Angiopoietin-related protein 7-specific antibody and its use

Abstract

The present disclosure relates to the treatment and / or prevention of glaucoma and other diseases affecting the optic nerve and retinal ganglion cells. In particular, the present disclosure provides novel therapeutic antibodies that target angiopoietin-related protein 7 (ANGPTL7) to reduce intraocular pressure (IOP) to prevent optic nerve damage and restore vision, as well as related compositions and methods.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and benefit under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 336,747, filed Apr. 29, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Sequence Listing The text of the computer - readable sequence listing, entitled "40185_601_SequenceListing", having a file size of 410,410 bytes and generated on Mar. 30, 2023, submitted herewith, is hereby incorporated by reference in its entirety.

[0003] Embodiments of the present disclosure relate to the treatment and / or prevention of glaucoma and other diseases affecting the optic nerve and retinal ganglion cells. In particular, the present disclosure provides novel therapeutic antibodies that target angiopoietin - related protein 7 (ANGPTL7) to reduce intraocular pressure (IOP), prevent optic nerve damage, and restore vision, as well as related compositions and methods.

Background Art

[0004] Glaucoma is a group of optic nerve disorders associated with characteristic structural changes in the optic nerve head that can lead to visual field loss and ultimately blindness. Blindness is most commonly defined as a visual acuity of 20 / 200 or worse on the Snellen eye chart or a visual field of less than 20 degrees. Legal blindness refers to a condition that meets these criteria in the better-seeing eye. By 2020, an estimated 79.6 million people worldwide had glaucoma, and more than 11 million were blind from glaucoma in both eyes. More than 2 million Americans aged 40 and older have glaucoma, and in studies of the U.S. population, it is estimated that more than half of these cases may be undiagnosed or untreated. In blacks and Hispanics, glaucoma is a leading cause of irreversible blindness. Glaucoma accounts for more than 25% of blindness cases in these populations, making it a more common cause of blindness than diabetic retinopathy (which accounts for 7.3% and 14.3% of cases in blacks and Hispanics, respectively) and age-related macular degeneration (which accounts for 4.4% and 14.3% of cases in blacks and Hispanics, respectively). Among Hispanics, glaucoma is more often a cause of blindness than cataracts (28.6% vs. 14.3%). In 2009, Medicare beneficiaries spent $748 million on glaucoma-related hospital visits, tests, and treatments. Glaucoma patients who are not blind may have limited functionality, leading to driving cessation and reduced reading ability.

[0005] The two most common forms of glaucoma are primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and in the United States and Europe, the former is approximately seven times more common than the latter. If left untreated, the typical disease course of POAG and PACG is chronic, progressive, and irreversible visual field loss, which can progress to tunnel vision and ultimately result in the loss of central vision. Treatments that lower intraocular pressure have been shown to improve the outcomes of randomized clinical trials. The angle of the eye is the junction between the iris and the cornea, and 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 retinal ganglion cells in the optic nerve, causing cell death. However, approximately 50% of glaucoma patients have intraocular pressure within the so-called "normal" range of 10 - 21 mmHg at the time of diagnosis. Visual field defects are present on visual field testing only after 30% of retinal ganglion cells have been lost. In PACG, the peripheral iris obstructs normal aqueous humor outflow. This can lead to an increase in intraocular pressure and damage to the optic nerve. Eyes at risk for PACG tend to be short and have a shallow anterior chamber. Patients with PACG may experience acute or subacute events that occur after a rapid increase in intraocular pressure, or acute or subacute events that arise from chronic PACG, which has a latent onset and is mostly asymptomatic. SUMMARY OF THE INVENTION

[0006] Embodiments of the present disclosure include an antibody that specifically binds to human angiopoietin-like protein 7 (ANGPTL7), or an antigen-binding fragment thereof, and optionally, the human ANGPTL7 is a polypeptide comprising or consisting of any one of the amino acid sequences of SEQ ID NOs: 370 - 374.

[0007] In some embodiments, the antibody, or antigen-binding fragment thereof, exhibits any one or more of the following functional characteristics: when administered to the eye of a subject, it increases the aqueous humor outflow ability compared to a control, optionally, the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein and isotype control antibody treatment, and / or has a K of about 100 nM or less D that binds to ANGPTL7 at D , and / or binds to the same epitope on ANGPTL7 as an antibody comprising the VH and VL sequences of any one of the exemplary antibodies presented in Table 11, and / or competes with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies presented in Table 11 for binding to ANGPTL7.

[0008] In some embodiments, the antibody, or antigen-binding fragment thereof, is monoclonal and optionally recombinant. In some embodiments, the antibody, or antigen-binding fragment thereof, is human, humanized, or chimeric.

[0009] In some embodiments, the antibody, or antigen-binding fragment thereof, is a full-length antibody, single-chain antibody, single-chain variable fragment (scFv), variable fragment (Fv), antigen-binding region (Fab), Fab-C, Fab’-SH, (Fab’)2, single-domain antibody (sdAb), VHH antibody, nanobody, single-domain antibody derived from camelids, single-domain antibody fragment derived from shark IgNAR (VNAR), diabody, triabody, anticalin or aptamer, and optionally the antibody is a full-length antibody comprising an Fc region, for example, a human IgG1, IgG2, IgG3 or IgG4 region.

[0010] In some embodiments, the antibody, or antigen-binding fragment thereof, is conjugated to an additional moiety selected from at least one additional moiety, optionally any of the following: an antigen-binding moiety such as an antibody or antigen-binding fragment thereof that can specifically bind to a target that is not human ANGPTL7, preferably a target expressed in the human eye, a therapeutic moiety or cytotoxic moiety, a detection moiety, a purification moiety, a half-life extension moiety, optionally a polypeptide at least 20 amino acids in length and comprising any combination of G, A, S, T, E, and P residues, conjugated to the C or N terminus of the antibody.

[0011] In some embodiments, the antibody, or antigen-binding fragment thereof, is any of the following: one, two, or all three of the HCDRs of any one of the exemplary antibodies whose sequences are presented in Table 11, and optionally also one, two, or all three of the corresponding LCDRs of the 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 presented in Table 11, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably a sequence in which changes in the HCDR or LCDR are not tolerated, and / or all six CDRs of any one of the exemplary antibodies whose sequences are presented in Table 11; and / or the VH and VL sequences of any one of the exemplary antibodies whose sequences are presented in Table 11; and / or the full-length heavy chain (VH + constant) sequence of any one of the exemplary antibodies whose sequences are presented in Table 11, and optionally also the corresponding full-length light chain (VL + constant) sequence of the exemplary antibody.

[0012] Embodiments of the present disclosure also include a polynucleotide encoding an antibody, or antigen-binding fragment thereof, described in any of the preceding paragraphs, optionally comprising or consisting of a nucleic acid sequence having at least 70%, 80%, 90%, or 100% identity to the nucleic acid sequence of any one of the exemplary antibodies whose sequences are presented in Table 11.

[0013] Embodiments of the present disclosure also include an expression vector comprising the polynucleotide of the preceding paragraph, optionally an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

[0014] Embodiments of the present disclosure also include a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof, a polynucleotide, or a vector according to any one of the preceding paragraphs, and optionally the following: at least one pharmaceutically acceptable carrier, diluent, or preservative, and / or at least one additional active ingredient. In some embodiments, the pharmaceutical composition is suitable for ophthalmic administration to a subject, optionally by delivery using a conjunctival insert, contact lens, gel, nanoparticle, mucoadhesive polymer, ointment, solution, suspension, eye drop, and / or implant, preferably by injection into the vitreous humor.

[0015] Embodiments of the present disclosure also include any antibody, or an antigen-binding fragment thereof, polynucleotide, vector, or composition of any of the preceding paragraphs for use as a medicament, optionally for use in a method of treating a disease of the eye of a subject. In some embodiments, the disease is characterized by an increase in intraocular pressure and / or a decrease in aqueous humor outflow ability in the eye of the subject. In some embodiments, the method preferably comprises ophthalmic administration of the antibody by injection into the vitreous humor, which administration preferably alleviates at least one symptom selected from eye pain, intraocular pressure, headache, colored halos around lights, reduced vision, blurred vision, visual field constriction, peripheral visual field impairment, blind spots, nausea, vomiting, and red eyes in the subject. In some embodiments, the disease is glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, and optionally, the glaucoma is primary or glucocorticoid-induced glaucoma.

[0016] Embodiments of the present disclosure are antibodies against angiopoietin-like protein 7 (ANGPTL7) peptides, or antigen-binding fragments thereof, comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDR) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) containing complementarity-determining regions (CDR) 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 is S or D, X 2 is G or Y, and 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 is V, S, D, or T, X 2 is Y, H, or F, X 3 is D, G, S, or A, X 4 is H, S, or N, or (d) SX 1 SX 2 YWX 3 (SEQ ID NO: 74), wherein X 1 is S or G, X 2 is S or Y, and 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 YAQX 7 X 8 X 9 G (SEQ ID NO: 7), wherein X 1 is S, I, or N, X 2 is A or P, X 3 is Y or N, X 4 is N or T, X 5 is N or A, X6 is N or K, and X 7 is N or K, and X 8 is L or F, and X 9 is R or Q, and (b) LIYWNDDKX 1 YSPSLKS (SEQ ID NO: 21), wherein X 1 is R or Q, and (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, and X 2 is I or M, and X 3 is D, N, T, S, or G, and X 4 is P, W, S, G, or Y, and X 5 is D, A, N, S, or Y, and X 6 is G or S, and X 7 is D, G, Y, S, I, or N, and X 8 is T, S, N, I, Y, or D, and X 9 is Y, T, F, M, K, G, or I, and X 10 is Y, G, or F, and X 11 is P, Y, or A, and X 12 is G, D, or A, and X 13 is S or D, and X 14 is V, L, or S, and X 15 is K or M, or (d) X 1 IYYSGSTX 2 SNPSLKS (SEQ ID NO: 78), wherein X 1 is S, or Y, and X 2is Y or S. In some embodiments, HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NOs: 13-17, (b) X 1 X 2 X 3 X 4 X 5 X 6 FFDX 7 (SEQ ID NO: 24), wherein X 1 is S, D, or N, and X 2 is Y or P, and X 3 is G or D, and X 4 is D or Y, and X 5 is Y or G, and X 6 is W or D, and X 7 is L or Y, (c) SEQ ID NOs: 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 is Q or A, and X 2 is Y or K, and X 3 is I or W, and X 4 is S or E, and X 5 is T or D, and X 6 is E or Y, and X 7 is Y or F, and X 8 is F or D, and X 9 is Q or Y.

[0017] According to the above embodiments, the LCDR1 of the anti-ANGPTL7 antibody of the present disclosure comprises any one of the amino acid sequences of SEQ ID NOs: 87-97, SEQ ID NOs: 123-127, or SEQ ID NOs: 141-149; the LCDR2 comprises any one of the amino acid sequences of SEQ ID NOs: 99-109, SEQ ID NOs: 129-133, or SEQ ID NOs: 151-159; and the LCDR3 comprises any one of the amino acid sequences of SEQ ID NOs: 111-121, SEQ ID NOs: 135-139, or SEQ ID NOs: 161-169.

[0018] In some embodiments, the present disclosure provides an antibody against an ANGPTL7 peptide, or an antigen-binding fragment thereof, the antibody comprising a VH comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a 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 is G or S, X 2 is S, R, or Y, X 3 is S, N, or I, X 4 is W, D, or Y, X 5 is A, G, or N, (b) RSSQSLX 1 X 2 SX 3 X 4 X 5 X 6 YLX 7 (SEQ ID NO: 122), wherein X 1 is L or V, X 2 is H, Y, or F, X 3 is N or D, X 4 is R or G, X 5 is Y or N, X 6 is 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 is S, N, or R, X 2 is Y or S, X 3 is 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 1is A or T, X 2 is Q or P, (b)X 1 X 2 SNRX 3 S (SEQ ID NO: 128), wherein X 1 is L, K, or E, X 2 is G or V, X 3 is A or D, or (c)X 1 ASX 2 RAT (SEQ ID NO: 150), wherein X 1 is 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 is L or Q, X 2 is A, H, S, or D, X 3 is N, F, or Y, X 4 is S, T, or N, X 5 is F, Y, or T, X 6 is 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 is T or G, X 2 is L or T, X 3 is 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 is R, Y, or G, X 2is S, G, or Q, and X 3 is N, S, or V, and X 4 is W, S, or I, and X 5 is P or L, and X 6 is L, S, P, or T.

[0019] According to the above embodiments, the HCDR1 of the anti-ANGPTL7 antibody of the present disclosure includes any one of the amino acid sequences of SEQ ID NOs: 2-6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42, or SEQ ID NOs: 75-77; the HCDR2 includes any one of the amino acid sequences 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 includes any one of the amino acid sequences of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73, or SEQ ID NOs: 83-85.

[0020] 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.

[0021] In some embodiments, the VH of the anti-ANGPTL7 antibody of the present disclosure comprises an amino acid sequence that is at least 90% identical to any one 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. In some embodiments, the VL of the anti-ANGPTL7 antibody of the present disclosure comprises an amino acid sequence that is at least 90% identical to any one 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. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 170, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 180. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 171, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 181. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 172, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 182. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 173, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 183. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 174, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 184. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 190, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 194. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 191, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 195. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 198, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 228. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 199, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 229.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 200, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 230. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 201, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 231. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 202, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 232. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 203, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 233. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 204, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 234. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 205, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 235. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 206, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 236. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 207, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 237. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 208, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 238. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 209, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 239. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 210, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 240. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 211, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 241.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 212, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 242. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 258, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 264. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 259, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 265. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 260, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 266.

[0022] 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 aqueous humor outflow ability as 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 that is at least 90% identical to SEQ ID NO: 210 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 240, (b) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 200 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 230, (c) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 258 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 264, (d) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 207 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 237, (e) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 204 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 234, (f) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 260 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 266, (g) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 205 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 235, (h) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 206 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 236, (i) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 208 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 238, (j) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 191 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 195, (k) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 203 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 233,(l) A VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 212 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 242, (m) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 198 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 228, (n) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 190 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 194, (o) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 202 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 232, (p) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 211 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 241, or (q) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 199 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 229.

[0023] In some embodiments, the anti-ANGPTL7 antibody comprises: (a) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 210 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 240, (b) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 200 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 230, or (c) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 258 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 264.

[0024] In some embodiments, the anti-ANGPTL7 antibody comprises (a) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 207 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 237, (b) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 204 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 234, (c) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 260 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 266, (d) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 205 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 235, (e) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 206 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 236, (f) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 208 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 238, (g) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 191 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 195, (h) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 203 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 233, (i) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 212 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 242, (j) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 198 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 228, or (k) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 190 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 194.

[0025] In some embodiments, the anti-ANGPTL7 antibody comprises (a) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 202 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 232, (b) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 211 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 241, or (c) a VH comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 199 and a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 229.

[0026] According to the above embodiments, the anti-ANGPTL7 antibody of the present disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFV, and (Fab') 2 fragment. 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, trivalent, or tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0027] In some embodiments, the antibody comprises a detection moiety. In some embodiments, the antibody comprises a purification moiety. In some embodiments, the antibody comprises a half-life extension moiety. In some embodiments, the half-life extension moiety comprises a polypeptide that is at least 20 amino acids in length and comprises any combination of G, A, S, T, E, and P residues. In some embodiments, the half-life extension polypeptide is attached to the C-terminus or N-terminus of the antibody.

[0028] The anti-ANGPTL7 antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount for treating eye diseases (such as glaucoma and / or diseases affecting the optic nerve or retinal ganglion cells). In some embodiments, the composition is suitable for ophthalmic administration. In some embodiments, ophthalmic administration includes injection into the vitreous humor. In some embodiments, ophthalmic administration includes delivering the antibody using a conjunctival insert, contact lens, gel, nanoparticle, mucoadhesive polymer, ointment, solution, suspension, eye drop, and / or implant.

[0029] Embodiments of the present disclosure also include methods of treating glaucoma and / or diseases affecting the optic nerve and / or retinal ganglion cells. According to these embodiments, the method includes administering a pharmaceutical composition comprising a therapeutically effective amount of the anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the pharmaceutical composition is administered to the eye to treat 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 includes eye pain, intraocular pressure, headache, colored halos around lights, low vision, blurred vision, visual field constriction, peripheral vision impairment, blind spots, nausea, vomiting, and red eyes. In some embodiments, administering the pharmaceutical composition reduces the intraocular pressure in the subject's eye and / or increases the aqueous humor outflow ability. In some embodiments, the pharmaceutical composition is administered at a dose in the range of about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the pharmaceutical composition is administered at a dose in the range of about 0.0001 mg / ml to about 100 mg / ml.

[0030] 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 that is at least 70% 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 70% 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 80% 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 80% 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.

[0031] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises: (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.

[0032] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises (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.

[0033] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises (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.

[0034] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises (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.

[0035] According to these embodiments, the present disclosure includes an expression vector comprising any of the polynucleotides encoding the anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the expression vector is suitable for producing the anti-ANGPTL7 antibody of the present disclosure for delivering the antibody to a subject. In some embodiments, the expression vector is suitable for use in gene therapy (e.g., an expression vector for delivering a polynucleotide encoding the 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.

[0036] According to these embodiments, the present disclosure also provides a method of administering it to a subject in need of gene therapy of the eye, the method comprising injecting a pharmaceutical composition comprising an effective amount of the 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 the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). In some embodiments, administering the pharmaceutical composition treats at least one symptom of glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells.

[0037] According to the above embodiments, the anti-ANGPTL7 antibody of the present disclosure binds to an epitope derived from an ANGPTL7 polypeptide having any one of the amino acid sequences of SEQ ID NOs: 370 to 374 or a variant thereof. In some embodiments, the anti-ANGPTL7 antibody of the present disclosure binds to an epitope derived from an ANGPTL7 polypeptide with a K D of about 100 nM or less.

Brief Description of the Drawings

[0038]

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Mode for Carrying Out the Invention

[0039] Embodiments of the present disclosure relate to the treatment and / or prevention of glaucoma and other eye diseases that affect the optic nerve and retinal ganglion cells. In particular, the present disclosure provides novel therapeutic antibodies that target angiopoietin-related protein 7 (ANGPTL7) as a means to lower intraocular pressure (IOP) and / or increase aqueous humor outflow facility, thereby preventing damage to the optic nerve and / or restoring vision.

[0040] Angiopoietin-like proteins (ANGPTLs) are a family of proteins that have structural similarity to angiopoietin proteins. Seven proteins were initially classified into this family (ANGPTL1-7), and more recently, another protein called ANGPTL8 has been identified. ANGPTL proteins have an amino-terminal coiled-coil domain and a carboxyl-terminal fibrinogen-like domain (except for ANGPTL8, which lacks the subsequent domain). ANGPTL proteins are not known to bind to tyrosine kinase receptors, such as Tie 1 and Tie 2, which is the point that differentiates them from angiopoietin proteins. ANGPTL proteins have been shown to play different physiological roles in metabolism, inflammation, and cancer. Evidence associating these proteins with obesity and insulin resistance is increasing. For example, ANGPTL2 has been shown to be associated with adiposity and insulin resistance, as well as the development of type 2 diabetes. ANGPTL3, 4, and 8 have been shown to play major roles in the regulation of lipid metabolism through inhibition of lipoprotein lipase. Similarly, ANGPTL6 has been shown to be higher in subjects with metabolic syndrome and to have a positive correlation with HDL levels. Levels of ANGPTL8 have been shown to be higher in subjects with obesity and diabetes and to have a positive correlation with insulin resistance and fasting plasma glucose in non-diabetic subjects.

[0041] However, ANGPTL7 is a member of the ANGPTL protein family first discovered in the stromal layer of the cornea and is poorly studied. The level of ANGPTL7 has been shown to increase in glaucoma, and its overexpression increases the expression level of collagen, while its induction by glucocorticoids causes upregulation of important glaucoma-related proteins including fibronectin, myocilin, and MMP1. These data suggest that ANGPTL7 may regulate the extracellular matrix of the trabecular meshwork and its response to steroids. Furthermore, ANGPTL7 is potentially associated with various cancers through its interaction with the WNT / β-catenin signaling pathway. Currently, there is no therapeutic approach targeting ANGPTL7.

[0042] Glaucoma is the leading cause of global irreversible vision loss characterized by progressive optic neuropathy. The most common form of glaucoma is primary open-angle glaucoma (POAG), which is always accompanied by elevated intraocular pressure (IOP), a central risk factor for the etiology of POAG. In some cases, long-term use of dexamethasone (DEX) has a high risk of increasing IOP and results in secondary glaucoma, which has many features in common with POAG. The etiology of POAG can be inferred from the mechanism underlying DEX-induced elevated IOP. Understanding the DEX-induced molecular mechanism can help in the development of treatment methods for glucocorticoid-induced glaucoma and POAG. Furthermore, elevated IOP is caused by an increase in the outflow resistance of aqueous humor (AH). Accumulating evidence suggests that the actin cytoskeleton reorganization of the trabecular meshwork (TM), which forms a cross-linked actin network, is a decisive inducer of this increased resistance. Previous studies have found that the concentration of angiopoietin-like 7 (ANGPTL7) is elevated in glaucomatous AH and that overexpression of ANGPTL7 in TM changes the components of the extracellular matrix (ECM). Recent studies have found that variants that change the ANGPTL7 protein exert a strong protective effect against glaucoma, suggesting ANGPTL7 as a therapeutic target for glaucoma. Therefore, ANGPTL7 may play an important role in regulating the ECM of TM and in regulating IOP.

[0043] In view of this, experiments were conducted to determine the role that ANGPTL7 may play in the etiology of glaucoma and other related diseases that affect the optic nerve and retinal ganglion cells, and accordingly, to develop a therapeutic platform based on the regulation of ANGPTL7 activity using anti-ANGPTL7 antibodies.

[0044] Definitions To facilitate the understanding of this technology, several terms and phrases are defined below. Additional definitions are described throughout the detailed description of the invention.

[0045] In the context of the embodiments of the present disclosure (in particular, from the perspective of the following claims), the use of the terms "a", "an", and "the" and the use of the terms "at least one" and the like to refer to an object shall, unless otherwise indicated in this specification or unless clearly contradicted by the context, be construed to cover both the singular and the plural. The use of the term "at least one" following an enumeration of one or more items (for example, "at least one of A and B") shall, unless otherwise indicated in this specification or unless clearly contradicted by the context, be construed to mean one item selected from the enumerated items (A or B), or any combination of two or more of the enumerated items (A and B). The terms "comprising", "having", "including", and "containing" shall, unless otherwise noted, be construed as non-limiting terms (i.e., meaning "including but not limited to"). The recitation of a range of values herein is, unless otherwise indicated in this specification, merely intended to serve as a shorthand way of referring individually to each of the individual values that fall within that range, and each individual value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or unless clearly contradicted by the context. The use of some and all examples provided herein or exemplary language (e.g., "such as") is merely intended to illustrate the various embodiments of the present disclosure well and, unless otherwise claimed, does not limit the scope of these embodiments. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the various embodiments of the present disclosure.

[0046] Furthermore, 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 additional factors not recited, unless the context clearly dictates otherwise. Additionally, throughout this specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in" includes "in" and "on".

[0047] As used in the claims of this application, the transitional phrase "consisting essentially of" limits the claim to the specified materials or steps of the claimed invention "and those that do not materially affect the basic and novel characteristics (s) thereof", as set forth 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 unrecited contaminants at a level that does not change the function of the recited composition as compared to the pure composition, i.e., the composition "consisting of" the recited components.

[0048] As used herein, the term "one or more" refers to a number greater than one. For example, the term "one or more" includes any of the following: 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, one hundred or more, or even more.

[0049] "One or more, but less than a greater number", "Two or more, but less than a greater number", "Three or more, but less than a greater number", "Four or more, but less than a greater number", "Five or more, but less than a greater number", "Six or more, but less than a greater number", "Seven or more, but less than a greater number", "Eight or more, but less than a greater number", "Nine or more, but less than a greater number", "Ten or more, but less than a greater number", "Eleven or more, but less than a greater number", "Twelve or more, but less than a greater number", "Thirteen or more, but less than a greater number", "Fourteen or more, but less than a greater number", or "Fifteen or more, but less than a greater number" is not limited to a higher number. For example, the greater number can be 10,000, 1,000, 100, 50, etc. For example, the greater number can be composed of 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).

[0050] As used herein, the terms "immunoglobulin" or "antibody" refer to proteins found in the blood or other body fluids of vertebrates and 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 includes at least one complementarity determining region (CDR). The CDRs form the "hypervariable regions" of the antibody, which are involved in antigen binding (further described below). An entire antibody typically consists 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 has one N-terminal variable (V H ) region and three C-terminal constant (C H1 , C H2 , and C H3 ) regions, and each light chain has one N-terminal variable (V L ) region and one C-terminal constant (C L) The domain is included. The light chains of antibodies can be assigned to one of two different types, either kappa (κ) or lambda (λ), based on the amino acid sequences of their constant domains. In a typical antibody, each light chain is linked to the heavy chain by a disulfide bond, and the two heavy chains are linked to each other by a disulfide bond. The variable region of the light chain is aligned with the variable region of the heavy chain, and the constant region of the light chain is aligned with the first constant region of the heavy chain. The remaining constant regions of the heavy chain are aligned with each other.

[0051] The variable regions of each pair of light and heavy chains form the antigen-binding site of the antibody. V H and V L regions have the same general structure where each region contains four framework (FW or FR) regions. As used herein, the term "framework region" refers to a relatively conserved amino acid sequence within the variable region located between the CDRs. There are four framework regions in each variable domain, which are called FR1, FR2, FR3, and FR4. The framework regions form beta-sheets that provide the structural framework of the variable region (see, for example, C.A. Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N.Y. (2001)).

[0052] The framework regions are connected by three CDRs. As discussed above, the three CDRs, known as CDR1, CDR2, and CDR3, form the "hypervariable regions" of the antibody, which are involved in antigen binding. The CDRs connect the beta-sheet structure formed by the framework regions and form loops that, in some cases, constitute part of it. The constant regions of the light and heavy chains are not directly involved in the binding of the antibody to the antigen, but the constant regions can affect the orientation of the variable regions. The constant regions also exhibit various effector functions such as involvement in antibody-dependent complement-mediated lysis or antibody-dependent cell cytotoxicity through interaction with effector molecules and cells.

[0053] As used herein, an antibody or other entity (e.g., an antigen-binding domain) "specifically recognizes" or "specifically binds to" an antigen or epitope if it preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules and binds to the antigen or epitope with a substantially higher affinity than to other entities that do not present the antigen or epitope. In this regard, "substantially higher affinity" means an affinity high enough to enable detection of the antigen or epitope that is distinguishable from the entity using the desired assay or measuring device. Typically, it is 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 etc.) binding constant (K a ). In certain such embodiments, an antibody can bind to different antigens so long as the different antigens contain its particular epitope. In certain cases, for example, homologous proteins from different species can contain the same epitope.

[0054] The terms "antibody fragment of an antibody", "antibody fragment", and "antigen-binding fragment" are used interchangeably herein and 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 preferably include, for example, one or more CDRs, variable regions (or portions thereof), constant regions (or portions thereof), or combinations thereof. Examples of antibody fragments include (i) V L , V H , CL and C H1 a Fab fragment which is a monovalent fragment consisting of a domain, (ii) an F(ab’)2 fragment which is a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region, (iii) the V L and V H an Fv fragment consisting of domains, (iv) a Fab’ fragment resulting from cleavage of the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a single-chain variable region domain (V H or V L ) a domain antibody (dAb) which is a polypeptide, but is not limited thereto.

[0055] As used herein, the term “monoclonal antibody” refers to an antibody produced by a single clone of B lymphocytes against a single epitope on an antigen. Monoclonal antibodies are typically produced using hybridoma technology as first described in Kohler and Milstein, Eur. J. Immunol., 5:511-519 (1976). Monoclonal antibodies can also be produced using recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), or 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 from transgenic mice carrying a fully 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 various B cell lineages in an animal. Polyclonal antibodies are an aggregate of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0056] In this specification, the terms "nucleic acid", "polynucleotide", "nucleotide sequence", and "oligonucleotide" are used interchangeably 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, at 793-800 (Worth Pub. 1982)). These terms encompass any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component, and any chemical variants thereof such as methylated, hydroxymethylated, or glycosylated forms of these bases. The polymer or oligomer can have a heterogeneous or homogeneous composition and can be isolated from a naturally occurring source or generated artificially or synthetically. Further, the nucleic acid can be DNA or RNA, or a mixture thereof, and can exist permanently or transiently in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. In some embodiments, the nucleic acid or nucleic acid sequence includes other types of nucleic acid structures such as, for example, DNA / RNA helices, peptide nucleic acids (PNA) (see, e.g., Braasch and Corey, Biochemistry, 41(14):4503-4510 (2002), and U.S. Patent No. 5,034,506), locked nucleic acids (LNA; see Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 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" can also encompass strands containing unnatural nucleotides, modified nucleotides, and / or non-nucleotide components (e.g., "nucleotide analogs") that can exhibit the same function as natural nucleotides.

[0057] The terms "peptide", "polypeptide", and "protein" are used interchangeably herein and refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having a modified peptide backbone.

[0058] As used herein, the term "nucleic acid" or "nucleic acid molecule" generally refers to any ribonucleic acid or deoxyribonucleic acid, which may be unmodified or modified DNA or RNA. "Nucleic acids" include, but are not limited to, single-stranded and double-stranded nucleic acids. As used herein, the term "nucleic acid" also includes DNA as described above that contains one or more modified bases. Thus, DNA with a modified backbone for reasons of stability or otherwise is a "nucleic acid". As used herein, the term "nucleic acid" encompasses chemically, enzymatically, or metabolically modified forms of nucleic acids, as well as characteristic chemical forms of DNA in viruses and cells, including, for example, simple and complex cells.

[0059] The terms "oligonucleotide" or "polynucleotide" or "nucleotide" or "nucleic acid" refer to a molecule containing two or more, preferably more than three, and usually more than ten deoxyribonucleotides or ribonucleotides. The exact size will depend on many factors and on the ultimate function or use of the oligonucleotide. Oligonucleotides can be generated in any manner, including chemical synthesis, DNA replication, reverse transcription, or combinations thereof. The typical deoxyribonucleotides of DNA are thymine, adenine, cytosine, and guanine. The typical ribonucleotides of RNA are uracil, adenine, cytosine, and guanine.

[0060] The terms "complementary" and "complementarity" refer to nucleotides (e.g., a single nucleotide) or polynucleotides (e.g., a nucleotide sequence) that are related by base pairing rules. For example, the sequence 5'-A-G-T-3' is complementary to the sequence 3'-T-C-A-5'. Complementarity may be "partial", in which case only some of the nucleobases match according to the base pairing rules. Or, there may be "complete" or "total" complementarity between nucleic acids. The degree of complementarity between strands of nucleic acids results in the efficiency and strength of hybridization between the strands of nucleic acids. This is particularly important in amplification reactions and in detection methods that rely on binding between nucleic acids.

[0061] The term "gene" refers to a nucleic acid (e.g., DNA or RNA) sequence that includes the coding sequence necessary for the production of RNA, or a polypeptide or its precursor. A functional polypeptide can be encoded by the full-length coding sequence or by any part of the coding sequence, as long as the desired activity or functional properties of the polypeptide (e.g., enzyme activity, ligand binding, signal transduction, etc.) are retained. When used in reference to a gene, the term "portion" refers to a fragment of that gene. These fragments can range in size from a few nucleotides to one nucleotide less than the sequence of the entire gene. Thus, "a nucleotide containing at least a portion of a gene" can include a fragment of the gene or the entire gene.

[0062] The term "gene" also includes the coding region of a structural gene and sequences (e.g., including coding sequences, control sequences, structural sequences and other sequences) that flank the coding region at both the 5' and 3' ends at a distance of about 1 kb from the coding region at either end so that the gene corresponds to the length of the full-length mRNA. The sequence that is located 5' to the coding region and is present on the mRNA is referred to as the 5' non-translated or untranslated sequence. The sequence that is located 3' to or downstream of the coding region and is present on the mRNA is referred to as the 3' non-translated or 3' untranslated sequence. The term "gene" encompasses both the cDNA and genomic forms of the gene. In some organisms (e.g., eukaryotes), the genomic form or clone of a gene contains a coding region interrupted by non-coding sequences, which are referred to as "introns", "intervening regions", or "intervening sequences". Introns are segments of a gene that are transcribed into nuclear RNA (hnRNA), and introns may contain regulatory elements such as enhancers. Since introns are removed from the nucleus or the primary transcript or "spliced out", introns are not present in messenger RNA (mRNA) transcripts. mRNA functions during translation to specify the amino acid sequence or order in a nascent polypeptide.

[0063] In addition to containing introns, the genomic form of a gene may also include sequences located at both the 5' and 3' ends of the sequences present in the RNA transcript. These sequences are referred to as "flanking" sequences or regions (these flanking sequences are located 5' or 3' to the untranslated sequences present in the mRNA transcript). The 5' flanking region may contain regulatory sequences such as promoters and enhancers that control or affect the transcription of the gene. The 3' flanking region may contain sequences that direct transcription termination, post-transcriptional cleavage, and polyadenylation.

[0064] When referring to a gene, the term "wild-type" refers to a gene having the characteristics of a gene isolated from a naturally occurring source. When referring to a gene product, the term "wild-type" refers to a gene product having the characteristics of a gene product isolated from a naturally occurring source. When referring to a protein, the term "wild-type" refers to a protein having the characteristics of a naturally occurring protein. The term "naturally occurring" when used with respect to an object refers to the fact that the object can be found in nature. For example, a polypeptide or polynucleotide sequence present in an organism (including a virus) that can be isolated from a natural source and has not been intentionally modified by human hand in the laboratory is naturally occurring. Since the wild-type gene is the most frequently observed within a population, it is often that gene or allele arbitrarily designated as the "normal" or "wild-type" form of the gene. In contrast, when referring to a gene or gene product, the terms "modified" or "mutant" refer respectively to a gene or gene product that shows a modification (i.e., an altered characteristic) in sequence and / or functional properties when compared to the wild-type gene or gene product. Note that naturally occurring variants can be isolated and are identified by the fact that they have altered characteristics when compared to the wild-type gene or gene product.

[0065] The term "allele" refers to variants of a gene, and these variants include, but are not limited to, variants and mutants, polymorphic loci, as well as single nucleotide polymorphic loci, frameshifts, and splice variants. An allele can occur naturally in a population or it can arise during the lifetime of any particular individual in that population.

[0066] Thus, when used with reference to a nucleotide sequence, the terms "variant" and "mutant" refer to a nucleic acid sequence that differs from another, usually related, nucleotide acid sequence by one or more nucleotides. A "variant" is the difference between two different nucleotide sequences, and generally, one sequence is the reference sequence.

[0067] 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 involve, for example, antibody production and / or activation of immune effector cells. An antigen in the context of the present disclosure can include any subunit, fragment, or epitope of any proteinaceous or non-proteinaceous (e.g., carbohydrate or lipid) molecule that elicits an immune response in a mammal. The term "epitope" refers to the sequence of an antigen that is recognized by an antibody or antigen receptor. Epitopes are also referred to in the art as "antigenic determinants". In certain embodiments, an epitope is the region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope can include groupings of chemically active surface groups of a molecule, such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope can have specific three-dimensional structural features (e.g., "conformational" epitopes) and / or specific charge characteristics. An antigen can be a virus, bacterium, parasite, fungus, protozoan, prion, cell, or protein or peptide of extracellular origin, which elicits an immune response in a mammal and preferably leads to protective immunity.

[0068] As used herein, the term "pharmaceutically acceptable carrier" generally refers to a component in a pharmaceutical formulation that is non-toxic to the subject other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0069] As used herein, the term "pharmaceutical formulation" generally refers to a preparation that is in a form that permits the biological activity of the active ingredient (e.g., an anti-ANGPTL7 antibody, antibody conjugate, fusion protein, or polymeric formulation) contained therein to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0070] As used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") generally refers to a clinical intervention that is performed for the purpose of altering the natural course of an individual being treated, and can be performed prophylactically or during a clinical pathological process. Desirable effects of treatment include, but are not limited to, prevention of the development or recurrence of a disease, alleviation of symptoms, reduction of any direct or indirect pathological consequence of the disease, prevention of metastasis, reduction of the rate of disease progression, recovery or amelioration of a medical condition, and remission or improvement of the 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 polymeric formulations), are used to delay the onset of a disease or to slow the progression of a disease.

[0071] 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, an antibody conjugate, a fusion protein (e.g., a Fab fusion protein), or a polymeric formulation) to decrease by one-half in vivo (e.g., within the eye (e.g., within the vitreous)) or in vitro.

[0072] As used herein, an "effective amount" of an agent, e.g., a pharmaceutical formulation, generally refers to an amount effective to achieve the desired therapeutic or prophylactic result at the dosage and for the period required to achieve it.

[0073] "Individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, 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, the individual or subject is a human. A "subject" can be a "patient".

[0074] Anti-ANGPTL7 antibody Embodiments of the present disclosure relate to the treatment and / or prevention of glaucoma and other eye diseases that affect the optic nerve and retinal ganglion cells. In particular, the present disclosure provides novel therapeutic antibodies that target angiopoietin-related protein 7 (ANGPTL7) as a means of reducing intraocular pressure (IOP) and / or increasing aqueous humor outflow facility, thereby preventing optic nerve damage and / or restoring vision.

[0075] As further described herein, embodiments of the present disclosure include an antibody that specifically binds to human angiopoietin-like protein 7 (ANGPTL7), or an antigen-binding fragment thereof, optionally, the human ANGPTL7 is a polypeptide comprising or consisting of any one of the amino acid sequences of SEQ ID NOs: 370-374.

[0076] In some embodiments, the antibody, or antigen-binding fragment thereof, exhibits any one or more of the following functional characteristics: when administered to the eye of a subject, increases aqueous humor outflow facility compared to a control, optionally, the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein and isotype control antibody treatment, and / or binds to ANGPTL7 with a K D of about 100 nM or less, and / or binds to the same epitope on ANGPTL7 as an antibody comprising the VH and VL sequences of any one of the exemplary antibodies presented in Table 11, and / or competes with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies presented in Table 11 for binding to ANGPTL7.

[0077] In some embodiments, the antibody, or antigen-binding fragment thereof, is monoclonal and optionally recombinant. In some embodiments, the antibody, or antigen-binding fragment thereof, is human, humanized, or chimeric.

[0078] In some embodiments, the antibody, or antigen-binding fragment thereof, is a full-length antibody, single-chain antibody, single-chain variable fragment (scFv), variable fragment (Fv), antigen-binding region (Fab), Fab-C, Fab’-SH, (Fab’)2, single-domain antibody (sdAb), VHH antibody, nanobody, single-domain antibody from camelids, single-domain antibody fragment derived from shark IgNAR (VNAR), diabody, triabody, anticalin or aptamer, and optionally the antibody is a full-length antibody comprising an Fc region, e.g., a human IgG1, IgG2, IgG3 or IgG4 region.

[0079] In some embodiments, the antibody, or antigen-binding fragment thereof, is conjugated to an additional moiety selected from at least one additional moiety optionally including: an antigen-binding moiety such as an antibody or antigen-binding fragment thereof that specifically binds to a target that is not human ANGPTL7, preferably a target expressed in the human eye, a therapeutic moiety or a cytotoxic moiety, a detection moiety, a purification moiety, a half-life extending moiety, and optionally a polypeptide that is at least 20 amino acids in length and comprises any combination of G, A, S, T, E, and P residues and is conjugated to the C- or N-terminus of the antibody.

[0080] In some embodiments, the antibody, or antigen-binding fragment thereof, is any one, two, or all three of the HCDRs of any one of the exemplary antibodies whose sequences are presented in Table 11, and optionally also any one, two, or all three of the corresponding LCDRs of the 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 presented in Table 11, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, wherein preferably changes in the HCDR or LCDR are not permitted, and / or all six CDRs of any one of the exemplary antibodies whose sequences are presented in Table 11; and / or the VH and VL sequences of any one of the exemplary antibodies whose sequences are presented in Table 11; and / or the full-length heavy chain (VH + constant) sequence of any one of the exemplary antibodies whose sequences are presented in Table 11, and optionally also the corresponding full-length light chain (VL + constant) sequence of the exemplary antibody, a polypeptide comprising.

[0081] Embodiments of the present disclosure are also polynucleotides encoding the antibodies, or antigen-binding fragments thereof, described in any of the preceding paragraphs, optionally comprising or consisting of a nucleic acid sequence having at least 70%, 80%, 90% or 100% identity to the nucleic acid sequence of any one of the exemplary antibodies whose sequences are presented in Table 11.

[0082] Embodiments of the present disclosure also include expression vectors comprising the polynucleotides of the preceding paragraphs, which are optionally adeno-associated virus (AAV) vectors, lentivirus (LV) vectors, herpes simplex virus (HSV) vectors, or retroviral vectors.

[0083] 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 one of the preceding paragraphs, and optionally the following: at least one pharmaceutically acceptable carrier, diluent, or preservative, and / or at least one additional active ingredient. In some embodiments, the pharmaceutical composition is suitable for ophthalmic administration to a subject, optionally by delivery using a conjunctival insert, contact lens, gel, nanoparticle, mucoadhesive polymer, ointment, solution, suspension, eye drop, and / or implant, preferably by injection into the vitreous humor.

[0084] Embodiments of the present disclosure also include an antibody, or antigen-binding fragment thereof, polynucleotide, vector, or composition according to any of the preceding paragraphs for use as a medicament, optionally for use in a method of treating a disease of the eye of a subject. In some embodiments, the disease is characterized by an increase in intraocular pressure and / or a decrease in aqueous humor outflow ability in the eye of the subject. In some embodiments, the method preferably includes ophthalmic administration of the antibody by injection into the vitreous humor, which preferably alleviates at least one symptom selected from eye pain, intraocular pressure, headache, colored halos around lights, reduced vision, blurred vision, visual field constriction, peripheral visual field impairment, blind spots, nausea, vomiting, and red eyes in the subject. In some embodiments, the disease is glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, and optionally, the glaucoma is primary or glucocorticoid-induced glaucoma.

[0085] As further described herein, anti-ANGPTL7 antibodies were generated and their structural and functional properties were characterized. Based on these data, embodiments of the present disclosure include an anti-ANGPTL7 antibody, or antigen-binding fragment thereof, which antibody includes a heavy chain variable region (VH) comprising complementarity determining regions (CDR) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDR) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 includes one of the following amino acid sequences: (a) X 1 YX 2 IX3 (SEQ ID NO:1), wherein X 1 is S or D, and X 2 is G or Y, and 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 is V, S, D, or T, and X 2 is Y, H, or F, and X 3 is D, G, S, or A, and X 4 is H, S, or N, or (d) SX 1 SX 2 YWX 3 (SEQ ID NO:74), wherein X 1 is S or G, and X 2 is S or Y, and 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 YAQX 7 X 8 X 9 G (SEQ ID NO:7), wherein X 1 is S, I, or N, and X 2 is A or P, and X 3 is Y or N, and X 4 is N or T, and X 5 is N or A, and X 6 is N or K, and X 7 is N or K, and X 8 is L or F, and 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 5X 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, and X 2 is I or M, and X 3 is D, N, T, S, or G, and X 4 is P, W, S, G, or Y, and X 5 is D, A, N, S, or Y, and X 6 is G or S, and X 7 is D, G, Y, S, I, or N, and X 8 is T, S, N, I, Y, or D, and X 9 is Y, T, F, M, K, G, or I, and X 10 is Y, G, or F, and X 11 is P, Y, or A, and X 12 is G, D, or A, and X 13 is S or D, and X 14 is V, L, or S, and X 15 is K or M, or (d) X 1 IYYSGSTX 2 SNPSLKS (SEQ ID NO: 78), wherein X 1 is S, or Y, and X 2 is Y or S. In some embodiments, HCDR3 comprises one of the following amino acid sequences: (a) SEQ ID NOs: 13 - 17, (b) X 1 X 2 X 3 X 4 X 5 X 6 FFDX 7 (SEQ ID NO: 24), wherein X 1 is S, D, or N, and X 2 is Y or P, and X 3 is G or D, and X 4 is D or Y, and X 5is Y or G, and X 6 is W or D, and 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 is Q or A, and X 2 is Y or K, and X 3 is I or W, and X 4 is S or E, and X 5 is T or D, and X 6 is E or Y, and X 7 is Y or F, and X 8 is F or D, and X 9 is Q or Y.

[0086] In addition to the above HCDR1, HCDR2, and HCDR3 sequences, the anti-ANGPTL7 antibodies of the present disclosure include LCDR1 comprising any one of the amino acid sequences of SEQ ID NO: 87-97, SEQ ID NO: 123-127, or SEQ ID NO: 141-149, LCDR2 comprising any one of the amino acid sequences of SEQ ID NO: 99-109, SEQ ID NO: 129-133, or SEQ ID NO: 151-159, and LCDR3 comprising any one of the amino acid sequences of SEQ ID NO: 111-121, SEQ ID NO: 135-139, or SEQ ID NO: 161-169.

[0087] In some embodiments, the present disclosure provides an anti-ANGPTL7 antibody, or an antigen-binding fragment thereof, comprising a VH comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementarity-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 1X is G or S 2 X is S, R, or Y 3 X is S, N, or I 4 X is W, D, or Y 5 (b) RSSQSLX, where X is A, G, or N 1 X 2 SX 3 X 4 X 5 X 6 YLX 7 (SEQ ID NO: 122), wherein X 1 X is L or V 2 X is H, Y, or F 3 X is N or D 4 X is R or G 5 X is Y or N 6 X is N or T 7 Or (c) RASQSVSX, where X is D or N 1 X 2 X 3 X 4 A (SEQ ID NO: 140), wherein X 1 X is S, N, or R 2 X is Y or S 3 X is L or Y 4 X 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 X is A or T 2 Or (b) X, where X is Q or P 1 X 2 SNRX 3 S (SEQ ID NO: 128), wherein X 1 X is L, K, or E 2 X is G or V 3 Or (c) X, where X is A or D 1 ASX 2 RAT (SEQ ID NO: 150), wherein X 1 X is D or G 2is 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 is L or Q, X 2 is A, H, S, or D, X 3 is N, F, or Y, X 4 is S, T, or N, X 5 is F, Y, or T, X 6 is 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 is T or G, X 2 is L or T, X 3 is 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 is R, Y, or G, X 2 is S, G, or Q, X 3 is N, S, or V, X 4 is W, S, or I, X 5 is P or L, X 6 is L, S, P, or T.

[0088] According to the above LCDR1, LCDR2, and LCDR3 arrays, the anti-ANGPTL7 antibody of the present disclosure includes an HCDR1 containing an amino acid sequence of any one of SEQ ID NOs: 2 to 6, SEQ ID NOs: 19 to 20, SEQ ID NOs: 28 to 42, or SEQ ID NOs: 75 to 77, an HCDR2 contains an amino acid sequence of any one of SEQ ID NOs: 8 to 12, SEQ ID NOs: 22 to 23, SEQ ID NOs: 44 to 58, or SEQ ID NOs: 79 to 81, and an HCDR3 contains an amino acid sequence of any one of SEQ ID NOs: 13 to 17, SEQ ID NOs: 25 to 26, SEQ ID NOs: 59 to 73, or SEQ ID NOs: 83 to 85.

[0089] In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 13. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 3, HCDR2 of SEQ ID NO: 9, and HCDR3 of SEQ ID NO: 14. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 10, and HCDR3 of SEQ ID NO: 15. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 5, HCDR2 of SEQ ID NO: 11, and HCDR3 of SEQ ID NO: 16. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 12, and HCDR3 of SEQ ID NO: 17. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 7, HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, and HCDR3 of SEQ ID NO: 20. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 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, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 20, HCDR2 of SEQ ID NO: 23, and HCDR3 of SEQ ID NO: 26. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 28, HCDR2 of SEQ ID NO: 44, and HCDR3 of SEQ ID NO: 59. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 29, HCDR2 of SEQ ID NO: 45, and HCDR3 of SEQ ID NO: 60. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 30, HCDR2 of SEQ ID NO: 46, and HCDR3 of SEQ ID NO: 61. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 31, HCDR2 of SEQ ID NO: 47, and HCDR3 of SEQ ID NO: 62. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 32, HCDR2 of SEQ ID NO: 48, and HCDR3 of SEQ ID NO: 63. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 49, and HCDR3 of SEQ ID NO: 64.In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 34, HCDR2 of SEQ ID NO: 50, and HCDR3 of SEQ ID NO: 65. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 35, HCDR2 of SEQ ID NO: 51, and HCDR3 of SEQ ID NO: 66. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 52, and HCDR3 of SEQ ID NO: 67. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 37, HCDR2 of SEQ ID NO: 53, and HCDR3 of SEQ ID NO: 68. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 38, HCDR2 of SEQ ID NO: 54, and HCDR3 of SEQ ID NO: 69. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 39, HCDR2 of SEQ ID NO: 55, and HCDR3 of SEQ ID NO: 70. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 40, HCDR2 of SEQ ID NO: 56, and HCDR3 of SEQ ID NO: 71. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 41, HCDR2 of SEQ ID NO: 57, and HCDR3 of SEQ ID NO: 72. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 42, HCDR2 of SEQ ID NO: 58, and HCDR3 of SEQ ID NO: 73. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 75, HCDR2 of SEQ ID NO: 79, and HCDR3 of SEQ ID NO: 83. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 76, HCDR2 of SEQ ID NO: 80, and HCDR3 of SEQ ID NO: 84. In some embodiments, the anti-ANGPTL7 antibody comprises HCDR1 of SEQ ID NO: 77, HCDR2 of SEQ ID NO: 81, and HCDR3 of SEQ ID NO: 85.

[0090] In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 87, LCDR2 of SEQ ID NO: 99, and LCDR3 of SEQ ID NO: 111. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 88, LCDR2 of SEQ ID NO: 100, and LCDR3 of SEQ ID NO: 112. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 89, LCDR2 of SEQ ID NO: 101, and LCDR3 of SEQ ID NO: 113. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 90, LCDR2 of SEQ ID NO: 102, and LCDR3 of SEQ ID NO: 114. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 91, LCDR2 of SEQ ID NO: 103, and LCDR3 of SEQ ID NO: 115. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 92, LCDR2 of SEQ ID NO: 104, and LCDR3 of SEQ ID NO: 116. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 93, LCDR2 of SEQ ID NO: 105, and LCDR3 of SEQ ID NO: 117. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 94, LCDR2 of SEQ ID NO: 106, and LCDR3 of SEQ ID NO: 118. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 95, LCDR2 of SEQ ID NO: 107, and LCDR3 of SEQ ID NO: 119. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 96, LCDR2 of SEQ ID NO: 108, and LCDR3 of SEQ ID NO: 120. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 97, LCDR2 of SEQ ID NO: 109, and LCDR3 of SEQ ID NO: 121. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 123, LCDR2 of SEQ ID NO: 129, and LCDR3 of SEQ ID NO: 135. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 124, LCDR2 of SEQ ID NO: 130, and LCDR3 of SEQ ID NO: 136. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 125, HCDR2 of SEQ ID NO: 131, and LCDR3 of SEQ ID NO: 137.In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 126, LCDR2 of SEQ ID NO: 132, and LCDR3 of SEQ ID NO: 138. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 127, LCDR2 of SEQ ID NO: 133, and LCDR3 of SEQ ID NO: 139. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 141, LCDR2 of SEQ ID NO: 151, and LCDR3 of SEQ ID NO: 161. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 142, LCDR2 of SEQ ID NO: 152, and LCDR3 of SEQ ID NO: 162. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 143, LCDR2 of SEQ ID NO: 153, and LCDR3 of SEQ ID NO: 163. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 144, LCDR2 of SEQ ID NO: 154, and LCDR3 of SEQ ID NO: 164. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 145, LCDR2 of SEQ ID NO: 155, and LCDR3 of SEQ ID NO: 165. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 146, LCDR2 of SEQ ID NO: 156, and LCDR3 of SEQ ID NO: 166. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 147, LCDR2 of SEQ ID NO: 157, and LCDR3 of SEQ ID NO: 167. In some embodiments, the anti-ANGPTL7 antibody comprises LCDR1 of SEQ ID NO: 148, LCDR2 of SEQ ID NO: 158, and 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.

[0091] In some embodiments, the VH of the 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 NO: 170-174, (b) SEQ ID NO: 190-191, (c) SEQ ID NO: 198-212, or (d) SEQ ID NO: 258-260. In some embodiments, the VL of the 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 NO: 180-184, (b) SEQ ID NO: 194-195, (c) SEQ ID NO: 228-242, or (d) SEQ ID NO: 264-266.

[0092] In some embodiments, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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... comprising an amino acid sequence that is at least 98%, at least 99%, or 100% identical. In some embodiments, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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, 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 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.

[0093] The "identity" of a nucleic acid or amino acid sequence 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 are known for obtaining an optimal alignment and calculating the identity between two or more sequences, 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 their subsequent versions), and FASTA programs (e.g., FASTA 3x, FAS™, and SSEARCH) (for sequence alignment and sequence similarity searching). Sequence alignment algorithms are also disclosed, for example, in 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)).

[0094] As will be appreciated by those skilled in the art based on the present disclosure, one or more amino acids of the aforementioned anti-ANGPTL7 antibody, or antigenic fragments thereof, may be replaced or substituted with different amino acids. The "replacement" or "substitution" of an amino acid refers to the replacement of one amino acid at a given position or residue with another amino acid at the same position or residue within the polypeptide sequence. Amino acids are broadly classified as "aromatic" or "aliphatic". Aromatic amino acids contain an aromatic ring. 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), glutamic acid (E or Glu), aspartic acid (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 further subdivided into four subgroups. The "large aliphatic non-polar subgroup" consists of valine, leucine, and isoleucine. The "aliphatic low-polar subgroup" consists of methionine, serine, threonine, and cysteine. The "aliphatic polar / charged subgroup" consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The "small residue subgroup" consists of glycine and alanine. The group of charged / polar amino acids can be further 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. Aromatic amino acids can be further subdivided into two subgroups: the "nitrogen ring subgroup" consisting of histidine and tryptophan and the "phenyl subgroup" consisting of phenylalanine and tyrosine.

[0095] Amino acid replacements or substitutions can be conservative, semi-conservative, or non-conservative. The terms "conservative amino acid substitution" or "conservative mutation" refer to the replacement of one amino acid by another amino acid having common properties. A functional way to define the common properties among 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 an analysis, for a group of amino acids, if the amino acids within the group preferentially exchange with each other, they can be defined as being most similar to each other in terms of the impact on the overall structure of the protein. Examples of conservative amino acid substitutions include substitutions of amino acids within the above-described subgroups, for example, substitution of arginine by lysine and vice versa such that the positive charge can be maintained, substitution of aspartic acid by glutamic acid and vice versa such that the negative charge can be maintained, substitution of threonine by serine such that the free OH can be maintained, and substitution of asparagine by glutamine such that the free NH 2 can be maintained. "Semi-conservative mutations" include amino acid substitutions within the same group listed above, but not amino acid substitutions within the same subgroup. For example, substitution of asparagine by aspartic acid, or substitution of lysine by asparagine, involves amino acids within the same group but different subgroups. "Non-conservative mutations" involve amino acid substitutions between different groups (e.g., from tryptophan to lysine, or from serine to phenylalanine, etc.).

[0096] Furthermore, one or more amino acids can be inserted into the anti-ANGPTL7 antibody, or an antigen-binding fragment thereof (e.g., insertion into the heavy and / or light chain variable region amino acid sequences). Any number of suitable amino acids can be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. In this regard, at least one amino acid (e.g., two or more, five or more, or ten or more amino acids), but 20 or fewer amino acids (e.g., 18 or fewer, 15 or fewer, or 12 or fewer) can be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. For example, 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) can be inserted into the amino acid sequence of a monoclonal antibody or its antigen-binding fragment. In this regard, the amino acid(s) can be inserted into the antibody or its antigen-binding fragment at any suitable position. Preferably, the amino acid(s) is inserted into the CDR (e.g., CDR1, CDR2, or CDR3) of the antibody or its antigen-binding fragment.

[0097] The amino acid sequence of the anti-ANGPTL7 antibody, or an antigen-binding fragment thereof, is not limited to the specific amino acid sequences described herein. Indeed, the anti-ANGPTL7 antibody or its antigen-binding fragment can include any heavy chain polypeptide or light chain polypeptide that competes with the anti-ANGPTL7 antibody or its antigen-binding fragment for conformational binding to ANGPTL7. Antibody competition can be assayed using conventional peptide competition assays such as ELISA, Western blot, or immunohistochemistry (see, e.g., U.S. Patents 4,828,981 and 8,568,992, and Braitbard et al., Proteome Sci., 4:12 (2006)).

[0098] The anti-ANGPTL7 antibodies of the disclosure can be whole antibodies, or antigen-binding fragments of whole antibodies. As defined herein, antigen-binding antibody fragments encompassed by the disclosure include F(ab’) 2, including but not limited to Fab’, Fab, Fv, scFv, dsFv, dAb, and single-chain binding polypeptides. Antibody fragments and their therapeutic utility are further described, for example, in Nelson, A.L., MAbs. 2010 Jan-Feb;2(1):77-83, Joosten et al., Microbial Cell Factories volume 2, Article number: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 the fusion of the heavy chain (VH) and light chain (VL) of an immunoglobulin via a short polypeptide linker. Single-chain variable domain (Fv) fragments (scFv) are used in various clinical and therapeutic applications in the art, which may include, among other things, improved pharmacokinetic properties compared to the parent monoclonal antibody and relatively easy production 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).

[0099] The anti-ANGPTL7 antibodies of the present disclosure can be diabodies. A diabody is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. See, for example, 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 tetra-bodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). The anti-ANGPTL7 antibodies of the present disclosure can be single-domain antibodies (also referred to as nanobodies). A single-domain antibody is an antibody fragment that includes 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 (see, e.g., U.S. Patent No. 6,248,516 B1 to Domantis, Inc., Waltham, Mass.). Antibody fragments can be made by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies as described herein, as well as production by recombinant host cells (e.g., E. coli or phage).

[0100] In other embodiments, the anti-ANGPTL7 antibody is a full antibody. As defined herein, a full antibody typically includes two identical copies of a heavy (H)-chain polypeptide and two identical copies of a light (L)-chain polypeptide. Each heavy chain has one N-terminal variable (V H ) region and three C-terminal constant (C H1 , C H2 , and C H3 ) regions, and each light chain has one N-terminal variable (V L ) region and one C-terminal constant (C L) is included. The heavy chain C-terminal constant region contains a fragment of the crystallizable (Fc) domain, which determines the class of the antibody and is involved in humoral and cellular effector functions. Antibodies are classified into five major classes (i.e., "isotypes") with different functions in the immune system, IgG, IgM, IgA, IgD, and IgE. IgG is the most abundant immunoglobulin in the blood, accounting for 60% of total serum antibodies in humans. IgG antibodies can be subclassified into IgG1, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgG1 being the most abundant) (Vidarsson et al., Frontiers in Immunology. 5:520 (2014)). All anti-ANGPTL7 monoclonal antibodies described herein can be of any suitable class and / or subclass. In some embodiments, the monoclonal antibody is of the IgG class (e.g., IgG1, IgG2, IgG3, or IgG4). For example, the monoclonal antibody can be an IgG1 antibody.

[0101] As described above, the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (causing effector functions that eliminate antigens). In some embodiments, the Fc domain can be modified or engineered to alter its effector functions. For example, the Fc domain can be modified to improve antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP), as well as to control serum half-life. In some embodiments, the Fc domain of the anti-ANGPTL7 antibody can be engineered to modulate its affinity for Fc receptors such as Fcγ receptor (FcγR) and neonatal Fc receptor (FcRn). Indeed, optimization of the interaction between antibodies and FcγR has emerged as a promising approach for enhancing the activity of therapeutic antibodies for the treatment of 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, T.H., Jung, S.T., Exp Mol Med 51, 1-9 (2019)). The Fc domain can also be modified to improve serum half-life, for example, by engineering the IgG Fc for 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 create monovalency or bispecificity of the antibody to improve therapeutic efficacy. For example, an Fc domain can be generated that remains as a soluble monomer, mFc, that does not form homodimers, exhibits high affinity for FcγRI, but has no detectable binding to FcγRIIIa.In other embodiments, the heterodimeric Fc domain can be generated to obtain bispecific antigen-binding properties that avoid homodimer formation. The engineered Fc domain can be generated by introducing point mutations or by altering the glycosylation of the Fc domain (Saunders, K.O., Front Immunol. 2019;10:1296, Kelley, R.F., Meng, Y.G., 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 U S A. 2017;114:3485-90, and Lin et al., Proc Natl Acad Sci U S A. 2015;112:10611-6, Kang and Jung, supra).

[0102] Multispecific anti-ANGPTL7 antibody As described above, the anti-ANGPTL7 antibodies of the present disclosure can 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 fragments. 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, trivalent, or tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0103] In some embodiments, the anti-ANGPTL7 antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent 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, e.g., a monkey) and a human constant domain. In a further example, the 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 their antigen-binding fragments.

[0104] In certain embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or a portion thereof), are derived from a non-human antibody and the FRs (or a portion thereof) are derived from a human antibody sequence. Optionally, the humanized antibody also comprises at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

[0105] Humanized antibodies and methods for making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633, (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988), Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989), U.S. Patent 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”), Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a “guided selection” approach to FR shuffling).

[0106] According to the above embodiments, the anti-ANGPTL7 antibody of the present disclosure can be prepared in a bivalent, trivalent, or tetravalent format. For example, the anti-ANGPTL7 antibody of the present disclosure can be a bivalent bispecific antibody having a heteromeric heavy chain (e.g., triomab, knob-into-hole (KIH), duo-body, etc.). The anti-ANGPTL7 antibody of the present disclosure can be a tetravalent multispecific antibody composed of IgG with another binding domain fused to either the N-terminus or C-terminus of either the heavy chain or the light chain (e.g., double variable domain [DVD], IgG-scFv fusion, mAbzillin (IgG having a non-antibody binding scaffold "centyrin" fused to the C-terminus of the heavy chain)). The anti-ANGPTL7 antibody of the present disclosure can be composed of IgG with an additional antigen binding site added into the structure (e.g., two-in-one antibody, F-Star's MAT "Modular Antibody Technology" platform). The anti-ANGPTL7 antibody of the present disclosure can be engineered antibody fragments linked by short peptide linkers prepared in a bivalent, trivalent, or tetravalent format that address 2 to 3 targets (e.g., bispecific T cell engager (BiTE), nanobody platform, dual affinity retargeting (DART) antibody, "tandem antibody" structure (TandAb)). Also, the anti-ANGPTL7 antibody of the present disclosure can be composed of chemically conjugated IgG.

[0107] In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure are multispecific antibodies such as bispecific antibodies having binding specificities 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., the 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, other antigens include, but are not limited to, interleukin-1 beta (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); angiopoietin; 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 age-related macular degeneration (AMD) risk, 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.

[0108] In some embodiments, the bispecific antibodies of the present disclosure comprise an anti-ANGPTL7 antibody, or an antigen-binding fragment thereof, and an anti-VEGF antibody, or an antigen-binding fragment thereof. Such bispecific antibodies can be used to target different mechanisms and thus provide additional therapeutic effects. For example, the anti-ANGPTL7 arm can be any of the anti-ANGPTL7 antibodies of the present disclosure, and the anti-VEGF arm can be an anti-VEGF antibody (e.g., bevacizumab, cecizumab, and ranibizumab), an anti-VEGFR2 antibody and related molecules (e.g., ramucirumab, tanibirumab, aflibercept), an anti-VEGFR1 antibody and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye; EYLEA®), and ziv-aflibercept (VEGF Trap, ZALTRAP®)), a VEGF bispecific antibody (e.g., MP-0250, vanucizumab (VEGF-ANG2)) (including anti-VEGF, anti-VEGFR1, and anti-VEGFR2 arms), or any VEGF antagonist not limited thereto.

[0109] Functional characteristics of the anti-ANGPTL7 antibody According to the above embodiments, the present disclosure provides anti-ANGPTL7 antibodies comprising various functional characteristics. 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, through interaction with its antigenic determinant (epitope). In some embodiments, the anti-ANGPTL7 antibodies described herein bind to an antigen / epitope from the human ANGPTL7 fibrinogen domain (e.g., ATX-P-60, SEQ ID NO: 373), an antigen / epitope from the full-length human ANGPTL7 monomer variant L59P_L84P (ATX-P-62, SEQ ID NO: 371), an antigen / epitope derived from the full-length human ANGPTL7 monomer variant L59 GGPGG (ATX-P-63, SEQ ID NO: 372), and an antigen / epitope derived from the human wild-type ANGPTL7 multimer (PExt-1, SEQ ID NO: 374).

[0110] In some embodiments, the binding of the anti-ANGPTL7 antibody to the ANGPTL7 polypeptide reduces intraocular pressure and / or increases aqueous humor outflow ability (see, for example, Example 9 and FIG. 7). In some embodiments, the anti-ANGPTL7 antibody has a K of about 100 nM or less for an epitope on human ANGPTL7 DBind with (see, for example, Example 10). In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase the aqueous humor outflow ability as 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 / polypeptide and isotype control antibody treatment (see, for example, FIG. 7). 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, the anti-ANGPTL7 antibody comprises a VH having 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 having 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%,... It includes a VL comprising an amino acid sequence that is at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some embodiments, the anti-ANGPTL7 antibody includes 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, the anti-ANGPTL7 antibody includes 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, the anti-ANGPTL7 antibody includes 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, 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: 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.

[0111] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase aqueous humor outflow ability as compared to a control. In some embodiments, the control is any of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and / or ANGPTL7 protein / polypeptide and isotype control antibody treatment. 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: 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, 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: 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.

[0112] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase the aqueous humor outflow ability as compared to a control. In some embodiments, the control is either dexamethasone treatment, ANGPTL7 protein treatment, and / or ANGPTL7 protein / polypeptide and isotype control antibody treatment. 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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, 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: 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.

[0113] In some embodiments, the anti-ANGPTL7 antibodies described herein bind to ANGPTL7 (or a fragment thereof) and increase the aqueous humor outflow ability as compared to a control. In some embodiments, the control is either dexamethasone treatment and / or ANGPTL7 protein treatment. 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: 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, 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: 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.

[0114] Polypeptide and expression vector Embodiments of the present disclosure also include polynucleotides encoding any of the anti-ANGPTL7 antibodies of the present disclosure. In some embodiments, the polynucleotide 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 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 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 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 has 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 has 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 has 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 that is at least 85% identical (e.g., at least 85%, at least 90%, at least 95%, or 100% identical) to any one 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 90% identical (e.g., at least 90%, at least 95%, or 100% identical) to any one 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 one 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 one 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 one 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.

[0115] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure is (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: 186, (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: 177 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: 187, (d) 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: 178 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: 188, (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%,comprising a nucleic acid sequence that is at least 85%, at least 90%, at least 95%, or 100% identical),

[0116] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure is (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: 244, (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: 215 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: 245, (d) 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: 216 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: 246, (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: 217 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: 247, (f) 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: 218 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: 248, (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: 250, (i) 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 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: 251, (j) 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: 222 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: 252, (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, (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: 255, (n) 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: 226 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, (o) 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: 227 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: 257, (p) 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: 228 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: 258, (q) 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: 229 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: 259, (r) 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: 230 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: 260, (s) 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: 231 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: 261, (t) 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: 232 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: 262, (u) 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: 233 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, (v) 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: 234 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: 264, (w) 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: 235 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: 265, (x) 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: 236 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: 266, (y) 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: 237 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, (z) 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: 238 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: 268, (aa) 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: 239 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, (bb) 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: 240 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: 270, (cc) a nucleic acid sequence thata nucleic acid sequence that is at least 85%, at least 90%, at least 95%, or 100% identical; (f) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 218 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 248 (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 to SEQ ID NO: 219 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 249 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); (h) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 220 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 250 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); (i) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 221 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 251 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); or (j) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 222 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 252 (e.g., at least 70%, at least 75%,a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical; (k) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 223 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 253 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); (l) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 224 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 254 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); or (m) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 225 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 255 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); (n) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 226 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 256 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical); or (o) a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 227 (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical), a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 257 (e.g., at least 70%,comprising a nucleic acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical.

[0117] In some embodiments, the polynucleotide encoding the anti-ANGPTL7 antibody of the present disclosure comprises: (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: 268; (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.

[0118] According to these embodiments, the present disclosure includes an expression vector comprising any of the polynucleotides encoding the anti-ANGPTL7 antibodies of the present disclosure. In some embodiments, the expression vector is suitable for producing the anti-ANGPTL7 antibodies of the present disclosure for delivering 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, episome, cosmid, viral vector (e.g., retrovirus or adenovirus), or 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, N.Y. (2012), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994)).

[0119] In addition to the nucleic acid encoding the anti-ANGPTL7 antibody or antigen-binding fragment thereof, the vector desirably includes expression control sequences such as a promoter, enhancer, polyadenylation signal, transcription terminator, internal ribosome entry site (IRES), etc., which provide for the expression of the nucleic acid sequence encoding the antibody in a host cell. Exemplary expression control sequences are known in the art and are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0120] A vector containing a nucleic acid sequence encoding an anti-ANGPTL7 antibody or an antigen-binding fragment thereof can be introduced into a host cell (including any suitable prokaryotic or eukaryotic cell) that can express the polypeptide encoded thereby. Examples of suitable prokaryotic cells include, but are not limited to, cells derived from the genera 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 number 33694), DH5α, DH10, MC1061 (ATCC number 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 those derived from the genera Hansenula, Kluyveromyces, Pichia, Rhinosporidium, Saccharomyces, and Schizosaccharomyces. Suitable insect cells include Sf-9 and HIS cells (Invitrogen, Carlsbad, Calif.), as described, for example, in 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 number CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97:4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC number CRL1573), and 3T3 cells (ATCC number CCL92).Other suitable mammalian cell lines include the monkey COS-1 cell line (ATCC number CRL1650) and the COS-7 cell line (ATCC number CRL1651), as well as the CV-1 cell line (ATCC number 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 in vitro culture of primary tissues, and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, and BHK or HaK hamster cell lines, all available from the ATCC. Methods for selecting suitable mammalian host cells, as well as methods for transformation, culture, amplification, screening, and purification of such cells, are well known in the art (see, for example, Ausubel et al., eds., Short Protocols in Molecular Biology, 5th ed., John Wiley & Sons, Inc., Hoboken, N.J. (2002)). Preferably, the mammalian cells are human cells.

[0121] In some embodiments, the vector may include means for binding a detection moiety to the anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the vector may include means for binding a purification moiety to the anti-ANGPTL7 antibody of the present disclosure. Exemplary detection and / or purification moieties / tags that can be bound to the 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), fluorophore (e.g., green fluorescent protein (GFP), red fluorescent protein (RFP), mCherry, chromophore, and / or luminescent peptide (e.g., luciferase).

[0122] In some embodiments, the expression vector is suitable for use in gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-ANGPTL7 antibody of the present disclosure). 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, an AAV vector for use in gene transfer comprises a replication-deficient AAV genome lacking functional Rep and Cap coding viral sequences. Such replication-deficient AAV vectors more preferably lack most or all of the Rep and Cap coding sequences and essentially retain one or two AAV ITR sequences and a packaging sequence. The defective genome is packaged into viral particles, forming a defective recombinant AAV virus, also referred to as an "AAV vector." Methods for generating such AAV vectors are disclosed in the literature, including using 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; W02005 / 072364). Methods for generating pseudotyped AAV vectors (e.g., WO00 / 28004), as well as various modifications or formulations of AAV vectors for reducing immunogenicity upon in vivo administration (e.g., see WO01 / 23001, WOOO / 73316, WO04 / 112727, W005 / 005610, WO99 / 06562) have also been reported. AAV vectors can be prepared or derived from various serotypes of AAV, which can further be combined with or mixed with other types of viruses to generate chimeric (e.g., pseudotyped) AAV viruses.Examples of tAAV include human AAV4 vector, human AAV7 vector, human AAV9 vector, human AAV10 vector, or bovine AAV vector. The AAV vector can be derived from a single AAV serotype or can contain sequences or components derived from at least two different AAV serotypes (pseudotyped AAV vector), for example, an AAV vector containing an AAV genome derived from one AAV serotype (e.g., AAV9) and a capsid that is at least partially derived from a distinct AAV serotype. As used herein, an AAV vector is a vector that contains at least one component that can be derived from an adeno-associated virus. Preferably, the component is involved in the biological mechanism by which the vector infects or transduces a target cell and expresses the anti-ANGPTL7 antibody of the present disclosure (e.g., ocular delivery / expression).

[0123] In other embodiments, the expression vector is a lentiviral vector (LV) or comprises an LV backbone. Lentiviruses are part of a larger retrovirus group. A detailed list of lentiviruses can be found in Coffin et al (1997) “Retroviruses” Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758 - 763). For example, lentiviruses can be classified into primate and non - primate groups. Examples of primate lentiviruses include, but are not limited to, human immunodeficiency virus (HIV), the causative agent of human acquired immunodeficiency syndrome (AIDS), and simian immunodeficiency virus (SIV). The non - primate lentivirus group includes the prototype “slow - release virus” visna / maedi virus (VMV), as well as 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 Visna lentivirus. The lentivirus family differs from retroviruses in that lentiviruses have the ability to infect both dividing and non - dividing cells (Lewis et al (1992) EMBO J 11(8):3053 - 3058 and Lewis and Emerman (1994) J Virol 68(1):510 - 516). In contrast, other retroviruses such as MLV cannot infect non - dividing cells or cells that divide slowly, such as cells that make up muscle, brain, lung, and liver tissues. As used herein, a lentiviral vector is a vector that contains at least one component that can be derived from a lentivirus. Preferably, the component is involved in the biological mechanism by which the vector infects or transduces a target cell and expresses the anti - ANGPTL7 antibody of the present disclosure (e.g., ocular delivery / expression).

[0124] Additional compositions and methods for ocular gene therapy can be found, for example, in Bordet, T., and Behar-Cohen, F., “Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives,” Drug Discovery Today, Volume 24, Issue 8, August 2019, Pages 1685-1693). In some embodiments, gene therapy platforms, methods, and compositions that can be used to deliver (e.g., ocular delivery) the anti-ANGPTL7 antibodies of the present disclosure include the platforms, methods, and compositions 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 that can be used to deliver (e.g., ocular delivery) the anti-ANGPTL7 antibodies of the present disclosure include platforms, methods, and compositions based on HMR59 (Hemera Biosciences) (which blocks the membrane attack complex formed during the final step of the complement cascade via its protein product, soluble CD59). HMR59 is designed to be administered as a single intravitreal injection.

[0125] According to these embodiments, the present disclosure also provides a method of administering it to a subject in need of gene therapy of the eye, the method comprising injecting a pharmaceutical composition comprising an effective amount of the 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 methods of treating glaucoma and other eye 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 the 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 eye diseases that affect the optic nerve or retinal ganglion cells.

[0126] Pharmaceutical Compositions and Treatment Methods The anti-ANGPTL7 antibody 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 ophthalmic administration. In some embodiments, ophthalmic administration includes injection into the vitreous humor. In some embodiments, ophthalmic administration includes delivering the antibody using a conjunctival insert, contact lens, gel, nanoparticle, mucoadhesive polymer, ointment, solution, suspension, eye drop, and / or implant (e.g., Susvimo™). Recent methods and formulations for ophthalmic administration can be found, for example, in Souto, E.B., et al. “Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents,” Pharmaceutics, 2019 Sep;11(9):460.

[0127] 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 administered to the eye to treat at least one symptom associated with glaucoma or other eye diseases that affect the optic nerve or retinal ganglion cells. In some embodiments, the at least one symptom includes eye pain, intraocular pressure, headache, colored halos around lights, low vision, blurred vision, visual field constriction, peripheral vision impairment, blind spots, nausea, vomiting, and red eyes. In some embodiments, administering the pharmaceutical composition reduces or attenuates the intraocular pressure in the subject's eye and / or increases or improves the aqueous humor outflow ability.

[0128] 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 in the range of about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.001 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.01 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.1 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 1.0 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 10 mg / dose to about 100 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.0001 mg / dose to about 10 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.0001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.0001 mg / dose to about 0.1 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.0001 mg / dose to about 0.001 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.01 mg / dose to about 10 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose in the range of about 0.1 mg / dose to about 10 mg / dose.

[0129] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of the anti-ANGPTL7 antibody of the present disclosure is administered at a dosage in the range of about 0.0001 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.001 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.01 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.1 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 1.0 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 10 mg / ml to about 100 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.0001 mg / ml to about 10 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.0001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.0001 mg / ml to about 0.1 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.0001 mg / ml to about 0.01 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.0001 mg / ml to about 0.001 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.01 mg / ml to about 10 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dosage in the range of about 0.1 mg / ml to about 10 mg / ml.

[0130] As used herein, terms such as "treatment," "treating," etc. 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 a disease and / or a deleterious symptom caused by the disease. For this purpose, 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 effective amount at the dosage and for the period required to achieve the desired therapeutic result. The therapeutically effective amount may vary depending on factors such as the medical condition of the individual, age, gender, and weight, as well as the ability of the monoclonal antibody to elicit the desired response in the individual. For example, a therapeutically effective amount of the anti-ANGPTL7 antibody of the present disclosure is an amount that treats at least one symptom of glaucoma or other eye diseases that affect the optic nerve and retinal ganglion cells of a subject. In some embodiments, the pharmacological and / or physiological effect may be prophylactic, i.e., the effect completely or partially prevents a 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 effective amount at the dosage and for the period required to achieve a desired prophylactic result (e.g., prevention of glaucoma or at least one symptom associated with glaucoma).

[0131] Typical dosages of the disclosed anti-ANGPTL7 antibodies in a therapeutically effective amount can range, for example, from about 0.0001 mg / dose to about 100 mg / dose for each eye being treated. In some embodiments, the therapeutically effective amount of the disclosed anti-ANGPTL7 antibodies can 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 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, the therapeutically effective concentration of the disclosed anti-ANGPTL7 antibodies can be, for example, about 0.0001 mg to about 100 mg of antibody per milliliter of solution. In some embodiments, the therapeutically effective concentration of the disclosed anti-ANGPTL7 antibodies can range from about 0.001 mg / ml to about 100 mg / ml, from about 0.01 mg / ml to about 100 mg / ml, from about 0.1 mg / ml to about 100 mg / ml, from about 1.0 mg / ml to about 100 mg / ml, from about 0.001 mg / ml to about 50 mg / ml, from about 0.01 mg / ml to about 50 mg / ml, from 0.1 mg / ml to about 50 mg / ml, from about 0.1 mg / ml to about 25 mg / ml, from about 0.1 mg / ml to about 10 mg / ml, and from about 1.0 mg / ml to about 10 mg / ml. In some embodiments, the therapeutically effective dose of the disclosed anti-ANGPTL7 antibodies 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, or can fall within a range delimited by any two of the foregoing values.For example, in certain embodiments, a sustained release formulation (e.g., an ocular implant) can be an amount of anti-ANGPTL7 antibody that is 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 an amount that falls within a range delimited by any two of the foregoing values.

[0132] Therapeutic or prophylactic efficacy can be monitored by regular evaluation of the treated patient. In the case of repeated dosing over several days, depending on the condition, treatment is repeated until the desired suppression of disease symptoms occurs. However, other dosing regimens may be useful and are within the scope of the present disclosure. The desired dose can be delivered by single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. A composition comprising an anti-ANGPTL7 antibody, or an antigen-binding fragment thereof, can be administered to a mammal using standard administration techniques including, but not limited to, ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. The composition is preferably suitable for transocular administration.

[0133] In accordance with the compositions and methods of treatment described herein, embodiments of the present disclosure include anti-ANGPTL7 antibodies having an enhanced half-life (e.g., after ophthalmic administration), such that the anti-ANGPTL7 antibodies can be administered to a subject less frequently. In some embodiments, the antibody includes a half-life extension moiety. In some embodiments, the half-life extension moiety includes a polypeptide that can be conjugated 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 conjugated to the anti-ANGPTL7 antibody of the present disclosure is at least 20 amino acids in length and includes any combination of G, A, S, T, E, and P residues. In some embodiments, the half-life extension polypeptide is conjugated 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.

[0134] The present disclosure also provides a composition comprising any of the anti-ANGPTL7 antibodies or antigen-binding fragments thereof described herein. The composition is preferably a pharmaceutically acceptable (e.g., physiologically acceptable) composition comprising a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and a therapeutic agent and / or an anti-ANGPTL7 antibody or antigen-binding fragment thereof. Any suitable carrier can be used within the context of the present disclosure, and such carriers are well known in the art. For example, the composition may include preservatives such as, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. Optionally, a mixture of two or more preservatives can be used. Further, a buffer can 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 can optionally be used. Methods for preparing pharmaceutical compositions are known to those of skill in the art and are described, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0135] After administration 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 evaluated by determining the stability of the anti-ANGPTL7 antibody. The biological activity of the anti-ANGPTL7 antibody can also be evaluated by determining its binding affinity for the ANGPTL7 peptide and / or by evaluating its binding affinity for peptides that may cross-react therewith. The term "affinity" refers to the equilibrium constant for the reversible binding of two agents and the dissociation constant (K D) It is represented as. The affinity of a binder for a ligand, for example, the affinity of an antibody for an epitope, includes, for example, from about 1 femtomolar (fM) to about 1 millimolar (mM) (for example, from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (μM)). In some embodiments, the affinity of the anti-ANGPTL7 antibody can be from about 1 nm to about 20 nm, and desirably can be from about 5 nm to about 10 nm. The antibody affinity for the antigen or epitope of interest can be measured using any assay recognized in the art. Such methods include, for example, fluorescence-activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, for example, Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, N.Y., 2001).

[0136] In some embodiments, the anti-ANGPTL7 antibody, or a composition comprising the anti-ANGPTL7 antibody, can be administered alone or in combination with other drugs / therapeutic agents. For example, the anti-ANGPTL7 antibody can be administered in combination with other agents for the treatment or prevention of glaucoma or other eye diseases that affect the optic nerve or retinal ganglion cells, as disclosed herein. For example, the anti-ANGPTL7 antibody of the present disclosure, or an antibody conjugate, fusion protein, or polymeric formulation thereof, can be used alone or in combination with other agents in therapy. For example, the anti-ANGPTL7 antibody of the present invention can be co-administered with at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is another antibody, chemotherapeutic agent, cytotoxic agent, anti-angiogenic agent, immunosuppressive agent, prodrug, cytokine, cytokine antagonist, cytotoxic radiation therapy, corticosteroid, antiemetic, cancer vaccine, analgesic, or growth inhibitor, or a combination thereof.

[0137] In certain embodiments, the anti-ANGPTL7 antibodies of the present disclosure are administered with a drug / therapeutic agent for treating / preventing glaucoma or other eye diseases that affect the optic nerve or retinal ganglion cells. Any suitable glaucoma therapeutic agent can 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 polymeric formulations thereof, for the treatment of eye diseases (e.g., for example, glaucoma, or other diseases associated with or affecting the optic nerve or retinal ganglion cells). For example, in some embodiments, the anti-ANGPTL7 antibodies of the present disclosure can be administered with agents that reduce intraocular pressure by promoting the drainage of body fluids from the eye, such as prostaglandins (e.g., Xalatan (latanoprost), Travatan Z (travoprost), Zioptan (tafluprost), and Lumigan (bimatoprost)), Rho kinase inhibitors (e.g., Rhopresa (netarsudil)), nitric oxide (e.g., Vyzulta (latanoprostene bunod), and miotics or cholinergic agents (e.g., Isopto Carpine (pilocarpine)), but not limited thereto. In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure can be administered with agents that reduce intraocular pressure by reducing the amount of body fluids produced in the eye, such as 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)), but not limited thereto. Further, one or more of these therapeutic agents can be administered in combination with the anti-ANGPTL7 antibodies of the present disclosure, along with other treatments such as laser treatment (e.g., trabeculoplasty) and surgery (e.g., glaucoma implant surgery, as well as minimally invasive glaucoma surgery (MIGS)).

[0138] In some embodiments, the anti-ANGPTL7 antibodies, antibody conjugates, fusion proteins, or polymeric formulations of the present disclosure are administered concomitantly with an additional therapeutic agent. In some embodiments, the anti-ANGPTL7 antibodies, antibody conjugates, fusion proteins, or polymeric formulations of the present disclosure are administered before or after an additional therapeutic agent. In some embodiments, the additional therapeutic agent(s) bind 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 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. In some embodiments, the additional therapeutic agent is an antibody or an antigen-binding fragment thereof. In some embodiments according to any of the above embodiments (or applicable to any of the above embodiments), the ocular disorder is an intraocular angiogenesis disorder 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 retinopathies, diabetic macular edema, pathologic myopia, von Hippel-Lindau disease, ocular histoplasmosis, retinal vein occlusion (RVO) (including CRVO and BRVO), corneal angiogenesis, retinal angiogenesis, retinopathy of prematurity (ROP).

[0139] In some embodiments, the anti-ANGPTL7 antibodies, or antibody conjugates, fusion proteins, and / or polymeric formulations of the present disclosure can be administered in combination with at least one additional therapeutic agent for the treatment of an eye disorder (e.g., an eye disorder described herein (e.g., glaucoma, or other diseases associated with or affecting the optic nerve or retinal ganglion cells)).Exemplary additional therapeutic agents for combination therapy for the treatment of eye disorders include, for example, anti-angiogenic agents such as VEGF antagonists including anti-VEGF antibodies (e.g., anti-VEGF Fab LUCENTIS® (ranibizumab)), soluble receptor fusion proteins (e.g., recombinant soluble receptor fusion protein EYLEA® (aflibercept, also known as VEGF Trap Eye, Regeneron / Aventis)), aptamers (e.g., anti-VEGF pegylated aptamer MACUGEN® (pegaptanib sodium, NeXstar Pharmaceuticals / OSI Pharmaceuticals)), and 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), batatinib (PTK787), semaxanib (SU5416, SUGEN), and SUTENT® (sunitinib)); tryptophanyl-tRNA synthetase (TrpRS); squalamine; RETAANE® (anechortate acetate for depot suspension, Alcon, Inc.); combretastatin A4 prodrug (CA4P); MIFEPREX® (mifepristone-ru486); subtenon triamcinolone acetonide; intravitreal crystalline triamcinolone acetonide; matrix metalloprotease inhibitors (e.g., Prinomastat (AG3340, Pfizer)); fluocinolone acetonide (including fluocinolone intravitreal implant, Bausch & Lomb / Control Delivery Systems); linomid; inhibitors of integrin β3 function; angiostatin, and combinations thereof, but are not limited thereto.

[0140] For the treatment of eye disorders (e.g., glaucoma or other diseases related to or affecting the optic nerve or retinal ganglion cells), further examples of additional therapeutic agents that can be used in combination with the anti-ANGPTL7 antibodies, or antibody conjugates, fusion proteins, and / or polymeric formulations of the present disclosure include VISUDYNE® (verteporfin, a photoactivating drug commonly used in combination with non-thermal laser photodynamic therapy), PKC412, Endovion (NS 3728, NeuroSearch A / S), neurotrophic factors (e.g., glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF)), diltiazem, dorzolamide, PHOTOTROP® , 9-cis-retinal, eye drops (e.g., phospholine iodide, echothiophate, or carbonic anhydrase inhibitors), bevacizumab (AE-941, AEterna Laboratories, Inc.), Sirna-027 (AGF-745, Sirna Therapeutics, Inc.), neurotrophins (by way of example only, including 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 (when used, e.g., 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-beta2 (Genzyme / Celtrix), tyrosine kinase inhibitors (e.g., manufactured by Allergan, SUGEN, or Pfizer), NX-278-L (NeXstar Pharmaceuticals / Gilead Sciences), Opt-24 (OPTIS France SA), retinal ganglion cell neuroprotective agents (Cogent Neurosciences), N-nitropyrazole derivatives (Texas A&M University System), KP-102 (Krenitsky Pharmaceuticals), cyclosporin A, therapeutic agents used in photodynamic therapy (e.g., VISUDYNE®; receptor-targeted PDT, Bristol-Myers Squibb, Co.; porfimer sodium for injection with PDT; verteporfin, QLT Inc.; rostaporfin using PDT, Miravent Medical Technologies; talaporfin sodium containing PDT, Nippon Petroleum; and motexafin lutetium (Pharmacyclics, Inc.)), antisense oligonucleotides (including, for example, products tested by Novagali Pharma SA and ISIS-13650, Isis Pharmaceuticals), and combinations thereof, but not limited to these.

[0141] The anti-ANGPTL7 antibody, or antibody conjugate, fusion protein, and / or polymeric formulation of the present disclosure may be administered in combination with a therapy or surgical procedure for treating an eye disorder (e.g., glaucoma or other diseases associated with or affecting the optic nerve or retinal ganglion cells), such as laser photocoagulation (e.g., panretinal photocoagulation (PRP)), drusen laser treatment, macular hole surgery, macular translocation surgery, implantable miniature telescope, PHI motion angiography (also known as micro-laser therapy and feeder vessel treatment), proton beam therapy, microstimulation therapy, retinal detachment and vitreous surgery, scleral buckle, submacular surgery, transpupillary thermotherapy, photosystem I therapy, use of RNA interference (RNAi), extracorporeal leukapheresis (also known as membrane fraction filtration and rheopheresis), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy of hypoxia response element, Oxford Biomedica; Lentipak, Genetix, and PDEF gene therapy, GenVec), photoreceptor / retinal cell transplantation (including transplantable retinal epithelial cells, Diacrin, Inc., retinal cell transplantation, Cell Genesys, Inc.), acupuncture treatment, and combinations thereof.

[0142] In some embodiments, the anti-ANGPTL7 antibodies, or antibody conjugates, fusion proteins, and / or polymeric formulations of the present disclosure can be administered in combination with an anti-angiogenic agent for the treatment of eye disorders (e.g., glaucoma, or other diseases associated with or affecting the optic nerve or retinal ganglion cells). Any suitable anti-angiogenic agent can be used in combination with the antibodies of the present disclosure, including but not limited to those listed by Carmeliet et al. Nature 407:249-257, 2000. In some embodiments, the anti-angiogenic agent is a VEGF antagonist, including an anti-VEGF antibody (e.g., anti-VEGF Fab LUCENTIS® (ranibizumab), RTH-258 (formerly 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, e.g., RG-7716, Roche)), a soluble recombinant receptor fusion protein (e.g., EYLEA® (aflibercept)), a VEGF variant, a soluble VEGFR fragment, a VEGF (e.g., pegaptanib) or an aptamer that can block VEGFR, a neutralizing anti-VEGFR antibody, a small molecule inhibitor of VEGFR tyrosine kinase, an anti-VEGF DARPin® (e.g., abicipar pegol), a small interfering RNA that inhibits the expression of VEGF or VEGFR, a VEGFR tyrosine kinase inhibitor (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), batatinib (PTK787), semaxanib (SU5416, SUGEN), and SUTENT® (sunitinib)), and combinations thereof.

[0143] For the treatment of eye disorders (e.g., glaucoma or other diseases related to or affecting the optic nerve or retinal ganglion cells), other suitable anti-angiogenic agents that can be administered in combination with the antibodies, antibody conjugates, fusion proteins, and / or polymeric formulations of the present disclosure include corticosteroids, angiogenesis-inhibiting steroids, anecortave acetate, angiostatin, endostatin, tyrosine kinase inhibitors, matrix metalloproteinase (MMP) inhibitors, insulin-like growth factor binding protein 3 (IGFBP3), stromal cell-derived factor (SDF-1) antagonists (e.g., anti-SDF-1 antibodies), pigment epithelium-derived factor (PEDF), gamma-secretase, delta-like ligand 4, integrin antagonists, hypoxia-inducible factor (HIF)-1α antagonists, protein kinase CK2 antagonists, agents that inhibit stem cells (e.g., endothelial progenitor cells) that home to the site of angiogenesis (e.g., anti-vascular endothelial cadherin (CD-144) antibodies and / or anti-SDF-1 antibodies), and combinations thereof.

[0144] In some embodiments, the anti-ANGPTL7 antibodies, or antibody conjugates, fusion proteins, and / or polymeric formulations of the present disclosure can be administered in combination with agents having activity against angiogenesis for the treatment of eye disorders (e.g., glaucoma or other diseases related to or affecting the optic nerve or retinal ganglion cells), such as anti-inflammatory agents, mammalian target of rapamycin (mTOR) inhibitors of rapamycin (e.g., rapamycin, AFINITOR® (everolimus)), and TORISEL® (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, non-steroidal anti-inflammatory agents (NSAIDs), or combinations thereof.

[0145] In addition to therapeutic use, the anti-ANGPTL7 antibodies or antigen-binding fragments described herein can be used for diagnostic or research purposes. As research purposes, for example, methods for detecting ANGPTL7 polypeptides or proteins in a sample (e.g., in human body fluids or in cell or tissue extracts) using anti-ANGPTL7 antibodies and labels can be mentioned. The anti-ANGPTL7 antibody or its antigen-binding fragment can be used in any suitable assay for measuring 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, Förster 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. Pat. Nos. 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).

[0146] An anti-ANGPTL7 antibody or an antigen-binding fragment thereof can be provided in a kit, for example, packaged together with a predetermined amount of reagent and instructions for performing an assay (e.g., an assay for detecting ANGPTL7) using the antibody. Accordingly, the present disclosure provides a kit comprising the antibody or antigen-binding fragment described herein and instructions for its use. The instructions can be in either paper form or a computer-readable form such as a disk, CD, DVD, etc. Alternatively or additionally, the kit can include a calibrator or control, and / or at least one container (e.g., a tube, microtiter plate, or strip) for performing the assay, and / or a buffer such as an assay buffer or a wash buffer. Ideally, the kit includes all the components necessary for performing the assay, i.e., reagents, standards, buffers, diluents, etc. Further, other additives such as stabilizers, buffers (e.g., blocking buffer or lysis buffer) can be included in the kit. The relative amounts of the various reagents can be widely varied to provide concentrations of the reagents in solution that substantially optimize the sensitivity of the assay. The reagents can be provided as dry powders (usually lyophilized), which include excipients that provide a reagent solution having an appropriate concentration upon dissolution.

[0147] The following examples further illustrate various embodiments of the present disclosure, but of course should not be construed as limiting the scope thereof in any way.

Example

[0148] It will be apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and recognizable, and may be made using appropriate equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having described the present disclosure in detail, the following examples are provided for reference, by which the present disclosure may be more clearly understood. These are intended to merely illustrate some aspects and embodiments of the disclosure and should not be considered as limiting the scope of the disclosure. All journal references, U.S. patents, and publication disclosures referred to herein are incorporated herein by reference in their entirety.

[0149] The present disclosure has a plurality of aspects illustrated by the following non-limiting examples.

[0150] Example 1 In this example, the dexamethasone-induced changes in gene expression in primary human trabecular meshwork cells are described. After death, primary trabecular meshwork cells isolated from a human donor were treated with dexamethasone (DEX). The change in ANGTPL7 gene expression compared to the vehicle was quantified using qPCR as shown in Figure 1. Using these data, those with a strong DEX response were selected for subsequent tests such as RNAseq.

[0151] Specifically, primary human trabecular meshwork cells were passaged in DMEM containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. Cells were seeded at 20,000 cells / well in a 96-well plate. The medium was changed three times a week. After one week, the cells were further differentiated using DMEM containing 1% FBS and 1% penicillin / streptomycin. The cells were incubated for at least one additional week in low serum, and the medium was changed three times a week.

[0152] 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 replaced after 2 - 3 days, and cells were harvested for qPCR using the Cells to Ct kit on day 5. qPCR was performed using the ANGPTL7 TaqMan assay from Life Technologies on a Quantstudio6 qPCR machine. Gene expression was normalized against the EtOH control.

[0153] Example 2 In this example, RNAseq of ANGPTL7 - treatment - induced changes in gene expression in human trabecular meshwork (TM) and Schlemm's canal (SC) cells is described (Figure 2). Briefly, primary human trabecular meshwork and Schlemm's canal cells were passaged into DMEM with 10% fetal bovine serum (PBS) containing 1% penicillin / streptomycin. Cells were seeded at 200,000 cells / well in a 6 - well format. Cells were differentiated in low serum for 1 week with medium changes three times a week. For ANGPTL7 treatment, the medium was removed and replaced with medium containing 50 ng / mL of ANGPTL7 protein from BIORTUS. The treatment medium was changed daily for 3 days. After 3 days, the cells were pelleted by centrifugation and frozen, and then stored in an - 80°C freezer until shipped to SeqMatic for processing.

[0154] Example 3 Experiments were conducted to identify the effect of ANGPTL7 on aqueous humor outflow facility in an ex - vivo bioengineered human eye tissue model. Glauconix has developed a unique technology that enables the multilayer growth of bioengineered 3D human trabecular meshwork (HTM) cells co - cultured with human Schlemm's canal (HSC) cells, thereby mimicking the structure of the tissue involved in increased pressure in the human eye (Figure 3A). This allows 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 increase IOP), and human ANGPTL7 protein on aqueous humor outflow facility.

[0155] Briefly, HTM cells were thawed and grown for approximately 7 days (media was changed every 2 days). HTM cells were seeded on the scaffold and HSC cells were thawed on the same day. HTM cells were grown on the scaffold for 7 days with media change every 2 days. HSCs were co-cultured on the back side of the HTM scaffold and grown for 10 - 12 days while changing the media every 2 days. The HTM / HSC construct was serum-starved in 1% media on the day before treatment. The first treatment day was designated as day 0. The supernatant was collected and re-treated on day 3, and this process was repeated on days 6 and 9. Perfusion was performed on day 10.

[0156] Figure 3B includes representative data showing the aqueous humor outflow ability of 3D-HTM donor 2 treated with vehicle (DMSO), 500 nM dexamethasone, and 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 < 0.001 per treatment group, N = 4). Figure 3C includes representative data showing the aqueous humor outflow ability of 3D-HTM donor 3 treated with vehicle (DMSO), 500 nM dexamethasone, and 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 < 0.001 per treatment group, N = 4). These data indicate that, similar to DEX treatment, ANGPTL7 treatment decreased the aqueous humor outflow ability in both donors.

[0157] Example 4 Experiments were conducted to identify the effect of ANGPTL7 on aqueous humor outflow facility in an ex vivo bioengineered human eye tissue model. Glauconix has developed a unique technology that enables the multilayer growth of bioengineered 3D human trabecular meshwork (HTM) cells co-cultured with human Schlemm's canal (HSC) cells, thereby mimicking the structure of the tissue involved in the pressure increase in the human eye (see also Figure 3A and the exemplary protocol of Example 3). This enables endpoint analysis related to IOP regulation.

[0158] In this experiment, three different doses (25, 50, and 150 μg / ml) of ANGPTL7 protein were compared for aqueous humor outflow facility in three different donor HTM cell lines (Figures 4A - 4C). In this example, the focus of the experiment was on the reproducibility of the effect of ANGPTL7 and the dose - response effect on aqueous humor outflow facility (from SOW1) in three different HTM donors.

[0159] Example 5 Production of recombinant ANGPTL7 protein. Recombinant protein preparation was performed to generate specific proteins that could be used as immunogens / antigens, screening reagents, and / or control reagents. All efforts were made towards the goal of generating a panel of anti - ANGPTL7 antibodies with desired properties. In this particular example, an outsourced material manufactured by Biortus was used for the human ANGPTL7 multimer, and the work of protein engineering was used to generate mutant human monomers. Human ANGPTL7 monomers with only the wild - type fibrinogen domain that was cleaved but not engineered were also produced.

[0160] Proteins with sequences corresponding to human, African green monkey, and rabbit ANGPTL7 were produced. The human and African green monkey sequences were engineered to prioritize the production of monomeric material, while the rabbit protein was a mixture of monomer, trimer, and hexamer. At the end, the purity of all protein preparations exceeded 90% by analytical methods, and the endotoxin units were less than 1 per milliliter.

[0161] Starting from in-silico analysis, the appropriate wild-type amino acid sequences of human, rabbit, and African green monkey ANGPTL7 were identified and extracted from publicly available databases. Next, the sequences were further analyzed and manually corrected using Geneious Prime software according to the experimental plan. Specifically, regarding the production of monomeric ANGPTL7, the mechanism of multimerization was investigated in detail. Structurally, ANGPTL7 consists of two domains, namely, a small N-terminal coiled-coil domain and a larger C-terminal fibrinogen-like domain. Considering the similarity with fibrinogen proteins at the domain level, previously published studies, and the well-documented biological functions of the coiled-coil domain, the N-terminal region was identified as the region to focus on for manipulating monomeric variants. The coiled-coil domain is accompanied by a clearly defined 7-amino acid repeat of hydrophobic and charged amino acids. Combined with the property of approximately 7 amino acids every two turns of the alpha helix and the aqueous environment of either the extracellular or intracellular space, this repeat prefers that the hydrophobic side chains are tucked inside the coil, while the charged amino acids face the aqueous environment. Dimerization, trimerization, or other higher-order multimerizations result in each linear alpha helix depending on each other and reaching an energetically favorable "packed" state. Approaches that disrupt the linearity and / or hydrophobicity and charged 7 amino acids may result in monomers. Based on this theoretical framework, two strategies were designed. Constructs in which leucine is replaced by proline at both positions 59 and 84 of the amino acid, or leucine at position 59 is replaced by glycine-glycine-proline-glycine-glycine, were constructed in silico and added to the panel of sequences designed for the project. It was found that replacing leucine at position 59 with 5 amino acids had the highest success rate. Further, a truncated form of human ANGPTL7 corresponding only to the C-terminal fibrinogen-like domain sequence was added to the panel of sequences.

[0162] All sequences were modified to add additional amino acid sequences encoding "tags" to facilitate screening for susceptibility, purification, reduce immunogenicity, or simplify analytical screening. Examples of protein tags used in this study include HIS tag and Avi tag. The tags were separated from each other and from the ANGPTL7 sequence using short linker sequences. All tags were added to the C-terminus of the sequence. Furthermore, the native signal peptide was removed and replaced with a signal peptide that promotes recombinant expression.

[0163] After all modifications were completed, the amino acid sequences were reverse translated into DNA sequences and optimized for the codon bias found in the human genome. These optimized DNA sequences were sent to Integrated DNA Technologies and generated as DNA fragments (s) with DNA overhangs added to the 5' and 3' ends. Using the DNA overhangs and the Gibson cloning method, these DNA fragments were assembled into the predicted sequence and cloned into a mammalian expression plasmid driven by the CMV promoter. The plasmid was grown in E. coli with appropriate antibiotic selection and prepared on a scale useful for recombinant expression using a commercially available preparation kit purchased from Qiagen. Subsequently, the sequences of the plasmid and the expressed gene were confirmed using Sanger sequencing.

[0164] Plasmids that had been verified for the sequences using polyethyleneimine were transfected into human fetal kidney cells adapted for recombinant expression. One day after transfection, the cells were supplemented with chemicals and nutrients designed to increase the expression of the recombinant protein. These supplements included sodium propionate, valproic acid, glucose, glutamine, and various yeast lysates. Five days after transfection, the expressing cell cultures were harvested. As the recombinant protein was secreted into the growth medium, cells, cell fragments, and cell debris were removed by centrifugation and filtration through a membrane with pores of 0.22 microns or less. The clarified medium conditioned with the recombinant protein was then ready for purification at this point. The protein of interest was purified from the cell culture medium using FPLC (fast protein liquid chromatography) and appropriate commercially available prepacked affinity chromatography columns for the C-terminal tag(s). For HIS-tagged proteins, Ni-NTA agarose columns were used. Multiple column washes followed, each specialized for the column / tag / chromatography type. For HIS-tagged proteins, the protein of interest was eluted from the column with 300 mM imidazole.

[0165] SDS-PAGE gel electrophoresis, spectrophotometry, and analytical SEC (size exclusion chromatography) were used in combination to evaluate the quality and quantity of proteins. Most proteins for this project required further purification. To further purify the proteins, FPLC and a second chromatography column were used. Size-based separation achieved using a size exclusion column enabled an increase in protein purity up to >90%. SEC also enabled buffer exchange from the affinity chromatography elution buffer to the final selection buffer (PBS). Next, the quality control of the protein samples was carried out. If it was necessary to increase the protein concentration at any point during purification, the protein was concentrated by separating the protein from the buffer using an Amicon Ultra molecular weight cut-off (MWCO) filtration unit. The MWCO was selected to ensure compatibility with the size of the target protein. Before moving on to the final quality control, all final samples were concentrated to more than 1 milligram per milliliter.

[0166] The endotoxin contamination in the final protein samples was assayed using the Charles River EndoSafe PTS system. The final protein concentration was determined by spectrophotometry. Three micrograms of the final sample were injected into an analytical SEC column (YMC Diol 300) to determine its final purity. Additionally, SDS-PAGE electrophoresis was performed in some cases to judge the final quality. Once all final measurement criteria were met, the protein was sterilized using a sterile 0.22-micron filter in a biosafety cabinet. Subsequently, it was aseptically dispensed, rapidly frozen in liquid nitrogen, and then stored at -80 °C.

[0167] Example 6 Recovery of ANGPTL7 antibody sequences from immunized mice. ANGPTL7 immunization: Four cohorts of Alloy Therapeutic transgenic humanized mice, ATX-GK, were immunized with various human ANGPTL7 antigens using the following standard 5-week RIMMS protocol: 10 μg of antigen emulsified in complete Freund's adjuvant was administered subcutaneously, followed by five weekly administrations of antigen emulsified in incomplete Freund's adjuvant.

[0168] 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 full-length human ANGPTL7 monomer variant L59P_L84P (ATX-P-62, SEQ ID NO: 371). Cohort 3: Three ATX-GK mice immunized with full-length human ANGPTL7 monomer variant L59P 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).

[0169] Samples were collected at week 4 and tested by ELISA for antigen-positive serum titers and purified tag-negative serum titers. ELISA plates were coated with either 1 μg / ml of the ANGPTL7 immunogen or an irrelevant protein with the same purification tag as the immunogen. Antigen-coated plates were incubated with seven 10-fold serial dilutions of serum starting at 1:300. Antibodies bound to the antigen were detected with an anti-mouse IgG HRP secondary antibody and a one-step TMB solution. Absorbance signals at 450 nm were measured with an ELISA microplate reader (Figures 5A - 5D).

[0170] Hybridoma: Immunized tissues from high-titer mice were collected and stored for antibody discovery. Hybridoma cell lines producing ANGPTL7 antibodies were generated by fusing single B cells derived from the spleens and lymph nodes of titer-positive mice with myeloma cells. Twenty 96-well plates of hybridoma fusions were generated and grown. Hybridomas expressing ANGPTL7-specific antibodies were detected by antigen binding using ELISA. The affinity of the antibodies in the hybridoma supernatants was measured using an Octet instrument by SPR. ANGPTL7 antibodies in the hybridoma supernatants were loaded onto the biosensor. The response was measured as the nm shift of the interference pattern and was proportional to the number of antibodies bound to the surface of the biosensor. The binding interaction of ANGPTL7 to the immobilized antibody was measured as association (kon). After analyte association, the biosensor was immersed in PBS without ANGPTL7 to dissociate the bound antigen from the antibody (kdis). The KD (M), or affinity, of the antibody for ANGPTL7 was measured as kdis / kon.

[0171] The heavy and light chains from the confirmed hybridomas were sequenced. RNA was isolated from the ANGPTL7 antibodies secreted by the hybridomas, and the variable regions of the heavy and light chains were cloned by reverse transcription using gene-specific primers followed by PCR amplification using variable-chain gene-specific primers. The PCR products were sequenced by standard Sanger sequencing methods.

[0172] Phage display: Variable heavy and light chains were amplified from the spleens of hyperimmunized mice using reverse transcription with gene-specific primers followed by PCR amplification with variable region gene-specific primers. The variable regions were cloned into a phage display vector designed to express Fab with the phage g3p protein. A library of phages expressing native Fab was amplified and purified. The phages were bound to biotinylated ANGPTL7 antigen captured on streptavidin magnetic beads. After several stringent washes, the phages remaining bound to the antigen beads were eluted using a basic 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. As described, purified phages expressing Fab were selected for antigen binding. Phages from the second round onwards were diluted and infected into TG1 cells. The polyclonal pool of phages released from two rounds of panning was tested by ELISA to confirm that the pool contained ANGPTL7-specific phages. Rolling circle amplification and standard Sanger sequencing were used to sequence the variable heavy and light chain regions from a single infected bacterial colony.

[0173] Antibody sequencing: Pairs of native variable heavy and light chains from hybridoma and phage display campaigns were cloned into a vector designed to express full-length antibodies as IgG in HEK293 cells under the control of the CMV promoter. The antibody expression vector was 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 an agarose-based protein A resin. After several stringent washes, the antibodies were eluted in glycine solution (pH 3), neutralized with Hepes (pH 9), and the buffer was exchanged to PBS.

[0174] Example 7 Differential Scanning Fluorimetry (DSF) of Human ANGPTL7 Monoclonal Antibodies. The development of effective monoclonal antibodies depends not only on their biological activities but also on their physicochemical properties such as homogeneity and stability. The stability of mAbs can be affected by their formulation. Among the many techniques used to examine the stability of mAbs, differential scanning fluorimetry (DSF) offers both excellent throughput and minimal material consumption. DSF measures the temperature (Tm) of protein unfolding transitions based on the change in fluorescence intensity of an environmentally sensitive dye.

[0175] An experiment was conducted to evaluate the thermal stability of the human ANGPTL7 monoclonal antibody (the "ATX" antibody) of the present disclosure by determining the melting temperature. The thermal stability was evaluated by differential scanning fluorimetry (DSF) using the Protein Thermal Shift (PTS) assay manufactured by Applied Biosystems. The assay was performed according to the manufacturer's instructions. Briefly, the antibody to be evaluated was prepared in triplicate by mixing it with the protein thermal shift dye and buffer. A real-time melting experiment from 25°C to 95°C was performed on a QuantStudio 3. The data was analyzed by using the Protein Thermal Shift software, and the melting temperature (Tm) was calculated from the melting curve (Table 1).

[0176] [Table 1]

[0177] Example 8 Cross-blocking of ANGPTL7 antibodies. High-throughput epitope binning experiments were performed on a real-time label-free biosensor (Carterra LSA), and a large panel of mAbs was sorted into bins based on their ability to block each other with respect to binding to the antigen. In pairwise epitope binning analysis, the antigen and antibody 2 (analyte antibody) are sequentially applied to a sensor chip (HC200M) that has been covalently loaded with antibody 1 (ligand antibody). An increase in response upon exposure to the analyte antibody indicates non-competition between the two antibodies, and the absence of a change in signal indicates competition. Antibodies having the same blocking profile relative to each other within a test set are grouped into one bin. Community network plots are used to investigate the clustering of mAbs that share similar but not necessarily identical competition profiles.

[0178] Rather than relying strictly on the sandwich / blocking assignment of the heatmap, as in the bin network plot (Figure 6A), hierarchical clustering is applied to the sorted heatmap to generate various dendrograms and network plots that successively group the mAbs based on various binning parameters (Figures 6B-6I). Figure 6B contains data from a fine-grained binning network. Figure 6C contains data from a combined binary dendrogram (colors indicate bins within the community binning network). Figure 6D contains data from the community binning network. Figure 6E contains binning data based on affinity for huANGPTL7-his (P62). Figure 6F contains binning data based on the antibody source (hybridoma or phage). Figure 6G contains binning data based on fibrinogen domain (P60P) binding. Figure 6H contains binning data based on rabbit ANGPTL7 (p66) binding. Figure 6I contains binning data based on mouse ANGPTL7 binding.

[0179] Example 9 ANGPTL7 function evaluation. An experiment was conducted to examine the effect of an anti-ANGPTL7 antibody on the conventional aqueous humor outflow ability using a 3D HTM / HSC tissue model (see Figure 3A / Example 3). The purpose of this study is to screen antibodies that bind to ANGPTL7 and determine whether they can block the inhibition of aqueous humor outflow ability by ANGPTL7 in the organoid model of the aqueous humor outflow pathway. Antibodies that can increase the aqueous humor outflow ability by blocking the activity of ANGPTL7 are drug candidates for further testing.

[0180] The test was carried out using the above-described ex vivo bioengineered human outflow pathway model. Glauconix has developed a unique technology that enables the multilayer growth of bioengineered 3D human trabecular meshwork (HTM) cells co-cultured with human Schlemm's canal (HSC) cells, thereby mimicking the structure of the tissue involved in the increased pressure in the human eye. This enables endpoint analysis related to IOP regulation. Previous experiments described above have shown that both dexamethasone and ANGPTL7 significantly decreased the aqueous humor outflow ability in a 3D human tissue model. In this experiment, the effects of 20 anti-AMPTL7 antibodies on the aqueous humor outflow ability by ANGPTL7 treatment were investigated.

[0181] As shown in Figure 7, the aqueous humor outflow ability of a single donor cell line treated with vehicle (DMSO), 500 nM dexamethasone, 50 ng / mL ANGPTL7 (1.1 nM) alone, 50 ng ANGPTL7 + 11.1 nM isotype control antibody (330), and 11.1 nM of 20 different anti-ANGPTL7 antibodies plus 50 ng / mL ANGPTL7. Samples were analyzed for their effects on the isotype control (330) using one-way ANOVA (GraphPad Prism Software, Inc., La Jolla, CA) (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 per treatment group, N = 3). These data clearly show that the efficacy of the anti-ANGPTL7 antibodies of the present disclosure restores the aqueous humor outflow ability.

[0182] Example 10 Kinetics of the ANGPTL7 antibody. Experiments were conducted to determine the reactivity and dissociation constant (K D ) with the human fibrinogen domain of the anti-ANGPTL7 antibody and ANGPTL7 protein. The binding experiment was performed with Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. Antibodies at a concentration of 50 nM were loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in monovalent P60 (huANGPTL7-fibrinogen-his) at a concentration of 200 nM for 5 minutes for association, followed by 10 minutes of dissociation. The results were analyzed with ForteBio Data Analysis 11.1 and fitted to a 1:1 binding model to determine the monovalent K D . The response (nm) at the end of association was also determined (Table 2).

[0183] [Table 2-1] [Table 2-2]

[0184] Experiments were also conducted to determine the reactivity and dissociation constant (K D ) between the anti-ANGPTL7 antibody and human ANGPTL7-his protein. The binding experiment was performed with Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. To measure the monovalent binding reaction rate, antibodies at a concentration of 50 nM were loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in monovalent P62 (huANGPTL7-his) in the concentration range of 0.343 - 250 nM (serial 3-fold dilution) for 5 minutes, followed by 10 minutes of dissociation. The results were analyzed with ForteBio Data Analysis 11.1 and all fitted to a 1:1 binding model to determine the monovalent K D (Table 3).

[0185]

Table 3-1

Table 3-2

[0186] Reactivity and dissociation constant (K D ) of anti-ANGPTL7 antibody with human ANGPTL7 GGPGG_sub-his protein were also determined. The binding experiment was performed on an Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. Antibody at a concentration of 50 nM was loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in monovalent P63 (huANGTPL7-GGPGG_sub-his) at a concentration of 100 nM for 5 minutes for association and then dissociated for 10 minutes. The results were analyzed with ForteBio Data Analysis 11.1 and fitted to a 1:1 binding model to determine the monovalent K D . The response (nm) at the end of association was also determined (Table 4).

[0187]

Table 4-1

Table 4-2

[0188] Reactivity and dissociation constant (K DExperiments were also conducted to determine D . The binding experiment was performed using Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. Antibodies at a concentration of 50 nM were loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in monovalent muANGPTL7-his (R&D Systems) at a concentration of 200 nM for 5 minutes for association and then dissociated for 10 minutes. The results were analyzed using ForteBio Data Analysis 11.1 and fitted to a 1:1 binding model to determine the monovalent K

[0189]

Table 5-1

Table 5-2

[0190] The reactivity and dissociation constant (K D ) between the anti-ANGPTL7 antibody and rabbit ANGPTL7 protein were also determined. The binding experiment was performed using Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. Antibodies at a concentration of 50 nM were loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in monovalent P66 (rabbit ANGPTL7-his) at a concentration of 200 nM for 5 minutes for association and then dissociated for 10 minutes. The results were analyzed using ForteBio Data Analysis 11.1 and fitted to a 1:1 binding model to determine the monovalent KD. The response (nm) at the end of association was also determined (Table 6).

[0191]

Table 6-1

Table 6-2

[0192] Experiments were also conducted to determine the reactivity and dissociation constant (K D ) of the anti-ANGPTL7 antibody with the human ANGPTL7 multimeric protein. The binding experiment was performed using Octet HTX (ForteBio) in 1×PBS, pH 7.4, 0.1 mg / ml BSA, 0.05% sodium azide, and 0.02% Tween 20. Antibody at a concentration of 50 nM was loaded onto pre-hydrated AHC biosensors for 5 minutes. The loaded sensors were immersed in Pext-01 (huANGTPL7-FLAG) at a concentration of 100 nM for 5 minutes for association and then dissociated for 10 minutes. The results were analyzed using ForteBio Data Analysis 11.1 and fitted to a 1:1 binding model to determine the apparent KD. The response (nm) at the end of association was also determined (Table 7).

[0193]

Table 7-1

Table 7-2

[0194] Example 11 ANGPTL7 is a member of the ANGPTL family, but its function has not been fully characterized. Previous studies have shown that loss-of-function variants of the ANGPTL7 gene are associated with protection from glaucoma and a decrease in intraocular pressure (IOP). Therefore, experiments were conducted to investigate the role of ANGPTL7 in IOP homeostasis and its potential as a target for the development of therapeutic agents.

[0195] Briefly, the ANGPTL7 knockout model was generated in a 129SvEv-C57BL / 6 mixed genetic background with Lexicon therapeutics. Osmotic pumps filled with PBS or dexamethasone-cyclodextrin solution (4 mg / kg / day) were implanted into ANGPTL7 WT (N = 14) and ANGPTL7 KO (N = 17) mice for 28 days. Body weight and IOP were measured 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 mg / kg / day for mice with an average weight of 30 g. Next, the pumps were incubated in 0.9% saline at 37°C for 48 hours and then implanted. Body weight and IOP were measured on day 0, and then the mice were randomized into the following four treatment groups using this: Angptl7 KO + PBS, N = 8. Angptl7 KO + dexamethasone, N = 9, Angptl7 WT + PBS, N = 5, and Angptl7 WT + dexamethasone, N = 14. PBS or dexamethasone pumps were implanted subcutaneously in the mice. IOP and body weight were collected weekly on days 7, 14, 21, and 28. On day 28, final body weight and IOP measurements were taken. The left / right eyes were enucleated and snap-frozen in liquid nitrogen. The mice were euthanized according to humane IACUC procedures.

[0196] Representative results of the effect of dexamethasone-induced ocular hypertension in ANGPTL7 knockout mice are provided in FIGS. 8A-8C. FIG. 8A includes the body weight data of the mice after transplantation surgery. Dexamethasone impaired weight gain in male mice compared to PBS-treated mice, thereby confirming that the dexamethasone osmotic pump was functioning properly. FIG. 8B includes the intraocular pressure (IOP) data of ANGPTL7 WT and ANGPTL7 KO mice administered PBS control or dexamethasone (4 mg / kg / day). The osmotic pump was implanted on day 0. FIG. 8C includes representative data of the change in IOP over 28 days of 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 the baseline (day 0) reading.

[0197] Example 12 In vivo tolerability. An experiment was conducted to examine the in vivo tolerability of an anti-ANGPTL7 antibody using single intravitreal (IVT) injection in New Zealand White rabbits. Representative data are shown in FIGS. 9A-9R. The indicated anti-ANGPTL7 antibodies (the "BTX" label is interchangeable with the "ATX-P" label) were injected into the right eye (OD) at either a 0.5 mg dose (FIGS. 9C, 9D, 9G, 9H, 9K, 9L, 9O, 9P) or a 2.0 mg dose (FIGS. 9E, 9F, 9I, 9J, 9M, 9N, 9Q, 9R), or into the left eye (OS) at the corresponding vehicle dose. (FIGS. 9A and 9B include data from the control at a 2 mg dose). Intraocular pressure (IOP) measurements (FIGS. 9A, 9C, 9E, 9G, 9I, 9K, 9M, 9O, 9Q) and changes in IOP (FIGS. 9B, 9D, 9F, 9H, 9J, 9L, 9N, 9P, 9R) were measured over 21 days at the indicated time points.

[0198] Briefly stated, animals were dosed on day 0, and IOP was normalized against day - 3 (N = 3 per treatment group, p<0.05). Animals were medicated on day 0. The experimental eye (OD) was compared with the vehicle eye (OS) using two - way ANOVA. For intravitreal injection (day 0), rabbit pupils were dilated with 1% tropicamide HCl, and buprenorphine (0.01 - 0.05 mg / kg) was administered SC. Rabbits were sedated by IM administration of ketamine / xylazine cocktail (4 - 10 / 20 - 50 mg / kg), the eyes were prepared aseptically using topical 5% betadine solution, followed by rinsing with sterile eye wash solution, and 1 drop of 0.5% proparacaine HCl was administered. The conjunctiva was gently grasped with Colibri forceps, and the injection was made (through the pars plana) 2 - 3 mm posterior to the superior limbus using a 27 - 30G needle, with the needle directed slightly posteriorly to avoid contact with the lens. After dosing the contents of the syringe, the needle was slowly withdrawn. After the injection procedure, 1 drop of antibiotic eye drops was added topically to the eye surface. For each injection group, baseline eye examinations and IOP measurements were performed 24 hours after dosing and on days 3, 8, 14, and 21. Final blood collection for PK analysis (see below) was obtained on day 21.

[0199] At the indicated time points, intraocular pressure (IOP) was measured in both eyes of all animals. The measurements were performed without using topical anesthesia using a Tonovet probe (iCare Tonometer, Espoo, Finland). The tip of the Tonovet probe was oriented to gently contact the center of the cornea. Six consecutive measurements were obtained. After the sixth measurement, the indicated mean IOP was recorded. It was not necessary to sedate the animals for this procedure.

[0200] Example 13 Pharmacokinetics (PK) evaluation. Previous tests (the above-mentioned ones) showed that both doses of 0.5 mg and 2.0 mg of several novel anti-ANGPTL7 antibodies had good tolerance in rabbits over a period of 21 days. Therefore, an experiment was conducted to evaluate the pharmacokinetics (PK) of several anti-ANGPTL7 antibodies with good tolerance. New Zealand white rabbits were injected unilaterally (OU) once with each of ATX-P-424 (Figures 10A - 10C), ATX-P-439 (Figures 11A - 11C), and ATX-P-448 (Figures 12A - 12C). (The "BTX" label is compatible with the "ATX-P" label.) The representative pharmacokinetic (PK) data of the indicated ANGPTL7 antibodies included intraocular pressure (IOP) measurements (Figures 10A, 11A, and 12A) dosed at 0.5 mg or 2.0 mg (OU) compared to the vehicle, the change in IOP compared to the baseline (Figures 10B, 11B, and 12B), and the total ophthalmic examination score (OE) (Figures 10C, 11C, and 12C).

[0201] Briefly stated, to collect serum at the indicated time points, at least 1 mL of whole blood was collected from the marginal ear vein or by cardiac puncture (for final blood collection only) and placed into plastic tubes with red caps (without anticoagulant or with serum separator gel). Alternatively, if veins were not accessible or reuse was not optimal for further collections, the central auricular artery was utilized. Lidocaine 5% ointment was thinly applied topically to the skin covering the vessel prior to needle insertion. Wintergreen oil was also applied, if necessary, to promote vasodilation. After collection, the tubes were inverted 3 - 5 times to mix gently. The blood samples were stored at room temperature for 30 - 60 minutes before processing. The whole blood samples were centrifuged at 2,000 × g for 10 minutes at 4°C in a refrigerated centrifuge. Immediately after centrifugation, the clear serum was aliquoted into four 200 μL samples and stored frozen at -80°C until shipment for analysis. Additionally, an animal ophthalmologist performed a detailed eye examination using a slit lamp biomicroscope and indirect ophthalmoscope to evaluate the morphology of the ocular surface and anterior and posterior segment inflammation in all animals prior to dosing and at the indicated time points to serve as baselines. A routine eye examination was performed on all animals to consider their participation in the study. For scoring, the modified Hackett and McDonald ocular evaluation system was used, with additional scoring parameters for the posterior segment of the globe.

[0202] To analyze 0.5 mg of ATX-P-424, it was administered to animals every other day in two different cohorts (N = 6 and N = 4). The animals were administered on day 0 and euthanized at 24 hours, 7, 14, and 21 days (N = 2 per time point). The number of eyes per single measurement included N = 20 eyes on day 0 and day 1, N = 12 eyes on day 7, N = 8 eyes on day 14, and N = 4 eyes on day 21. In the analysis of 2.0 mg of ATX-P-424, rabbits (N = 6) showed an OE score of over 20 on day 0 and were euthanized. In the analysis of ATX-P-439, the measurement included N = 20 eyes on day 0 and day 1. Animals (N = 6 per group) administered ATX-P-439 at both doses showed an OE score of over 20 after 24 hours and were euthanized. No further administration to additional animals was performed from the second cohort. To analyze ATX-P-448, it was administered to animals every other day in two different cohorts (N = 6 and N = 4). The animals were administered on day 0 and euthanized at 24 hours, 7, 14, and 21 days (N = 2 per time point). The number of eyes per single measurement included N = 20 eyes on day 0 and day 1, N = 12 eyes on day 7, N = 8 eyes on day 14, and N = 4 eyes on day 21.

[0203] Example 14 In vivo tolerance (non-human primates). In non-human primates (African green monkeys), an experiment was also conducted to examine the in vivo tolerance of anti-ANGPTL7 antibody using single intravitreal (IVT) injection. Figures 13A to 13C include representative data of absolute IOP values (Figure 13A) 6 hours after baseline (day 3) and day 10, and local administration of saline and latanoprost, changes in IOP 6 hours after local administration of either saline (day 3) or latanoprost (day 10) (Figure 13B), and changes in IOP between vehicle and latanoprost administration (Figure 13C). Figures 14A to 14H include representative IOP measurement values (Figures 14A, 14C, 14E, and 14G) and changes in IOP (Figures 14B, 14D, 14F, and 14H) in African green monkeys administered 2 mg of the indicated anti-ANGPTL7 antibody compared to isotype control (BTX-330) and single vehicle eyes. Figure 15 includes representative clinical scores of ocular examination (OE) across all dosing groups.

[0204] Briefly stated, the monkeys were pre-screened to identify animals with a baseline IOP value greater than 16 mmHg and less than 26 mmHg. For pre-screening, the monkeys were sedated with ketamine / xylazine (8 mg / kg and 1.6 mg / kg, respectively), and IOP measurements were performed using a rebound tonometer (Tonovet®) between 8:00 AM and 10:00 AM. If the animals were not fully sedated, additional ketamine / xylazine was administered until an effect was achieved. Any animals that required more than 25% of the target dose for IOP measurement were preferentially excluded from the study. IOP measurements were performed 5 - 10 minutes after the initial sedation (T = 0). One minute before IOP measurement, the animals were placed in the supine position (OS was analyzed immediately before OD), and otherwise were placed in the prone position while sedated. Six hours after the first pre-screening evaluation (T = 6 hours), the procedures for sedation, positioning, and IOP measurement were repeated in the same manner. Any monkeys that showed a decrease in IOP of more than 5 mmHg (IOP sensitivity to sedation) between T = 0 hours and T = 6 hours were excluded from the study. After completion of the IOP measurement at T = 6 hours, the monkeys were subjected to ophthalmic screening, and the ocular and systemic health status was evaluated by slit-lamp biomicroscopy, fundus examination, and color fundus photography (CFP). Monkeys with normal examination findings were enrolled in the study and randomized into treatment groups based on the pre-screening T = 0 IOP.

[0205] At least 7 days after completion of the screening activities and at least 7 days before the start of Phase 2, the animals were sedated and IOP was evaluated using the same method as used in the screening. Immediately after completion of the IOP measurement at T = 0, 1 gtt (approximately 35 μL) of 0.005% latanoprost eye drops (Xalatan® or equivalent) was administered to one eye, and 0.9% saline was administered to the other eye. The dosing was performed between 8:00 AM and 10:00 AM. A follow-up IOP evaluation was performed 6 hours after T = 0 to identify the IOP reduction response for each animal. The absolute change in IOP during screening and between T = 0 hours and T = 6 hours during Phase 1 was calculated for each eye, and then the percent difference in ΔIOP (ΔΔIOP%) between sedation alone and latanoprost was determined using the following formula.

Number

[0206] Subsequently, animals were ranked based on the mean %ΔΔIOP response to timolol. Animals with little effect of sedation on IOP and little response to timolol administration compared to sedation alone ("timolol responders") were enrolled in the study. If fewer than 15 animals were identified for inclusion based on these criteria, up to 8 additional animals were screened in the same manner to complete enrollment in the study.

[0207] For IVT administration, topical proparacaine 0.5% was administered and allowed to act for 30 seconds, an eyelid speculum was placed, and then the ocular surface was rinsed with 5% betadine solution followed by 0.9% sterile saline. IVT injections were performed in both eyes (OU) according to the treatment assignment at the height of the limbus approximately 2 mm posterior to the corneal limbus, inserted in a low temporal direction using a 31-gauge 5 / 16-inch needle / syringe (Ulticare VetRx U-100 or equivalent). After injection, topical antibiotic ophthalmic ointment (neomycin, polymyxin, bacitracin or equivalent) was administered.

[0208] At the indicated time points, intraocular pressure (IOP) measurements were collected using a TonoVet (iCare, Finland) tonometer set to the canine (d) calibration setting. The TonoVet rebound tonometer had good tolerability and did not require additional topical analgesia. All IOP measurements were performed while the animals were sedated with ketamine and xylazine. The animals were sedated 5 - 10 minutes prior to each scheduled measurement, placed in dorsal recumbency 1 minute prior to each IOP measurement (OS was analyzed immediately prior to OD), and in ventral recumbency for all other times during sedation. After completion of each IOP assessment, the animals were moved to ventral recumbency and maintained in this position until recovery from sedation. Three measurements were taken from each eye at each time point and the mean value was used for IOP analysis.

[0209] Furthermore, at the specified time point, slit lamp biomicroscopy was performed on both eyes (OU). Scoring was applied to qualitative ophthalmic clinical findings using a summary score derived from the non-human primate ophthalmic scoring system and the test content. At the specified time point, bilateral color fundus images of the retina were captured in a 50° view 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 the specified time point, blood samples (0.5 - 1 mL) were collected and transferred to a K 2 vacutainer with a lavender cap, gently inverted several times, and kept on ice until CBC and differential analysis were performed using an Abaxis VetScan HM5 hematology analyzer. At the specified time point, whole blood (3 mL) was collected via the femoral vein or the saphenous vein. The blood was transferred to a vacutainer tube (in the absence of anticoagulant), incubated at room temperature for approximately 1 hour, then centrifuged at 4000 rpm for 10 minutes at 4°C to separate serum aliquots (approximately 0.5 mL × 2 aliquots per time point). The aliquots were stored at less than -70°C and shipped at that temperature to the testing institution designated for NAb analysis. At the specified time point, 0.5% topical proparacaine was administered and allowed to act for 30 seconds, an eyelid speculum was placed, then the eye surface was rinsed with 5% povidone-iodine solution, followed by rinsing with 0.9% sterile saline. Aqueous humor (50 μL) was sampled using a 0.3 mL insulin syringe, and a 31-gauge needle was advanced into the anterior chamber approximately 2 mm anterior to the limbus of the temporal cornea. The aqueous sample was transferred to a cryotube, rapidly frozen, stored at less than -70°C, and shipped at that temperature to the requester or the laboratory designated by the requester for analysis. The subjects were further evaluated twice a day on the cage side for overall health and evidence of eye lesions. Data generated from the endpoints defined in the protocol were collated, summarized, and analyzed. Specific statistical analyses were performed if the data met the required assumptions. If the data did not meet the assumptions of the defined statistical methods, alternative methods were used if possible. A P-value ≤ 0.05 was considered statistically significant. sequence

[0210] The various amino acid sequences and nucleic acid sequences referred to in this specification are provided below.

[0211]

Table 8-1

Table 8-2

Table 8-3

Table 8-4

Table 8-5

Table 8-6

Table 8-7

Table 8-8

Table 8-9

[0212]

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 9-5

Table 9-6

Table 9-7

Table 9-8

Table 9-9

Table 9-10

Table 9-11

Table 9-12

Table 9-13

Table 9-14

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Table 9-19

Table 9-20

Table 9-21

Table 9-22

Table 9-23

Table 9-24

Table 9-25

Table 9-26

Table 9-27

Table 9-28

[0213]

Table 10-1

Table 10-2

Table 10-3

Table 10-4

Table 10-5

Table 10-6

Table 10-7

Table 10-8

Table 10-9

Table 10-10

Table 10-11

Table 10-12

Table 10-13

Table 10-14

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Table 10-16

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Table 10-19

Table 10-20

Table 10-21

Table 10-22

Table 10-23

Table 10-24

Table 10-25

Table 10-26

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Table 10-28

Table 10-29

Table 10-30

Table 10-31

Table 10-32

Table 10-33

Table 10-34

Table 10-35

Table 10-36

Table 10-37

Table 10-38

Table 10-39

Table 10-40

Table 10-41

Table 10-42

Table 10-43

Table 10-44

Table 10-45

Table 10-46

Table 10-47

Table 10-48

Table 10-49

Table 10-50

Table 10-51

Table 10-52

Table 10-53

Table 10-54

Table 10-55

Table 10-56

Table 10-57

Table 10-58

Table 10-59

Table 10-60

Table 10-61

Table 10-62

Table 10-63

Table 10-64

Table 10-65

Table 10-66

Table 10-67

Table 10-68

Table 10-69

Table 10-70

Table 10-71

Table 10-72

Table 10-73

Table 10-74

Table 10-75

Table 10-76

Table 10-77

Table 10-78

Table 10-79

Table 10-80

Table 10-81

[0214] Human angiopoietin-related protein 7 (UniProt accession number O43827): MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVANLSSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDFKP (SEQ ID NO: 370).

[0215] Human angiopoietin-related protein 7 L59P_L84P variant (ATX-P-62):

Chemical formula

[0216] Human angiopoietin-related protein 7 L59 GGPGG variant (ATX-P-63):

Chemical formula

[0217] Human angiopoietin-related protein 7 fibronogen domain (ATX-P-60): YDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPED (SEQ ID NO: 373).

[0218] Human angiopoietin-related protein 7 wild-type multimer (PExt-1):

[0219] MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVANLSSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTIIQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGWHGSTYSLKRVEMKIRPEDFKP (SEQ ID NO: 374).

[0220]

Table 11

[0221] Various embodiments of the present disclosure are described herein. Variations of those embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to utilize such variations as appropriate, and the inventors intend for the various embodiments of the present disclosure to be practiced in ways other than those specifically described herein. Accordingly, the embodiments of the present disclosure include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Further, unless otherwise indicated herein or clearly contradicted by context, any combination of the foregoing elements in all possible variations thereof are included in the various embodiments of the present disclosure.

Claims

1. An antibody that specifically binds to human angiopoietin-like protein 7 (ANGPTL7), wherein the human ANGPTL7 is a polypeptide comprising or consisting of one of the amino acid sequences of SEQ ID NOs. 370 to 374, the antibody comprising complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3 in the heavy chain variable region (VH), and complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 in the light chain variable region (VL), the HCDR and LCDR amino acid sequences for each individual antibody being represented by the SEQ ID NOs listed in the table below.

2. The antibody according to claim 1, wherein the antibody comprises VH and VL amino acid sequences indicated by the sequence numbers listed individually in the table below for each antibody.

3. The antibody according to claim 1, which is monoclonal and optionally recombinant.

4. The antibody according to claim 1, which is human, humanized, or chimeric.

5. The antibody according to claim 1, wherein the antibody is a full-length antibody comprising an Fc region, for example, a human IgG1, IgG2, IgG3, or IgG4 region.

6. The antibody according to claim 1, which is conjugated to at least one additional portion optionally selected from the following: a. An antigen-binding portion, such as an antibody or its antigen-binding fragment, that can specifically bind to a target other than human ANGPTL7, wherein the target is expressed in the human eye, the antigen-binding portion, b. The area to be treated or the cytotoxic area, c. Detection section, d. Purification part, e. The half-life extension portion is optionally a polypeptide having a length of at least 20 amino acids and comprising any combination of G, A, ST, E, and P residues, which is conjugated to the C or N terminus of the antibody.

7. A polynucleotide encoding the antibody according to claim 1.

8. An expression vector comprising a polynucleotide according to claim 7, which is optionally an adeno-associated virus (AAV) vector, a lentivirus (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

9. The antibodies, polynucleotides, or vectors according to claims 1 to 8, and optionally, a. At least one pharmaceutically acceptable carrier, diluent, or preservative, and / or b. A pharmaceutical composition comprising at least one additional active ingredient.

10. The pharmaceutical composition according to claim 9, which is suitable for administration by delivery using, optionally, conjunctival implants, contact lenses, gels, nanoparticles, mucosal adhesion polymers, ointments, solutions, suspensions, eye drops, and / or implants, preferably suitable for administration by injection into vitreous solution, and suitable for transocular administration to a subject.

11. The composition according to claim 9, for use as a pharmaceutical, and optionally for use in a method for treating a disease of the eye.

12. The composition for use according to claim 11, wherein the disease is characterized by an increase in intraocular pressure and / or a decrease in aqueous humor outflow in the eye of the subject.

13. The composition for use according to claim 11, formulated for transocular administration, preferably for injection into vitreous solution, wherein the administration preferably relieves at least one symptom selected from among eye pain, intraocular pressure, headache, iridescent halos around lights, low vision, blurred vision, constricted field of vision, peripheral vision impairment, blind spots, nausea, vomiting, and red-eye in the subject.

14. The composition for use according to claim 11, wherein the disease is glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, and optionally the glaucoma is primary or glucocorticoid-induced glaucoma.

15. The antibody according to claim 1, wherein the antibody binds to an epitope from an ANGPTL7 polypeptide having any amino acid sequence of SEQ ID NOs. 370 to 374.

16. An antibody against angiopoietin-like protein 7 (ANGPTL7) peptide, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) containing complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, The HCDR1 comprises one of the following amino acid sequences: (a) X 1 YX 2 IX 3 (Sequence No. 1), in the formula, X 1 is S or D; X 2 is G or Y; X 3 is either S or H; (b) TSGVGVG (Sequence ID 18); (c) X 1 X 2 X 3 MX 4 (SEQ ID NO: 27), wherein X 1 is V, S, D, or T; X 2 is Y, H, or F; X 3 is D, G, S, or A; X 4 is H, S, or N; or (d) SX 1 SX 2 YWX 3 (Sequence ID 74), where X 1 is S or G; X 2 is S or Y; X 3 is G or S; The HCDR2 comprises one of the following amino acid sequences: (a) WIX 1 X 2 X 3 X 4 GX 5 TX 6 YAQX 7 X 8 X 9 G (Sequence No. 7), in the formula, X 1 is S, I, or N; X 2 is A or P; X 3 is Y or N; X 4 is N or T; X 5 is N or A; X 6 is N or K; X 7 is N or K; X 8 is L or F; X 9 is either R or Q; (b) LIYWNDDKX 1 YSPSLKS (Sequence No. 21), where X 1 is either 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 (Sequence No. 43), in the formula, X 1 is G, T, S, A, V, H, or I; X 2 is 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 is 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 is P, Y, or A; X 12 is G, D, or A; X 13 is S or D; X 14 is V, L, or S; X 15 is K or M; or (d) X 1 IYYSGSTX 2 SNPSLKS (Sequence ID 78), in the formula, X 1 is S or Y; X 2 is either Y or S; The HCDR3 comprises one of the following amino acid sequences: (a) Sequence IDs 13-17; (b) X 1 X 2 X 3 X 4 X 5 X 6 FFDX 7 (Sequence No. 24), where X 1 is S, D, or N; X 2 is Y or P; X 3 is G or D; X 4 is D or Y; X 5 is Y or G; X 6 is W or D; X 7 is either L or Y; (c) Sequence IDs 59-73; or (d)X 1 X 2 X 3 X 4 GX 5 X 6 X 7 X 8 X 9 Y (array number 82), wherein X 1 is Q or A; X[[ID=2(1]] 2 is Y or K; X 3 is I or W; X 4 is S or E; X 5 is T or D; X 6 is E or Y; X 7 is Y or F; X 8 is F or D; X 9 is Q or Y; and The antibody, or its antigen-binding fragment, wherein LCDR1 comprises any of the amino acid sequences of SEQ ID NOs. 87-97, 123-127, or 141-149; LCDR2 comprises any of the amino acid sequences of SEQ ID NOs. 99-109, 129-133, or 151-159; and LCDR3 comprises any of the amino acid sequences of SEQ ID NOs. 111-121, 135-139, or 161-169.

17. An antibody against angiopoietin-like protein 7 (ANGPTL7) peptide, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) containing complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, The aforementioned LCDR1 comprises one of the following amino acid sequences: (a) RASQX 1 IX 2 X 3 X 4 LX 5 (Sequence No. 86), where X 1 is G or S; X 2 is S, R, or Y; X 3 is S, N, or I; X 4 is W, D, or Y; X 5 is A, G, or N; (b) RSSQSLX 1 X 2 SX 3 X 4 X 5 X 6 YLX 7 (Sequence No. 122), in the formula, X 1 is L or V; X 2 is H, Y, or F; X 3 is N or D; X 4 is R or G; X 5 is Y or N; X 6 is N or T; X 7 is D or N; or (c) RASQSVSX 1 X 2 X 3 X 4 A (Sequence No. 140), in the formula, X 1 is S, N, or R; X 2 is Y or S; X 3 is L or Y; X 4 is A or L; The aforementioned LCDR2 comprises one of the following amino acid sequences: (a) AX 1 SSLX 2 S (Sequence ID 98), in the formula, X 1 is A or T; X 2 is either Q or P; (b) X 1 X 2 SNRX 3 S (Sequence No. 128), in the formula, X 1 is L, K, or E; X 2 is G or V; X 3 is A or D; or (c) X 1 ASX 2 RAT (Sequence ID 150), in the formula, X 1 is D or G; X 2 is N, S, or T; The aforementioned LCDR3 comprises one of the following amino acid sequences: (a) X 1 QX 2 X 3 X 4 X 5 PX 6 X 7 (Sequence No. 110), in the formula, X 1 is L or Q; X 2 is A, H, S, or D; X 3 is N, F, or Y; X 4 is S, T, or N; X 5 is F, Y, or T; X 6 is W, L, I, P, or Y; X 7 is either T or Y; (b) MQX 1 X 2 X 3 X 4 PX 5 T (Sequence ID 134), in the formula, X 1 is T or G; X 2 is L or T; X 3 is 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 (Sequence ID 160), in the formula, X 1 is R, Y, or G; X 2 is S, G, or Q; X 3 is N, S, or V; X 4 is W, S, or I; X 5 is P or L; X 6 is L, S, P, or T; and The antibody, or its antigen-binding fragment, wherein HCDR1 comprises any of the amino acid sequences of SEQ ID NOs: 2-6, 19-20, 28-42, or 75-77; HCDR2 comprises any of the amino acid sequences of SEQ ID NOs: 8-12, 22-23, 44-58, or 79-81; and HCDR3 comprises any of the amino acid sequences of SEQ ID NOs: 13-17, 25-26, 59-73, or 83-85.

18. 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; The antibody according to claim 16 or claim 17, wherein 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.

19. 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; The antibody according to claim 16 or 17, wherein 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.

20. The antibody according to claim 16 or 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to any of the following: (a) Sequence IDs 170-174, (b) Sequence IDs 190-191, (c) Sequence IDs 198-212, or (d) Sequence IDs 258-260.

21. The antibody according to claim 16 or 17, wherein the VL comprises an amino acid sequence that is at least 90% identical to any of the following: (a) Sequence IDs 180-184, (b) Sequence IDs 194-195, (c) Sequence IDs 228-242, or (d) Sequence IDs 264-266.

22. The antibody according to claim 16 or claim 17, which binds to ANGPTL7 and increases aqueous humor outflow capacity compared to a control.

23. An antibody according to claim 16 or claim 17, (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 antibody wherein VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 199, and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO:

229.

24. The antibody according to claim 16 or claim 17, which is a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody.

25. Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab') 2 The antibody according to claim 16 or claim 17, wherein the fragment is selected from the group consisting of fragments.

26. The antibody according to claim 16 or claim 17, which is a single-specific antibody.

27. The antibody according to claim 16 or claim 17, which is a bispecific antibody.

28. The antibody according to claim 16 or claim 17, comprising a detection portion, a purification portion, and / or a half-life extension portion.

29. A pharmaceutical composition comprising the antibody described in claim 16 or claim 17, and suitable for transocular administration.

30. A pharmaceutical composition used in a method for treating glaucoma and / or a disease affecting the optic nerve or retinal ganglion cells, comprising the antibody described in claim 16 or claim 17, wherein the method comprises administering the pharmaceutical composition comprising an effective amount of the antibody described in claim 16 or claim 17 to a subject in need thereof, wherein administration of the pharmaceutical composition reduces intraocular pressure and / or increases aqueous humor outflow capacity in the eye of the subject.

31. Polynucleotides having at least 80% identity to any of the following nucleic acid sequences: (a) Sequence IDs 175-179, (b) Sequence IDs 185-189, (c) Sequence IDs 192-193, (d) Sequence IDs 196-197, (e) Sequence IDs 213-227, (f) Sequence IDs 243-257, (g) Sequence IDs 261-263, or (h) Sequence IDs 267-269.

32. An epitope derived from the ANGPTL7 polypeptide containing any of sequence numbers 370-374, and K100 nM or less. D The antibody according to claim 16 or claim 17, which binds to the antibody.

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