fluid of the individual is at least 0.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody. In some embodiments, at about 42 days after administration of the anti-sortilin antibody, the level of PGRN protein in the cerebrospinal fluid of the individual is at least 0.2-fold higher than the level of PGRN protein in the cerebrospinal fluid of the individual before administration of the anti-sortilin antibody.

[0236] In some embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual is determined by performing lumbar punctures at multiple time points. In certain embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual is determined by performing lumbar punctures 8, 5, 3, 2, 1 and / or 0 days before administration of the anti-sortilin antibody and 1 day, 30 hours, 2 days, 12 days, 24 days and / or 42 days after administration of the anti-sortilin antibody. In certain embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual is determined by performing lumbar punctures up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody and at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks and / or at least 60 weeks after administration of the first dose of the anti-sortilin antibody. In certain embodiments, the level of PGRN protein in the cerebrospinal fluid of an individual is determined by performing lumbar punctures up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody and during week 25 and during week 61 after administration of the first dose of the anti-sortilin antibody.

[0237] In some embodiments, any method known in the art for quantifying proteins is used to determine the level of PGRN protein in the plasma or cerebrospinal fluid of an individual. Non-limiting examples of methods that can be used to quantify PGRN protein include the SOMASCAN assay (see, e.g., Candia et al. (2017) Sci Rep 7, 14248), western blotting, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). In certain embodiments, an ELISA assay is used to determine the level of PGRN protein in the plasma or cerebrospinal fluid of an individual.

[0238] SORT1 level

[0239] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual, wherein the level of SORT1 protein expression on the peripheral white blood cells of the individual is reduced after administration of the anti-sortilin antibody as compared to the level of SORT1 protein expression on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of SORT1 protein expression on the peripheral white blood cells of the individual is reduced by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% after administration of the anti-sortilin antibody as compared to the level of SORT1 protein expression on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of SORT1 protein expression on the peripheral white blood cells of the individual is reduced by at least 50% after administration of the anti-sortilin antibody as compared to the level of SORT1 protein expression on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody. In some embodiments, the level of SORT1 protein expression on the peripheral white blood cells of the individual is reduced by at least 70% after administration of the anti-sortilin antibody as compared to the level of SORT1 protein expression on the peripheral white blood cells of the individual before administration of the anti-sortilin antibody.

[0240] In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 21 days or more, 22 days or more, 23 days or more, 24 days or more, 25 days or more, 26 days or more, 27 days or more, 28 days or more, 29 days or more, 30 days or more, 31 days or more, 32 days or more, 33 days or more, 34 days or more, 35 days or more, 36 days or more, 37 days or more, 38 days or more, 39 days or more, 40 days or more, 41 days or more, 42 days or more, 43 days or more, 44 days or more, or 45 days or more after administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about twelve days or more after administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about seventeen days or more after administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about forty days or more after administration of the anti-sortilin antibody.

[0241] In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 21 days or more, 22 days or more, 23 days or more, 24 days or more, 25 days or more, 26 days or more, 27 days or more, 28 days or more, 29 days or more, 30 days or more, 31 days or more, 32 days or more, 33 days or more, 34 days or more, 35 days or more, 36 days or more, 37 days or more, 38 days or more, 39 days or more, 40 days or more, 41 days or more, 42 days or more, 43 days or more, 44 days or more, or 45 days or more after the last administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about twelve days or more after the last administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about seventeen days or more after the last administration of the anti-sortilin antibody. In some embodiments, a decrease in the expression level of SORT1 in the peripheral white blood cells of an individual is present about forty days or more after the last administration of the anti-sortilin antibody.

[0242] In some aspects, the methods of the present disclosure include intravenously administering an anti-sortilin antibody to an individual, wherein the level of SORT1 protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is reduced compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is reduced by at least 50% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody. In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of the individual after administering the anti-sortilin antibody is reduced by at least 70% compared to the level of SORT1 protein in the cerebrospinal fluid of the individual before administering the anti-sortilin antibody.

[0243] In some embodiments, the level of SORT1 protein on peripheral white blood cells of an individual is determined by drawing blood at multiple time points. In certain embodiments, the level of SORT1 on peripheral white blood cells of an individual is determined by drawing blood 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-sortilin antibody and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 30, 42, 43, 57, 85, and / or 113 days after administration of the anti-sortilin antibody. In certain embodiments, the level of SORT1 on peripheral white blood cells of an individual is determined by drawing blood 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-sortilin antibody and 1, 2, 3, 6, 8, 9, 13, 18, 30, 43, 57, 85, and 113 days after administration of the anti-sortilin antibody. In certain embodiments, the level of SORT1 protein on peripheral white blood cells of an individual is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody, on the day of each administration of the anti-sortilin antibody, and 10 weeks, 20 weeks, 30 weeks, 40 weeks, 50 weeks, 60 weeks, and / or 70 weeks after administration of the first dose of the anti-sortilin antibody. In certain embodiments, the level of SORT1 protein on peripheral white blood cells of an individual is determined by drawing blood up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sortilin antibody, on the day of each administration of the anti-sortilin antibody, and during week 61 after administration of the first dose of the anti-sortilin antibody.

[0244] In some embodiments, the level of SORT1 protein in the cerebrospinal fluid of an individual is determined by performing a lumbar puncture at multiple time points. In certain embodiments, the level of SORT1 protein in the cerebrospinal fluid of an individual is determined by performing a lumbar puncture 8, 5, 3, 2, 1, and / or 0 days before administration of the anti-sorting protein antibody and 1 day, 30 hours, 12 days, 24 days, and / or 42 days after administration of the anti-sorting protein antibody. In certain embodiments, the level of SORT1 protein in the cerebrospinal fluid of an individual is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sorting protein antibody and at least 10 weeks, at least 15 weeks, at least 20 weeks, at least 25 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, and / or at least 60 weeks after administration of the first dose of the anti-sorting protein antibody. In certain embodiments, the level of SORT1 protein in the cerebrospinal fluid of an individual is determined by performing a lumbar puncture up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, up to 2 weeks, up to 1 week, up to 7 days, up to 6 days, up to 5 days, up to 4 days, up to 3 days, up to 2 days, up to 1 day, and / or 0 days before administration of the first dose of the anti-sorting protein antibody and during week 25 and during week 61 after administration of the first dose of the anti-sorting protein antibody.

[0245] In some embodiments, any method known in the art for quantifying proteins is used to determine the level of SORT1 protein on the peripheral white blood cells of an individual or the level of soluble SORT1 protein in the cerebrospinal fluid. Non-limiting examples of methods that can be used to quantify SORT1 protein include the SOMASCAN assay (see, e.g., Candia et al. (2017) Sci Rep 7, 14248), Western blotting, mass spectrometry, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). In certain embodiments, an ELISA assay is used to determine the level of SORT1 protein on the peripheral white blood cells of an individual or in the cerebrospinal fluid. In certain embodiments, an ELISA assay using an anti-idiotypic antibody specific for the anti-sorting protein antibody is used to determine the level of SORT1 protein on the peripheral white blood cells of an individual or in the cerebrospinal fluid.

[0246] Pharmacokinetics of the anti-sorting protein antibody

[0247] In some embodiments, the half-life of the anti-sorting protein antibody in plasma is about 5 days, about 6 days, about 7 days, about 8 days, or about 9 days. In some embodiments, the half-life of the anti-sorting protein antibody in plasma is about 5 days. In some embodiments, the half-life of the anti-sorting protein antibody in plasma is about 8 days.

[0248] Diagnostic use

[0249] The isolated antibodies of the present disclosure (such as the anti-sortilin antibodies described herein) also have diagnostic utility. Accordingly, the present disclosure provides methods of using the antibodies of the present disclosure, or functional fragments thereof, for diagnostic purposes such as detecting sortilin in an individual or in a tissue sample derived from an individual.

[0250] In some embodiments, the individual is a human. In some embodiments, the individual is a human patient suffering from or at risk of developing a disease, disorder, or injury of the present disclosure. In some embodiments, the diagnostic method involves detecting sortilin in a biological sample such as a biopsy sample, tissue, or cell. An anti-sortilin antibody as described herein is contacted with the biological sample, and antigen-bound antibody is detected. For example, a biopsy sample can be stained with an anti-sortilin antibody as described herein to detect and / or quantify disease-related cells. The detection method can involve quantification of the antigen-bound antibody. Detection of the antibody in the biological sample can be performed using any method known in the art including, but not limited to, immunofluorescence microscopy, immunocytochemical analysis, immunohistochemical analysis, ELISA, FACS analysis, immunoprecipitation, or micro-positron emission tomography. In certain embodiments, for example, the antibody is radiolabeled with 18 F and then detected using micro-positron emission tomography analysis. Antibody binding in an individual can also be quantified by non-invasive techniques such as positron emission tomography (PET), X-ray computed tomography, single photon emission computed tomography (SPECT), computed tomography (CT), and computed axial tomography (CAT).

[0251] In other embodiments, the isolated antibodies of the present disclosure (such as the anti-sortilin antibodies described herein) can be used to detect and / or quantify, for example, microglia in brain samples taken from preclinical disease models (such as non-human disease models). Accordingly, the isolated antibodies of the present disclosure (such as the anti-sortilin antibodies described herein) can be used to evaluate the treatment response after treatment, compared to a control, in a model of a neurological disease or injury such as frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, atherosclerotic vascular disease, Nasu-Hakola disease, or multiple sclerosis.

[0252] Sortilin antibody

[0253] Certain aspects of the present disclosure relate to anti-sortilin antibodies comprising one or more improved and / or enhanced functional features. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise one or more improved and / or enhanced functional features relative to the anti-sortilin antibody S-60 having heavy and light chain variable regions as described in WO2016164637. In some embodiments, the anti-sortilin antibodies of the present disclosure have a higher affinity for sortilin (e.g., human sortilin) than a control anti-sortilin antibody (e.g., a control anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60). In some embodiments, compared to a control antibody (e.g., a control anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60), the anti-sortilin antibodies of the present disclosure reduce the cellular level (e.g., cell surface level) of sortilin to a greater extent and at a lower half-maximal effective concentration (EC 50 ). In some embodiments, relative to an anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60, the anti-sortilin antibodies of the present disclosure improve the maximal reduction of the cell surface level of sortilin. In some embodiments, relative to an anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60, the anti-sortilin antibodies of the present disclosure increase the secretion of progranulin (PGRN). In some embodiments, compared to a control antibody (e.g., a control anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60), 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 (EC 50 ). In some embodiments, relative to an anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60, the anti-sortilin antibodies of the present disclosure improve the maximal blockage of the binding of PGRN to sortilin.

[0254] Also contemplated herein are anti-sortilin antibodies having different Fc variants, which exhibit one or more improved and / or enhanced functional features relative to an anti-sortilin antibody comprising heavy and light chain variable regions corresponding to S-60, including reducing the half-maximal effective concentration (EC 50 ) for reducing the cell surface level of sortilin, improving the maximal reduction of the cell surface level of sortilin, increasing the extracellular secretion of PGRN, reducing the half-maximal effective concentration (EC 50 ) for blocking the binding of PGRN to sortilin, and improving the maximal blockage of the binding of PGRN to sortilin.

[0255] 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.

[0256] In a preferred embodiment, the anti-sortilin antibody of the present disclosure is a monoclonal antibody.

[0257] Anti-sortilin antibody heavy and light chain variable regions

[0258] A. Heavy chain HVR

[0259] 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 11 to 13). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11 to 13).

[0260] In some embodiments, HVR-H1 comprises the sequence YYSISSGYYWG (SEQ ID NO:1). In some embodiments, HVR-H2 comprises a sequence according to Formula I: TIYHSGSTYYNPSLX1S (SEQ ID NO:4), where X1 is K or E. In some embodiments, HVR-H2 comprises a sequence selected from SEQ ID NOs: 2-3. In some embodiments, HVR-H3 comprises a sequence according to Formula II: ARQGSIX1QGYYGMDV (SEQ ID NO:7). In some embodiments, HVR-H3 comprises a sequence selected from SEQ ID NOs: 5-6.

[0261] In some embodiments, HVR-H1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to the amino acid sequence of SEQ ID NO:1. In some embodiments, HVR-H1 comprises an amino acid sequence containing 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 sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-H1 amino acid sequence of SEQ ID NO:1. In some embodiments, HVR-H2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NO:2-3. In some embodiments, HVR-H2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NO:2-3), but retains the ability to bind sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-H2 amino acid sequence selected from SEQ ID NO:2-3. In some embodiments, HVR-H3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NO:5-6. In some embodiments, HVR-H3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NO:5-6), but retains the ability to bind sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-H3 amino acid sequence selected from SEQ ID NO:5-6.

[0262] In some embodiments, the heavy chain variable region comprises HVR-H1 containing the sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 containing the sequence according to Formula I, and HVR-H3 containing the sequence according to Formula II.

[0263] In some embodiments, the heavy chain variable region comprises HVR-H1 containing the sequence of SEQ ID NO:1, HVR-H2 containing a sequence selected from SEQ ID NO:2-3, and HVR-H3 containing a sequence selected from SEQ ID NO:5-6.

[0264] In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24 or any combination thereof (as shown in Tables 11 to 13).

[0265] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region, wherein the heavy chain variable region comprises one or more of the following: (a) an HVR-H1 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H1 amino acid sequence 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[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; (b) an HVR-H1 comprising an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H1 amino acid sequence 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[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.The HVR-H2 of the amino acid sequence of 17[N33L], S-60-16, S-60-18, S-60-19, or S-60-24 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity; and (c) the HVR-H3 of the amino acid sequence of the 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 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity.

[0266] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise an HVR-H1 comprising the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6).

[0267] B. Light chain HVR

[0268] In some embodiments, the anti-sortilin antibodies of the disclosure comprise a light chain variable region that comprises one or more (e.g., one or more, two or more, or all three) HVRS selected from HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14 to 16). In some embodiments, the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14 to 16).

[0269] In some embodiments, HVR-L1 comprises a sequence according to Formula III: RSSQX1LLX2SX3GYNYLD (SEQ ID NO:28), where X1 is S or G, X2 is R or H, and X3 is N, T, S, G, R, D, H, K, Q, Y, E, W, F, I, V, A, M or L. In some embodiments, HVR-L1 comprises a sequence selected from SEQ ID NO:8-27. In some embodiments, HVR-L1 comprises RSSQSLLRSNGYNYLD (SEQ ID NO:8), RSSQSLLRSTGYNYLD (SEQ ID NO:9), RSSQSLLRSSGYNYLD (SEQ ID NO:10), RSSQSLLRSGGYNYLD (SEQ ID NO:11), RSSQSLLRSRG YNYLD (SEQ ID NO:12), RSSQSLLRSDGYNYLD (SEQ ID NO:13), RSSQSLLRSHGYNYLD (SEQ ID NO:14), RSSQSLLRSKGYNYLD (SEQ ID NO:15), RSSQSLLRSQGYNYLD (SEQ ID NO:16), RSSQSLLRSYGYNYLD (SEQ ID NO:17), RSSQSLLRSEGYNYLD (SEQ ID NO:18), RSSQSLLRSWGYNYLD (SEQ ID NO:19), RSSQSLLRSFGYNYLD (SEQ ID NO:20), RSSQSLLRSIGYNYLD (SEQ ID NO:21), RSSQSLLRSVGYNYLD (SEQ ID NO:22), RSSQSLLRSAG YNYLD (SEQID NO:23), RSSQSLLRSMGYNYLD (SEQ ID NO:24), RSSQSLLRSLGYNYLD (SEQ ID NO:25), RSSQSLLHSNGYNYLD (SEQ ID NO:26), or RSSQGLLRSNGYNYLD (SEQ ID NO:27). In one specific embodiment, 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 14).

[0270] In some embodiments, HVR-L2 comprises a sequence according to Formula IV: LGSNRX1S (SEQ ID NO: 31), where X1 is A or V. In some embodiments, HVR-L2 comprises a sequence selected from SEQ ID NO: 29-30.

[0271] In some embodiments, HVR-L3 comprises a sequence according to Formula V: MQQQEX1PLT (SEQ ID NO: 34), where X1 is A or T. In some embodiments, HVR-L3 comprises a sequence selected from SEQ ID NO: 32-33.

[0272] In some embodiments, HVR-L1 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NO: 8-27. In some embodiments, HVR-L1 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence selected from SEQ ID NO: 8-27), but retains the ability to bind sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-L1 amino acid sequence selected from SEQ ID NO: 8-27. In some embodiments, HVR-L2 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NO: 29-30. In some embodiments, HVR-L2 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence selected from SEQ ID NO: 29-30), but retains the ability to bind sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-L2 amino acid sequence selected from SEQ ID NO: 29-30. In some embodiments, HVR-L3 comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NO: 32-33. In some embodiments, HVR-L3 comprises an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to the amino acid sequence selected from SEQ ID NO: 32-33), but retains the ability to bind sorting proteins. In certain embodiments, up to 1, up to 2, up to 3, up to 4, or up to 5 amino acids have been substituted, inserted, and / or deleted in the HVR-L3 amino acid sequence selected from SEQ ID NO: 32-33.

[0273] In some embodiments, the light chain variable region comprises HVR-L1 containing a sequence according to Formula III, HVR-L2 containing a sequence according to Formula IV, and HVR-L3 containing a sequence according to Formula V. In some embodiments, the light chain variable region comprises HVR-L1 containing a sequence selected from SEQ ID NO: 8-27, HVR-L2 containing a sequence selected from SEQ ID NO: 29-30, and HVR-L3 containing a sequence selected from SEQ ID NO: 32-33.

[0274] In some embodiments, the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 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[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24 or any combination thereof (as shown in Tables 14 to 16).

[0275] In some embodiments, the anti-sortilin antibodies of the present disclosure include a light chain variable region, wherein the light chain variable region comprises one or more of the following: (a) an HVR-L1 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L1 amino acid sequence 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[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; (b) an HVR-L1 comprising an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L1 amino acid sequence 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[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.The HVR-L2 of the amino acid sequence of 17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity; and (c) comprising an HVR-L3 having an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-L3 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[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..

[0276] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise an HVR-L1 containing the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), an HVR-L2 containing the amino acid sequence LGSNRAS (SEQ ID NO:29), and an HVR-L3 containing the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0277] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO:9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO:29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0278] C. Heavy chain HVRs and light chain HVRs

[0279] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region that comprises one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11 to 13), and a light chain variable region that comprises one or more (e.g., one or more, two or more, or all three) HVRs selected from HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14 to 16). In some embodiments, the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 (as shown in Tables 11 to 13), and the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 (as shown in Tables 14 to 16).

[0280] In some embodiments, the heavy chain variable region comprises an HVR-H1 comprising the sequence YYSISSGYYWG (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 sequences of SEQ ID NOs: 2-3, and an HVR-H3 comprising a sequence selected from the sequences of SEQ ID NOs: 5-6, and the light chain variable region comprises an HVR-L1 comprising a sequence selected from the sequences of SEQ ID NOs: 8-27, an HVR-L2 comprising a sequence selected from the sequences of SEQ ID NOs: 29-30, and an HVR-L3 comprising a sequence selected from the sequences of SEQ ID NOs: 32-33.

[0281] In some aspects, the heavy chain variable region comprises HVR-H1 containing the sequence of SEQ ID NO:1, HVR-H2 containing a sequence selected from SEQ ID NOs:2-3, and HVR-H3 containing a sequence selected from SEQ ID NOs:5-6, and the light chain variable region comprises HVR-L1 containing a sequence selected from SEQ ID NOs:8-27, HVR-L2 containing a sequence selected from SEQ ID NOs:29-30, and HVR-L3 containing the sequence of SEQ ID NO:32.

[0282] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region that comprises HVR-H1, HVR-H2, and 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[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 11 to 13); and a light chain variable region that comprises HVR-L1, HVR-L2, and HVR-L3 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[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[N33Y], S-60-15.10[N33E], S-60-15.11[N33W], S-60-15.12[N33F], S-60-15.13[N33I], S-60-15.14[N33V], S-60-15.15[N33A], S-60-15.16[N33M], S-60-15.17[N33L], S-60-16, S-60-18, S-60-19, S-60-24 or any combination thereof (as shown in Tables 14 to 16).

[0283] In some embodiments, the anti-sortilin antibodies of the disclosure comprise a heavy chain variable region containing HVR-H1, HVR-H2, and HVR-H3 and a light chain variable region containing HVR-L1, HVR-L2, and HVR-L3, wherein the antibody comprises the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 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[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 11 to 16).

[0284] 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) an HVR-H1 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H1 amino acid sequence 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[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; (b) an HVR-H1 comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H1 amino acid sequence 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[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.The HVR-H2 of the amino acid sequence of 17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 has an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity; and (c) contains an HVR-H3 having an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the HVR-H3 amino acid sequence of 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; and wherein the light chain variable region contains one or more of the following: (a) contains an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable region amino acid sequence 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[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.The HVR-L1 amino acid sequence of 17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 having an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity; (b) The HVR-L2 amino acid sequence of the 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 having an amino acid sequence with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity; and (c) The 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.The HVR-L3 amino acid sequence of 17[N33L], S-60-16, S-60-18, S-60-19 or S-60-24 has an amino acid sequence of HVR-L3 with at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity.

[0285] In some embodiments, the anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0286] In some embodiments, the anti-sortilin antibody of the present disclosure comprises a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRVS (SEQ ID NO:30), and HVR-L3 having the amino acid sequence MQQQETPLT (SEQ ID NO:33).

[0287] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLES (SEQ ID NO:3), and HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0288] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0289] In some aspects, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region comprising HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO:9), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0290] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region that comprises HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region that comprises HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQETPLT (SEQ ID NO:33).

[0291] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region that comprises HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIQQGYYGMDV (SEQ ID NO:5); and a light chain variable region that comprises HVR-L1 having the amino acid sequence RSSQSLLHSNGYNYLD (SEQ ID NO:26), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQETPLT (SEQ ID NO:33).

[0292] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region that comprises HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region that comprises HVR-L1 having the amino acid sequence RSSQGLLRSNGYNYLD (SEQ ID NO:27), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0293] D. Heavy chain variable region

[0294] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56. In some embodiments, the heavy chain variable region comprises an amino acid sequence containing substitutions (such as conservative substitutions, insertions, or deletions relative to the amino acid sequence selected from SEQ ID NOs: 54-56), but retains the ability to bind sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56.

[0295] In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 56.

[0296] In some embodiments, the anti-sortilin antibodies of the present disclosure include the heavy chain variable regions of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[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 25).

[0297] In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region that comprises HVR-H1 having the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 having the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 having the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6).

[0298] E. Light chain variable region

[0299] In some embodiments, the anti-sortilin antibodies of the present disclosure include a light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the light chain variable region comprises an amino acid sequence having 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 sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable region amino acid sequences selected from SEQ ID NOs: 57-80.

[0300] 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.

[0301] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise the light 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], 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 26).

[0302] In some embodiments, the anti-sortilin antibodies of the present disclosure include a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSNGYNYLD (SEQ ID NO:8), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0303] In some embodiments, the anti-sortilin antibodies of the present disclosure include a light chain variable region comprising HVR-L1 having the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO:9), HVR-L2 having the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 having the amino acid sequence MQQQEAPLT (SEQ ID NO:32).

[0304] F. Heavy chain variable region and light chain variable region

[0305] 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 having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 54-56, and the light chain variable region comprises an amino acid sequence having at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to an amino acid sequence selected from SEQ ID NOs: 57-80. In some embodiments, the anti-sortilin antibodies of the present disclosure include a heavy chain variable region comprising an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 54-56), and a light chain variable region comprising an amino acid sequence containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to an amino acid sequence selected from SEQ ID NOs: 57-80); but retaining the ability to bind sortilin. In certain embodiments, up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable region amino acid sequence selected from SEQ ID NOs: 54-56; and up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, or up to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable region amino acid sequence selected from SEQ ID NOs: 57-80.

[0306] 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: 57-58, 60-78, and 80.

[0307] In some embodiments, the anti-sortilin antibodies of the present disclosure bind 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: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.

[0308] In one aspect, the 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.

[0309] In one aspect, the 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.

[0310] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise the heavy chain variable regions of antibodies S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-15.2[N33S], S-60-15.3[N33G], S-60-15.4[N33R], S-60-15.5[N33D], S-60-15.6[N33H], S-60-15.7[N33K], S-60-15.8[N33Q], S-60-15.9[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 25), and the light 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], 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 26).

[0311] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable region having the amino acid sequence of SEQ ID NO:56 and a light chain variable region having an amino acid sequence selected from SEQ ID NO:57 and 60. In some embodiments, the antibody comprises the heavy chain variable region of S-60-15[N33(wt)] (as shown in Table 25) and the light chain variable region of antibody S-60-15[N33(wt)] (as shown in Table 26). In some embodiments, the antibody comprises the heavy chain variable region of S-60-15.1[N33T] (as shown in Table 25) and the light chain variable region of antibody S-60-15.1[N33T] (as shown in Table 26).

[0312] Exemplary anti-sortilin antibodies

[0313] In some embodiments, the anti-sortilin antibody is an anti-sortilin monoclonal antibody comprising the heavy chain variable region and the light chain variable region of an antibody selected from 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 chain and the light chain of an antibody selected from S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[NззT], 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.

[0314] (1)S-60-10

[0315] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-10. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-10. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-10 or in the amino acid sequence of SEQ ID NO:54.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-10 or in the amino acid sequence of SEQ ID NO:54. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-10 or SEQ ID NO:54, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-10, (b) the HVR-H2 amino acid sequence of antibody S-60-10, and (c) the HVR-H3 amino acid sequence of antibody S-60-10. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-10 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-10 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-10 or SEQ ID NO:57, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-10, (b) the HVR-L2 amino acid sequence of antibody S-60-10, and (c) the HVR-L3 amino acid sequence of antibody S-60-10.

[0316] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain containing the amino acid sequence of SEQ ID NO: 92.

[0317] (2)S-60-11

[0318] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-11. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-11 or in the amino acid sequence of SEQ ID NO:54.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-11 or in the amino acid sequence of SEQ ID NO:54. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-11 or SEQ ID NO:54, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-11, (b) the HVR-H2 amino acid sequence of antibody S-60-11, and (c) the HVR-H3 amino acid sequence of antibody S-60-11. In some embodiments, the anti-sortilin antibody of the present disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-11 or in the amino acid sequence of SEQ ID NO:58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-11 or in the amino acid sequence of SEQ ID NO:58. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-11 or SEQ ID NO:58, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-11, (b) the HVR-L2 amino acid sequence of antibody S-60-11, and (c) the HVR-L3 amino acid sequence of antibody S-60-11.

[0319] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence comprising SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain having an amino acid sequence comprising SEQ ID NO: 93. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence comprising SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain having an amino acid sequence comprising SEQ ID NO: 93.

[0320] (3)S-60-12

[0321] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-12. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-12. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-12 or in the amino acid sequence of SEQ ID NO:54.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-12 or in the amino acid sequence of SEQ ID NO:54. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-12 or SEQ ID NO:54, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-12, (b) the HVR-H2 amino acid sequence of antibody S-60-12, and (c) the HVR-H3 amino acid sequence of antibody S-60-12. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-12 or in the amino acid sequence of SEQ ID NO:59. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-12 or in the amino acid sequence of SEQ ID NO:59. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-12 or SEQ ID NO:59, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-12, (b) the HVR-L2 amino acid sequence of antibody S-60-12, and (c) the HVR-L3 amino acid sequence of antibody S-60-12.

[0322] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO: 94. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain containing the amino acid sequence of SEQ ID NO: 94.

[0323] (4)S-60-13

[0324] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-13. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-13. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (such as conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-13 or in the amino acid sequence of SEQ ID NO:55.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-13 or in the amino acid sequence of SEQ ID NO:55. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-13 or SEQ ID NO:55, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-13, (b) the HVR-H2 amino acid sequence of antibody S-60-13, and (c) the HVR-H3 amino acid sequence of antibody S-60-13. In some embodiments, the anti-sortilin antibody of the present disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-13 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-13 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-13 or SEQ ID NO:57, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-13, (b) the HVR-L2 amino acid sequence of antibody S-60-13, and (c) the HVR-L3 amino acid sequence of antibody S-60-13.

[0325] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO:88 or SEQ ID NO:89. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO:92. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO:88 or SEQ ID NO:89 and a light chain containing the amino acid sequence of SEQ ID NO:92.

[0326] (5)S-60-14

[0327] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-14. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-14. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-1 or in the amino acid sequence of SEQ ID NO:55.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-14 or in the amino acid sequence of SEQ ID NO:55. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-14 or SEQ ID NO:55, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-14, (b) the HVR-H2 amino acid sequence of antibody S-60-14, and (c) the HVR-H3 amino acid sequence of antibody S-60-14. In some embodiments, the anti-sortilin antibody of the present disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-14 or in the amino acid sequence of SEQ ID NO:58. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-14 or in the amino acid sequence of SEQ ID NO:58. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-14 or SEQ ID NO:58, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-14, (b) the HVR-L2 amino acid sequence of antibody S-60-14, and (c) the HVR-L3 amino acid sequence of antibody S-60-14.

[0328] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO: 93. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 88 or SEQ ID NO: 89 and a light chain containing the amino acid sequence of SEQ ID NO: 93.

[0329] (6)S-60-15

[0330] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a 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 have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-15 or in the amino acid sequence of SEQ ID NO:56.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-15 or in the amino acid sequence of SEQ ID NO:56. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-15 or SEQ ID NO:56, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-15, (b) the HVR-H2 amino acid sequence of antibody S-60-15, and (c) the HVR-H3 amino acid sequence of antibody S-60-15. In some embodiments, the anti-sortilin antibody of the present disclosure comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-15 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-15 or in the amino acid sequence of SEQ ID NO:57. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-15 or SEQ ID NO:57, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-15, (b) the HVR-L2 amino acid sequence of antibody S-60-15, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.

[0331] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence containing SEQ ID NO:90 or SEQ ID NO:91. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain having an amino acid sequence containing SEQ ID NO:92. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence containing SEQ ID NO:90 or SEQ ID NO:91 and a light chain having an amino acid sequence containing SEQ ID NO:92.

[0332] (7)S-60-15.1

[0333] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-15.1. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-15.1. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-15.1 or in the amino acid sequence of SEQ ID NO:56.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-15.1 or in the amino acid sequence of SEQ ID NO:56. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-15.1 or SEQ ID NO:56, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-15.1, (b) the HVR-H2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-H3 amino acid sequence of antibody S-60-15.1. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-15.1 or in the amino acid sequence of SEQ ID NO:60. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-15.1 or in the amino acid sequence of SEQ ID NO:60. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-15.1 or SEQ ID NO:60, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-15.1, (b) the HVR-L2 amino acid sequence of antibody S-60-15.1, and (c) the HVR-L3 amino acid sequence of antibody S-60-15.1.

[0334] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0335] (8)S-60-16

[0336] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-16. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-16. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (such as conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-16 or in the amino acid sequence of SEQ ID NO:56.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-16 or in the amino acid sequence of SEQ ID NO:56. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-16 or SEQ ID NO:56, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-16, (b) the HVR-H2 amino acid sequence of antibody S-60-16, and (c) the HVR-H3 amino acid sequence of antibody S-60-16. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 9%0, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-16 or in the amino acid sequence of SEQ ID NO:77. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-16 or in the amino acid sequence of SEQ ID NO:77. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-16 or SEQ ID NO:77, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-16, (b) the HVR-L2 amino acid sequence of antibody S-60-16, and (c) the HVR-L3 amino acid sequence of antibody S-60-16.

[0337] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence containing SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain having an amino acid sequence containing SEQ ID NO: 112. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain having an amino acid sequence containing SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain having an amino acid sequence containing SEQ ID NO: 112.

[0338] (9)S-60-18

[0339] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-18. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-18 or in the amino acid sequence of SEQ ID NO: 56.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-18 or in the amino acid sequence of SEQ ID NO:56. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-18 or SEQ ID NO:56, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-18, (b) the HVR-H2 amino acid sequence of antibody S-60-18, and (c) the HVR-H3 amino acid sequence of antibody S-60-18. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-18 or in the amino acid sequence of SEQ ID NO:78. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-18 or in the amino acid sequence of SEQ ID NO:78. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside of the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-18 or SEQ ID NO:78, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-18, (b) the HVR-L2 amino acid sequence of antibody S-60-18, and (c) the HVR-L3 amino acid sequence of antibody S-60-18.

[0340] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO: 113. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 90 or SEQ ID NO: 91 and a light chain containing the amino acid sequence of SEQ ID NO: 113.

[0341] (10)S-60-19

[0342] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-19 or in the amino acid sequence of SEQ ID NO: 54.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-19 or in the amino acid sequence of SEQ ID NO:54. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-19 or SEQ ID NO:54, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-19, (b) the HVR-H2 amino acid sequence of antibody S-60-19, and (c) the HVR-H3 amino acid sequence of antibody S-60-19. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), provided that the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-19 or in the amino acid sequence of SEQ ID NO:79. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-19 or in the amino acid sequence of SEQ ID NO:79. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-19 or SEQ ID NO:79, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-19, (b) the HVR-L2 amino acid sequence of antibody S-60-19, and (c) the HVR-L3 amino acid sequence of antibody S-60-19.

[0343] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain containing the amino acid sequence of SEQ ID NO: 114. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 86 or SEQ ID NO: 87 and a light chain containing the amino acid sequence of SEQ ID NO: 114.

[0344] (11)S-60-24

[0345] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, the anti-sortilin antibodies of the present disclosure comprise a heavy chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody S-60-24. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain containing an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody S-60-24. In some embodiments, the anti-sortilin antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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 contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising the sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-24 or in the amino acid sequence of SEQ ID NO: 56.In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the heavy chain variable domain of antibody S-60-24 or in the amino acid sequence of SEQ ID NO:56. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VH sequence of antibody S-60-24 or SEQ ID NO:56, including post-translational modifications of said sequence. In a particular embodiment, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody S-60-24, (b) the HVR-H2 amino acid sequence of antibody S-60-24, and (c) the HVR-H3 amino acid sequence of antibody S-60-24. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the 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, and containing substitutions (e.g., conservative substitutions, insertions, or deletions relative to a reference sequence), but the anti-sortilin antibody comprising said sequence retains the ability to bind sortilin. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-24 or in the amino acid sequence of SEQ ID NO:80. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of the light chain variable domain of antibody S-60-24 or in the amino acid sequence of SEQ ID NO:80. In certain embodiments, the substitution, insertion, or deletion occurs in a region outside the HVRs (i.e., in the FR regions). In some embodiments, the substitution, insertion, or deletion occurs in the FR regions. Optionally, the anti-sortilin antibody comprises the VL sequence of antibody S-60-24 or SEQ ID NO:80, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody S-60-24, (b) the HVR-L2 amino acid sequence of antibody S-60-24, and (c) the HVR-L3 amino acid sequence of antibody S-60-24.

[0346] In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:91. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a light chain comprising the amino acid sequence of SEQ ID NO:115. In some embodiments, the anti-sortilin antibodies of the present disclosure comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:91 and a light chain comprising the amino acid sequence of SEQ ID NO:115.

[0347] In some embodiments, the anti-sortilin antibodies of the present disclosure bind to substantially the same sortilin epitope as an antibody comprising the heavy chain variable domain and the light chain variable domain of an antibody selected from the group consisting of S-60-10, S-60-11, S-60-12, S-60-13, S-60-14, S-60-15[N33(wt)], S-60-15.1[N33T], S-60-16, S-60-18, S-60-19, and S-60-24.

[0348] 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 sortilin epitope 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.

[0349] 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 sortilin epitope 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.

[0350] 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 a substantially identical sortilin epitope 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.

[0351] 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 a substantially identical sortilin epitope 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.

[0352] 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 a substantially identical sortilin epitope as S-60-14. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-14. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the 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 the monoclonal antibody S-60-14.

[0353] 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 a substantially identical sortilin epitope as S-60-15. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the heavy chain variable region of the monoclonal antibody S-60-15. In some embodiments, the anti-sortilin antibody is an isolated antibody comprising the light chain variable region of the 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 the monoclonal antibody S-60-15.

[0354] 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 sortilin epitope as S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region of the monoclonal antibody S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the light chain variable region of the monoclonal antibody S-60-15.1. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-15.1.

[0355] 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 sortilin epitope as S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region of the monoclonal antibody S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the light chain variable region of the monoclonal antibody S-60-16. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-16.

[0356] 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 sortilin epitope as S-60-18. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region of the monoclonal antibody S-60-18. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the light chain variable region of the monoclonal antibody S-60-18. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-18.

[0357] 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 sortilin epitope as S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region of the monoclonal antibody S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the light chain variable region of the monoclonal antibody S-60-19. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-19.

[0358] 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 sortilin epitope as S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region of the monoclonal antibody S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the light chain variable region of the monoclonal antibody S-60-24. In some embodiments, the anti-sortilin antibody is an isolated antibody that comprises the heavy chain variable region and the light chain variable region of the monoclonal antibody S-60-24.

[0359] 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 belong to the IgG class, IgM class, or IgA class. In some embodiments, the anti-sortilin antibodies of the present disclosure belong to the IgG class and have an IgG1, IgG2, IgG3, or IgG4 isotype.

[0360] The physical / chemical properties and / or biological activities of additional anti-sortilin antibodies, such as antibodies that specifically bind the sortilin of the present disclosure, can be identified, screened, and / or characterized by various assays known in the art.

[0361] Certain aspects of the present disclosure relate to the ...

Claims

1. Use of an anti-sortilin antibody in the preparation of a medicament for treating a disease or injury in an individual and / or delaying the progression of said disease or injury, wherein the anti-sortilin antibody is administered intravenously at a dose of at least about 30 mg / kg once every four weeks or more frequently, and wherein the antibody comprises: a heavy chain variable region comprising HVR-H1 as shown by the amino acid sequence YYSISSGYYWG (SEQ ID NO:1), HVR-H2 as shown by the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO:2), and HVR-H3 as shown by the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO:6); and a light chain variable region comprising HVR-L1 as shown by the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO:9), HVR-L2 as shown by the amino acid sequence LGSNRAS (SEQ ID NO:29), and HVR-L3 as shown by the amino acid sequence MQQQEAPLT (SEQ ID NO:32); and wherein the disease or injury is selected from the group consisting of amyotrophic lateral sclerosis and frontotemporal dementia.

2. The use according to claim 1, wherein the anti-sortilin antibody is administered at a dose of 60 mg / kg once every four weeks.

3. The use according to claim 1, wherein the antibody comprises: (i) a heavy chain variable region containing the amino acid sequence of SEQ ID NO:56 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

60.

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

5. The use according to claim 1, wherein the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO:90 or SEQ ID NO:91 and a light chain containing the amino acid sequence of SEQ ID NO:95.

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