Angiopoietin-associated protein 7-specific antibodies and uses thereof

Abstract

The present disclosure relates to the treatment and / or prevention of glaucoma and other diseases that affect optic nerve and retinal ganglion cells. Specifically, the present disclosure provides novel therapeutic antibodies and related compositions and methods that target angiopoietin-associated protein 7 (ANGPTL7) to reduce intraocular pressure (IOP), thereby preventing optic nerve injury and restoring vision.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 336,747, filed on April 29, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0003] Sequence Listing

[0004] The text of the computer-readable sequence listing submitted herewith, entitled "40185_601_SequenceListing," was created on March 30, 2023, has a file size of 410,410 bytes, and is hereby incorporated by reference in its entirety. Technical Field

[0005] Embodiments of the present disclosure relate to treating and / or preventing glaucoma and other diseases affecting the optic nerve and retinal ganglion cells. Specifically, the present disclosure provides novel therapeutic antibodies and related compositions and methods that target angiopoietin-related protein 7 (ANGPTL7) to reduce intraocular pressure (IOP), thereby preventing optic nerve damage and restoring vision. Background Art

[0006] Glaucoma is a group of optic neuropathy associated with characteristic structural changes at the optic nerve head, which may lead to loss of visual field and ultimately blindness. Blindness is most commonly defined as visual acuity of 20 / 200 or worse on the Snellen eye chart, or a visual field of less than 20 degrees. Legal blindness means that the better eye meets these criteria. By 2020, approximately 79.6 million people worldwide will have glaucoma, and more than 11 million people will be blind in both eyes due to glaucoma. More than 2 million Americans aged 40 and over have glaucoma, and studies of the U.S. population estimate that more than half of these cases may be undiagnosed or untreated. For black people and Hispanics, glaucoma is the leading cause of irreversible blindness. Glaucoma accounts for more than 25% of blindness cases in these groups, making it a more common cause of blindness than diabetic retinopathy (7.3% and 14.3% in blacks and Hispanics, respectively) and age-related macular degeneration (4.4% and 14.3% in blacks and Hispanics, respectively). Among Hispanics, glaucoma causes blindness more frequently than cataracts (28.6% vs. 14.3%). In 2009, Medicare beneficiaries spent $748 million on glaucoma-related visits, tests and surgeries. Patients who have glaucoma but are not yet blind may have functional limitations, resulting in the inability to drive and reduced reading ability.

[0007] The two most common forms of glaucoma are primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), with the former being approximately seven times more common than the latter in the United States and Europe. If POAG and PACG are left untreated, the typical disease course is chronic, progressive, and irreversible visual field loss, which may progress to tunnel vision and ultimately central vision loss. Treatments that reduce intraocular pressure have been shown to improve outcomes in randomized clinical trials. The angle of the eye is the junction between the iris and cornea where the trabecular meshwork drains aqueous humor from the anterior chamber of the eye. In POAG, the angle remains open because the trabecular meshwork is not blocked by iris tissue. Intraocular pressure is transmitted as mechanical stress to the axons of the retinal ganglion cells at the optic nerve, resulting in cell death. However, approximately 50% of glaucoma patients have intraocular pressure within the so-called "normal" range (10 mm to 21 mm Hg) at the time of diagnosis. Visual field loss will only occur on perimetry testing after 30% of the retinal ganglion cells have been lost. In PACG, the peripheral iris obstructs normal outflow of aqueous humor. This can lead to increased intraocular pressure and optic nerve damage. Eyes at risk for PACG are often shorter and have shallow anterior chambers. Patients with PACG may experience acute or subacute events that occur after a sudden increase in intraocular pressure or as a result of chronic PACG, which has an insidious onset and is mostly asymptomatic. Summary of the invention

[0008] Embodiments of the present disclosure include antibodies or antigen-binding fragments thereof that specifically bind to human angiopoietin-like protein 7 (ANGPTL7), optionally wherein the human ANGPTL7 is a polypeptide comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 370 to 374.

[0009] In some embodiments, the antibody or antigen-binding fragment thereof exhibits any one or more of the following functional characteristics: when administered to an eye of a subject, increases outflow facility compared to a control, optionally wherein the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein and isotype control antibody treatment; and / or increases the outflow facility compared to a control when administered to the eye of the subject; and / or increases the outflow facility compared to a control when administered to the eye of the subject; and / or increases the outflow facility compared to a control when administered to the subject; D Binds to ANGPTL7; and / or binds to the same epitope on ANGPTL7 as an antibody comprising the VH and VL sequences of any of the exemplary antibodies (sequences of which are provided in Table 11); and / or competes for binding to ANGPTL7 with an antibody comprising the VH and VL sequences of any of the exemplary antibodies (sequences of which are provided in Table 11).

[0010] In some embodiments, the antibody or antigen-binding fragment thereof is monoclonal, optionally recombinant. In some embodiments, the antibody or antigen-binding fragment thereof is human, humanized or chimeric.

[0011] In some embodiments, the antibody or antigen-binding fragment thereof is a full-length antibody, a single-chain antibody, a single-chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), Fab-C, Fab'-SH, (Fab')2, a single domain antibody (sdAb), a VHH antibody, a nanobody, a camel-derived single domain antibody, a shark IgNAR-derived single domain antibody fragment (VNAR), a diabody, a triabody, anticalin or an aptamer, optionally wherein the antibody is a full-length antibody comprising an Fc region (such as a human IgG1, IgG2, IgG3 or IgG4 region).

[0012] In some embodiments, the antibody or antigen-binding fragment thereof is conjugated to at least one other moiety, optionally selected from: an antigen-binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specifically binding to a target of non-human ANGPTL7, preferably wherein the target is expressed in the human eye; a therapeutic or cytotoxic moiety; a detection moiety; a purification moiety; a half-life extending moiety, optionally a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E and P residues, which is conjugated to the C-terminus or N-terminus of the antibody.

[0013] In some embodiments, the antibody or antigen-binding fragment thereof is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising one, two or all three corresponding LCDRs of an exemplary antibody; and / or a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising a VL sequence having at least 90% identity to the corresponding VL sequence of an exemplary antibody, preferably wherein variation in the HCDRs or LCDRs is not allowed; and / or all six CDRs of any one of the exemplary antibodies (whose sequences are provided in Table 11); and / or the VH and VL sequences of any one of the exemplary antibodies (whose sequences are provided in Table 11); and / or the full-length heavy chain (VH+constant) sequence of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising the corresponding full-length light chain (VL+constant) sequence of the exemplary antibodies.

[0014] Embodiments of the present disclosure also include polynucleotides encoding the antibodies or antigen-binding fragments thereof of any of the preceding paragraphs, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence that is at least 70%, 80%, 90% or 100% identical to the nucleic acid sequence of any of the exemplary antibodies (sequences of which are provided in Table 11).

[0015] Embodiments of the present disclosure also include an expression vector comprising the polynucleotide of the preceding paragraph, the vector optionally being an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

[0016] Embodiments of the present disclosure also include a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, a polynucleotide or a vector according to any of the preceding paragraphs, and optionally: at least one pharmaceutically acceptable carrier, diluent or preservative; and / or at least one other active ingredient. In some embodiments, the pharmaceutical composition is suitable for ocular administration to a subject, optionally by delivery using a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, an eye drop and / or an implant, preferably by injection into the vitreous humor.

[0017] Embodiments of the present disclosure also include antibodies or antigen-binding fragments thereof, polynucleotides, vectors or compositions of any of the foregoing paragraphs, which are used as medicines, optionally for treating methods of eye diseases in subjects. In some embodiments, the disease is characterized by increased intraocular pressure in the subject and / or decreased outflow smoothness of the eye. In some embodiments, the method includes ocular administration of antibodies, preferably by injection into the vitreous humor, and wherein the administration preferably alleviates at least one symptom selected from the following in the subject: eye pain, intraocular pressure, headache, rainbow-colored halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting and red eyes. In some embodiments, the disease is glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, optionally wherein the glaucoma is primary glaucoma or glucocorticoid-induced glaucoma.

[0018] Embodiments of the present disclosure include antibodies or antigen-binding fragments thereof directed against angiopoietin-like protein 7 (ANGPTL7) peptides, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X 1 YX 2 IX 3(SEQ ID NO: 1), wherein X 1 S or D; X 2 G or Y; X 3 is S or H; (b) TSGVGVG (SEQ ID NO: 18); (c) X 1 X 2 X 3 MX 4 (SEQ ID NO: 27), wherein X 1 V, S, D or T; X 2 is Y, H or F; X 3 D, G, S or A; X 4 is H, S or N; or (d) SX 1 SX 2 YW 3 (SEQ ID NO: 74), wherein X 1 S or G; X 2 S or Y; X 3 is G or S. In some embodiments, HCDR2 comprises one of the following amino acid sequences: (a) WIX 1 X 2 X 3 X 4 GX 5 TX 6 YQ 7 X 8 X 9 G (SEQ ID NO: 7), wherein X 1 S, I or N; X 2 A or P; X 3 Y or N; X 4 N or T; X 5 N or A; X 6 N or K; X 7 N or K; X 8 L or F; X 9 is R or Q; (b) LIYWNDDKX 1 YSPSLKS (SEQ ID NO: 21), wherein X 1 is R or Q; (c) X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X14 X 15 G (SEQ ID NO: 43), wherein X 1 is G, T, S, A, V, H or I; X 2 I or M; X 3 is D, N, T, S or G; X 4 is P, W, S, G or Y; X 5 is D, A, N, S or Y; X 6 G or S; X 7 is D, G, Y, S, I or N; X 8 is T, S, N, I, Y or D; X 9 is Y, T, F, M, K, G or I; X 10 is Y, G or F; X 11 P, Y or A; X 12 G, D or A; X 13 S or D; X 14 V, L or S; X 15 is K or M; or (d) X 1 IYYSGSTX 2 SNPSLKS (SEQ ID NO: 78), wherein X 1 S or Y; X 2 is Y or S. In some embodiments, HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 13-17; (b) X 1 X 2 X 3 X 4 X 5 X 6 FFDX 7 (SEQ ID NO: 24), wherein X 1 S, D or N; X 2 is Y or P; X 3 G or D; X 4 D or Y; X 5 is Y or G; X 6 W or D; X 7 is L or Y; (c) SEQ ID NO: 59-73; or (d) X 1 X 2 X 3 X 4 GX 5 X 6 X 7 X 8 X 9 Y (SEQ ID NO: 82), wherein X 1 Q or A; X 2 is Y or K; X3 I or W; X 4 S or E; X 5 is T or D; X 6 is E or Y; X 7 is Y or F; X 8 F or D; X 9 It is Q or Y.

[0019] According to the above embodiments, the LCDR1 of the anti-ANGPTL7 antibody of the present disclosure comprises the amino acid sequence of any one of SEQ ID NOs: 87-97, SEQ ID NOs: 123-127, or SEQ ID NOs: 141-149; LCDR2 comprises the amino acid sequence of any one of SEQ ID NOs: 99-109, SEQ ID NOs: 129-133, or SEQ ID NOs 151-159; and LCDR3 comprises the amino acid sequence of any one of SEQ ID NOs: 111-121, SEQ ID NOs: 135-139, or SEQ ID NOs: 161-169.

[0020] In some embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof against an ANGPTL7 peptide, the antibody or antigen-binding fragment thereof comprising a VH and a VL, the VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein LCDR1 comprises one of the following amino acid sequences: (a) RASQX 1 IX 2 X 3 X 4 LX 5 (SEQ ID NO: 86), wherein X 1 G or S; X 2 S, R or Y; X 3 S, N or I; X 4 W, D or Y; X 5 A, G or N; (b)RSSQSLX 1 X 2 SX 3 X 4 X 5 X 6 YXX 7 (SEQ ID NO: 122), wherein X 1 L or V; X 2 H, Y or F; X 3 N or D; X 4 R or G; X 5 Y or N; X 6 N or T; X7 is D or N; or (c)RASQSVSX 1 X 2 X 3 X 4 A (SEQ ID NO: 140), wherein X 1 S, N or R; X 2 Y or S; X 3 L or Y; X 4 is A or L. In some embodiments, LCDR2 comprises one of the following amino acid sequences: (a) AX 1 SSLX 2 S (SEQ ID NO: 98), wherein X 1 A or T; X 2 is Q or P; (b) X 1 X 2 SNRX 3 S (SEQ ID NO: 128), wherein X 1 L, K or E; X 2 G or V; X 3 is A or D; or (c) X 1 ASX 2 RAT (SEQ ID NO: 150), wherein X 1 D or G; X 2 is N, S or T. In some embodiments, LCDR3 comprises one of the following amino acid sequences: (a) X 1 QX 2 X 3 X 4 X 5 PX 6 X 7 (SEQ ID NO: 110), wherein X 1 L or Q; X 2 A, H, S or D; X 3 N, F or Y; X 4 S, T or N; X 5 F, Y or T; X 6 W, L, I, P or Y; X 7 is T or Y; (b) MQX 1 X 2 X 3 X 4 PX 5 T (SEQ ID NO: 134), wherein X 1 T or G; X 2 L or T; X 3 Q or H; X 4 is T or W; X 5is Y or W; or (c) QQX 1 X 2 X 3 X 4 X 5 X 6 T (SEQ ID NO: 160), wherein X 1 R, Y or G; X 2 S, G or Q; X 3 N, S or V; X 4 W, S or I; X 5 P or L; X 6 It is L, S, P or T.

[0021] According to the above embodiments, the HCDR1 of the anti-ANGPTL7 antibodies of the present disclosure comprises the amino acid sequence of any one of SEQ ID NOs: 2-6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42, or SEQ ID NOs: 75-77; the HCDR2 comprises the amino acid sequence of any one of SEQ ID NOs: 8-12, SEQ ID NOs: 22-23, SEQ ID NOs 44-58, or SEQ ID NOs: 79-81; and the HCDR3 comprises the amino acid sequence of any one of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73, or SEQ ID NOs: 83-85.

[0022] In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:2; HCDR2 comprises the amino acid sequence of SEQ ID NO:8; and HCDR3 comprises the amino acid sequence of SEQ ID NO:13. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:9; and HCDR3 comprises the amino acid sequence of SEQ ID NO:14. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:4; HCDR2 comprises the amino acid sequence of SEQ ID NO:10; and HCDR3 comprises the amino acid sequence of SEQ ID NO:15. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:5; HCDR2 comprises the amino acid sequence of SEQ ID NO:11; and HCDR3 comprises the amino acid sequence of SEQ ID NO:16. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:6; HCDR2 comprises the amino acid sequence of SEQ ID NO:12; and HCDR3 comprises the amino acid sequence of SEQ ID NO:17. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:7; HCDR2 comprises the amino acid sequence of SEQ ID NO:14; and HCDR3 comprises the amino acid sequence of SEQ ID NO:20. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:19; HCDR2 comprises the amino acid sequence of SEQ ID NO:22; and HCDR3 comprises the amino acid sequence of SEQ ID NO:25. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:20; HCDR2 comprises the amino acid sequence of SEQ ID NO:23; and HCDR3 comprises the amino acid sequence of SEQ ID NO:26. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:28; HCDR2 comprises the amino acid sequence of SEQ ID NO:44; and HCDR3 comprises the amino acid sequence of SEQ ID NO:59. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:29; HCDR2 comprises the amino acid sequence of SEQ ID NO:45; and HCDR3 comprises the amino acid sequence of SEQ ID NO:60. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:30; HCDR2 comprises the amino acid sequence of SEQ ID NO:46; and HCDR3 comprises the amino acid sequence of SEQ ID NO:61.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:31; HCDR2 comprises the amino acid sequence of SEQ ID NO:47; and HCDR3 comprises the amino acid sequence of SEQ ID NO:62. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:32; HCDR2 comprises the amino acid sequence of SEQ ID NO:48; and HCDR3 comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:33; HCDR2 comprises the amino acid sequence of SEQ ID NO:49; and HCDR3 comprises the amino acid sequence of SEQ ID NO:64. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:34; HCDR2 comprises the amino acid sequence of SEQ ID NO:50; and HCDR3 comprises the amino acid sequence of SEQ ID NO:65. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:35; HCDR2 comprises the amino acid sequence of SEQ ID NO:51; and HCDR3 comprises the amino acid sequence of SEQ ID NO:66. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:36; HCDR2 comprises the amino acid sequence of SEQ ID NO:52; and HCDR3 comprises the amino acid sequence of SEQ ID NO:67. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:37; HCDR2 comprises the amino acid sequence of SEQ ID NO:53; and HCDR3 comprises the amino acid sequence of SEQ ID NO:68. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:38; HCDR2 comprises the amino acid sequence of SEQ ID NO:54; and HCDR3 comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:39; HCDR2 comprises the amino acid sequence of SEQ ID NO:55; and HCDR3 comprises the amino acid sequence of SEQ ID NO:70. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:40; HCDR2 comprises the amino acid sequence of SEQ ID NO:56; and HCDR3 comprises the amino acid sequence of SEQ ID NO:71. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:41; HCDR2 comprises the amino acid sequence of SEQ ID NO:57; and HCDR3 comprises the amino acid sequence of SEQ ID NO:72.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:42; HCDR2 comprises the amino acid sequence of SEQ ID NO:58; and HCDR3 comprises the amino acid sequence of SEQ ID NO:73. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:75; HCDR2 comprises the amino acid sequence of SEQ ID NO:79; and HCDR3 comprises the amino acid sequence of SEQ ID NO:83. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:76; HCDR2 comprises the amino acid sequence of SEQ ID NO:80; and HCDR3 comprises the amino acid sequence of SEQ ID NO:84. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO:77; HCDR2 comprises the amino acid sequence of SEQ ID NO:81; and HCDR3 comprises the amino acid sequence of SEQ ID NO:85. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:87; LCDR2 comprises the amino acid sequence of SEQ ID NO:99; and LCDR3 comprises the amino acid sequence of SEQ ID NO:111. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:88; LCDR2 comprises the amino acid sequence of SEQ ID NO:100; and LCDR3 comprises the amino acid sequence of SEQ ID NO:112. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:89; LCDR2 comprises the amino acid sequence of SEQ ID NO:101; and LCDR3 comprises the amino acid sequence of SEQ ID NO:113. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:90; LCDR2 comprises the amino acid sequence of SEQ ID NO:102; and LCDR3 comprises the amino acid sequence of SEQ ID NO:114. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:91; LCDR2 comprises the amino acid sequence of SEQ ID NO:103; and LCDR3 comprises the amino acid sequence of SEQ ID NO:115. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:92; LCDR2 comprises the amino acid sequence of SEQ ID NO:104; and LCDR3 comprises the amino acid sequence of SEQ ID NO:116. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:93; LCDR2 comprises the amino acid sequence of SEQ ID NO:105; and LCDR3 comprises the amino acid sequence of SEQ ID NO:117.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:94; LCDR2 comprises the amino acid sequence of SEQ ID NO:106; and LCDR3 comprises the amino acid sequence of SEQ ID NO:118. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:95; LCDR2 comprises the amino acid sequence of SEQ ID NO:107; and LCDR3 comprises the amino acid sequence of SEQ ID NO:119. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:96; LCDR2 comprises the amino acid sequence of SEQ ID NO:108; and LCDR3 comprises the amino acid sequence of SEQ ID NO:120. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:97; LCDR2 comprises the amino acid sequence of SEQ ID NO:109; and LCDR3 comprises the amino acid sequence of SEQ ID NO:121. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:123; LCDR2 comprises the amino acid sequence of SEQ ID NO:129; and LCDR3 comprises the amino acid sequence of SEQ ID NO:135. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 124; LCDR2 comprises the amino acid sequence of SEQ ID NO: 130; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 125; LCDR2 comprises the amino acid sequence of SEQ ID NO: 131; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 126; LCDR2 comprises the amino acid sequence of SEQ ID NO: 132; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 127; LCDR2 comprises the amino acid sequence of SEQ ID NO: 133; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO:141; LCDR2 comprises the amino acid sequence of SEQ ID NO:151; and LCDR3 comprises the amino acid sequence of SEQ ID NO:161.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 142; LCDR2 comprises the amino acid sequence of SEQ ID NO: 152; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 162. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 143; LCDR2 comprises the amino acid sequence of SEQ ID NO: 153; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 163. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 144; LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 145; LCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; LCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 148; LCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 149; LCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 169.

[0023] In some embodiments, the VH of the anti-ANGPTL7 antibodies of the present disclosure comprises an amino acid sequence having at least 90% identity to any of the following: (a) SEQ ID NOs: 170-174; (b) SEQ ID NOs: 190-191; (c) SEQ ID NOs: 198-212 or (d) SEQ ID NOs: 258-260. In some embodiments, the VL of the anti-ANGPTL7 antibodies of the present disclosure comprises an amino acid sequence having at least 90% identity to any of the following: (a) SEQ ID NOs: 180-184; (b) SEQ ID NOs: 194-195; (c) SEQ ID NOs: 228-242 or (d) SEQ ID NOs: 264-266. In some embodiments, the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 170, and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 180. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 171, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 181. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 172, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 182. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 173, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 183. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 174, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 184. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 190, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 194. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 191, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 195. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 198, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 228. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 199, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 229.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 200, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 230. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 201, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 231. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 202, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 232. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 203, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 233. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 204, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 234. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 205, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 235. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 206, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 236. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 207, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 237. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 208, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 238. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 209, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 239. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 210, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 240. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 211, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 241.In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 212, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 242. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 258, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 264. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 259, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 265. In some embodiments, the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 260, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 266.

[0024] According to the above embodiments, the present disclosure provides anti-ANGPTL7 antibodies comprising various functional features. In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase the outflow smoothness compared to a control. In some embodiments, the control is selected from the group consisting of: vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and ANGPTL7 protein and isotype control antibody treatment. In some embodiments, the anti-ANGPTL7 antibody comprises: (a) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 210, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 240; (b) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 200, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 230; (c) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 258, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 264; (d) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 207, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 237; (e) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 204, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:234 ​​having at least 90% identity; (f) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:260, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:266; (g) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:205, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:235; (h) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:206, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:236; (i) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:208, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:238; (j) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:191, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO: 195 has a VL with an amino acid sequence that is at least 90% identical;(k) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 203, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 233; (l) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 212, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 242; (m) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 198, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 228; (n) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 190, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 194; (o) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 202, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 232; (p) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 198; ID NO: 211 having at least 90% identity to a VH, and a VL comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 241; or (q) a VH comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 199, and a VL comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 229. ;

[0025] In some embodiments, the anti-ANGPTL7 antibody comprises: (a) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 210, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 240; (b) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 200, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 230; or (c) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 258, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 264.

[0026] In some embodiments, the anti-ANGPTL7 antibody comprises: (a) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 207, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 237; (b) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 204, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 234; (c) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 260, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 266; (d) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 205, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 235; (e) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 206, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:236 having at least 90% identity; (f) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:208, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:238; (g) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:191, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:195; (h) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:203, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:233; (i) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:212, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:242; (j) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:198, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:228 having a VL with an amino acid sequence at least 90% identical to; or (k) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:190, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:194.

[0027] In some embodiments, the anti-ANGPTL7 antibody comprises: (a) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 202, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 232; (b) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 211, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 241; or (c) a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO: 199, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO: 229.

[0028] According to the above embodiments, the anti-ANGPTL7 antibodies of the present disclosure may be monoclonal antibodies, human antibodies, humanized antibodies and / or chimeric antibodies. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab′-SH, Fv, scFv and (Fab′) 2 In some embodiments, the anti-ANGPTL7 antibody is a monospecific antibody. In some embodiments, the anti-ANGPTL7 antibody is a bispecific antibody. In some embodiments, the anti-ANGPTL7 antibody comprises two or more single domain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0029] In some embodiments, the antibody comprises a detection portion. In some embodiments, the antibody comprises a purification portion. In some embodiments, the antibody comprises a half-life extension portion. In some embodiments, the half-life extension portion comprises a polypeptide having a length of at least 20 amino acids and comprising any combination of G, A, ST, E and P residues. In some embodiments, the half-life extension polypeptide is attached to the C-terminus or N-terminus of the antibody.

[0030] The anti-ANGPTL7 antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat eye diseases (e.g., glaucoma and / or diseases affecting the optic nerve or retinal ganglion cells). In some embodiments, the composition is suitable for ocular administration. In some embodiments, ocular administration comprises injection into the vitreous humor. In some embodiments, ocular administration comprises delivering the antibody using conjunctival inserts, contact lenses, gels, nanoparticles, mucoadhesive polymers, ointments, solutions, suspensions, eye drops, and / or implants.

[0031] Embodiments of the present disclosure also include methods for treating glaucoma and / or diseases affecting the optic nerve and / or retinal ganglion cells. According to these embodiments, the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the pharmaceutical composition is ocularly administered and treats at least one symptom associated with glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells. In some embodiments, at least one symptom associated with glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells comprises: eye pain, intraocular pressure, headache, the appearance of rainbow-colored halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes. In some embodiments, administering the pharmaceutical composition reduces intraocular pressure and / or increases outflow smoothness in the subject's eye. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

[0032] Embodiments of the present disclosure also include polynucleotides encoding any of the anti-ANGPTL7 antibodies of the present disclosure. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity to any one of the following nucleic acid sequences: (a) SEQ ID NO: 175-179; (b) SEQ ID NO: 192-193; (c) SEQ ID NO: 213-227 or (d) SEQ ID NO: 261-263. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity to any one of the following nucleic acid sequences: (a) SEQ ID NO: 185-189; (b) SEQ ID NO: 196-197; (c) SEQ ID NO: 243-257 or (d) SEQ ID NO: 267-269.

[0033] In some embodiments, the polynucleotides encoding the anti-ANGPTL7 antibodies of the present disclosure comprise: (a) a nucleic acid sequence at least 70% identical to SEQ ID NO: 175 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 185; (b) a nucleic acid sequence at least 70% identical to SEQ ID NO: 176 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 186; (c) a nucleic acid sequence at least 70% identical to SEQ ID NO: 177 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 187; (d) a nucleic acid sequence at least 70% identical to SEQ ID NO: 178 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 188; or (e) a nucleic acid sequence at least 70% identical to SEQ ID NO: 179 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 189.

[0034] In some embodiments, the polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure comprises: (a) a nucleic acid sequence at least 70% identical to SEQ ID NO: 192 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 196 or (b) a nucleic acid sequence at least 70% identical to SEQ ID NO: 193 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 197.

[0035] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises: (a) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 213 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: 243; (b) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 214 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: 244; (c) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 215 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: 245; (d) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 216 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: 246; (e) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 217 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: 247; (f) a nucleic acid sequence having at least 70% identity to SEQ ID NO: 218 and a nucleic acid sequence having at least 70% identity to SEQ ID NO: NO:248 has at least 70% identity; (g) a nucleic acid sequence having at least 70% identity with SEQ ID NO:219 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:249; (h) a nucleic acid sequence having at least 70% identity with SEQ ID NO:220 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:250; (i) a nucleic acid sequence having at least 70% identity with SEQ ID NO:221 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:251; (j) a nucleic acid sequence having at least 70% identity with SEQ ID NO:222 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:252; or (k) a nucleic acid sequence having at least 70% identity with SEQ ID NO:223 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:253; (l) a nucleic acid sequence having at least 70% identity with SEQ ID NO:224 and a nucleic acid sequence having at least 70% identity with SEQ ID NO:225. NO:254 has a nucleic acid sequence that is at least 70% identical to it; (m) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:225 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:255; (n) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:226 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:256; or (o) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:227 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:257.

[0036] In some embodiments, the polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure comprises: (a) a nucleic acid sequence at least 70% identical to SEQ ID NO: 261 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 267; (b) a nucleic acid sequence at least 70% identical to SEQ ID NO: 262 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 268 or (c) a nucleic acid sequence at least 70% identical to SEQ ID NO: 263 and a nucleic acid sequence at least 70% identical to SEQ ID NO: 269.

[0037] According to these embodiments, the present disclosure includes expression vectors comprising any polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the expression vector is suitable for manufacturing an anti-ANGPTL7 antibody of the present disclosure to deliver the antibody to a subject. In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure to a subject). In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or comprises an AAV backbone. In some embodiments, the expression vector is a lentiviral vector (LV) or comprises an LV backbone. In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector.

[0038] According to these embodiments, the present disclosure also provides a method of administering an ocular gene therapy to a subject in need thereof, the method comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). According to these embodiments, the present disclosure also provides a method of treating glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, the method comprising administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). In some embodiments, administration of the pharmaceutical composition treats at least one symptom of glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells.

[0039] According to the above embodiments, the anti-ANGPTL7 antibodies of the present disclosure bind to an epitope of an ANGPTL7 polypeptide having any amino acid sequence of SEQ ID NO: 370-374 or a variant thereof. In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure bind to an epitope of an ANGPTL7 polypeptide having any amino acid sequence of SEQ ID NO: 370-374 or a variant thereof with a K of about 100 nM or less. D Binds to an epitope of an ANGPTL7 polypeptide. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1: Representative data showing ANGTPL7 gene expression levels relative to controls after 5 days of treatment with dexamethasone.

[0041] Figure 2 : Representative data of treatment-induced gene changes in human TM and SC cells after 3 days of ANGPTL7 (50 mg / ml) treatment using an RNAseq panel.

[0042] FIG3A-3C: Representative schematics of 3D-HTM scaffold technology (Glauconix) used as an ex vivo human eye tissue model to evaluate the effect of ANGPTL7 on outflow fluency ( FIG3A ). FIG3B includes representative data showing outflow fluency of 3D-HTM donor 2 treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=4 per treatment group. FIG3C includes representative data showing outflow fluency of 3D-HTM donor 3 treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P < 0.05, **P < .0.01, ***P < .001, N = 4 per treatment group.

[0043] FIG4A-4C: FIG4A includes representative data showing the outflow fluency of donor 1 treated with vehicle (DMSO), 500 nM dexamethasone, or 25, 50, 150 ng / mL of ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=3 per treatment group. FIG4B includes representative data showing the outflow fluency of donor 2 treated with vehicle (DMSO), 500 nM dexamethasone, or 25, 50, 150 ng / mL of ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=3 per treatment group. FIG4C includes representative data showing the outflow smoothness of donor 3 treated with vehicle (DMSO), 500 nM dexamethasone, or 25, 50, 150 ng / mL of ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=3 per treatment group. (See FIG3A for a schematic diagram of the 3D-HTM scaffold technology used to generate the data in FIG4A to FIG4C.)

[0044] FIG. 5A to FIG. 5D : Representative ELISA results for determining antigen-positive serum titers of mice immunized with ANGPTL7 according to four different immunization schedules / cohorts ( FIG. 5A - Cohort 1 ; FIG. 5B - Cohort 2; FIG. 5C - Cohort 3; FIG. 5D - Cohort 4).

[0045] Figures 6A to 6I: Representative results of ANGPTL7 antibody cross-blocking experiments, including data from a representative heatmap analyzing the ability of antibodies to block each other's binding to the antigen (Figure 6A), and a dendrogram that progressively groups antibodies with similar competitive characteristics. Figure 6B includes data from a granular binning network. Figure 6C: includes data from a combined binary dendrogram (colors represent bins in a community binning network). Figure 6D includes data from a community binning network. Figure 6E includes binned data based on affinity for huANGPTL7-his (P62). Figure 6F includes binned data based on antibody source (hybridoma or phage). Figure 6G includes binned data based on fibrinogen domain (P60P) binding. Figure 6H includes binned data based on rabbit ANGPTL7 (p66) binding. Figure 6I includes binned data based on mouse ANGPTL7 binding.

[0046] Figure 7 : Representative results of the effect of anti-ANGPTL7 antibodies on conventional outflow fluency using the 3D HTM / HSC tissue model (see FIG3A ). Outflow fluency of one donor cell line treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7 alone (1.1 nM), 50 ng ANGPTL7 + isotype control antibody (330) at 11.1 nM, and twenty different anti-ANGPTL7 antibodies with 50 ng / mL ANGPTL7 at 11.1 nM. The effect of samples on isotype control (330) was analyzed using a one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001, ****P<.0001 N=3 per treatment group.

[0047] Figures 8A to 8C: Representative data for the effects of dexamethasone-induced ocular hypertension in ANGPTL7 knockout mice. Figure 8A includes weight data for mice after implantation surgery; dexamethasone impaired weight gain in male mice compared to mice treated with PBS, confirming the normal function of the dexamethasone osmotic pump. Figure 8B includes intraocular pressure (IOP) data for ANGPTL7 WT and ANGPTL7 KO mice dosed with PBS control or dexamethasone (4 mg / kg / day); osmotic pumps were implanted on day 0. Figure 8C includes representative data for changes in IOP over 28 days for ANGPTL7 WT and ANGPTL7 KO mice implanted with osmotic pumps containing PBS vehicle or dexamethasone (4 mg / kg / day). All IOP values ​​were normalized to baseline (day 0) readings.

[0048] Figures 9A-9R: Representative data demonstrating in vivo tolerability of anti-ANGPTL7 antibodies using a single intravitreal (IVT) injection in New Zealand white rabbits. The indicated anti-ANGPTL7 antibodies were injected into the right eye (OD) at a 0.5 mg dose (Figure 9C, Figure 9D, Figure 9G, Figure 9H, Figure 9K, Figure 9L, Figure 9O, Figure 9P) or a 2.0 mg dose (Figure 9E, Figure 9F, Figure 9I, Figure 9J, Figure 9M, Figure 9N, Figure 9Q, Figure 9R), or injected into the left eye (OS) with the corresponding vehicle dose. (Figures 9A and 9B include data from a 2 mg dose control). Intraocular pressure (IOP) measurements ( FIG. 9A , FIG. 9C , FIG. 9E , FIG. 9G , FIG. 9I , FIG. 9K , FIG. 9M , FIG. 9O , FIG. 9Q ) and IOP changes ( FIG. 9B , FIG. 9D , FIG. 9F , FIG. 9H , FIG. 9J , FIG. 9L , FIG. 9N , FIG. 9P , FIG. 9R ) were collected at designated time points over a 21-day period.

[0049] Figures 10A-10C: Representative pharmacokinetic (PK) data for the ANGPTL7 antibody ATX-P-424, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle (Figure 10A); IOP change compared to baseline (Figure 10B); and total ocular examination score (OE) (Figure 10C).

[0050] Figures 11A-11C: Representative pharmacokinetic (PK) data for the ANGPTL7 antibody ATX-P-439, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle (Figure 11A); IOP change compared to baseline (Figure 11B); and total ocular examination score (OE) (Figure 11C).

[0051] Figures 12A-12C: Representative pharmacokinetic (PK) data for the ANGPTL7 antibody ATX-P-448, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle (Figure 12A); IOP change compared to baseline (Figure 12B); and total ocular examination score (OE) (Figure 12C).

[0052] Figures 13A to 13: Representative data demonstrating in vivo tolerability of anti-ANGPTL7 antibodies using a single intravitreal (IVT) injection in African green monkeys. Data include absolute IOP values ​​at baseline (Day 3) and Day 10, 6 hours after topical application of saline and latanoprost (Latanoprost) (Figure 13A); IOP change 6 hours after topical application of saline (Day 3) or latanoprost (Day 10) (Figure 13B); and IOP change between vehicle and latanoprost administration (Figure 13C).

[0053] Figures 14A-14H: Representative IOP measurements (Figures 14A, 14C, 14E, and 14G) and IOP changes (Figures 14B, 14D, 14F, and 14H) in African green monkeys dosed with 2 mg of the indicated anti-ANGPTL7 antibodies compared to isotype control (BTX-330) and a single vehicle eye.

[0054] Fig.15 : Representative clinical scores of ocular examination (OE) for all dosing groups in Figures 14A to 14H. DETAILED DESCRIPTION

[0055] Embodiments of the present disclosure relate to treating and / or preventing glaucoma and other eye diseases that affect the optic nerve and retinal ganglion cells. Specifically, the present disclosure provides novel therapeutic antibodies targeting angiopoietin-related protein 7 (ANGPTL7) as a means for reducing intraocular pressure (IOP) and / or increasing outflow smoothness, thereby preventing optic nerve damage and / or restoring vision.

[0056] Angiopoietin-like proteins (ANGPTLs) are a family of proteins with structural similarities to angiopoietin proteins. Seven proteins were originally classified into this family (ANGPTL1-7), and another protein named ANGPTL8 has recently been identified. ANGPTL proteins have an amino-terminal coiled-coil domain and a carboxyl-terminal fibrinogen-like domain, except for ANGPTL8, which lacks the latter domain. ANGPTL proteins are known not to bind to tyrosine kinase receptors (such as Tie 1 and Tie 2), which distinguishes ANGPTL proteins from angiopoietin proteins. ANGPTL proteins have been shown to play different physiological roles in metabolism, inflammation, and cancer. There is increasing evidence that these proteins are associated with obesity and insulin resistance. For example, ANGPTL2 has been shown to be associated with excess fat and insulin resistance and the development of type 2 diabetes. ANGPTL3, 4, and 8 have been shown to play an important role in regulating lipid metabolism through their inhibition of lipoprotein lipase. Similarly, ANGPTL6 has been shown to be higher in subjects with metabolic syndrome and is positively correlated with HDL levels. ANGPTL8 levels have been shown to be higher in obese and diabetic subjects and positively correlated with insulin resistance and fasting glucose in non-diabetic subjects.

[0057] However, ANGPTL7 is a less studied member of the ANGPTL protein family, which was originally discovered in the corneal stroma. ANGPTL7 levels have been shown to be elevated in glaucoma, and overexpression of ANGPTL7 increases collagen expression levels, while induction of ANGPTL7 by glucocorticoids causes upregulation of important glaucoma-related proteins, including fibronectin, myocilin, and MMP1. These data suggest that ANGPTL7 coordinates the extracellular matrix of the trabecular meshwork and its response to steroids. In addition, ANGPTL7 is potentially associated with various cancers through its interaction with the WNT / -β-catenin signaling pathway. Currently, there are no therapeutic approaches targeting ANGPTL7.

[0058] Glaucoma is the leading cause of irreversible vision loss worldwide, characterized by progressive optic neuropathy. The most common form of glaucoma is primary open-angle glaucoma (POAG), which is often accompanied by high intraocular pressure (IOP) (a key risk factor for the pathogenesis of POAG). In some cases, long-term use of dexamethasone (DEX) causes a high risk of elevated IOP and leads to secondary glaucoma, which has many common features with POAG. The pathogenesis of POAG can be inferred from the mechanism of DEX-induced ocular hypertension. Understanding the molecular mechanism of DEX induction may help develop therapies for glucocorticoid-induced glaucoma and POAG. In addition, high IOP is caused by increased outflow resistance of aqueous humor (AH). Increasing evidence shows that the rearrangement of the actin cytoskeleton of the trabecular meshwork (TM) to form a cross-linked actin network is a key factor leading to this increased resistance. Previous studies have found that the concentration of angiopoietin-like 7 (ANGPTL7) is increased in glaucomatous AH, and overexpression of ANGPTL7 in TM alters the components of the extracellular matrix (ECM). Recent studies have found that variants with altered ANGPTL7 protein have a strong protective effect against glaucoma and suggest ANGPTL7 as a therapeutic target for glaucoma. Therefore, ANGPTL7 may play an important role in regulating the ECM of TM and regulating IOP.

[0059] In light of this, experiments were conducted to determine the role that ANGPTL7 may play in the etiology of glaucoma and other related diseases affecting the optic nerve and retinal ganglion cells, and in parallel to develop a therapeutic platform based on modulation of ANGPTL7 activity using anti-ANGPTL7 antibodies.

[0060] definition

[0061] To facilitate understanding of the present technology, various terms and phrases are defined below. Additional definitions are set forth throughout the detailed description.

[0062] Unless otherwise specified herein or obviously contradictory with context, otherwise the use of the terms "one / kind" and "described" and "at least one / kind" and similar indicators in the context of the embodiments of the present disclosure (especially in the context of the following claims) should be interpreted as including both singular and plural. Unless otherwise specified herein or obviously contradictory with context, the use of the term "at least one / kind" followed by a list of one or more items (such as "at least one of A and B") should be interpreted as meaning an item (A or B) selected from the listed items or any combination (A and B) of two or more of the listed items. Unless otherwise specified, the terms "comprising", "having", "including" and "containing" should be interpreted as open terms (that is, meaning "including but not limited to"). Unless otherwise specified herein, the enumeration of the value range herein is only intended to be used as a shorthand method for individually referring to each individual value falling within the scope, and each individual value is incorporated into this specification as if individually listed herein. Unless otherwise specified herein or obviously contradictory with context, all methods described herein can be carried out in any suitable order. Unless otherwise required, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the various embodiments of the present disclosure and does not impose limitations on the scope of these embodiments. Language in this specification should not be construed as indicating any non-claimed element as essential to the practice of the various embodiments of the present disclosure.

[0063] As used herein, the term "or" is an inclusive "or" operator and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a / an" and "the" include plural references. The meaning of "in..." includes "in..." and "on...".

[0064] The transition phrase "consisting essentially of" as used in the claims of this application limits the scope of the claim to the specified materials or steps "and those materials or steps that do not materially affect the basic and novel characteristics of the claimed invention," as discussed in In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For example, a composition "consisting essentially of the recited elements" may contain a level of unrecited contaminants such that the contaminants, while present, do not alter the function of the recited composition as compared to the pure composition (i.e., a composition "consisting of the recited components").

[0065] As used herein, the term "one or more" refers to a number greater than one. For example, the term "one or more" encompasses any of two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, twenty or more, fifty or more, 100 or more, or an even larger number.

[0066] The terms "one or more but less than a higher number", "two or more but less than a higher number", "three or more but less than a higher number", "four or more but less than a higher number", "five or more but less than a higher number", "six or more but less than a higher number", "seven or more but less than a higher number", "eight or more but less than a higher number", "nine or more but less than a higher number", "ten or more but less than a higher number", "eleven or more but less than a higher number", "twelve or more but less than a higher number", "thirteen or more but less than a higher number", "fourteen or more but less than a higher number" or "fifteen or more but less than a higher number" are not limited to higher numbers. For example, the higher number may be 10,000, 1,000, 100, 50, etc. For example, the higher number can be about 50 (e.g., 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 32, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2).

[0067] As used herein, the term "immunoglobulin" or "antibody" refers to a protein found in the blood or other body fluids of vertebrates that is used by the immune system to identify and neutralize foreign substances, such as bacteria and viruses. Typically, an immunoglobulin or antibody is a protein that contains at least one complementary determining region (CDR). The CDRs form the "hypervariable region" of the antibody that is responsible for antigen binding (discussed further below). A complete antibody is typically composed of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V H ) region and three C-terminal constant (C H1 , C H2 and C H3 ) region, and each light chain contains an N-terminal variable (V L) region and a C-terminal constant (C L ) region. The light chain of an antibody can be assigned to one of two different types, kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain. In a typical antibody, each light chain is linked to a heavy chain by a disulfide bond, and the two heavy chains are linked to each other by disulfide bonds. The light chain variable region is aligned with the heavy chain variable region, and the light chain constant region is aligned with the first constant region of the heavy chain. The remaining constant regions of the heavy chains are aligned with each other.

[0068] The variable regions of each pair of light and heavy chains form the antibody's antigen-binding site. VH and VL The regions have the same overall structure, each region comprising four framework (FW or FR) regions. As used herein, the term "framework region" refers to a relatively conserved amino acid sequence located between the CDRs within the variable region. Each variable domain has four framework regions, which are designated as FR1, FR2, FR3, and FR4. The framework regions form a beta sheet that provides a structural framework for the variable region (see, e.g., CA Janeway et al. (eds.), Immunobiology, 5th edition, Garland Publishing, New York, NY (2001)).

[0069] The framework regions are connected by three CDRs. As discussed above, three CDRs (called CDR1, CDR2 and CDR3) form the "hypervariable region" of the antibody responsible for antigen binding. The CDRs form loops that connect, and in some cases constitute a portion of, the β-sheet structure formed by the framework regions. Although the constant regions of the light and heavy chains are not directly involved in the binding of the antibody to the antigen, the constant regions can affect the orientation of the variable regions. The constant regions also exhibit various effector functions, such as participating in antibody-dependent complement-mediated lysis or antibody-dependent cellular toxicity via interactions with effector molecules and cells.

[0070] As used herein, when an antibody or other entity (e.g., an antigen binding domain) "specifically recognizes" or "specifically binds" an antigen or epitope, the antibody or other entity preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules, and binds to the antigen or epitope with significantly higher affinity than other entities that do not display the antigen or epitope. In this regard, "significantly higher affinity" means that the affinity is high enough to enable the use of a desired assay or measurement device to detect an antigen or epitope different from the entity. Generally, it means that the binding affinity has at least 10 7 M -1 (e.g., >10 7 M -1 、>10 8 M -1、>10 9 M -1 、>10 10 M -1 、>10 11 M -1 、>10 12 M -1 、>10 13 M -1 The binding constant (K a ). In certain such embodiments, the antibody is capable of binding to different antigens as long as the different antigens contain the particular epitope. For example, in some cases, homologous proteins from different species may contain the same epitope.

[0071] The terms "antibody fragment", "antibody fragment" and "antigen-binding fragment" of an antibody are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (see generally, Holliger et al., Nat. Biotech., 23(9): 1126-1129 (2005)). Any antigen-binding fragment of an antibody described herein is within the scope of the present disclosure. Antibody fragments desirably include, for example, one or more CDRs, a variable region (or a portion thereof), a constant region (or a portion thereof), or a combination thereof. Examples of antibody fragments include, but are not limited to: (i) a Fab fragment, which is a fragment consisting of a V L 、V H , C L and C H1 (ii) F(ab')2 fragment, which is a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge at the hinge region, and (iii) Fv fragment, which is composed of the V domain of a single antibody arm. L and V H domain composition, (iv) Fab' fragments, which are caused by cleavage of disulfide bridges of F(ab')2 fragments using mild reducing conditions, (v) disulfide-stabilized Fv fragments (dsFv), and (vi) domain antibodies (dAbs), which are antibody single variable domains (V H or V L ) polypeptide.

[0072] As used herein, the term "monoclonal antibody" refers to an antibody directed against a single epitope on an antigen produced by a single clone of B lymphocytes. Monoclonal antibodies are typically produced using hybridoma technology, such as in and Milstein, Eur. J. Immunol., 5: 511-519 (1976). Monoclonal antibodies can also be produced using recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), isolated from phage display antibody libraries (see, e.g., Clackson et al. Nature, 352: 624-628 (1991)); and Marks et al., J. Mol. Biol., 222: 581-597 (1991)) or produced by transgenic mice carrying a full human immunoglobulin system (see, e.g., Lonberg, Nat. Biotechnol., 23 (9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)). In contrast, "polyclonal" antibodies are antibodies secreted by different B cell lineages in an animal. Polyclonal antibodies are collections of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0073] The terms "nucleic acid", "polynucleotide", "nucleotide sequence" and "oligonucleotide" are used interchangeably herein and refer to polymers or oligomers of pyrimidine and / or purine bases, preferably cytosine, thymine and uracil, and adenine and guanine, respectively (see Albert L. Lehninger, Principles of Biochemistry, pp. 793-800 (Worth Pub. 1982)). The term encompasses any deoxyribonucleotide, ribonucleotide or peptide nucleic acid component and any chemical variant thereof, such as methylated, hydroxymethylated or glycosylated forms of these bases. The polymer or oligomer may be heterogeneous or homogeneous in composition, may be isolated from a naturally occurring source, or may be artificially or synthetically produced. In addition, the nucleic acid may be DNA or RNA or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplexes, heteroduplexes and hybrid states. In some embodiments, the nucleic acid or nucleic acid sequence comprises other types of nucleic acid structures, such as, for example, DNA / RNA helices, peptide nucleic acids (PNA), morpholino nucleic acids (see, for example, Braasch and Corey, Biochemistry, 41(14):4503-4510 (2002) and U.S. Pat. No. 5,034,506), locked nucleic acids (LNA; see Wahlestedt et al., Proc. Natl. Acad. Sci. USA, 97:5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, J. Am. Chem. Soc., 122:8595-8602 (2000)) and / or ribozymes. The terms "nucleic acid" and "nucleic acid sequence" may also encompass chains comprising non-natural nucleotides, modified nucleotides and / or non-nucleotide building blocks (e.g., "nucleotide analogs") that can exhibit the same function as natural nucleotides.

[0074] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and refer to a polymeric form of amino acids of any length, which may include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified peptide backbones.

[0075] As used herein, "nucleic acid" or "nucleic acid molecule" generally refers to any ribonucleic acid or deoxyribonucleic acid, which can be unmodified or modified DNA or RNA. "Nucleic acid" includes but is not limited to single-stranded and double-stranded nucleic acids. As used herein, the term "nucleic acid" also includes DNA as described above containing one or more modified bases. Therefore, DNA modified to the backbone for stability or other reasons is a "nucleic acid". As used herein, the term "nucleic acid" encompasses such chemically, enzymatically or metabolically modified forms of nucleic acids, as well as DNA chemical forms specific to viruses and cells (including, for example, simple and complex cells).

[0076] The term "oligonucleotide" or "polynucleotide" or "nucleotide" or "nucleic acid" refers to a molecule having two or more, preferably more than three and usually more than ten deoxyribonucleotides or ribonucleotides. The exact size will depend on many factors, which in turn depend on the ultimate function or use of the oligonucleotide. Oligonucleotides can be produced by any means, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof. The typical deoxyribonucleotides of DNA are thymine, adenine, cytosine and guanine. The typical ribonucleotides of RNA are uracil, adenine, cytosine and guanine.

[0077] The terms "complementary" and "complementarity" refer to nucleotides (e.g., 1 nucleotide) or polynucleotides (e.g., a sequence of nucleotides) that are related by the base pairing rules. For example, the sequence 5'-AGT-3' is complementary to the sequence 3'-TCA-5'. Complementarity can be "partial", in which only the bases of some nucleic acids are matched according to the base pairing rules. Alternatively, there may be "complete" or "total" complementarity between nucleic acids. The degree of complementarity between nucleic acid chains affects the efficiency and intensity of hybridization between nucleic acid chains. This is particularly important in amplification reactions and detection methods that depend on binding between nucleic acids.

[0078] The term "gene" refers to a nucleic acid (e.g., DNA or RNA) sequence comprising a coding sequence necessary for producing RNA or a polypeptide or its precursor. A functional polypeptide can be encoded by a full-length coding sequence or by any portion of the coding sequence, as long as the desired activity or functional properties of the polypeptide (e.g., enzymatic activity, ligand binding, signal transduction, etc.) are retained. When used to refer to a gene, the term "portion" refers to a fragment of the gene. The size range of a fragment can be from a few nucleotides to the entire gene sequence minus one nucleotide. Therefore, "nucleotides comprising at least a portion of a gene" can include a gene fragment or the entire gene.

[0079] The term "gene" also encompasses the coding region of a structural gene, and includes sequences adjacent to the coding region located at both the 5' and 3' ends, such as a distance of about 1 kb at either end, such that the gene corresponds to the length of the full-length mRNA (e.g., including coding sequences, regulatory sequences, structural sequences, and other sequences). The sequence located 5' of the coding region and present on the mRNA is referred to as a 5' non-translated or untranslated sequence. The sequence located 3' or downstream of the coding region and present on the mRNA is referred to as a 3' non-translated or 3' untranslated sequence. The term "gene" encompasses cDNA and genomic forms of a gene. In some organisms (e.g., eukaryotes), the genomic form or clone of a gene contains a coding region interrupted by a non-coding sequence called an "intron" or "insertion region" or "insertion sequence". Introns are gene segments transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements, such as enhancers. Introns are removed or "spliced ​​out" from nuclear transcripts or primary transcripts; therefore, introns are not present in messenger RNA (mRNA) transcripts. mRNA functions during the translation process to specify the sequence, or order, of amino acids in a nascent polypeptide.

[0080] In addition to containing introns, the genomic form of a gene may also include sequences at the 5' and 3' ends of the sequences present on the RNA transcript. These sequences are referred to as "flanking" sequences or regions (these flanking sequences are located 5' or 3' to the non-translated sequences present on the mRNA transcript). The 5' flanking region may contain regulatory sequences, such as promoters and enhancers, which control or affect the transcription of the gene. The 3' flanking region may contain sequences that direct transcription termination, post-transcriptional cleavage, and polyadenylation.

[0081] The term "wild type" when referring to a gene refers to a gene having the characteristics of a gene isolated from a naturally occurring source. The term "wild type" when referring to a gene product refers to a gene product having the characteristics of a gene product isolated from a naturally occurring source. The term "wild type" when referring to a protein refers to a protein having the characteristics of a naturally occurring protein. The term "naturally occurring" as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that can be isolated from a natural source and has not been intentionally modified by a laboratory person that exists in an organism (including a virus) is naturally occurring. A wild-type gene is usually the gene or allele most commonly observed in a population, and is therefore arbitrarily designated as the "normal" or "wild-type" form of a gene. In contrast, the term "modified" or "mutated" when referring to a gene or gene product refers to a gene or gene product that shows sequence and / or functional property modifications (e.g., characteristic changes) compared to a wild-type gene or gene product, respectively. Note that naturally occurring mutants can be isolated; these are identified by the fact that they have changed characteristics compared to a wild-type gene or gene product.

[0082] The term "allele" refers to a variation of a gene; said variation includes, but is not limited to, variants and mutants, polymorphic loci and single nucleotide polymorphic loci, frameshift and splice mutations. An allele may occur naturally in a population, or may occur during the lifetime of any particular individual in a population.

[0083] Thus, the terms "variant" and "mutant" when used in reference to nucleotide sequences refer to a nucleic acid sequence that differs from another, generally related, nucleotide sequence by one or more nucleotides. A "variation" is a difference between two different nucleotide sequences; typically, one sequence is a reference sequence.

[0084] The terms "immunogen" and "antigen" are used interchangeably herein and refer to any molecule, compound or substance that induces an immune response in an animal (e.g., a mammal). An "immune response" can result in, for example, the production of antibodies and / or the activation of immune effector cells. Antigens in the context of the present disclosure may include any subunit, fragment or epitope of any protein or non-protein (e.g., carbohydrate or lipid) molecule that causes an immune response in a mammal. The term "epitope" refers to an antigen sequence that is recognized by an antibody or antigen receptor. Epitopes are also referred to as "antigenic determinants" in the art. In certain embodiments, an epitope is an antigenic region that an antibody specifically binds to. In certain embodiments, an epitope may include chemically active surface groups of a molecule, such as amino acids, sugar side chains, phosphoryl or sulfonyl groups. In certain embodiments, an epitope may have specific three-dimensional structural features (e.g., "conformational" epitopes) and / or specific charge characteristics. Antigens may be proteins or peptides of viral, bacterial, parasitic, fungal, protozoan, prion, cellular or extracellular origin that cause an immune response in a mammal, preferably resulting in protective immunity.

[0085] As used herein, "pharmaceutically acceptable carrier" refers to ingredients other than active ingredients in a pharmaceutical preparation that are non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0086] The term "pharmaceutical formulation" as used herein generally refers to a preparation whose form permits the biological activity of the active ingredient (e.g., anti-ANGPTL7 antibody, antibody conjugate, fusion protein or polymer formulation) contained therein to be effective and which does not contain other components that are unacceptably toxic to a subject to which the formulation would be administered.

[0087] As used herein, "treatment" (and grammatical variations such as "treat" or "treating") generally refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desired therapeutic effects include, but are not limited to, preventing disease occurrence or recurrence, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating the disease state, and alleviating or improving prognosis. In some embodiments, the anti-ANGPTL7 antibodies of the disclosure or other compositions comprising the anti-ANGPTL7 antibodies of the disclosure (e.g., antibody conjugates, fusion proteins, or polymer formulations) are used to delay the development of a disease or slow the progression of a disease.

[0088] As used herein, the term "half-life" generally refers to the time required for the concentration of a substance (e.g., an anti-ANGPTL7 antibody, antibody conjugate, fusion protein (e.g., Fab fusion protein) or polymer formulation) to be reduced by half in vivo (e.g., in the eye (e.g., vitreous)) or in vitro.

[0089] As used herein, an "effective amount" of an agent (eg, a pharmaceutical formulation) generally refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0090] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, an individual or subject is a human. A "subject" may be a "patient."

[0091] Anti-ANGPTL7 Antibodies

[0092] Embodiments of the present disclosure relate to treating and / or preventing glaucoma and other eye diseases that affect the optic nerve and retinal ganglion cells. Specifically, the present disclosure provides novel therapeutic antibodies targeting angiopoietin-related protein 7 (ANGPTL7) as a means for reducing intraocular pressure (IOP) and / or increasing outflow smoothness, thereby preventing optic nerve damage and / or restoring vision.

[0093] As further described herein, embodiments of the present disclosure include antibodies or antigen-binding fragments thereof that specifically bind to human angiopoietin-like protein 7 (ANGPTL7), optionally wherein the human ANGPTL7 is a polypeptide comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 370 to 374.

[0094] In some embodiments, the antibody or antigen-binding fragment thereof exhibits any one or more of the following functional characteristics: when administered to an eye of a subject, increases outflow facility compared to a control, optionally wherein the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein and isotype control antibody treatment; and / or increases the outflow facility compared to a control when administered to the eye of the subject; and / or increases the outflow facility compared to a control when administered to the eye of the subject; and / or increases the outflow facility compared to a control when administered to the subject; D Binds to ANGPTL7; and / or binds to the same epitope on ANGPTL7 as an antibody comprising the VH and VL sequences of any of the exemplary antibodies (sequences of which are provided in Table 11); and / or competes for binding to ANGPTL7 with an antibody comprising the VH and VL sequences of any of the exemplary antibodies (sequences of which are provided in Table 11).

[0095] In some embodiments, the antibody or antigen-binding fragment thereof is monoclonal, optionally recombinant. In some embodiments, the antibody or antigen-binding fragment thereof is human, humanized or chimeric.

[0096] In some embodiments, the antibody or antigen-binding fragment thereof is a full-length antibody, a single-chain antibody, a single-chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), Fab-C, Fab'-SH, (Fab')2, a single domain antibody (sdAb), a VHH antibody, a nanobody, a camel-derived single domain antibody, a shark IgNAR-derived single domain antibody fragment (VNAR), a diabody, a triabody, anticalin or an aptamer, optionally wherein the antibody is a full-length antibody comprising an Fc region (such as a human IgG1, IgG2, IgG3 or IgG4 region).

[0097] In some embodiments, the antibody or antigen-binding fragment thereof is conjugated to at least one other moiety, optionally selected from: an antigen-binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specifically binding to a target of non-human ANGPTL7, preferably wherein the target is expressed in the human eye; a therapeutic or cytotoxic moiety; a detection moiety; a purification moiety; a half-life extending moiety, optionally a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E and P residues, which is conjugated to the C-terminus or N-terminus of the antibody.

[0098] In some embodiments, the antibody or antigen-binding fragment thereof is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising one, two or all three corresponding LCDRs of an exemplary antibody; and / or a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising a VL sequence having at least 90% identity to the corresponding VL sequence of an exemplary antibody, preferably wherein variation in the HCDRs or LCDRs is not allowed; and / or all six CDRs of any one of the exemplary antibodies (whose sequences are provided in Table 11); and / or the VH and VL sequences of any one of the exemplary antibodies (whose sequences are provided in Table 11); and / or the full-length heavy chain (VH+constant) sequence of any one of the exemplary antibodies (whose sequences are provided in Table 11), and optionally further comprising the corresponding full-length light chain (VL+constant) sequence of the exemplary antibodies.

[0099] Embodiments of the present disclosure also include polynucleotides encoding the antibodies or antigen-binding fragments thereof of any of the preceding paragraphs, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence that is at least 70%, 80%, 90% or 100% identical to the nucleic acid sequence of any of the exemplary antibodies (sequences of which are provided in Table 11).

[0100] Embodiments of the present disclosure also include an expression vector comprising the polynucleotide of the preceding paragraph, the vector optionally being an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

[0101] Embodiments of the present disclosure also include a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, a polynucleotide or a vector according to any of the preceding paragraphs, and optionally: at least one pharmaceutically acceptable carrier, diluent or preservative; and / or at least one other active ingredient. In some embodiments, the pharmaceutical composition is suitable for ocular administration to a subject, optionally by delivery using a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, an eye drop and / or an implant, preferably by injection into the vitreous humor.

[0102] Embodiments of the present disclosure also include antibodies or antigen-binding fragments thereof, polynucleotides, vectors or compositions of any of the foregoing paragraphs, which are used as medicines, optionally for treating methods of eye diseases in subjects. In some embodiments, the disease is characterized by increased intraocular pressure in the subject and / or decreased outflow smoothness of the eye. In some embodiments, the method includes ocular administration of antibodies, preferably by injection into the vitreous humor, and wherein the administration preferably alleviates at least one symptom selected from the following in the subject: eye pain, intraocular pressure, headache, rainbow-colored halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting and red eyes. In some embodiments, the disease is glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, optionally wherein the glaucoma is primary glaucoma or glucocorticoid-induced glaucoma.

[0103] As further described herein, anti-ANGPTL7 antibodies were generated and their structural and functional properties were elucidated. Based on these data, embodiments of the present disclosure include anti-ANGPTL7 antibodies or antigen-binding fragments thereof, which are composed of a heavy chain variable region (VH) comprising complementary determining regions (CDRs) HCDR1, HCDR2, and HCDR3 and a light chain variable region (VL) comprising complementary determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X 1 YX 2 IX 3 (SEQ ID NO: 1), wherein X 1 S or D; X 2 G or Y; X 3 is S or H; (b) TSGVGVG (SEQ ID NO: 18); (c) X 1 X 2 X 3 MX 4 (SEQ ID NO: 27), wherein X 1 V, S, D or T; X 2 is Y, H or F; X 3 D, G, S or A; X 4 is H, S or N; or (d) SX 1 SX 2 YW 3 (SEQ ID NO: 74), wherein X 1 S or G; X 2 S or Y; X 3 is G or S. In some embodiments, HCDR2 comprises one of the following amino acid sequences: (a) WIX 1 X2 X 3 X 4 GX 5 TX 6 YQ 7 X 8 X 9 G (SEQ ID NO: 7), wherein X 1 S, I or N; X 2 A or P; X 3 Y or N; X 4 N or T; X 5 N or A; X 6 N or K; X 7 N or K; X 8 L or F; X 9 is R or Q; (b) LIYWNDDKX 1 YSPSLKS (SEQ ID NO: 21), wherein X 1 is R or Q; (c) X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 G (SEQ ID NO: 43), wherein X 1 is G, T, S, A, V, H or I; X 2 I or M; X 3 is D, N, T, S or G; X 4 is P, W, S, G or Y; X 5 is D, A, N, S or Y; X 6 G or S; X 7 is D, G, Y, S, I or N; X 8 is T, S, N, I, Y or D; X 9 is Y, T, F, M, K, G or I; X 10 is Y, G or F; X 11 P, Y or A; X 12 G, D or A; X 13 S or D; X 14 V, L or S; X 15 is K or M; or (d) X 1 IYYSGSTX 2SNPSLKS (SEQ ID NO: 78), wherein X 1 S or Y; X 2 is Y or S. In some embodiments, HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 13-17; (b) X 1 X 2 X 3 X 4 X 5 X 6 FFDX 7 (SEQ ID NO: 24), wherein X 1 S, D or N; X 2 is Y or P; X 3 G or D; X 4 D or Y; X 5 is Y or G; X 6 W or D; X 7 is L or Y; (c) SEQ ID NO: 59-73; or (d) X 1 X 2 X 3 X 4 GX 5 X 6 X 7 X 8 X 9 Y (SEQ ID NO: 82), wherein X 1 Q or A; X 2 is Y or K; X 3 I or W; X 4 S or E; X 5 is T or D; X 6 is E or Y; X 7 is Y or F; X 8 F or D; X 9 It is Q or Y.

[0104] In addition to the above-mentioned HCDR1, HCDR2 and HCDR3 sequences, the anti-ANGPTL7 antibodies of the present disclosure further include: a LCDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 87-97, SEQ ID NOs: 123-127 or SEQ ID NOs: 141-149; a LCDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 99-109, SEQ ID NOs: 129-133 or SEQ ID NOs 151-159; and a LCDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 111-121, SEQ ID NOs: 135-139 or SEQ ID NOs: 161-169.

[0105] In some embodiments, the present disclosure provides an anti-ANGPTL7 antibody or antigen-binding fragment thereof, comprising a VH comprising complementary determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementary determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, LCDR1 comprises one of the following amino acid sequences: (a) RASQX 1 IX 2 X 3 X 4 LX 5 (SEQ ID NO: 86), wherein X 1 G or S; X 2 S, R or Y; X 3 S, N or I; X 4 W, D or Y; X 5 A, G or N; (b)RSSQSLX 1 X 2 SX 3 X 4 X 5 X 6 YXX 7 (SEQ ID NO: 122), wherein X 1 L or V; X 2 H, Y or F; X 3 N or D; X 4 R or G; X 5 Y or N; X 6 N or T; X 7 is D or N; or (c)RASQSVSX 1 X 2 X 3 X 4 A (SEQ ID NO: 140), wherein X 1 S, N or R; X 2 Y or S; X 3 L or Y; X 4 is A or L. In some embodiments, LCDR2 comprises one of the following amino acid sequences: (a) AX 1 SSLX 2 S (SEQ ID NO: 98), wherein X 1 A or T; X 2 is Q or P; (b) X 1 X 2 SNRX 3 S (SEQ ID NO: 128), wherein X 1 L, K or E; X 2 G or V; X3 is A or D; or (c) X 1 ASX 2 RAT (SEQ ID NO: 150), wherein X 1 D or G; X 2 is N, S or T. In some embodiments, LCDR3 comprises one of the following amino acid sequences: (a) X 1 QX 2 X 3 X 4 X 5 PX 6 X 7 (SEQ ID NO: 110), wherein X 1 L or Q; X 2 A, H, S or D; X 3 N, F or Y; X 4 S, T or N; X 5 F, Y or T; X 6 W, L, I, P or Y; X 7 is T or Y; (b) MQX 1 X 2 X 3 X 4 PX 5 T (SEQ ID NO: 134), wherein X 1 T or G; X 2 L or T; X 3 Q or H; X 4 is T or W; X 5 is Y or W; or (c) QQX 1 X 2 X 3 X 4 X 5 X 6 T (SEQ ID NO: 160), wherein X 1 R, Y or G; X 2 S, G or Q; X 3 N, S or V; X 4 W, S or I; X 5 P or L; X 6 It is L, S, P or T.

[0106] In addition to the above-mentioned LCDR1, LCDR2 and LCDR3 sequences, the anti-ANGPTL7 antibodies of the present disclosure further include: a HCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 2-6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42 or SEQ ID NOs: 75-77; a HCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 8-12, SEQ ID NOs: 22-23, SEQ ID NOs 44-58 or SEQ ID NOs: 79-81; and a HCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73 or SEQ ID NOs: 83-85.

[0107] In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:2, a HCDR2 of SEQ ID NO:8, and a HCDR3 of SEQ ID NO: 13. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:3, a HCDR2 of SEQ ID NO:9, and a HCDR3 of SEQ ID NO:14. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:4, a HCDR2 of SEQ ID NO:10, and a HCDR3 of SEQ ID NO:15. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:5, a HCDR2 of SEQ ID NO:11, and a HCDR3 of SEQ ID NO:16. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:6, a HCDR2 of SEQ ID NO:12, and a HCDR3 of SEQ ID NO:17. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:7, a HCDR2 comprising an amino acid sequence of SEQ ID NO:14, and a HCDR3 of SEQ ID NO:20. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:19, a HCDR2 comprising an amino acid sequence of SEQ ID NO:22, and a HCDR3 comprising an amino acid sequence of SEQ ID NO:25. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:20, a HCDR2 of SEQ ID NO:23, and a HCDR3 of SEQ ID NO:26. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:28, a HCDR2 of SEQ ID NO:44, and a HCDR3 of SEQ ID NO:59. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:29, a HCDR2 of SEQ ID NO:45, and a HCDR3 of SEQ ID NO:60. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 30, a HCDR2 of SEQ ID NO: 46, and a HCDR3 of SEQ ID NO: 61. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 31, a HCDR2 of SEQ ID NO: 47, and a HCDR3 of SEQ ID NO: 62.In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:32, a HCDR2 of SEQ ID NO:48, and a HCDR3 of SEQ ID NO:63. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:33, a HCDR2 of SEQ ID NO:49, and a HCDR3 of SEQ ID NO:64. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:34, a HCDR2 of SEQ ID NO:50, and a HCDR3 of SEQ ID NO:65. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:35, a HCDR2 of SEQ ID NO:51, and a HCDR3 of SEQ ID NO:66. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:36, a HCDR2 of SEQ ID NO:52, and a HCDR3 of SEQ ID NO:67. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:37, a HCDR2 of SEQ ID NO:53, and a HCDR3 of SEQ ID NO:68. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:38, a HCDR2 of SEQ ID NO:54, and a HCDR3 of SEQ ID NO:69. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:39, a HCDR2 of SEQ ID NO:55, and a HCDR3 of SEQ ID NO:70. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:40, a HCDR2 of SEQ ID NO:56, and a HCDR3 of SEQ ID NO:71. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO:41, a HCDR2 of SEQ ID NO:57, and a HCDR3 of SEQ ID NO:72. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 42, a HCDR2 of SEQ ID NO: 58, and a HCDR3 of SEQ ID NO: 73. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 75, a HCDR2 of SEQ ID NO: 79, and a HCDR3 of SEQ ID NO: 83.In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 76, a HCDR2 of SEQ ID NO: 80, and a HCDR3 of SEQ ID NO: 84. In some embodiments, the anti-ANGPTL7 antibody comprises a HCDR1 of SEQ ID NO: 77, a HCDR2 of SEQ ID NO: 81, and a HCDR3 of SEQ ID NO: 85.

[0108] In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:87, a LCDR2 of SEQ ID NO:99, and a LCDR3 of SEQ ID NO: 111. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:88, a LCDR2 of SEQ ID NO:100, and a LCDR3 of SEQ ID NO:112. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:89, a LCDR2 of SEQ ID NO:101, and a LCDR3 of SEQ ID NO:113. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:90, a LCDR2 of SEQ ID NO:102, and a LCDR3 of SEQ ID NO:114. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:91, a LCDR2 of SEQ ID NO:103, and a LCDR3 of SEQ ID NO:115. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:92, a LCDR2 of SEQ ID NO:104, and a LCDR3 of SEQ ID NO:116. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:93, a LCDR2 of SEQ ID NO:105, and a LCDR3 of SEQ ID NO:117. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:94, a LCDR2 of SEQ ID NO:106, and a LCDR3 of SEQ ID NO:118. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:95, a LCDR2 of SEQ ID NO:107, and a LCDR3 of SEQ ID NO:119. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO:96, a LCDR2 of SEQ ID NO:108, and a LCDR3 of SEQ ID NO:120. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 97, a LCDR2 of SEQ ID NO: 109, and a LCDR3 of SEQ ID NO: 121. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 123, a LCDR2 of SEQ ID NO: 129, and a LCDR3 of SEQ ID NO: 135.In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 124, a LCDR2 of SEQ ID NO: 130, and a LCDR3 of SEQ ID NO: 136. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 125, a HCDR2 of SEQ ID NO: 131, and a LCDR3 of SEQ ID NO: 137. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 126, a LCDR2 of SEQ ID NO: 132, and a LCDR3 of SEQ ID NO: 138. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 127, a LCDR2 of SEQ ID NO: 133, and a LCDR3 of SEQ ID NO: 139. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 141, a LCDR2 of SEQ ID NO: 151, and a LCDR3 of SEQ ID NO: 161. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 142, a LCDR2 of SEQ ID NO: 152, and a LCDR3 of SEQ ID NO: 162. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 143, a LCDR2 of SEQ ID NO: 153, and a LCDR3 of SEQ ID NO: 163. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 144, a LCDR2 of SEQ ID NO: 154, and a LCDR3 of SEQ ID NO: 164. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 145, a LCDR2 of SEQ ID NO: 155, and a LCDR3 of SEQ ID NO: 165. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 146, a LCDR2 of SEQ ID NO: 156, and a LCDR3 of SEQ ID NO: 166. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 147, a LCDR2 of SEQ ID NO: 157, and a LCDR3 of SEQ ID NO: 167. In some embodiments, the anti-ANGPTL7 antibody comprises a LCDR1 of SEQ ID NO: 148, a LCDR2 of SEQ ID NO: 158, and a LCDR3 of SEQ ID NO: 168.In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO:149, LCDR2 of SEQ ID NO:159, and LCDR3 of SEQ ID NO:169.

[0109] In some embodiments, the VH of an anti-ANGPTL7 antibody of the present disclosure comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any of: (a) SEQ ID NOs: 170-174; (b) SEQ ID NOs: 190-191; (c) SEQ ID NOs: 198-212; or (d) SEQ ID NOs: 258-260. In some embodiments, the VL of an anti-ANGPTL7 antibody of the present disclosure comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any of: (a) SEQ ID NOs: 180-184; (b) SEQ ID NOs: 194-195; (c) SEQ ID NOs: 228-242; or (d) SEQ ID NOs: 264-266.

[0110] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 170, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 180. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 171, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 181. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 172, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 182. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 173, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 183.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 174, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 184. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 190, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 194. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 191, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 195. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 198, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 228.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 199, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 229. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 200, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 230. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 201, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 231. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 202, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 232.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 203, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 233. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 204, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 234. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 205, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 235. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 206, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 236.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 207, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 237. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 208, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 238. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 209, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 239. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 210, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 240.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 211, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 241. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 212, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 242. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 258, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 264. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO:259, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO:265.In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 260, and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 266.

[0111] Nucleic acid or amino acid sequence "identity" as described herein can be determined by comparing the nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence. Many mathematical algorithms for obtaining optimal alignments and calculating the identity between two or more sequences are known and are incorporated into many available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ and subsequent versions thereof), and FASTA programs (e.g., FASTA3x, FAST3x, and FASTA4x). TM and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms are also disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3):403-410 (1990); Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10):3770-3775 (2009); Durbin et al., eds., Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009); Soding, Bioinformatics, 21(7):951-960 (2005); Altschul et al., Nucleic Acids Res., 25(17):3389-3402 (1997); and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).

[0112] As will be appreciated by one of ordinary skill in the art based on the present disclosure, one or more amino acids of the aforementioned anti-ANGPTL7 antibodies or antigenic fragments thereof may be replaced or substituted with different amino acids. Amino acid "replacement" or "substitution" refers to the replacement of one amino acid at a given position or residue within a polypeptide sequence by another amino acid at the same position or residue. Amino acids are broadly classified as "aromatic" or "aliphatic". Aromatic amino acids include aromatic rings. Examples of "aromatic" amino acids include histidine (H or His), phenylalanine (F or Phe), tyrosine (Y or Tyr) and tryptophan (W or Trp). Non-aromatic amino acids are broadly classified as "aliphatic". Examples of "aliphatic" amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine ​​(C or Cys), proline (P or Pro), glutamate (E or Glu), aspartate (A or Asp), asparagine (N or Asn), glutamine (Q or Gln), lysine (K or Lys), and arginine (R or Arg). Aliphatic amino acids can be subdivided into four subgroups. The "large aliphatic nonpolar subgroup" consists of valine, leucine, and isoleucine. The "aliphatic weakly polar subgroup" consists of methionine, serine, threonine, and cysteine. The "aliphatic polar / charged subgroup" consists of glutamate, aspartate, asparagine, glutamine, lysine, and arginine. The "small residue subgroup" consists of glycine and alanine. The group of charged / polar amino acids can be subdivided into three subgroups: the "positively charged subgroup" consisting of lysine and arginine, the "negatively charged subgroup" consisting of glutamic acid and aspartic acid, and the "polar subgroup" consisting of asparagine and glutamine. The aromatic amino acids can be subdivided into two subgroups: the "nitrogen ring subgroup" consisting of histidine and tryptophan, and the "phenyl subgroup" consisting of phenylalanine and tyrosine.

[0113] Amino acid replacement or substitution can be conservative, semi-conservative or non-conservative. The phrase "conservative amino acid replacement" or "conservative mutation" refers to an amino acid replacement by another amino acid with common properties. A functional way to define common properties between individual amino acids is to analyze the normalized frequency of amino acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analysis, amino acid groups can be defined, wherein the amino acids in the group are preferentially exchanged with each other, and therefore the effects on the overall protein structure are most similar to each other. Examples of conservative amino acid replacements include amino acid replacements within the above-mentioned subgroups, for example, lysine replaces arginine and vice versa, so that a positive charge can be maintained, glutamic acid replaces aspartic acid and vice versa, so that a negative charge can be maintained, serine replaces threonine, so that free-OH can be maintained, and glutamine replaces asparagine, so that free-NH 2 "Semi-conservative mutations" include amino acid substitutions within the same group listed above, but not within the same subgroup. For example, substitutions of aspartic acid for asparagine or asparagine for lysine involve amino acids in the same group but in different subgroups. "Non-conservative mutations" involve amino acid substitutions between different groups (e.g., lysine for tryptophan or phenylalanine for serine, etc.).

[0114] In addition, one or more amino acids may be inserted into the anti-ANGPTL7 antibody or antigen-binding fragment thereof (e.g., into the heavy chain and / or light chain variable region amino acid sequence). Any number of suitable amino acids may be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof. In this regard, at least one amino acid (e.g., 2 or more, 5 or more, or 10 or more amino acids) but no more than 20 amino acids (e.g., 18 or less, 15 or less, or 12 or less amino acids) may be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof. For example, 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) may be inserted into the amino acid sequence of the monoclonal antibody or antigen-binding fragment thereof. In this regard, the amino acids may be inserted into any suitable position of the antibody or antigen-binding fragment thereof. Preferably, the amino acids are inserted into the CDRs (e.g., CDR1, CDR2, or CDR3) of the antibody or antigen-binding fragment thereof.

[0115] The amino acid sequence of the anti-ANGPTL7 antibody or antigen-binding fragment thereof is not limited to the specific amino acid sequence described herein. In fact, the anti-ANGPTL7 antibody or antigen-binding fragment thereof may comprise any heavy chain polypeptide or light chain polypeptide that competes with the anti-ANGPTL7 antibody or antigen-binding fragment thereof for conformational binding to ANGPTL7. Antibody competition can be determined using conventional peptide competition assays, such as, for example, ELISA, Western blot, or immunohistochemistry (see, for example, U.S. Pat. Nos. 4,828,981 and 8,568,992; and Braitbard et al., Proteome Sci., 4:12 (2006)).

[0116] The anti-ANGPTL7 antibodies of the present disclosure may be intact antibodies or antigen-binding fragments of intact antibodies. As defined herein, antigen-binding antibody fragments encompassed by the present disclosure include, but are not limited to: F(ab') 2 , Fab', Fab, Fv, scFv, dsFv, dAb and single chain binding polypeptides. Antibody fragments and their therapeutic utility are further described in, for example, Nelson, AL, MAbs. 2010 Jan-Feb; 2(1):77-83; Joosten et al., Microbial Cell Factories Vol. 2, Article No.: 1 (2003); and Bates A, Power CA., Antibodies (Basel). 2019; 8(2):28; doi:10.3390 / antib8020028). In some embodiments, the anti-ANGPTL7 antigen binding fragment is a single chain variable fragment (scFv), which is an engineered antibody generated by fusing the heavy chain (VH) and light chain (VL) of an immunoglobulin through a short polypeptide linker. Single-chain variable domain (Fv) fragments (scFv) are used in the art for a variety of clinical and therapeutic applications, primarily because they have improved pharmacokinetic properties compared to the parent monoclonal antibodies and are relatively easy to produce in large quantities at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org / 10.3390 / antib2020193; Safdari et al., Mol Med. 2016; 22: 258-270; and Lu, R., Hwang, Y., Liu, I. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1(2020). https: / / doi.org / 10.1186 / s12929-019-0592-z).

[0117] The anti-ANGPTL7 antibodies of the present disclosure may be diabodies. Diabodies are antibody fragments that may be bivalent or bispecific and have two antigen binding sites. See, e.g., EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). The anti-ANGPTL7 antibodies of the present disclosure may be single domain antibodies (also called nanobodies). Single domain antibodies are antibody fragments that contain all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516B1). Antibody fragments can be prepared by various techniques, including, but not limited to, proteolytic digestion of intact antibodies as described herein and production by recombinant host cells (e.g., E. coli or phage).

[0118] In other embodiments, the anti-ANGPTL7 antibody is an intact antibody. As defined herein, an intact antibody comprises two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V H ) region and three C-terminal constant (C H1 , C H2 and C H3 ) region, and each light chain contains an N-terminal variable (V L ) region and a C-terminal constant (C L) region. The C-terminal constant region of the heavy chain contains a crystallizable fragment (Fc) domain, which determines the antibody class and is responsible for humoral and cellular effector functions. Antibodies are divided into five major classes (or "isotypes"), IgG, IgM, IgA, IgD and IgE, which have different functions in the immune system. IgG is the most abundant immunoglobulin in the blood, accounting for 60% of the total antibodies in human serum. IgG antibodies can be subdivided into IgG1, IgG2, IgG3 and IgG4, named according to their abundance in serum (IgG1 is the most abundant) (Vidarsson et al., Frontiers in Immunology. 5:520 (2014)). The intact anti-ANGPTL7 monoclonal antibodies described herein can belong to any suitable class and / or subclass. In some embodiments, the monoclonal antibody belongs to the IgG class (e.g., IgG1, IgG2, IgG3 or IgG4). For example, the monoclonal antibody can be an IgG1 antibody.

[0119] As discussed above, the Fc domain mediates several effector functions of the antibody, such as binding to receptors on target cells and complement fixation (an effector function that triggers elimination of antigens). In some embodiments, the Fc domain can be modified or engineered to alter its effector function. For example, the Fc domain can be modified to increase antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and control serum half-life. In some embodiments, the Fc domain of an anti-ANGPTL7 antibody can be engineered to modulate affinity for Fc receptors, such as Fcγ receptors (FcγRs) and neonatal Fc receptors (FcRn). In fact, optimizing the interaction between antibodies and FcγRs has become a promising approach for enhancing the activity of therapeutic antibodies in treating various diseases (Mimoto et al., Curr. Pharm. Biotechnol. 17, 1298-1314 (2016); Lazar et al., Proc. Natl Acad. Sci. USA 103, 4005-4010 (2006); Richards et al., Mol. Cancer Ther. 7, 2517-2527 (2008); Nordstrom et al., Breast Cancer Res. 13, R123 (2011); and Kang, TH, Jung, ST, Exp Mol Med 51, 1-9 (2019)). The Fc domain can also be modified to improve serum half-life, for example by engineering IgG Fc to obtain higher FcRn binding (Zalevsky et al., Nat. Biotechnol. 28, 157-159 (2010); and Dall'Acqua et al., J. Immunol. 169, 5171-5180 (2002)). In other embodiments, the Fc domain can be modified to produce monovalent or antibody bispecificity, thereby improving therapeutic efficacy. For example, an Fc domain mFc that does not form homodimers but is still a soluble monomer can be generated, and the mFc exhibits high affinity for FcγRI, but has no detectable binding to FcγRIIIa. In other embodiments, a heterodimeric Fc domain can be generated to obtain the bispecific properties of antigen binding, thereby avoiding the formation of homodimers.Engineered Fc domains can be generated by inducing point mutations or by modifying the glycosylation of the Fc domain (Saunders, KO, Front Immunol. 2019; 10: 1296; Kelley, RF, Meng, YG, Liu et al., J Biol Chem. 2014; 289: 3571-90; Monnet et al., MAbs. 2014; 6: 422-36; Li et al., Proc Natl Acad Sci US A. 2017; 114: 3485-90; and Lin et al., Proc Natl Acad Sci US A. 2015; 112: 10611-6; Kang and Jung, supra).

[0120] Multispecific anti-ANGPTL7 antibody

[0121] As described above, the anti-ANGPTL7 antibodies of the present disclosure may be monoclonal antibodies, human antibodies, humanized antibodies and / or chimeric antibodies. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab′-SH, Fv, scFv and (Fab′) 2 In some embodiments, the anti-ANGPTL7 antibody is a monospecific antibody. In some embodiments, the anti-ANGPTL7 antibody is a bispecific antibody. In some embodiments, the anti-ANGPTL7 antibody comprises two or more single domain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0122] In some embodiments, the anti-ANGPTL7 antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA. 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and a human constant domain. In a further example, a chimeric antibody is a "class switched" antibody, in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0123] In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to reduce immunogenicity to people while retaining the specificity and affinity of the parent non-human antibody. Typically, humanized antibodies include one or more variable domains, in which HVR, such as CDR (or a portion thereof) are derived from non-human antibodies, and FR (or a portion thereof) are derived from human antibody sequences. Humanized antibodies will optionally also include at least a portion of a human constant region. In some embodiments, some FR residues in humanized antibodies are replaced by corresponding residues from non-human antibodies (e.g., antibodies from HVR residue sources), for example, to restore or improve antibody specificity or affinity.

[0124] Humanized antibodies and methods for making them are reviewed in, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described in, e.g., Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” method of FR shuffling).

[0125] According to the above embodiments, the anti-ANGPTL7 antibodies of the present disclosure can be prepared in a bivalent, trivalent or tetravalent form. For example, the anti-ANGPTL7 antibodies of the present disclosure can be bivalent, bispecific antibodies with heterologous heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc.). The anti-ANGPTL7 antibodies of the present disclosure may be tetravalent multispecific antibodies composed of IgG and other binding domains fused to the N-terminus or C-terminus of the heavy chain or light chain (e.g., dual variable domains [DVD], IgG-scFv fusion, Mabtyrin (IgG, in which a non-antibody binding scaffold "centyrin" is fused to the C-terminus of the heavy chain). The anti-ANGPTL7 antibodies of the present disclosure may be composed of IgG with additional antigen binding sites added to the structure (e.g., two-in-one antibodies, F-Star's MAT "modular antibody technology" platform). The anti-ANGPTL7 antibodies of the present disclosure may be engineered antibody fragments connected by short peptide linkers, which may be prepared in a bivalent, trivalent or tetravalent form against two to three targets (e.g., bispecific T cell engagers (BiTEs), nanobody platforms, dual affinity retargeting (DART) antibodies, "tandem antibody" structures (TandAbs)). And the anti-ANGPTL7 antibodies of the present disclosure may be composed of chemically coupled IgG.

[0126] In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure are multispecific antibodies, such as bispecific antibodies, which have binding specificity for at least two different antigens. In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure or antigen-binding fragments thereof can be used to form one arm (e.g., antigen-binding portion) of a bispecific antibody, while the other arm of the bispecific antibody can be specific for a different antigen. In some embodiments, the other antigens include, but are not limited to: interleukin-1β (IL-1β), interleukin-6 (IL-6); interleukin-6 receptor (IL-6R); interleukin-13 (IL-13); IL-13 receptor (IL-13R); PDGF (e.g., PDGF-BB); angiogenin; angiopoietin 2 (Ang2); Tie2; S1P; integrins αvβ3, αvβ5, and α5β1; betacellulin; apelin / APJ; erythropoietin; complement factor D; TNFα; HtrA1; VEGF receptors (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptor (mbVEGFR) or soluble VEGF receptor (sVEGFR)); ST-2 receptor; and proteins genetically associated with risk for age-related macular degeneration (AMD), such as complement pathway components C2, factor B, factor H, CFHR3, C3b, C5, C5a and C3a; HtrA1; ARMS2; TIMP3; HLA; interleukin 8 (IL-8); CX3CR1; TLR3; TLR4; CETP; LIPC; COL10A1; and TNFRSF10A.

[0127] In some embodiments, the bispecific antibodies of the present disclosure comprise an anti-ANGPTL7 antibody or antigen-binding fragment thereof and an anti-VEGF antibody or antigen-binding fragment thereof. Such bispecific antibodies can be used to target different mechanisms and thus provide other therapeutic benefits. For example, the anti-ANGPTL7 arm can be any anti-ANGPTL7 antibody of the present disclosure, and the anti-VEGF arm can be any VEGF antagonist, including but not limited to anti-VEGF antibodies (e.g., bevacizumab, sevacizumab, and ranibizumab), anti-VEGFR2 antibodies and related molecules (e.g., ramucirumab, tanibirumab, aflibercept), anti-VEGFR1 antibodies and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye; ) and ziv-aflibercept (VEGF Trap; )), an anti-VEGF arm of a VEGF bispecific antibody (e.g., MP-0250, vanucizumab (VEGF-ANG2)), comprising anti-VEGF, anti-VEGFR1 and anti-VEGFR2 arms.

[0128] Functional characterization of anti-ANGPTL7 antibodies

[0129] According to the above embodiments, the present disclosure provides anti-ANGPTL7 antibodies comprising various functional features. In some embodiments, the anti-ANGPTL7 antibodies described herein bind to an antigen on ANGPTL7 (SEQ ID NO: 370) or a variant or isoform thereof (via interaction with its antigenic determinant (epitope)). In some embodiments, the anti-ANGPTL7 antibodies described herein bind to an antigen / epitope from a human ANGPTL7 fibrinogen domain (e.g., ATX-P-60; SEQ ID NO: 373), an antigen / epitope from a full-length human ANGPTL7 monomer variant L59P_L84P (ATX-P-62; SEQ ID NO: 371), an antigen / epitope from a full-length human ANGPTL7 monomer variant L59 GGPGG (ATX-P-63; SEQ ID NO: 372), an antigen / epitope from a human wild-type ANGPTL7 multimer (PExt-1; SEQ ID NO: 374).

[0130] In some embodiments, the binding of an anti-ANGPTL7 antibody to an ANGPTL7 polypeptide reduces intraocular pressure and / or increases outflow smoothness (see, e.g., Examples 9 and Figure 7 In some embodiments, the anti-ANGPTL7 antibody has a K of about 100 nM or less. D Binds to an epitope of a human ANGPTL7 polypeptide (see, e.g., Example 10). In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase efflux smoothness compared to a control. In some embodiments, the control is selected from the group consisting of: vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and treatment with an ANGPTL7 protein / polypeptide and an isotype control antibody (see, e.g., Figure 7In some embodiments, the anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 210, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 240. In some embodiments, the anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 200, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 230. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 258, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 264. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 207, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 237.In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 204, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 234. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 260, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 266. In some embodiments, the anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 205, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 235. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 206, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 236.In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 208, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 238. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 191, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 195. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 203, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 233. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 212, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 242.In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 198, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 228. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 190, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 194. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 202, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 232. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 211, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 241.In some embodiments, the anti-ANGPTL7 antibody comprises: a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 199, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 229.

[0131] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase efflux fluency compared to a control. In some embodiments, the control is any of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and / or treatment with an ANGPTL7 protein / polypeptide and an isotype control antibody. In some embodiments, the anti-ANGPTL7 antibody comprises: a VH comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 210, and a VL comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 240. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 200, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 230. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 258, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 264.

[0132] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase efflux fluency compared to a control. In some embodiments, the control is any of dexamethasone treatment, ANGPTL7 protein treatment, and / or treatment with an ANGPTL7 protein / polypeptide and an isotype control antibody. In some embodiments, the anti-ANGPTL7 antibody comprises: a VH comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 207, and a VL comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 237. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 204, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 234. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 260, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 266.In some embodiments, the anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 205, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 235. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 206, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 236. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 208, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 238. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 191, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 195.In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 203, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 233. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 212, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 242. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 198, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 228. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 190, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 194.

[0133] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase efflux fluency compared to a control. In some embodiments, the control is any of dexamethasone treatment and / or ANGPTL7 protein treatment. In some embodiments, the anti-ANGPTL7 antibody comprises: a VH comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 202, and a VL comprising an amino acid sequence having at least 90% identity (e.g., 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 SEQ ID NO: 232. In some embodiments, an anti-ANGPTL7 antibody comprises a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 211, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 241. In some embodiments, the anti-ANGPTL7 antibody comprises: a VH comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 199, and a VL comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 229.

[0134] Peptides and expression vectors

[0135] Embodiments of the present disclosure also include polynucleotides encoding any of the anti-ANGPTL7 antibodies of the present disclosure. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263. In some embodiments, the polynucleotide comprises a sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity (e.g., at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263. In some embodiments, the polynucleotide comprises a sequence having at least 80% identity (e.g., at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269. In some embodiments, the polynucleotide comprises a sequence having at least 85% identity (e.g., at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263.In some embodiments, the polynucleotide comprises a sequence having at least 85% identity (e.g., at least 85%, at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269. In some embodiments, the polynucleotide comprises a sequence having at least 90% identity (e.g., at least 90%, at least 95%, or 100% identity) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263. In some embodiments, the polynucleotide comprises a sequence that is at least 90% identical (e.g., at least 90%, at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269. In some embodiments, the polynucleotide comprises a sequence that is at least 95% identical (e.g., at least 95% or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227 or (d) SEQ ID NOs: 261-263. In some embodiments, the polynucleotide comprises a sequence that is at least 95% identical (e.g., at least 95% or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257 or (d) SEQ ID NOs: 267-269.

[0136] In some embodiments, the polynucleotides encoding the anti-ANGPTL7 antibodies of the present disclosure comprise: (a) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 175, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 185; (b) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 176, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: NO:186 having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity); (c) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:177, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:187; (d) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:178, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:179. NO:188 has a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to; (e) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:179, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:189.

[0137] In some embodiments, the polynucleotides encoding the anti-ANGPTL7 antibodies of the present disclosure comprise: (a) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 213, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 243; (b) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 214, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: NO:244 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to nucleic acid sequence; (c) a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:215, and a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:245; (d) a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:216, and a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:217. NO:246 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to nucleic acid sequence; (e) a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:217, and a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:247; (f) a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:218, and a nucleic acid sequence at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:219. NO:248 has a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical);(g) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO: 219, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO: 249; (h) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO: 220, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO: 221. NO:250 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:250; (i) a nucleic acid sequence that has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:221, and a nucleic acid sequence that has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:251; or (j) a nucleic acid sequence that has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:222, and a nucleic acid sequence that has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:223. (k) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO:223, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO:253;(l) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:224, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:254 or (m) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:225, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:256. NO:255 has at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:255; (n) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:226, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:256 or (o) a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:227, and a nucleic acid sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity) to SEQ ID NO:228. NO:257 has a nucleic acid sequence with at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identity). ;

[0138] In some embodiments, the polynucleotides encoding the anti-ANGPTL7 antibodies of the present disclosure comprise: (a) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 261, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 267; (b) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 262, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 263; NO:268 has a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to; (c) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:263, and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical) to SEQ ID NO:269.

[0139] According to these embodiments, the present disclosure includes expression vectors comprising any polynucleotide encoding the anti-ANGPTL7 antibodies of the present disclosure. In some embodiments, the expression vector is suitable for manufacturing the anti-ANGPTL7 antibodies of the present disclosure to deliver the antibodies to a subject. In certain embodiments, the nucleic acid sequence is in the form of a vector. The vector can be, for example, a plasmid, an episome, a cosmid, a viral vector (e.g., a retrovirus or an adenovirus) or a phage. Suitable vectors and methods for preparing vectors are well known in the art (see, for example, Sambrook et al., Molecular Cloning, a Laboratory Manual, 4th edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, NY (1994)).

[0140] In addition to the nucleic acid encoding the anti-ANGPTL7 antibody or antigen-binding fragment thereof, the vector desirably comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), etc., to provide for expression of the antibody encoding nucleic acid sequence in a host cell. Exemplary expression control sequences are known in the art and are described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0141] The vector comprising the nucleic acid sequence encoding the anti-ANGPTL7 antibody or antigen-binding fragment thereof can be introduced into a host cell capable of expressing the polypeptide encoded thereby, including any suitable prokaryotic cell or eukaryotic cell. Examples of suitable prokaryotic cells include, but are not limited to, cells of the genus Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coli), Pseudomonas, Streptomyces, Salmonella, and Erwinia. Particularly useful prokaryotic cells include various strains of Escherichia coli (e.g., K12, HB101 (ATCC No. 33694), DH5α, DH10, MC1061 (ATCC No. 53338), and CC102). Suitable eukaryotic cells are known in the art, and include, for example, yeast cells, insect cells, and mammalian cells. Examples of suitable yeast cells include cells of yeasts of the genus Hansenula, Kluyveromyces, Pichia, Rhinosporidium, Saccharomyces, and Schizosaccharomyces. Suitable insect cells include Sf-9 cells and HIS cells (Invitrogen, Carlsbad, Calif.) and are described in, for example, Kitts et al., Biotechniques, 14: 810-817 (1993); Lucklow, Curr. Opin. Biotechnol., 4: 564-572 (1993); and Lucklow et al., J. Virol., 67: 4566-4579 (1993). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary cells (CHO) (ATCC No. CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)), human embryonic kidney (HEK) 293 cells or 293T cells (ATCC No. CRL1573) and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are monkey COS-1 cell line (ATCC No. CRL1650) and COS-7 cell line (ATCC No. CRL1651) and CV-1 cell line (ATCC No. CCL70). Further exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines.Normal diploid cells, cell lines derived from primary tissue in vitro culture, and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa cells, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from ATCC. Methods for selecting suitable mammalian host cells and methods for transforming, culturing, amplifying, screening, and purifying such cells are well known in the art (see, for example, Ausubel et al., ed., Short Protocols in Molecular Biology, 5th edition, John Wiley & Sons, Inc., Hoboken, NJ (2002)). Preferably, the mammalian cell is a human cell.

[0142] In some embodiments, the carrier may include means for attaching a detection moiety to an anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the carrier may include means for attaching a purification moiety to an anti-ANGPTL7 antibody of the present disclosure. Exemplary detection and / or purification moieties / tags that may be coupled to an anti-ANGPTL7 antibody of the present disclosure include, but are not limited to, hemagglutinin (HA), c-Myc, V5, DYKDDDDK, His tag (e.g., 6x-HIS), glutathione S-transferase (GST), maltose binding protein (MBP), fluorophores (e.g., green fluorescent protein (GFP), red fluorescent protein (RFP), mCherry, chromophores, and / or luminescent peptides (e.g., luciferase).

[0143] In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure to a subject). In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector. In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or comprises an AAV backbone. For example, AAV vectors have been designed, produced, and used to mediate gene delivery in human subjects, including for therapeutic purposes. Typically, AAV vectors for gene transfer comprise a replication-defective AAV genome that lacks functional Rep and Cap encoding viral sequences. Such replication-defective AAV vectors more preferably lack most or all of the Rep and Cap encoding sequences, and substantially retain one or two AAV ITR sequences and packaging sequences. The defective genome is packaged in viral particles to form a defective recombinant AAV virus, also referred to as an "AAV vector." Methods for producing such AAV vectors have been disclosed in the literature, including the use of packaging cells, helper viruses or plasmids and / or baculovirus systems (Samulski et al., (1989) J. Virology 63, 3822; Xiao et al., (1998) J. Virology 72, 2224; Inoue et al., (1998) J. Virol. 72, 7024; WO98 / 22607; WO2005 / 072364). Methods for producing pseudotyped AAV vectors (e.g., WO00 / 28004), as well as various modifications or formulations of AAV vectors that reduce their immunogenicity when administered in vivo (see, e.g., WO01 / 23001; WOOO / 73316; WO04 / 112727; WO05 / 005610; WO99 / 06562) have also been reported. AAV vectors can be prepared from or derived from various serotypes of AAV, and the various serotypes of AAV can even be mixed together or mixed with other types of viruses to produce chimeric (e.g., pseudotyped) AAV viruses. Examples of tAAV are human AAV4 vectors, human AAV7 vectors, human AAV9 vectors, human AAV10 vectors, or bovine AAV vectors. AAV vectors can be derived from a single AAV serotype, or contain sequences or components derived from at least two different AAV serotypes (pseudotyped AAV vectors), such as an AAV vector containing an AAV genome derived from one AAV serotype (e.g., AAV9) and a capsid derived at least in part from a different AAV serotype. As used herein, an AAV vector is a vector comprising at least one component that can be derived from an adeno-associated virus. Preferably, the component is involved in the biological mechanism (e.g., ocular delivery / expression) by which the vector infects or transduces target cells and expresses the anti-ANGPTL7 antibodies of the present disclosure.

[0144] In other embodiments, the expression vector is a lentiviral vector (LV) or comprises a LV backbone. A lentivirus is part of a large class of retroviruses. A detailed list of lentiviruses can be found in Coffin et al. (1997) "Retroviruses" Cold Spring Harbour Laboratory Press, ed.: JM Coffin, SM Hughes, HE Varmus, pp. 758-763). For example, lentiviruses can be divided into primate groups and non-primate groups. Examples of primate lentiviruses include, but are not limited to, human immunodeficiency virus (HIV), pathogens of human autoimmune deficiency syndrome (AIDS), and simian immunodeficiency virus (SIV). The non-primate lentivirus group includes the prototype "slow virus" visna / maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), maedi visna virus (MVV), and bovine immunodeficiency virus (BIV). In one embodiment, the lentiviral vector is derived from HIV-1, HIV-2, SIV, FIV, BIV, EIAV, CAEV or Vesna lentivirus. The lentiviral family differs from retroviruses in that lentiviruses are able to infect both dividing and non-dividing cells (Lewis et al. (1992) EM BOJ 11(8):3053-3058 and Lewis and Emerman (1994) J Virol 68(1):510-516). In contrast, other retroviruses, such as MLV, are unable to infect non-dividing or slowly dividing cells, such as those that constitute, for example, muscle, brain, lung and liver tissue. As used herein, a lentiviral vector is a vector comprising at least one component that is derivable from a lentivirus. Preferably, the component is involved in the biological mechanism by which the vector infects or transduces a target cell and expresses an anti-ANGPTL7 antibody of the present disclosure (e.g., ocular delivery / expression).

[0145] Other compositions and methods for ocular gene therapy can be found in, for example, Bordet, T. and Behar-Cohen, F., "Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives," Drug Discovery Today, Vol. 24, No. 8, August 2019, pp. 1685-1693). In some embodiments, gene therapy platforms, methods, and compositions that can be used to deliver the anti-ANGPTL7 antibodies of the present disclosure to a subject (e.g., ocular delivery) include those disclosed in US20220025396, US20220011308, US20210371877, US20210363192, US20190078099, US20190038724, and US10494646B2, which are incorporated herein by reference. In other embodiments, gene therapy platforms, methods, and compositions useful for delivering the anti-ANGPTL7 antibodies of the present disclosure to a subject (e.g., ocular delivery) include platforms, methods, and compositions based on HMR59 (Hemera Biosciences), which blocks the membrane attack complex formed during the terminal step in the complement cascade through its protein product, soluble CD59. HMR59 is designed to be administered by a single intraocular injection.

[0146] According to these embodiments, the present disclosure also provides a method of administering an ocular gene therapy to a subject in need thereof, the method comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). As further described below, the present disclosure also provides a method of treating glaucoma and other ocular diseases that affect the optic nerve and retinal ganglion cells. In some embodiments, the method comprises administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). In some embodiments, administration of the pharmaceutical composition treats at least one symptom of glaucoma or other ocular diseases that affect the optic nerve and retinal ganglion cells.

[0147] Compositions and methods of treatment

[0148] The anti-ANGPTL7 antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat eye diseases (e.g., glaucoma). In some embodiments, the composition is suitable for ocular administration. In some embodiments, ocular administration comprises injection into the vitreous humor. In some embodiments, ocular administration comprises the use of conjunctival inserts, contact lenses, gels, nanoparticles, mucoadhesive polymers, ointments, solutions, suspensions, eye drops, and / or implants (e.g., Susvimo TM ) to deliver antibodies. Recent methods and formulations for ocular administration can be found, for example, in Souto, EB et al. "Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents," Pharmaceutics, 2019 September; 11(9):460).

[0149] According to these embodiments, the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the pharmaceutical composition is ocularly administered and treats at least one symptom of glaucoma or other ocular diseases affecting the optic nerve and retinal ganglion cells. In some embodiments, the at least one symptom comprises: eye pain, intraocular pressure, headache, the appearance of rainbow-colored halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes. In some embodiments, administering the pharmaceutical composition reduces or alleviates intraocular pressure and / or increases or enhances outflow smoothness in the eye of the subject.

[0150] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 1.0 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 10 mg / dose to about 100 mg / dose. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 10 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.1 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.001 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg / dose to about 10 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg / dose to about 10 mg / dose.

[0151] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 1.0 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 10 mg / ml to about 100 mg / ml. In some embodiments, an anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 10 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.1 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.01 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.001 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg / ml to about 10 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg / ml to about 10 mg / ml.

[0152] As used herein, the terms "treatment", "treating" and the like refer to obtaining a desired pharmacological and / or physiological effect. In some embodiments, the effect is therapeutic, i.e., the effect partially or completely cures the disease and / or adverse symptoms attributable to the disease. To this end, the methods of the present disclosure include administering a "therapeutically effective amount" of an anti-ANGPTL7 antibody or a composition comprising an anti-ANGPTL7 antibody. A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic result at the necessary dosage and time period. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual and the ability of the monoclonal antibody to elicit a desired response in the individual. For example, a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is an amount that treats at least one symptom of glaucoma or other ocular diseases affecting the optic nerve and retinal ganglion cells in a subject. In some embodiments, the pharmacological and / or physiological effect may be preventive, i.e., the effect completely or partially prevents the disease or its symptoms. In this regard, the methods of the present disclosure include administering a "prophylactically effective amount" of an anti-ANGPTL7 antibody or a composition comprising an anti-ANGPTL7 antibody. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result (e.g., prevention of glaucoma or at least one symptom associated with glaucoma).

[0153] Typical dosages of therapeutically effective amounts of anti-ANGPTL7 antibodies of the present disclosure for each eye to be treated may range, for example, from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, therapeutically effective amounts of anti-ANGPTL7 antibodies of the present disclosure may range from about 0.001 mg / dose to about 100 mg / dose, from about 0.01 mg / dose to about 100 mg / dose, from about 0.05 mg / dose to about 50 mg / dose, from about 0.1 mg / dose to about 10 mg / dose, from about 0.5 mg / dose to about 5 mg / dose, and from about 1 mg / dose to about 10 mg / dose. In some embodiments, therapeutically effective concentrations of anti-ANGPTL7 antibodies of the present disclosure may range, for example, from about 0.0001 mg to about 100 mg of antibody per milliliter of solution. In some embodiments, the therapeutically effective concentration of the anti-ANGPTL7 antibodies of the present disclosure may range from about 0.001 mg / ml to about 100 mg / ml, about 0.01 mg / ml to about 100 mg / ml, about 0.1 mg / ml to about 100 mg / ml, about 1.0 mg / ml to about 100 mg / ml, about 0.001 mg / ml to about 50 mg / ml, about 0.01 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 25 mg / ml, about 0.1 mg / ml to about 10 mg / ml, and about 1.0 mg / ml to about 10 mg / ml. In some embodiments, a therapeutically effective dose of an anti-ANGPTL7 antibody of the present disclosure may be exactly or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg, or may fall within a range defined by any two of the foregoing values. For example, in certain embodiments, a sustained release formulation (e.g., an ocular implant) can be exactly or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg of an anti-ANGPTL7 antibody, or an amount falling within a range defined by any two of the foregoing values.

[0154] Therapeutic or prophylactic efficacy can be monitored by periodic assessment of the treated patient. For repeated administrations over several days or longer, depending on the conditions, the treatment is repeated until the desired suppression of disease symptoms occurs. However, other dosage regimens may also be useful and are within the scope of the present disclosure. The desired dose may be delivered by administering the composition as a single bolus, by administering the composition as multiple boluses, or by administering the composition as a continuous infusion. The composition comprising an anti-ANGPTL7 antibody or antigen-binding fragment thereof can be administered to a mammal using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. The composition is preferably suitable for ocular administration.

[0155] In accordance with the compositions and treatment methods described herein, embodiments of the present disclosure include anti-ANGPTL7 antibodies with enhanced half-life (e.g., after ocular administration), such that the anti-ANGPTL7 antibodies can be administered to a subject less frequently. In some embodiments, the antibody comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises a polypeptide that can be coupled to the anti-ANGPTL7 antibody of the present disclosure by any means known in the art (e.g., generation of a fusion protein). In some embodiments, the polypeptide that can be coupled to the anti-ANGPTL7 antibody of the present disclosure is at least 20 amino acids in length and comprises any combination of G, A, ST, E, and P residues. In some embodiments, the half-life extending polypeptide is linked to the C-terminus or N-terminus of the antibody. In some embodiments, this is referred to as "XTENylation" as further described in US8933197, US7846445, US7855279, US8492530, US9938331, US8673860, US9371369, US9926351, US10961287, US10172953, and US10953073.

[0156] The present disclosure also provides a composition comprising any anti-ANGPTL7 antibody or antigen-binding fragment thereof described herein. The composition is desirably a pharmaceutically acceptable (e.g., physiologically acceptable) composition comprising a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and an anti-ANGPTL7 antibody or antigen-binding fragment thereof. Any suitable carrier may be used in the context of the present disclosure, and such carriers are well known in the art. For example, the composition may contain a preservative, such as, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives may optionally be used. In addition, a buffer may be included in the composition. Suitable buffers include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffers may optionally be used. Methods for preparing compositions for pharmaceutical use are known to those skilled in the art and are described, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st Edition (May 1, 2005).

[0157] Once administered to a mammal (e.g., a human), the biological activity of the anti-ANGPTL7 antibody or antigen-binding fragment thereof can be measured by any suitable method known in the art. For example, the biological activity can be assessed by determining the stability of the anti-ANGPTL7 antibody. The biological activity of the anti-ANGPTL7 antibody can also be assessed by determining its binding affinity for the ANGPTL7 peptide and / or by assessing its binding affinity for peptides that may cross-react with it. The term "affinity" refers to the equilibrium constant for reversible binding of two agents and is expressed as the dissociation constant ( KD ). The affinity of a binding agent for a ligand, such as an antibody for an epitope, can be, for example, about 1 femtomolar (fM) to about 1 millimolar (mM) (e.g., about 1 picomolar (pM) to about 1 nanomolar (nM) or about 1 nM to about 1 micromolar (μM)). In some embodiments, the affinity of an anti-ANGPTL7 antibody can be about 1 nm to about 20 nm, and desirably about 5 nm to about 10 nm. The affinity of an antibody for an antigen or epitope of interest can be measured using any art-recognized assay. Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, NY, 2001).

[0158] In some embodiments, an anti-ANGPTL7 antibody or a composition comprising an anti-ANGPTL7 antibody may be administered alone or in combination with other drugs / therapeutic agents. For example, an anti-ANGPTL7 antibody may be administered in combination with other agents for treating or preventing glaucoma or other eye diseases affecting the optic nerve or retinal ganglion cells as disclosed herein. For example, an anti-ANGPTL7 antibody or an antibody conjugate, fusion protein, or polymer formulation thereof of the present disclosure may be used alone or in combination with other agents in therapy. For example, an anti-ANGPTL7 antibody may be co-administered with at least one other therapeutic agent. In certain embodiments, the other therapeutic agent is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressant, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiation therapy, a corticosteroid, an antiemetic, a cancer vaccine, an analgesic, a growth inhibitory agent, or a combination thereof.

[0159] In certain embodiments, the anti-ANGPTL7 antibodies of the present disclosure are administered with a drug / therapeutic agent for treating / preventing glaucoma or other ocular diseases affecting the optic nerve or retinal ganglion cells. Any suitable glaucoma therapeutic agent may be administered as an additional therapeutic agent in combination with the anti-ANGPTL7 antibodies of the present disclosure, or antibody conjugates, fusion proteins, and / or polymer formulations thereof, to treat an ocular disorder (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells). For example, in some embodiments, an anti-ANGPTL7 antibody of the disclosure may be administered with an agent that reduces intraocular pressure by promoting drainage of intraocular fluid, including, but not limited to, prostaglandins (e.g., Xalatan (latanoprost), Travatan Z (travoprost), Zioptan (tafluprost), and Lumigan (bimatoprost)), Rho kinase inhibitors (e.g., Rhopressa (netarsudil)), nitric oxide (e.g., Vyzulta (latanoprostenebunod)), and miotic or cholinergic agents (e.g., Isopto Carpine (pilocarpine)). In some embodiments, an anti-ANGPTL7 antibody of the present disclosure may be administered with an agent that reduces intraocular pressure by reducing the amount of fluid produced in the eye, including, but not limited to, alpha-adrenergic agonists (e.g., Iopidine (apraclonidine) and Alphagan P or Qoliana (brimonidine)), beta blockers (e.g., Betoptic (betaxolol) and Betimol, Istalol, or Timoptic (timolol)), and carbonic anhydrase inhibitors (e.g., Trusopt (dorzolamide) and Azopt (brinzolamide)). Furthermore, one or more of these therapeutic agents may be administered with an anti-ANGPTL7 antibody of the disclosure and in combination with other treatments, such as laser therapy (e.g., trabeculoplasty) and surgery (e.g., glaucoma implant surgery and minimally invasive glaucoma surgery (MIGS)).

[0160] In some embodiments, an anti-ANGPTL7 antibody, antibody conjugate, fusion protein, or polymer formulation of the present disclosure is administered simultaneously with other therapeutic agents. In some embodiments, an anti-ANGPTL7 antibody, antibody conjugate, fusion protein, or polymer formulation of the present disclosure is administered before or after other therapeutic agents. In some embodiments, the additional therapeutic agent binds to a second biomolecule selected from the group consisting of VEGF, IL-1β; IL-6; IL-6R; IL-13; IL-13R; PDGF; angiopoietin; Ang2; Tie2; S1P; integrins αvβ3, αvβ5, and α5β1; betacellulin; apelin / APJ; erythropoietin; complement factor D; TNFα; HtrA1; VEGF receptor; ST-2 receptor; and proteins genetically associated with AMD risk, such as complement pathway component C2, factor B, factor H, CFHR3, C3b, C5, C5a, and C3a; HtrA1; ARMS2; TIMP3; HLA; interleukin-8 (IL-8); CX3CR1; TLR3; TLR4; CETP; LIPC; COL10A1; and TNFRSF10A. In some embodiments, the additional therapeutic agent is an antibody or antigen-binding fragment thereof. In some embodiments according to (or as applied to) any of the embodiments above, the ocular disorder is an intraocular neovascular disease selected from the group consisting of proliferative retinopathy, choroidal neovascularization (CNV), glaucoma, diseases affecting the optic nerve, diseases affecting retinal ganglion cells, diabetes and other ischemia-related retinopathy, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, retinal vein occlusion (RVO), including CRVO and BRVO, corneal neovascularization, retinal neovascularization, and retinopathy of prematurity (ROP).

[0161] In some embodiments, the anti-ANGPTL7 antibodies or antibody conjugates, fusion proteins and / or polymer formulations thereof of the present disclosure may be administered in combination with at least one other therapeutic agent to treat an ocular disorder, such as an ocular disorder described herein (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells). Exemplary other therapeutic agents for combination therapy to treat an ocular disorder include, but are not limited to, anti-angiogenic agents such as VEGF antagonists, including, for example, anti-VEGF antibodies (e.g., anti-VEGF Fab (ranibizumab)), soluble receptor fusion proteins (e.g., recombinant soluble receptor fusion proteins (aflibercept, also known as VEGF Trap Eye; Regeneron / Aventis)), aptamers (e.g., anti-VEGF PEGylated aptamers (pegaptanib sodium; NeXstar Pharmaceuticals / OSI Pharmaceuticals)) and VEGFR tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787), semaglutide (SU5416; SUGEN), and (sunitinib); tryptophanyl-tRNA synthetase (TrpRS); squalamine; (anecortave acetate for extended-release suspension; Alcon, Inc.); Combretastatin A4 prodrug (CA4P); (mifepristone-ru486); subtenon triamcinoloneacetonide; intravitreal crystalline triamcinoloneacetonide; matrix metalloproteinase inhibitors (e.g., Prinomastat (AG3340; Pfizer)); fluocinolone acetonide (including fluocinolone acetonide intraocular implant; Bausch & Lomb / Control Delivery Systems); linomide; inhibitors of integrin β3 function; angiostatin and combinations thereof.

[0162] Further examples of other therapeutic agents that can be used in combination with the anti-ANGPTL7 antibodies or antibody conjugates, fusion proteins and / or polymer formulations of the present disclosure to treat ocular disorders (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells) include, but are not limited to (verteporfin; a light-activated drug that is often used in combination with photodynamic therapy using nonthermal lasers), PKC412, Endovion (NS 3728; NeuroSearch A / S), neurotrophic factors (e.g., glial-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF)), diltiazem, dorzolamide, 9-cis-retinal, ophthalmic agents (e.g., phospholineiodide, echothiophate, or carbonic anhydrase inhibitors), velvostat (AE-941; AEterna Laboratories, Inc.), Sirna-027 (AGF-745; Sirna Therapeutics, Inc.), neurotrophic factors (including, by way of example only, NT-4 / 5, Genentech), Cand5 (Acuity Pharmaceuticals), INS-37217 (Inspire Pharmaceuticals), integrin antagonists (including those from Jerini AG and Abbott Laboratories), EG-3306 (Ark Therapeutics Ltd.), BDM-E (BioDiem Ltd.), thalidomide (e.g., as used by EntreMed, Inc.), cardiotrophin-1 (Genentech), 2-methoxyestradiol (Allergan / Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), tetrathiomolybdate (University of Michigan), LYN-002 (Lynkeus Biotech), microalgae compounds (Aquasearch / Albany, Mera Pharmaceuticals), D-9120 (Celitech Group plc), ATX-S10 (Hamamatsu Photonics), TGF-β2 (Genzyme / Celtrix), tyrosine kinase inhibitors (e.g., those from Allergan, SUGEN, or Pfizer), NX-278-L (NeXstar Pharmaceuticals / Gilead Sciences), Opt-24 (OPTIS France SA), retinal cell ganglion neuroprotectants (Cogent Neurosciences), N-nitropyrazole derivatives (Texas A&M University System), KP-102 (Krenitsky Pharmaceuticals), cyclosporine A, therapeutic agents used in photodynamic therapy (e.g. Receptor-targeted PDT, Bristol-Myers Squibb, Co.; porfimer sodium for injection with PDT; verteporfin, QLT Inc.; rostaporfin with PDT, Miravent Medical Technologies; talaporfin with PDT, Nippon Petroleum; and motexafin lutetium, Pharmacyclics, Inc.), antisense oligonucleotides (including, for example, products tested by Novagali Pharma SA and ISIS-13650 of Isis Pharmaceuticals), and combinations thereof.

[0163] The anti-ANGPTL7 antibodies or antibody conjugates, fusion proteins and / or polymer formulations of the present disclosure may be administered in combination with therapy or surgery to treat an ocular disorder (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells), including, for example, laser photocoagulation (e.g., panretinal photocoagulation (PRP)), drusen laser, macular hole surgery, macular translocation surgery, implantable micro-macular lenses, PHI-motion angiography (also known as micro-laser therapy and feeding vessel therapy), proton beam therapy, microstimulation therapy, retinal detachment and vitreous surgery, scleral buckling, submacular surgery, transpupillary thermotherapy, photosystem I therapy, use of RNA interference (RNAi), in vitro rheotherapy (also known as filtration and rheotherapy of membrane differentiation), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy against hypoxia response elements, Oxford Biomedica; Lentipak, Genetix; and PDEF Gene Therapy, GenVec), photoreceptor / retinal cell transplantation (including transplantable retinal epithelial cells, Diacrin, Inc.; retinal cell transplants, Cell Genesys, Inc.), acupuncture, and combinations thereof.

[0164] In some embodiments, the anti-ANGPTL7 antibodies or antibody conjugates, fusion proteins and / or polymer formulations of the present disclosure may be administered in combination with an anti-angiogenic agent to treat an ocular disorder (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells). Any suitable anti-angiogenic agent may be used in combination with the antibodies of the present disclosure, including but not limited to those listed in Carmeliet et al., Nature 407:249-257, 2000. In some embodiments, the anti-angiogenic agent is a VEGF antagonist, including but not limited to: anti-VEGF antibodies (e.g., anti-VEGF Fab (ranibizumab), RTH-258 (formerly known as ESBA-1008, an anti-VEGF single-chain antibody fragment; Novartis) or a bispecific anti-VEGF antibody (e.g., an anti-VEGF / anti-Angiopoietin 2 bispecific antibody such as RG-7716; Roche)), a soluble recombinant receptor fusion protein (e.g., (aflibercept), VEGF variants, soluble VEGFR fragments, aptamers capable of blocking VEGF (e.g., pegaptanib) or VEGFR, neutralizing anti-VEGFR antibodies, small molecule inhibitors of VEGFR tyrosine kinase, anti-VEGF (e.g., abicipar pegol), small interfering RNA that inhibits VEGF or VEGFR expression, VEGFR tyrosine kinase inhibitors (e.g., 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474)), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787), semaglutide (SU5416; SUGEN), and (sunitinib) and combinations thereof.

[0165] Other suitable anti-angiogenic agents that can be administered in combination with the antibodies or antibody conjugates, fusion proteins and / or polymer formulations of the present disclosure to treat ocular disorders (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells) include corticosteroids, angiostatic steroids, anecortave acetate, angiostatin, endostatin, tyrosine kinase inhibitors, matrix metalloproteinase (MMP) inhibitors, insulin-like growth factor binding protein 3 (IGFBP3), stromal derived factor (SDF-1) antagonists (e.g., anti-SDF-1 antibodies), pigment epithelium derived factor (PEDF), γ-secretase, delta-like ligand 4, integrin antagonists, hypoxia-inducible factor (HIF)-1α antagonists, protein kinase CK2 antagonists, agents that inhibit homing of stem cells (e.g., endothelial progenitor cells) to sites of neovascularization (e.g., anti-vascular endothelial cadherin (CD-144) antibodies and / or anti-SDF-1 antibodies), and combinations thereof.

[0166] In some embodiments, the anti-ANGPTL7 antibodies or antibody conjugates, fusion proteins and / or polymer formulations of the present disclosure may be administered in combination with an agent having anti-neovascularization activity to treat an ocular disorder (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells), such as an anti-inflammatory drug, a mammalian target of rapamycin (mTOR) inhibitor (e.g., rapamycin, (everolimus) and (temsirolimus), cyclosporine, tumor necrosis factor (TNF) antagonists (e.g., anti-TNFα antibodies or antigen-binding fragments thereof (e.g., infliximab, adalimumab, certolizumab pegol, and golimumab) or soluble receptor fusion proteins (e.g., etanercept)), anti-complement agents, nonsteroidal anti-inflammatory agents (NSAIDs), or combinations thereof.

[0167] In addition to therapeutic uses, the anti-ANGPTL7 antibodies or antigen-binding fragments described herein can also be used in diagnostic or research applications. Research applications include, for example, methods using anti-ANGPTL7 antibodies and labels to detect ANGPTL7 polypeptides or proteins in a sample (e.g., in a human body fluid or a cell or tissue extract). The anti-ANGPTL7 antibodies or antigen-binding fragments thereof can be used in any suitable assay to measure ANGPTL7 in a sample for diagnostic and / or research purposes. Such assays include, but are not limited to, sandwich immunoassays, enzyme immunoassays (EIA), enzyme-linked immunosorbent assays (ELISA), lateral flow assays, competitive inhibition immunoassays (e.g., forward and reverse), competitive binding assays, Forster resonance energy transfer (FRET), one-step antibody detection assays, single molecule detection assays, radioimmunoassays (RIA), and FACS. Such methods are disclosed, for example, in U.S. Patents 6,143,576; 6,113,855; 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; 5,885,527; 5,851,776; 5,824,799; 5,679,526; 5,525,524 and 5,480,792; and Adamczyk et al., Anal. Chim. Acta, 579(1):61-67 (2006).

[0168] The anti-ANGPTL7 antibody or antigen-binding fragment thereof can be provided in a kit, e.g., a packaged combination of predetermined amounts of reagents and instructions for performing an assay (e.g., an assay to detect ANGPTL7) using the antibody. Thus, the present disclosure provides a kit comprising the antibodies or antigen-binding fragments described herein and instructions for use thereof. The instructions can be in paper form or in a computer-readable form, such as a disk, CD, DVD, etc. Alternatively or in addition, the kit can include a calibrator or control, and / or at least one container (e.g., a tube, microtiter plate, or test strip) for performing the assay, and / or a buffer, such as an assay buffer or a wash buffer. Ideally, the kit contains all components necessary to perform the assay, i.e., reagents, standards, buffers, diluents, etc. Other additives may be included in the kit, such as stabilizers, buffers (e.g., blocking buffers or lysis buffers), etc. The relative amounts of the various reagents can be varied to provide concentrations in the reagent solution, thereby significantly optimizing the sensitivity of the assay. The reagents can be provided in the form of a dry powder (usually a lyophilized powder), including excipients that will provide a reagent solution having an appropriate concentration when dissolved.

[0169] The following examples further illustrate various embodiments of the present disclosure but should not be construed as limiting the scope thereof in any way.

[0170] Example

[0171] It will be apparent to those skilled in the art that other suitable modifications and adaptations of the disclosed methods described herein are readily applicable and understandable, and may be performed using suitable equivalents without departing from the scope of the disclosure or the aspects and embodiments disclosed herein. Having now described the disclosure in detail, it will be more clearly understood by reference to the following examples, which are intended only to illustrate some aspects and embodiments of the disclosure and should not be construed as limiting the scope of the disclosure. All journal references, U.S. patents, and published disclosures cited herein are hereby incorporated by reference in their entirety.

[0172] The present disclosure has several aspects, which are illustrated by the following non-limiting examples.

[0173] Example 1

[0174] This example describes dexamethasone-induced changes in gene expression in primary human trabecular meshwork cells. Primary trabecular meshwork cells isolated from postmortem human donors were treated with dexamethasone (DEX). Figure 1 As shown, changes in ANGTPL7 gene expression relative to vehicle were quantified using qPCR. Using these data, strong DEX responders were selected for future studies, such as RNAseq.

[0175] Specifically, primary human trabecular meshwork cells were passaged in DMEM containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. The cells were seeded in 96-well plates at 20,000 cells / well. The medium was changed 3 times a week. After 1 week, the cells were further differentiated using DMEM containing 1% FBS and 1% penicillin / streptomycin. The cells were incubated with low serum for at least 1 week, and the medium was changed 3 times a week.

[0176] For dexamethasone (DEX) treatment, the medium was removed and replaced with medium containing 100 nM DEX or 0.1% ethanol (EtOH, vehicle). The medium was renewed after 2 to 3 days, and cells were harvested for qPCR using the Cells to Ct kit on day 5. qPCR was run using the ANGPTL7 TaqMan assay from Life Technologies on a Quantstudio6 qPCR machine. Gene expression was normalized to the EtOH control.

[0177] Example 2

[0178] This example describes RNAseq analysis of gene expression changes in human trabecular meshwork (TM) and Schlemm's Canal (SC) cells induced by ANGPTL7 treatment. Figure 2). Briefly, primary human trabecular meshwork and Schlemm's canal cells were passaged in DMEM containing 10% fetal bovine serum (PBS) and 1% penicillin / streptomycin. Cells were seeded at 200k cells / well in 6-well plates. The cells were differentiated in low serum for one week, and the medium was changed 3 times a week. For ANGPTL7 treatment, the medium was removed and replaced with medium containing 50ng / mL ANGPTL7 protein prepared by BIORTUS. The treatment medium was renewed daily for three days. After three days, the cells were spun down and frozen into pellets, and then stored in a -80°C freezer until shipped to SeqMatic for processing.

[0179] Example 3

[0180] Experiments were performed to determine the effect of ANGPTL7 on outflow smoothness in a bioengineered ex vivo human ocular tissue model. Glauconix has developed a proprietary technology that allows for co-cultured bioengineered 3D human trabecular meshwork (HTM) cells to be grown in multiple layers with human Schlemm's canal (HSC) cells, mimicking the tissue structure responsible for pressure accumulation in the eye (Figure 3A). This allowed for endpoint analysis related to IOP regulation. This cell scaffold was used to compare the therapeutic effects of vehicle (DMSO), dexamethasone (a steroid known to raise IOP), and human ANGPTL7 protein on outflow smoothness.

[0181] In brief, HTM cells were thawed and allowed to grow for about 7 days (with medium changed every 2 days). HTM cells were seeded onto the scaffold and HSC cells were thawed on the same day; HTM cells were allowed to grow on the scaffold for 7 days, with medium changed every 2 days. HSCs were co-cultured on the back of the HTM scaffold and grown for 10 to 12 days, with medium changed every 2 days. One day before treatment, the HTM / HSC constructs were serum starved in 1% medium. The first day of treatment was called day 0. On day 3, supernatants were collected, reprocessed, and the process was repeated on days 6 and 9. Perfusion was performed on day 10.

[0182] FIG3B includes representative data showing the outflow fluency of 3D-HTM donor 2 treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=4 per treatment group. FIG3C includes representative data showing the outflow fluency of 3D-HTM donor 3 treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7. Samples were analyzed using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001 N=4 per treatment group. These data show that, similar to DEX treatment, ANGPTL7 treatment reduced the outflow fluency of both donors.

[0183] Example 4

[0184] Experiments were conducted using bioengineered ex vivo human ocular tissue models to determine the effects of ANGPTL7 on outflow smoothness. Glauconix has developed a proprietary technology that allows for multi-layered growth of co-cultured bioengineered 3D human trabecular meshwork (HTM) cells with human Schlemm's canal (HSC) cells, thereby mimicking the tissue structure responsible for pressure accumulation in the eye ( FIG. 3A ; see also exemplary scheme in Example 3 ). This allows for endpoint analysis related to IOP regulation.

[0185] This experiment compared the effects of three different doses (25ug / ml, 50ug / ml and 150ug / ml) of ANGPTL7 protein on the outflow fluency in three different donor HTM cell lines (Figure 4A to Figure 4C). In this example, the experiment focused on the reproducibility of the effect of ANGPTL7 on the outflow fluency (from SOW1) in three different HTM donors and the dose-response effect.

[0186] Example 5

[0187] Generation of Recombinant ANGPTL7 Proteins. Recombinant protein production is performed to generate specific proteins that can be used as immunogens / antigens, screening agents, and / or control agents. All efforts are directed toward the goal of generating a panel of anti-ANGPTL7 antibodies with desired properties. In this particular example, outsourcing materials produced by Biortus were used for human ANGPTL7 multimers, while protein engineering was used to generate mutant human monomers. A truncated but non-engineered wild-type fibrinogen domain-only human ANGPTL7 monomer was also generated.

[0188] Proteins with sequences corresponding to human, African green monkey, and rabbit ANGPTL7 were produced. The human and African green monkey sequences were engineered to favor the production of monomeric material, while the rabbit protein was a mixture of monomers, trimers, and hexamers. Upon completion, all protein preparations were greater than 90% pure and had less than <1 endotoxin unit per mL by analytical methods.

[0189] Starting with the in silico analysis, the appropriate wild-type amino acid sequences of human, rabbit, and African green monkey ANGPTL7 were found and extracted from publicly available databases. The sequences were then further analyzed and manually modified using Geneious Prime software according to the experimental plan. Specifically, with regard to the generation of monomeric ANGPTL7, the mechanism of multimerization was carefully examined. Structurally, ANGPTL7 consists of two domains, a small N-terminal coiled-coil domain and a larger C-terminal fibrinogen-like domain. The N-terminal region was identified as a focus region for engineering monomeric mutants, given its similarity to fibrinogen at the domain level, previously published research results, and the well-established biological function of the coiled-coil domain. The coiled-coil domain follows a well-defined heptad repeat sequence of hydrophobic charged amino acids. This repeat sequence, combined with the property of approximately seven amino acids per two turns of the alpha helix and the aqueous environment of the extracellular or intracellular space, favors packing of the hydrophobic side chains into the interior of the helix, with the charged amino acids facing the aqueous environment. Since each linear alpha helix depends on the others to achieve an energetically favorable "stacking" state, dimers, trimers, or other higher order multimers can result. Approaches that disrupt linear and / or hydrophobic charged heptapeptides may result in monomers. Two strategies were designed based on this theoretical framework. Constructs replacing leucine with proline at amino acid positions 59 and 84 or replacing leucine at position 59 with glycine-glycine-proline-glycine-glycine were constructed in silico and added to the sequence panel designed for the project. Replacing the leucine at position 59 with five amino acids proved to be the most successful. Version A In addition, a truncated form of human ANGPTL7 corresponding only to the C-terminal fibrinogen-like domain sequence was added to the sequence panel.

[0190] All sequences were checked for defects and modified to add further amino acid sequences encoding "tags" that facilitate purification, reduce immunogenicity, or simplify analytical screening. Examples of protein tags used in this study include HIS tags and Avi tags. The tags were separated from each other and from the ANGPTL7 sequence by a short linker sequence. All tags were added to the C-terminus of the sequence. In addition, the native signal peptide was removed and replaced with a signal peptide that facilitates recombinant expression.

[0191] After all modifications were completed, the amino acid sequence was translated back into the DNA sequence, and the codon bias found in the human genome was optimized. These optimized DNA sequences were sent to Integrated DNA Technologies, and produced DNA fragments with DNA overhangs added to the 5' end and 3' end. Utilize DNA overhangs and Gibson cloning method, these DNA fragments are assembled into expected sequences, and cloned into the mammalian expression plasmid driven by the CMV promoter. Use appropriate antibiotics to select that plasmids are bred in E.coli, and utilize the commercially available preparation kit purchased from Qiagen to prepare on a scale that can be used for recombinant expression. Use Sanger sequencing to confirm the sequence of plasmids and expressed genes then.

[0192] Using polyethyleneimine, the sequence-verified plasmid is transfected into human embryonic kidney cells suitable for recombinant expression. One day after transfection, the cells are supplemented with chemicals and nutrients designed to increase the expression of recombinant proteins. These supplements include sodium propionate, valproic acid, glucose, glutamine and a variety of yeast lysates. After transfection for five days, the expression cell culture is harvested. When the recombinant protein is secreted into the growth medium, cells, cell fragments and cell debris are removed via centrifugation and filtration through a membrane having a pore size of no more than 0.22 microns. The clarified culture medium regulated with the recombinant protein is now ready for purification. Using FPLC (fast pressurized liquid chromatography) and appropriate commercially available pre-loaded affinity chromatography columns (for C-terminal tags), the protein of interest is purified from the cell culture medium and fixed on a chromatographic column. For HIS-tagged proteins, Ni-NTA agarose columns are used. Subsequently, multiple column washings are carried out, and each washing is directed to the type of column / label / chromatogram. For HIS-tagged proteins, the protein of interest is eluted from the column with 300mM imidazole.

[0193] The quality and quantity of the proteins were assessed using a combination of SDS-PAGE gel electrophoresis, spectrophotometry, and analytical-SEC (size exclusion chromatography). Most of the proteins used for this project required further purification. To further modify the proteins, FPLC and a second column were employed. Size separation was accomplished with a size exclusion column, which enabled protein purity to be increased to >90%. SEC also enabled buffer exchange between the affinity chromatography elution buffer and the final selected buffer (PBS). The protein samples were then quality controlled. If an increase in protein concentration was required at any point during purification, the protein was concentrated by separating it from the buffer using an Amicon Ultra molecular weight cutoff (MWCO) filter device. The MWCO was selected to ensure compatibility with the size of the protein of interest. All final samples were concentrated to >1 mg / mL before entering final quality control.

[0194] Endotoxin contamination in the final protein sample was determined using Charles River's Endosafe PTS system. Final protein concentration was determined spectrophotometrically. Three micrograms of the final sample was injected onto an analytical SEC column (YMC Diol 300) to determine its final purity. In addition, SDS-PAGE electrophoresis was sometimes performed to determine the final quality. Once all final indicators were passed, the protein was sterilized using a 0.22 micron sterile filter in a biosafety cabinet. It was then aseptically aliquoted and flash frozen in liquid nitrogen and then stored at -80°C.

[0195] Example 6

[0196] ANGPTL7 antibody sequences were recovered from immunized mice. ANGPTL7 Immunization: Four cohorts of Alloy Therapeutic transgenic humanized mice ATX-GK were immunized with various human ANGPTL7 antigens using a standard 5-week RIMMS regimen: 10 μg of antigen emulsified in complete Freund's adjuvant was administered subcutaneously first, followed by weekly subcutaneous administration of antigen emulsified in incomplete Freund's adjuvant for 5 weeks.

[0197] Cohort 1: Three ATX-GK mice immunized with the human ANGPTL7 fibrinogen domain (ATX-P-60; SEQ ID NO: 373). Cohort 2: Three ATX-GK mice immunized with the full-length human ANGPTL7 monomer variant L59P_L84P (ATX-P-62; SEQ ID NO: 371). Cohort 3: Three ATX-GK mice immunized with the full-length human ANGPTL7 monomer variant L59 GGPGG (ATX-P-63; SEQ ID NO: 372). Cohort 4: Three ATX-GK mice immunized with human wild-type ANGPTL7 multimer (PExt-1; SEQ ID NO: 374).

[0198] Blood samples were collected at week 4 and tested for antigen-positive serum titers and purification tag-negative serum titers by ELISA. ELISA plates were coated with 1 ug / ml of ANGPTL7 immunogen or an unrelated protein with the same purification tag as the immunogen. The antigen-coated plates were incubated with seven 10-fold serial dilutions of serum starting at 1:300. Antibodies bound to the antigen were detected by anti-mouse IgG HRP secondary antibody and one-step TMB solution. The absorbance signal at 450 nm was measured using an ELISA microplate reader (Figures 5A to 5D).

[0199] Hybridomas: Immune tissues from high titer mice were harvested and stored for antibody discovery. Hybridoma cell lines producing ANGPTL7 antibodies were generated by fusing single B cells from the spleen and lymph nodes of titer-positive mice with myeloma cells. Twenty 96-well plates of hybridoma fusions were generated and expanded. Hybridomas expressing ANGPTL7-specific antibodies were tested for antigen binding by ELISA. The affinity of antibodies in hybridoma supernatants was measured by SPR using an Octet instrument. ANGPTL7 antibodies in hybridoma supernatants were loaded onto the biosensor. The response was measured as a nm shift in the interference pattern and was proportional to the amount of antibody bound to the biosensor surface. The binding interaction of ANGPTL7 with the immobilized antibody was measured as association (kon). After analyte association, the biosensor was immersed in PBS without ANGPTL7 and the bound antigen was allowed to dissociate from the antibody (kdis). KD(M), or the affinity of the antibody for ANGPTL7, was measured as kdis / kon.

[0200] The heavy and light chains of validated hybridomas were sequenced. RNA was isolated from hybridomas secreting ANGPTL7 antibodies, and the heavy and light chain variable regions were cloned by reverse transcription using gene-specific primers followed by PCR amplification with variable chain gene-specific primers. The PCR products were sequenced by standard Sanger sequencing methods.

[0201] Phage display: Variable heavy and light chains were amplified from spleens of high titer immunized mice by reverse transcription using gene-specific primers followed by PCR amplification with variable chain gene-specific primers. The variable regions were cloned into a phage display vector designed to express Fab on phage g3p protein. The phage library expressing unique Fabs was amplified and purified. Phages were allowed to bind to biotinylated ANGPTL7 antigen captured on streptavidin magnetic beads. Phages still bound to the antigen beads after several stringent washes were eluted using alkaline triethylamine solution and neutralized with Tris buffer, pH 8.0. The eluted phages were reinfected into TG1 bacterial cells, amplified by co-infection with M13 helper phage, and purified by PEG precipitation. Purified phage expressing Fabs were selected for antigen binding as described. The second round of phages were diluted and infected into TG1 cells. The polyclonal pool of phages generated from the two rounds of panning was tested by ELISA to confirm that the pool contained ANGPTL7-specific phages. The variable heavy and light chain regions of individual infected bacterial colonies were sequenced using rolling circle amplification and standard Sanger sequencing.

[0202] Antibody Sequencing: Unique variable heavy and light chain pairs from hybridomas and phage display activities were cloned into vectors designed to express full-length antibodies as IgG in HEK293 cells under the control of a CMV promoter. The antibody expression vectors were complexed with polyethyleneimine and transfected into HEK293 cultures. After shaking at 37°C for 5 days in 293 cell culture medium, the antibodies were captured on agarose-based protein A resin. After several stringent washes, the antibodies were eluted in a glycine solution at pH 3, neutralized with Hepes at pH 9, and the buffer was exchanged to PBS.

[0203] Example 7

[0204] Differential scanning fluorimetry (DSF) of human ANGPTL7 monoclonal antibody. The development of effective monoclonal antibodies depends not only on their biological activity, but also on their physicochemical properties, such as homogeneity and stability. The stability of mAbs may be affected by their formulation. Among the many techniques used to study mAb stability, differential scanning fluorimetry (DSF) provides excellent throughput and minimal material consumption. DSF measures the temperature (Tm) of protein unfolding transition based on changes in fluorescence intensity of environmentally sensitive dyes.

[0205] Experiments were performed to evaluate the thermal stability of the human ANGPTL7 monoclonal antibodies ("ATX" antibodies) of the present disclosure by determining the melting temperature. Thermal stability was evaluated via differential scanning fluorimetry (DSF) using the Protein Thermal Shift (PTS) assay from Applied Biosystems. The assay was performed according to the manufacturer's instructions. Briefly, the antibodies to be evaluated were prepared in triplicate by mixing them with a protein thermal shift dye and buffer; real-time melting experiments were performed from 25°C to 95°C on a QuantStudio 3. Data were analyzed by using the Protein Thermal Shift software, and the melting temperature (Tm) was calculated from the melting curves (Table 1).

[0206] Table 1: DSF analysis of human anti-ANGPTL7 monoclonal antibodies.

[0207]

[0208]

[0209] Example 8

[0210] ANGPTL7 Antibody Cross-Blocking. A high-throughput epitope binning experiment was performed on a real-time label-free biosensor (Carterra LSA) to sort a large number of mAbs into bins based on their ability to block each other from binding to the antigen. In paired epitope binning analysis, antigen and antibody 2 (analyte antibody) were sequentially applied to a sensor chip (HC200M) covalently preloaded with antibody 1 (ligand antibody). An increase in response after exposure to the analyte antibody indicates the absence of competition between the two antibodies, while a lack of change in the signal indicates the presence of competition. Antibodies with the same blocking characteristics to other antibodies in the test set were grouped into a bin. Community network diagrams were used to explore clustering of mAbs with similar, but not necessarily identical, competition characteristics.

[0211] Unlike the bin network plots that do not strictly rely on the sandwich / blocking assignments in the heat map (Figure 6A), hierarchical clustering was applied to the sorted heat map to generate various dendrograms and network plots that progressively grouped mAbs based on various binning parameters. (Figures 6B to 6I). Figure 6B includes data from a granular binning network. Figure 6C: includes data from a combined binary dendrogram (colors represent bins in a community binning network). Figure 6D includes data from a community binning network. Figure 6E includes binning data based on affinity for huANGPTL7-his (P62). Figure 6F includes binning data based on antibody source (hybridoma or phage). Figure 6G includes binning data based on fibrinogen domain (P60P) binding. Figure 6H includes binning data based on rabbit ANGPTL7 (p66) binding. Figure 6I includes binning data based on mouse ANGPTL7 binding.

[0212] Example 9

[0213] ANGPTL7 functional assessment. Experiments were performed using a 3D HTM / HSC tissue model to test the effects of anti-ANGPTL7 antibodies on conventional outflow smoothness (see Figure 3A / Example 3). The purpose of this study was to screen antibodies that bind to ANGPTL7 to determine whether the antibodies can block ANGPTL7 inhibition of outflow smoothness in an organoid model of aqueous humor outflow tracts. Antibodies that can increase outflow smoothness by blocking ANGPTL7 activity are candidate drugs worthy of further study.

[0214] The studies were conducted using the bioengineered ex vivo human outflow tract model described above. Glauconix has developed a proprietary technology that allows for co-cultured bioengineered 3D human trabecular meshwork (HTM) cells to be grown in multiple layers with human Schlemm's canal (HSC) cells, mimicking the tissue structure responsible for intraocular pressure accumulation. This allows for endpoint analysis related to IOP regulation. The previous experiments described above showed that both dexamethasone and ANGPTL7 significantly reduced outflow smoothness in the 3D human tissue model. In this experiment, the effects of 20 anti-ANGPTL7 antibodies on outflow smoothness treated with ANGPTL7 were studied.

[0215] like Figure 7 As shown, the outflow fluency of one donor cell line treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7 alone (1.1 nM), 50 ng ANGPTL7 + isotype control antibody (330) at 11.1 nM, and 20 different anti-ANGPTL7 antibodies with 50 ng / mL ANGPTL7 at 11.1 nM. The effect of samples on the isotype control (330) was analyzed using a one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA), *P<0.05, **P<.0.01, ***P<.001, ****P<.0001 N=3 per treatment group. These data clearly demonstrate the efficacy of the anti-ANGPTL7 antibodies of the present disclosure in restoring outflow fluency.

[0216] Example 10

[0217] ANGPTL7 Antibody Kinetics. Experiments were performed to determine the reactivity and dissociation constant of anti-ANGPTL7 antibodies with the human fibrinogen domain of the ANGPTL7 protein ( KD Binding experiments were performed on Octet HTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. Antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in monovalent P60 (huANGPTL7-fibrinogen-his) at a concentration of 200 nM for 5 minutes of association followed by 10 minutes of dissociation. Results were analyzed using ForteBio DataAnalysis 11.1 and a 1:1 binding model was fitted to determine the monovalent K D The response (nm) at the end of the association was also determined (Table 2).

[0218] Table 2: Reactivity of anti-ANGPTL7 antibodies with the human fibrinogen domain of ANGPTL7 protein.

[0219]

[0220] Experiments were performed to determine the reactivity and dissociation constant (K) of anti-ANGPTL7 antibodies with human ANGPTL7-his protein. D ). Binding experiments were performed on Octet HTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. To measure monovalent binding kinetics, antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in monovalent P62 (huANGPTL7-his) at concentrations ranging from 0.343 nM to 250 nM (serial 3-fold dilutions) for 5 min of association followed by 10 min of dissociation. The results were analyzed using ForteBio DataAnalysis 11.1 and a 1:1 binding model was fitted globally to determine the monovalent K D (Table 3).

[0221] Table 3: Reactivity of anti-ANGPTL7 antibodies with human ANGPTL7-his protein.

[0222]

[0223] Experiments were performed to determine the reactivity and dissociation constant (K) of anti-ANGPTL7 antibodies with human ANGPTL7 GGPGG_sub-his protein. D Binding experiments were performed on Octet HTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. Antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in monovalent P63 (huANGTPL7-GGPGG_sub-his) at a concentration of 100 nM for 5 minutes of association followed by 10 minutes of dissociation. Results were analyzed using ForteBio Data Analysis 11.1 and a 1:1 binding model was fitted to determine the monovalent K D The response (nm) at the end of the association was also determined (Table 4).

[0224] Table 4: Reactivity of anti-ANGPTL7 antibodies with human ANGPTL7 GGPGG_sub-his protein.

[0225]

[0226] Experiments were performed to determine the reactivity and dissociation constant (K) of anti-ANGPTL7 antibodies with mouse ANGPTL7 protein. D Binding experiments were performed on Octet HTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. Antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in monovalent muANGPTL7-his (R&D Systems) at a concentration of 200 nM for 5 minutes of association followed by 10 minutes of dissociation. Results were analyzed using ForteBio Data Analysis 11.1 and fitted with a 1:1 binding model to determine the monovalent K D The response (nm) at the end of the association was also determined (Table 5).

[0227] Table 5: Reactivity of anti-ANGPTL7 antibodies with mouse ANGPTL7 protein.

[0228]

[0229] Experiments were performed to determine the reactivity and dissociation constant (K) of anti-ANGPTL7 antibodies with rabbit ANGPTL7 protein. D ). Binding experiments were performed on Octet HTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. Antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in monovalent P66 (rabbit ANGPTL7-his) at a concentration of 200 nM for 5 minutes of association followed by 10 minutes of dissociation. The results were analyzed using ForteBio Data Analysis 11.1 and a 1:1 binding model was fitted to determine the monovalent KD. The response (nm) at the end of association was also determined (Table 6).

[0230] Table 6: Reactivity of anti-ANGPTL7 antibodies with rabbit ANGPTL7 protein.

[0231]

[0232] Experiments were performed to determine the reactivity and dissociation constant (K) of anti-ANGPTL7 antibodies with human ANGPTL7 multimeric protein. D). Binding experiments were performed on OctetHTX (ForteBio) in 1x PBS, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20 at pH 7.4. Antibodies were loaded onto prehydrated AHC biosensors at a concentration of 50 nM for 5 minutes. The loaded sensors were immersed in Pext-01 (huANGTPL7-FLAG) at a concentration of 100 nM for 5 minutes of association followed by 10 minutes of dissociation. The results were analyzed using ForteBio Data Analysis 11.1 and a 1:1 binding model was fitted to determine the apparent KD. The response (nm) at the end of association was also determined (Table 7).

[0233] Table 7: Reactivity of anti-ANGPTL7 antibodies with human ANGPTL7 multimeric protein.

[0234]

[0235] Embodiment 11

[0236] ANGPTL7 is a member of the ANGPTL family, but its function is still unclear. Previous studies have demonstrated that loss-of-function variants of the ANGPTL7 gene are associated with protection against glaucoma and reduction of intraocular pressure (IOP). Therefore, experiments were performed to investigate the role of ANGPTL7 in IOP homeostasis and the potential of ANGPTL7 as a target for therapeutic development.

[0237] Briefly, an ANGPTL7 knockout model was generated by Lexicon Therapeutics on a 129SvEv-C57BL / 6 mixed genetic background. ANGPTL7 WT (N=14) and ANGPTL7 KO (N=17) mice were implanted with osmotic pumps filled with PBS or dexamethasone-cyclodextrin solution (4 mg / kg / day) for 28 days. Body weight and IOP measurements were collected weekly. Alzet osmotic pumps (model 1004) were aseptically filled with PBS or 45.45 mg / mL dexamethasone-cyclodextrin solution to provide a dose of 4 mgs / kg / day for mice weighing an average of 30 g. The pumps were then incubated in 0.9% saline at 37°C for 48 hours prior to implantation. On day 0, body weight and IOP measurements were collected and then used to randomize mice into the following 4 treatment groups: Angptl7 KO+PBS, N=8; Angplt7 KO+dexamethasone, N=9; Angptl7 WT+PBS, N=5; and Angptl7 WT+dexamethasone, N=14. PBS or dexamethasone pumps were implanted subcutaneously into mice. IOP and body weight were collected once a week on days 7, 14, 21, and 28. On day 28, final body weight and IOP measurements were collected. OS / OD were removed and snap frozen in liquid nitrogen. Mice were euthanized according to humane IACUC procedures.

[0238] Figures 8A to 8C provide representative results of the effects of dexamethasone-induced ocular hypertension in ANGPTL7 knockout mice. Figure 8A includes weight data for mice after implantation surgery; dexamethasone impaired weight gain in male mice compared to mice treated with PBS, confirming the normal function of the dexamethasone osmotic pump. Figure 8B includes intraocular pressure (IOP) data for ANGPTL7 WT and ANGPTL7 KO mice dosed with PBS control or dexamethasone (4 mg / kg / day); osmotic pumps were implanted on day 0. Figure 8C includes representative data of changes in IOP over 28 days for ANGPTL7 WT and ANGPTL7 KO mice implanted with osmotic pumps containing PBS vehicle or dexamethasone (4 mg / kg / day). All IOP values ​​were normalized to baseline (day 0) readings.

[0239] Example 12

[0240] In vivo Tolerability. Experiments were performed to test the in vivo tolerability of anti-ANGPTL7 antibodies using a single intravitreal (IVT) injection in New Zealand white rabbits. Representative data are provided in Figures 9A to 9R. The indicated anti-ANGPTL7 antibodies ("BTX" labels are interchangeable with "ATX-P" labels) were injected into the right eye (OD) at a 0.5 mg dose (Figure 9C, Figure 9D, Figure 9G, Figure 9H, Figure 9K, Figure 9L, Figure 9O, Figure 9P) or a 2.0 mg dose (Figure 9E, Figure 9F, Figure 9I, Figure 9J, Figure 9M, Figure 9N, Figure 9Q, Figure 9R), or injected into the left eye (OS) with the corresponding vehicle dose. (Figures 9A and 9B include data from the 2 mg dose control). Intraocular pressure (IOP) measurements ( FIG. 9A , FIG. 9C , FIG. 9E , FIG. 9G , FIG. 9I , FIG. 9K , FIG. 9M , FIG. 9O , FIG. 9Q ) and IOP changes ( FIG. 9B , FIG. 9D , FIG. 9F , FIG. 9H , FIG. 9J , FIG. 9L , FIG. 9N , FIG. 9P , FIG. 9R ) were collected at designated time points over a 21-day period.

[0241] Briefly, animals were dosed on day 0 and IOP was normalized to day -3 (N = 3 per treatment group; p < 0.05). Animals were dosed on day 0. Experimental eyes (OD) were compared to vehicle eyes (OS) using a two-way ANOVA. For intravitreal injections (day 0), rabbits were mydriatic with 1% tropicamide HCl and given buprenorphine (0.01-0.05 mg / kg) SC. Rabbits were sedated with a ketamine / xylazine mixture (4-10 / 20-50 mg / kg) IM and eyes were aseptically prepared with a topical 5% betadine solution, followed by irrigation with sterile eye drops and application of one drop of 0.5% proparacaine HCl. The conjunctiva was gently grasped with Colibri forceps and the injection was performed using a 27G-30G needle located 2mm-3mm posterior to the superior limbus (through the pars plana), with the needle pointed slightly posteriorly to avoid contact with the lens. After the contents of the syringe were dispensed, the needle was slowly withdrawn. After the injection procedure, 1 drop of antibiotic ophthalmic solution was applied topically to the ocular surface. For each injection group, baseline eye examinations and IOP measurements were obtained 24 hours after dosing and on days 3, 8, 14, and 21. Terminal blood collection was obtained on day 21 for PK analysis (see below).

[0242] Intraocular pressure (IOP) was measured in both eyes of all animals at designated time points. Measurements were collected using a Tonovet probe (iCareTonometer, Espoo, Finland) without the use of local anesthetics. The tip of the Tonovet probe was gently brought into contact with the center of the cornea. Six consecutive measurements were obtained. After the sixth measurement, the average IOP shown was recorded. Animals did not require sedation during the procedure.

[0243] Example 13

[0244] Pharmacokinetic (PK) Evaluation. Previous studies (described above) demonstrated that several novel anti-ANGPTL7 antibodies were well tolerated in rabbits at doses of 0.5 mg and 2.0 mg over a 21-day period. Therefore, experiments were performed to evaluate the pharmacokinetics (PK) of several well-tolerated anti-ANGPTL7 antibodies. New Zealand white rabbits received a single bilateral (OU) injection of each of ATX-P-424 (FIGS. 10A-10C), ATX-P-439 (FIGS. 11A-11C), and ATX-P-448 (FIGS. 12A-12C). (The "BTX" label is interchangeable with the "ATX-P" label.) Representative pharmacokinetic (PK) data for the designated ANGPTL7 antibodies include intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) compared to vehicle ( Figures 10A , 11A , and 12A ); IOP change from baseline ( Figures 10B , 11B , and 12B ); and total ocular examination score (OE) ( Figures 10C , 11C , and 12C ).

[0245] Briefly, at least 1 mL of whole blood was drawn from the marginal auricular vein or via cardiac puncture (terminal bleeding only) and placed into red-top plastic tubes (without anticoagulant or with serum separation gel) to obtain serum at designated time points. Alternatively, if the vein was inaccessible or unsuitable for further collection, the central auricular artery was utilized. Prior to needle insertion, a thin layer of 5% lidocaine ointment was applied topically to the skin above the vessel. Wintergreen oil may also be applied as needed to promote vasodilation. After collection, the tubes were gently mixed by inverting them 3 to 5 times. Blood samples were stored at room temperature for 30 to 60 minutes before processing. Whole blood samples were centrifuged at 2,000 x g for 10 minutes at 4°C in a refrigerated centrifuge. After centrifugation, the clarified serum was immediately divided into four (4) aliquots of 200 μL each and stored frozen at -80°C until shipped for analysis. In addition, a complete ocular examination was performed on all animals by a veterinary ophthalmologist using a slit-lamp biomicroscope and indirect ophthalmoscopy to assess ocular surface morphology and anterior and posterior segment inflammation prior to dosing for baseline and designated time points. All animals underwent a normal ocular examination to be considered for participation in this study. Scoring was performed using the modified Hackett and McDonald ocular grading system along with other posterior segment scoring parameters.

[0246] To analyze 0.5 mg of ATX-P-424, animals were dosed in different cohorts (N=6 and N=4), with dosing of the two cohorts staggered one day. Animals were dosed on day 0 and euthanized at 24 hours and on days 7, 14, and 21 (N=2 for each time point). The number of eyes measured at each time included N=20 eyes on days 0 and 1, N=12 eyes on day 7, N=8 eyes on day 14, and N=4 eyes on day 21. To analyze 2.0 mg of ATX-P-424, rabbits (N=6) showed an OE score of more than 20 on day 0 and were euthanized. To analyze ATX-P-439, measurements included N=20 eyes on days 0 and 1. Animals dosed with two doses of ATX-P-439 (N=6 per group) showed an OE score of more than 20 after 24 hours and were euthanized. No further dosing of the animals in the second cohort was performed. For analysis of ATX-P-448, animals were dosed in different cohorts of N=6 and N=4, with dosing staggered one day for the two cohorts. Animals were dosed on day 0 and euthanized at 24 hours and on days 7, 14, and 21 (N=2 per time point). The number of eyes measured at each time included N=20 eyes on days 0 and 1, N=12 eyes on day 7, N=8 eyes on day 14, and N=4 eyes on day 21.

[0247] Embodiment 14

[0248] In vivo tolerance (non-human primates). Experiments were also performed to test the in vivo tolerance of anti-ANGPTL7 antibodies in non-human primates (African green monkeys) using a single intravitreal (IVT) injection. Figures 13A to 13C include representative data of absolute IOP values ​​6 hours after topical administration of saline and latanoprost at baseline (Day 3) and Day 10 (Figure 13A); IOP changes 6 hours after topical administration of saline (Day 3) or latanoprost (Day 10) (Figure 13B); and IOP changes between vehicle and latanoprost administration (Figure 13C). Figures 14A to 14H include representative IOP measurements (Figures 14A, 14C, 14E, and 14G) and IOP changes (Figures 14B, 14D, 14F, and 14H) of African green monkeys dosed with 2 mg of the indicated anti-ANGPTL7 antibodies compared to an isotype control (BTX-330) and a single vehicle eye. And Fig.15 Representative clinical scores for ocular examination (OE) for all dosing groups are included.

[0249] Briefly, monkeys were prescreened to identify animals with basal IOP values ​​greater than 16 mmHg and less than 26 mmHg. For prescreening, monkeys were sedated with ketamine / xylazine (8 mg / kg and 1.6 mg / kg, respectively) between 8:00 AM and 10:00 AM to use rebound tonometer Measure IOP. If the event animal is not completely sedated, additional ketamine / xylazine is administered to achieve the result. Any animal that requires more than 25% of the target dose for IOP measurement is prioritized as an exclusion target. IOP measurements are performed 5 to 10 minutes after initial sedation (T=0). The animal is placed in a supine position one minute before IOP measurement (OS is analyzed immediately before OD), and the prone position is maintained at all other times of sedation. Sedation, body placement, and IOP measurement procedures are repeated in the same manner 6 hours after the initial prescreening assessment (T=6 hours). Any monkey that exhibits a drop in IOP of more than 5 mmHg between T=0 and T=6 hours (sensitivity of IOP to sedation) is excluded from the study. After completing the IOP measurement at T=6 hours, the monkeys are screened ophthalmologically, and the eyes and overall health are assessed by slit lamp biomicroscopy, funduscopy, and color fundus photography (CFP). Monkeys with normal examination results are included in the study and randomly assigned to treatment groups based on the prescreening T=0 IOP.

[0250] At least 7 days after the completion of the screening activity and at least 7 days before the start of Phase 2, the animals were sedated and the IOP was assessed using the same method as for screening. Immediately after the completion of the T=0 IOP measurement, 1 gt (approximately 35 μL) of latanoprost 0.005% ophthalmic solution ( or equivalent) and 0.9% saline was administered to the other eye. Dosing was performed between 8:00 AM and 10:00 AM. A follow-up IOP assessment was performed at T = 6 hours to determine the IOP lowering response of each animal. The absolute IOP change for each eye between T = 0 and T = 6 h during screening and Phase 1 was calculated, and then the percentage difference in ΔIOP between sedation alone and latanoprost (% ΔΔIOP) was determined using the following formula:

[0251]

[0252] The animals were then ranked based on the mean % ΔΔIOP of the animals' response to timolol. Animals with minimal effects of sedation on IOP and responses to timolol treatment compared to sedation alone ("timolol responders") were included in the study. If fewer than 15 animals were identified for recruitment based on these criteria, up to 8 additional animals would be screened in the same manner to complete study recruitment.

[0253] For IVT administration, topical 0.5% proparacaine was applied, allowed 30 seconds to take effect, and a lid speculum was placed, and the ocular surface was then irrigated with a 5% betadine solution, followed by a 0.9% sterile saline rinse. IVT injections were performed in both eyes (OU) according to treatment assignment, using a 31-gauge 5 / 16-inch needle / syringe (Ulticare VetRx U-100 or equivalent) inserted at the level of the infratemporal ora serrata, approximately 2 mm posterior to the limbus. After injection, a topical antibiotic ophthalmic ointment (neomycin, polymyxin, bacitracin, or equivalent) was applied.

[0254] At the indicated time points, intraocular pressure (IOP) measurements were collected using a TonoVet (iCare, Finland) tonometer set to dog (d) calibration settings. The TonoVet rebound tonometer was well tolerated and did not require additional local analgesia. All IOP measurements were performed when the animals were sedated with ketamine and xylazine. The animals were sedated 5 to 10 minutes before each scheduled measurement and placed in a supine position one minute before each IOP measurement (OS was analyzed immediately before OD), and in a prone position at all other times during sedation. After each IOP assessment was completed, the animal was moved to a prone position and maintained in this position until recovery from sedation. Three measurements were taken for each eye at each time point, and the average value was used for IOP analysis.

[0255] In addition, both eyes (OU) were examined by slit-lamp biomicroscopy at designated time points. Qualitative clinical ophthalmologic findings were scored using the nonhuman primate ophthalmologic scoring system and summary scores derived from the examination components. At designated time points, bilateral retinal color fundus images were captured with a 50° viewing angle centered on the fovea using a Topcon TRC-50EX retinal camera equipped with Canon 6D digital imaging hardware and New Vision Fundus Image Analysis System software. At designated time points, blood samples (0.5 mL to 1 mL) were collected and transferred to K 2 EDTA lavender top vacuum tubes were gently inverted several times and kept on ice until CBC differential analysis was performed on the Abaxis VetScan HM5 hematology analyzer. Whole blood (3 mL) was collected via the femoral vein or saphenous vein at the indicated time points. Blood was transferred to vacuum tubes (without anticoagulant) and incubated at room temperature for approximately 1 hour and then at 4 ℃ The samples were centrifuged at 4000 rpm for 10 minutes and serum aliquots were separated (approximately 0.5 mL x 2 aliquots for each time point). The aliquots were stored and shipped to designated laboratories for NAb analysis at below -70°C. At the designated time points, topical 0.5% proparacaine was applied, allowed to take effect for 30 seconds, a lid speculum was placed, and the ocular surface was then rinsed with 5% betadine solution, followed by 0.9% sterile saline without A. Aqueous humor (50 μL) was drawn using a 0.3 mL insulin syringe equipped with a 31-gauge needle and inserted into the anterior chamber approximately 2 mm in front of the temporal lobe margin. The aqueous samples were transferred to cryovials, quickly frozen and stored, and stored at below -70°C. ℃ Subjects were shipped to the sponsor or a laboratory designated by the sponsor for analysis. In addition, subjects were assessed twice daily at cage side for general health and evidence of ocular pathology. Data generated from protocol-defined endpoints were collected, summarized, and analyzed. Specified statistical analyses were performed when data met the required assumptions. If data did not meet the assumptions of the defined statistical methods, alternative methods were used whenever possible. P values ​​≤ 0.05 were considered statistically significant.

[0256] sequence

[0257] Provided below are various amino acid sequences and nucleic acid sequences cited herein.

[0258] Table 8: Anti-ANGPTL7 Antibodies (CDR Sequences)

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] Table 9: Anti-ANGPTL7 Antibodies (VH and VL Sequences)

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] Table 10: Anti-ANGPTL7 Antibodies (HC IgG1 Fc and LCκ Sequences)

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319] Human angiopoietin-related protein 7 (UniProt accession number O43827):

[0320] MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVANLSSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQ RRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDF(SEQ ID NO:370).

[0321] Human angiopoietin-related protein 7 L59P_L84P variant (ATX-P-62):

[0322] MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVAN P SSLLSELNKKQERDWVSVVMQVME PESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPT RLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDFKP(SEQ ID NO:371).

[0323] Human angiopoietin-related protein 7L59 GGPGG variant (ATX-P-63):

[0324] MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVAN GGPGG SSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWL GNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDFKP(SEQ ID NO:372).

[0325] Human angiopoietin-related protein 7 fibrinogen domain (ATX-P-60):

[0326] YDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHF VLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPED(SEQID NO:373).

[0327] Human angiopoietin-related protein 7 wild-type multimer (PExt-1):

[0328] MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVANLSSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQ RRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDF(SEQ ID NO:374).

[0329]

[0330]

[0331] Various embodiments of the present disclosure are described herein. After reading the foregoing description, variations of those embodiments may become apparent to those of ordinary skill in the art. The inventors hope that the technicians will adopt such variations as appropriate, and the inventors intend to practice the various embodiments of the present disclosure in a manner different from that specifically described herein. Therefore, the embodiments of the present disclosure include all modifications and equivalents of the subject matter listed in the appended claims as permitted by applicable law. In addition, unless otherwise specified herein or clearly contradictory to the context, the various embodiments of the present disclosure encompass any combination of the above-mentioned elements in all possible variations thereof.

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to human angiopoietin-like protein 7 (ANGPTL7), optionally wherein the human ANGPTL7 is a polypeptide comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 370 to 374.

2. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof exhibits any one or more of the following functional characteristics: a. increases outflow fluency when administered to an eye of a subject compared to a control, optionally wherein the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein and isotype control antibody treatment; and / or b. With a K of about 100 nM or lower D Binds to ANGPTL7; and / or c. binds to the same epitope on ANGPTL7 as an antibody comprising the VH and VL sequences of any of the exemplary antibodies, the sequences of which are provided in Table 11; and / or d. Competing for binding to ANGPTL7 with an antibody comprising the VH and VL sequences of any of the exemplary antibodies, whose sequences are provided in Table 11.

3. The antibody or antigen-binding fragment thereof of claim 1 or claim 2, which is monoclonal, optionally recombinant.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, which is human, humanized or chimeric.

5. The antibody or antigen-binding fragment thereof of any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is a full-length antibody, a single-chain antibody, a single-chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), Fab-C, Fab'-SH, (Fab')2, a single domain antibody (sdAb), a VHH antibody, a nanobody, a camel-derived single domain antibody, a shark IgNAR-derived single domain antibody fragment (VNAR), a diabody, a triabody, anticalin or an aptamer, optionally wherein the antibody is a full-length antibody comprising an Fc region such as a human IgG1, IgG2, IgG3 or IgG4 region.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, conjugated to at least one other moiety, the other moiety being optionally selected from: a. an antigen binding portion, such as an antibody or antigen binding fragment thereof, which is capable of specifically binding to a target other than human ANGPTL7, preferably wherein the target is expressed in the human eye; b. Therapeutic or cytotoxic moiety; c. Detection part; d. Purification part; e. A half-life extending moiety, optionally a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E and P residues, conjugated to the C-terminus or N-terminus of the antibody.

7. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, wherein the antibody or antigen-binding fragment thereof is a polypeptide comprising: a. one, two or all three HCDRs of any of the exemplary antibodies, and optionally further comprising one, two or all three corresponding LCDRs of said exemplary antibodies, the sequences of said exemplary antibodies being provided in Table 11; and / or b. a VH sequence that is at least 90% identical to the VH sequence of any one of the exemplary antibodies, and optionally further comprises a VL sequence that is at least 90% identical to the corresponding VL sequence of the exemplary antibodies, the sequences of the exemplary antibodies being provided in Table 11, preferably wherein no variation in the HCDR or LCDR is allowed; and / or c. all six CDRs of any of the exemplary antibodies whose sequences are provided in Table 11; and / or d. the VH and VL sequences of any of the exemplary antibodies whose sequences are provided in Table 11; and / or e. the full-length heavy chain (VH+constant) sequence of any one of the exemplary antibodies, and optionally also comprising the corresponding full-length light chain (VL+constant) sequence of the exemplary antibody, the sequences of the exemplary antibodies being provided in Table 11.

8. A polynucleotide encoding an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 7, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence that is at least 70%, 80%, 90% or 100% identical to the nucleic acid sequence of any one of the exemplary antibodies, the sequences of the exemplary antibodies being provided in Table 11.

9. An expression vector comprising the polynucleotide of claim 8, wherein the expression vector is optionally an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector or a retrovirus vector.

10. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, polynucleotide or vector according to any one of the preceding claims, and optionally: a. at least one pharmaceutically acceptable carrier, diluent or preservative; and / or b. at least one other active ingredient.

11. The pharmaceutical composition of claim 10, which is suitable for ocular administration to a subject, optionally delivered by use of a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops and / or an implant, preferably by injection into the vitreous humor.

12. The antibody or antigen-binding fragment thereof of any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9 or the composition of claim 10 or 11 for use as a medicament, optionally for use in a method of treating an eye disease in a subject.

13. The antibody, fragment, polynucleotide, vector or composition for use of claim 12, wherein the disease is characterized by increased intraocular pressure and / or decreased outflow smoothness in the eye of the subject.

14. The antibody, fragment, polynucleotide, vector or composition for use of claim 12 or 13, wherein the method comprises ocular administration of the antibody, preferably by injection into the vitreous humor, and wherein the administration preferably relieves the subject from at least one symptom selected from the group consisting of eye pain, intraocular pressure, headache, rainbow halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting and red eyes.

15. as any one in claim 12 to 14 for use antibody, fragment, polynucleotide, carrier or the compositions, wherein said disease is glaucoma and / or affects the disease of optic nerve or retinal ganglion cell, optionally wherein said glaucoma is primary glaucoma or glucocorticoid-induced glaucoma.

16. An antibody or antigen-binding fragment thereof against angiopoietin-like protein 7 (ANGPTL7) peptide, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and the light chain variable region comprising complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, wherein The HCDR1 comprises one of the following amino acid sequences: (a) X1YX2IX3 (SEQ ID NO: 1), wherein X1 is S or D; X2 is G or Y; X3 is S or H; (b) TSGVGVG (SEQ ID NO: 18); (c) X1X2X3MX4 (SEQ ID NO: 27), wherein X1 is V, S, D or T; X2 is Y, H or F; X3 is D, G, S or A; X4 is H, S or N; or (d) SX1SX2YWX3 (SEQ ID NO: 74), wherein X1 is S or G; X2 is S or Y; X3 is G or S; Wherein the HCDR2 comprises one of the following amino acid sequences: (a) WIX1X2X3X4GX5TX6YAQX7X8X9G (SEQ ID NO: 7), wherein X1 is S, I or N; X2 is A or P; X3 is Y or N; X4 is N or T; X5 is N or A; X6 is N or K; X7 is N or K; X8 is L or F; X9 is R or Q; (b) LIYWNDDKX1YSPSLKS (SEQ ID NO: 21), wherein X1 is R or Q; (c)X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 G (SEQ ID NO: 43), wherein X1 is G, T, S, A, V, H or I; X2 is I or M; X3 is D, N, T, S or G; X4 is P, W, S, G or Y; X5 is D, A, N, S or Y; X6 is G or S; X7 is D, G, Y, S, I or N; X8 is T, S, N, I, Y or D; X9 is Y, T, F, M, K, G or I; X 10 is Y, G or F; X 11 P, Y or A; X 12 G, D or A; X 13 S or D; X 14 V, L or S; X 15 is K or M; or (d) X1IYYSGSTX2SNPSLKS (SEQ ID NO: 78), wherein X1 is S or Y; X2 is Y or S; Wherein the HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NO: 13-17; (b) X1X2X3X4X5X6FFDX7 (SEQ ID NO: 24), wherein X1 is S, D or N; X2 is Y or P; X3 is G or D; X4 is D or Y; X5 is Y or G; X6 is W or D; X7 is L or Y; (c) SEQ ID NO: 59-73; or (d) X1X2X3X4GX5X6X7X8X9Y (SEQ ID NO: 82), wherein X1 is Q or A; X2 is Y or K; X3 is I or W; X4 is S or E; X5 is T or D; X6 is E or Y; X7 is Y or F; X8 is F or D; X9 is Q or Y; and wherein the LCDR1 comprises the amino acid sequence of any one of SEQ ID NOs:87-97, SEQ ID NOs:123-127 or SEQ ID NOs:141-149; the LCDR2 comprises the amino acid sequence of any one of SEQ ID NOs:99-109, SEQ ID NOs:129-133 or SEQ ID NOs151-159; and the LCDR3 comprises the amino acid sequence of any one of SEQ ID NOs:111-121, SEQ ID NOs:135-139 or SEQ ID NOs:161-169.

17. An antibody or antigen-binding fragment thereof against angiopoietin-like protein 7 (ANGPTL7) peptide, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprising complementarity determining regions (CDRs) HCDR1, HCDR2 and HCDR3, and the light chain variable region comprising complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, wherein The LCDR1 comprises one of the following amino acid sequences: (a) RASQX1IX2X3X4LX5 (SEQ ID NO: 86), wherein X1 is G or S; X2 is S, R or Y; X3 is S, N or I; X4 is W, D or Y; X5 is A, G or N; (b) RSSQSLX1X2SX3X4X5X6YLX7 (SEQ ID NO: 122), wherein X1 is L or V; X2 is H, Y or F; X3 is N or D; X4 is R or G; X5 is Y or N; X6 is N or T; X7 is D or N; or (c) RASQSVSX1X2X3X4A (SEQ ID NO: 140), wherein X1 is S, N or R; X2 is Y or S; X3 is L or Y; X4 is A or L; Wherein the LCDR2 comprises one of the following amino acid sequences: (a) AX1SSLX2S (SEQ ID NO: 98), wherein X1 is A or T; X2 is Q or P; (b) X1X2SNRX3S (SEQ ID NO: 128), wherein X1 is L, K or E; X2 is G or V; X3 is A or D; or (c) X1ASX2RAT ​​(SEQ ID NO: 150), wherein X1 is D or G; X2 is N, S or T; Wherein the LCDR3 comprises one of the following amino acid sequences: (a) X1QX2X3X4X5PX6X7 (SEQ ID NO: 110), wherein X1 is L or Q; X2 is A, H, S or D; X3 is N, F or Y; X4 is S, T or N; X5 is F, Y or T; X6 is W, L, I, P or Y; X7 is T or Y; (b) MQX1X2X3X4PX5T (SEQ ID NO: 134), wherein X1 is T or G; X2 is L or T; X3 is Q or H; X4 is T or W; X5 is Y or W; or (c) QQX1X2X3X4X5X6T (SEQ ID NO: 160), wherein X1 is R, Y or G; X2 is S, G or Q; X3 is N, S or V; X4 is W, S or I; X5 is P or L; X6 is L, S, P or T; and wherein the HCDR1 comprises the amino acid sequence of any one of SEQ ID NOs: 2-6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42 or SEQ ID NOs: 75-77; the HCDR2 comprises the amino acid sequence of any one of SEQ ID NOs: 8-12, SEQ ID NOs: 22-23, SEQ ID NOs 44-58 or SEQ ID NOs: 79-81; and the HCDR3 comprises the amino acid sequence of any one of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73 or SEQ ID NOs: 83-85.

18. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2; the HCDR2 comprises the amino acid sequence of SEQ ID NO:8; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

13.

19. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3; the HCDR2 comprises the amino acid sequence of SEQ ID NO:9; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

14.

20. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:4; the HCDR2 comprises the amino acid sequence of SEQ ID NO:10; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

15.

21. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:5; the HCDR2 comprises the amino acid sequence of SEQ ID NO:11; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

16.

22. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:6; the HCDR2 comprises the amino acid sequence of SEQ ID NO:12; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

17.

23. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

25.

24. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

26.

25. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:28; the HCDR2 comprises the amino acid sequence of SEQ ID NO:44; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

59.

26. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:29; the HCDR2 comprises the amino acid sequence of SEQ ID NO:45; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

60.

27. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:30; the HCDR2 comprises the amino acid sequence of SEQ ID NO:46; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

61.

28. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:31; the HCDR2 comprises the amino acid sequence of SEQ ID NO:47; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

62.

29. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:32; the HCDR2 comprises the amino acid sequence of SEQ ID NO:48; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

63.

30. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:33; the HCDR2 comprises the amino acid sequence of SEQ ID NO:49; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

64.

31. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:34; the HCDR2 comprises the amino acid sequence of SEQ ID NO:50; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

65.

32. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:35; the HCDR2 comprises the amino acid sequence of SEQ ID NO:51; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

66.

33. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:36; the HCDR2 comprises the amino acid sequence of SEQ ID NO:52; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

67.

34. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:37; the HCDR2 comprises the amino acid sequence of SEQ ID NO:53; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

68.

35. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:38; the HCDR2 comprises the amino acid sequence of SEQ ID NO:54; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

69.

36. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:39; the HCDR2 comprises the amino acid sequence of SEQ ID NO:55; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

70.

37. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:40; the HCDR2 comprises the amino acid sequence of SEQ ID NO:56; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

71.

38. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:41; the HCDR2 comprises the amino acid sequence of SEQ ID NO:57; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

72.

39. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:42; the HCDR2 comprises the amino acid sequence of SEQ ID NO:58; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

73.

40. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 75; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 79; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

83.

41. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 76; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 80; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

84.

42. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 77; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 81; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:

85.

43. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:87; the LCDR2 comprises the amino acid sequence of SEQ ID NO:99; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

111.

44. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:88; the LCDR2 comprises the amino acid sequence of SEQ ID NO:100; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

112.

45. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:89; the LCDR2 comprises the amino acid sequence of SEQ ID NO:101; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

113.

46. ​​The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:90; the LCDR2 comprises the amino acid sequence of SEQ ID NO:102; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

114.

47. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:91; the LCDR2 comprises the amino acid sequence of SEQ ID NO:103; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

115.

48. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:92; the LCDR2 comprises the amino acid sequence of SEQ ID NO:104; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

116.

49. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:93; the LCDR2 comprises the amino acid sequence of SEQ ID NO:105; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

117.

50. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:94; the LCDR2 comprises the amino acid sequence of SEQ ID NO:106; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

118.

51. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:95; the LCDR2 comprises the amino acid sequence of SEQ ID NO:107; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

119.

52. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:96; the LCDR2 comprises the amino acid sequence of SEQ ID NO:108; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

120.

53. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO:97; the LCDR2 comprises the amino acid sequence of SEQ ID NO:109; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

121.

54. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 123; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 129; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

135.

55. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 124; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 130; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

136.

56. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 125; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 131; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

137.

57. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 126; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 132; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

138.

58. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 127; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 133; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

139.

59. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 141; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 151; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

161.

60. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 142; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 152; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

162.

61. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 143; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 153; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

163.

62. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 144; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

164.

63. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 145; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

165.

64. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

166.

65. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

167.

66. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 148; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

168.

67. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 149; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

169.

68. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to any of: (a) SEQ ID NO: 170-174; (b) SEQ ID NO: 190-191; (c) SEQ ID NO: 198-212; or (d) SEQ ID NO: 258-260.

69. The antibody of claim 16 or claim 17, wherein the VL comprises an amino acid sequence at least 90% identical to any of: (a) SEQ ID NO: 180-184; (b) SEQ ID NO: 194-195; (c) SEQ ID NO: 228-242; or (d) SEQ ID NO: 264-266.

70. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 170, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

180.

71. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 171, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

181.

72. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 172, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

182.

73. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 173, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

183.

74. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 174, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

184.

75. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 190, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

194.

76. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 191, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

195.

77. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 198, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

228.

78. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 199, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

229.

79. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 200, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

230.

80. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 201, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

231.

81. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 202, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

232.

82. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 203, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

233.

83. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 204, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

234.

84. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 205, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

235.

85. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 206, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

236.

86. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 207, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

237.

87. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 208, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

238.

88. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 209, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

239.

89. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 210, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

240.

90. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 211, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

241.

91. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 212, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

242.

92. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 258, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

264.

93. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 259, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

265.

94. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 260, and the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO:

266.

95. The antibody of any one of claims 16 to 94, wherein the antibody binds ANGPTL7 and increases efflux fluency compared to a control.

96. The antibody of claim 95, wherein the control is selected from the group consisting of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and ANGPTL7 protein and isotype control antibody treatment.

97. The antibody of claim 95 or claim 96, wherein: (a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 210, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 240; (b) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 200, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 230; (c) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 258, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 264; (d) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 207, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 237; (e) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 204, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 234; (f) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 260, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 266; (g) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 205, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 235; (h) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 206, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 236; (i) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 208, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 238; (j) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 191, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 195; (k) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 203, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 233; (l) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 212, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 242; (m) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 198, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 228; (n) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 190, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 194; (o) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 202, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 232; (p) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 211, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 241; or (q) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 199, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

229.

98. The antibody of claim 81 or claim 82, wherein; (a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 210, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 240; (b) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 200, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 230; or (c) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:258, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

264.

99. The antibody of claim 95 or claim 96, wherein: (a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 207, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 237; (b) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 204, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 234; (c) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 260, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 266; (d) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 205, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 235; (e) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 206, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 236; (f) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 208, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 238; (g) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 191, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 195; (h) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 203, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 233; (i) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 212, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 242; (j) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 198, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 228; or (k) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:190, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

194.

100. The antibody of claim 95 or claim 96, wherein; (a) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 202, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 232; (b) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 211, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 241; or (c) the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 199, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

229.

101. The antibody of any one of claims 16 to 100, wherein the antibody is a monoclonal antibody, a human antibody, a humanized antibody and / or a chimeric antibody.

102. The antibody of any one of claims 16 to 101, wherein the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab'-SH, Fv, scFv and (Fab')2 fragment.

103. The antibody of any one of claims 16 to 102, wherein the antibody is a monospecific antibody.

104. The antibody of any one of claims 16 to 103, wherein the antibody is a bispecific antibody.

105. The antibody of any one of claims 16 to 104, wherein the antibody comprises a detection moiety.

106. The antibody of any one of claims 16 to 105, wherein the antibody comprises a purified fraction.

107. The antibody of any one of claims 16 to 106, wherein the antibody comprises a half-life extending moiety.

108. The antibody of claim 107, wherein the half-life extending moiety comprises a polypeptide of at least 20 amino acids in length and comprising any combination of G, A, ST, E, and P residues.

109. The antibody of claim 108, wherein the half-life extending polypeptide is linked to the C-terminus or N-terminus of the antibody.

110. A pharmaceutical composition comprising the antibody of any one of claims 1 to 109.

111. The composition of claim 110, wherein the composition is suitable for ocular administration.

112. The composition of claim 111, wherein the ocular administration comprises injection into the vitreous humor.

113. The composition of claim 111, wherein the ocular administration comprises delivering the antibody using a conjunctival insert, a contact lens, a gel, nanoparticles, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and / or an implant.

114. A method of treating glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of the antibody of claim 16 or claim 17.

115. The method of claim 114, wherein the pharmaceutical composition is administered ophthalmically and treats at least one symptom associated with glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells.

116. The method of claim 114 or claim 115, wherein the at least one symptom associated with glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells comprises: Eye pain, eye pressure, headaches, rainbow-colored halos around lights, poor vision, blurred vision, narrowed visual field, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes.

117. The method of any one of claims 114 to 116, wherein administering the pharmaceutical composition reduces intraocular pressure and / or increases outflow smoothness in the subject's eye.

118. The method of any one of claims 114 to 117, wherein the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose.

119. The method of any one of claims 114 to 117, wherein the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

120. A polynucleotide having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 175-179; (b) SEQ ID NO: 192-193; (c) SEQ ID NO: 213-227; or (d) SEQ ID NO: 261-263.

121. A polynucleotide having at least 70% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 185-189; (b) SEQ ID NO: 196-197; (c) SEQ ID NO: 243-257; or (d) SEQ ID NO: 267-269.

122. A polynucleotide having at least 80% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 175-179; (b) SEQ ID NO: 192-193; (c) SEQ ID NO: 213-227; or (d) SEQ ID NO: 261-263.

123. A polynucleotide having at least 80% identity to any of the following nucleic acid sequences: (a) SEQ ID NO: 185-189; (b) SEQ ID NO: 196-197; (c) SEQ ID NO: 243-257; or (d) SEQ ID NO: 267-269.

124. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 175 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 185; (b) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 176 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 186; (c) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 177 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 187; (d) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 178 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 188; or (e) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:179 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:

189.

125. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 192 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 196; or (b) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:193 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:

197.

126. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 213 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 243; (b) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 214 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 244; (c) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 215 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 245; (d) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 216 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 246; (e) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 217 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 247; (f) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 218 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 248; (g) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 219 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 249; (h) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 220 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 250; (i) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 221 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 251; (j) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 222 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 252; or (k) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 223 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 253; (l) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:224 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:254; (m) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 225 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 255; (n) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:226 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:256; or (o) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:227 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:

257.

127. A polynucleotide comprising: (a) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 261 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 267; (b) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 262 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 268; or (c) a nucleic acid sequence that is at least 70% identical to SEQ ID NO:263 and a nucleic acid sequence that is at least 70% identical to SEQ ID NO:

269.

128. An expression vector comprising the polynucleotide of any one of claims 120 to 127.

129. The expression vector of claim 128, wherein the expression vector is at least one of an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, and a retroviral vector.

130. A method of administering ocular gene therapy to a subject in need thereof, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector of claim 128 or claim 129.

131. A method for treating glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, the method comprising administering a pharmaceutical composition comprising an effective amount of an expression vector as described in claim 128 or claim 129, wherein administration of the pharmaceutical composition treats at least one symptom of glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells.

132. The antibody of claim 16 or claim 17, wherein the antibody binds to an epitope of an ANGPTL7 polypeptide having the amino acid sequence of any of SEQ ID NOs: 370-374.

133. The antibody of claim 16 or claim 17, wherein the antibody has a K of about 100 nM or less. D Binds to an epitope of an ANGPTL7 polypeptide.

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