WO2023212294A1 - Angiopoietin-related protein 7-specific antibodies and uses thereof - Google Patents

Angiopoietin-related protein 7-specific antibodies and uses thereof Download PDF

Info

Publication number
WO2023212294A1
WO2023212294A1 PCT/US2023/020354 US2023020354W WO2023212294A1 WO 2023212294 A1 WO2023212294 A1 WO 2023212294A1 US 2023020354 W US2023020354 W US 2023020354W WO 2023212294 A1 WO2023212294 A1 WO 2023212294A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
acid sequence
amino acid
antibody
ammo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/020354
Other languages
English (en)
French (fr)
Inventor
Andrew Peterson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Broadwing Bio LLC
Original Assignee
Broadwing Bio LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US18/860,128 priority Critical patent/US20250296996A1/en
Priority to CA3250430A priority patent/CA3250430A1/en
Priority to CN202380047683.3A priority patent/CN119630698A/zh
Priority to PE2024002370A priority patent/PE20250560A1/es
Priority to JP2024564495A priority patent/JP2025517111A/ja
Priority to KR1020247039794A priority patent/KR20250021399A/ko
Priority to EP23726246.4A priority patent/EP4514470A1/en
Priority to AU2023259251A priority patent/AU2023259251A1/en
Application filed by Broadwing Bio LLC filed Critical Broadwing Bio LLC
Priority to IL316603A priority patent/IL316603A/en
Publication of WO2023212294A1 publication Critical patent/WO2023212294A1/en
Priority to MX2024013138A priority patent/MX2024013138A/es
Anticipated expiration legal-status Critical
Priority to CONC2024/0016093A priority patent/CO2024016093A2/es
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • 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.
  • the present disclosure provides novel therapeutic antibodies, and related compositions and methods, that target angiopoietin-related protein 7 (ANGPTL7) to reduce intraocular pressure (IOP) in order to prevent optic nerve damage and restore vision.
  • ANGPTL7 angiopoietin-related protein 7
  • IOP intraocular pressure
  • Glaucoma is a group of optic neuropathies associated with characteristic structural changes at the optic nerve head that may lead to visual field loss and, ultimately, blindness. Blindness is most commonly defined as 20/200 or worse visual acuity on a Snellen eye chart or a visual field of less than 20 degrees. Legal blindness refers to the fulfillment of these criteria by the better-seeing eye.
  • Blindness is most commonly defined as 20/200 or worse visual acuity on a Snellen eye chart or a visual field of less than 20 degrees.
  • Legal blindness refers to the fulfillment of these criteria by the better-seeing eye.
  • Glaucoma is the leading cause of irreversible blindness. Glaucoma accounts for more than 25% of cases of blindness in these groups, making it a more common cause of blindness than diabetic retinopathy (accounting for 7.3% and 14.3% of cases in blacks and Hispanics, respectively) and age-related macular degeneration (accounting for 4.4% and 14.3% of cases in blacks and Hispanics, respectively). Among Hispanics, glaucoma causes blindness more often than cataracts do (28.6% vs. 14.3%). In 2009, Medicare beneficiaries spent $748 million on glaucoma-related visits, testing, and procedures. Patients with glaucoma who are not blind may have functional limitations, leading to driving cessation and decreased ability to read.
  • POAG primary open-angle glaucoma
  • PAG primary angle-closure glaucoma
  • POAG primary open-angle glaucoma
  • PACG primary angle-closure glaucoma
  • the angle of the eye is the junction between the iris and cornea, where the trabecular meshwork drains aqueous humor from the anterior chamber of the eye.
  • POAG the angle remains open as the trabecular meshwork is unblocked by iris tissue.
  • Intraocular pressure is transmitted to the axons of retinal ganglion cells at the optic nerve as mechanical stress, leading to cell death.
  • intraocular pressure within the so-called “normal” range of 10 to 21 mm Hg at diagnosis.
  • retinal ganglion cells Only after 30% of retinal ganglion cells have been lost are visual field defects present on perimetric testing.
  • PACG the peripheral iris obstructs normal aqueous outflow. This can lead to increased intraocular pressure and optic nerve damage. Eyes that are at risk of PACG tend to be shorter with a shallower anterior chamber. Patients with PACG may experience acute or subacute events that occur after a sudden rise in intraocular pressure or from chronic PACG that is insidious in onset and largely asymptomatic.
  • Embodiments of the present disclosure include an antibody, or an antigen binding fragment thereof, which specifically binds human Angiopoietin-Like Protein 7 (ANGPTL7), optionally wherein said human ANGPTL7 is a polypeptide which comprises or consists of the ammo acid sequence of any one of SEQ ID NOs: 370 to 374.
  • ANGPTL7 is a polypeptide which comprises or consists of the ammo acid sequence of any one of SEQ ID NOs: 370 to 374.
  • the antibody, or an antigen binding fragment thereof exhibits any one or more the following functional characteristics: increases outflow' facility compared to a control when administered to the eye of a subject, optionally wherein the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein with an isotype control antibody treatment; and/or binds to ANGPTL7 with a KD of about I OOnM or lower; 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 the sequences of which are provided in Table 11; and/or competes for binding to ANGPTL7 with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 11.
  • the antibody, or an antigen binding fragment thereof is monoclonal, optionally recombinant. In some embodiments, the antibody, or an antigen binding fragment thereof, is human, humanized, or chimeric.
  • the antibody, or an antigen binding fragment thereof is a full length antibody, a single chain antibody, a single chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), a Fab-C, a Fab’-SH, a (Fab’)2, a singledomain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalm or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.
  • an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.
  • the antibody, or an antigen binding fragment thereof) is conjugated to at least one additional moiety, optionally selected from: an antigen binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human ANGPTL7, preferably wherein said target is expressed in the human eye; a therapeutic or cytotoxic moiety; a detection moiety; a purification moiety, a half-life extension moiety, optionally a polypeptide that is at least 20 amino acids in length and comprises any combination of G, A, S T, E, and P residue, which polypeptide is conjugated to the C- or N- terminus of the antibody.
  • an antigen binding moiety such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human ANGPTL7, preferably wherein said target is expressed in the human eye
  • a therapeutic or cytotoxic moiety such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which
  • the antibody, or an antigen binding fragment thereof is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided 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 the sequences of which are provided in Table 11, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably wherein variation is not permitted in the HCDRs or LCDRs; and/or all six CDRs of any of the exemplary antibodies exemplary antibodies the sequences of which are provided in Table 11; and/or the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 11; and/or the full length heavy chain (VH + constant) sequence of any one of the exemplary antibodies the sequences of which are provided in Table 11, and optional
  • Embodiments of the present disclosure also include a polynucleotide encoding an antibody, or an antigen binding fragment thereof, of any of the preceding paragraphs, optionally wherein said polynucleotide comprises or consists of a nucleic acid sequence having at least 70%, 80%, 90% or 100% identity' to a nucleic acid sequence of any one of the exemplary’ antibodies the sequences of which are provided in Table 11.
  • Embodiments of the present disclosure also include an expression vector comprising the polynucleotide of the preceding paragraph, which is optionally an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retrovirus vector.
  • AAV adeno-associated virus
  • LV lentiviral
  • HSV herpes simplex virus
  • 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: at least one pharmaceutically acceptable carrier, diluent or preservative, and/or at least one additional active ingredient.
  • the pharmaceutical composition is suitable for ocular administration to a subject, optionally by delivery using a conjunctival insert, a contact lens, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and/or an implant, preferably by injection into the vitreous fluid.
  • Embodiments of the present disclosure also include the antibody, or an antigen binding fragment thereof, the polynucleotide, the vector, or the compositions of any of the preceding paragraphs, for use as a medicament, optionally for use in a method of treating a disease of the eye in a subject.
  • the disease is characterized by increased intraocular pressure and/or reduced outflow' facility in the eye of the subject.
  • the method comprises ocular administration of the antibody, preferably by injection into the vitreous fluid, and wherein said administration preferably relieves at least one symptom in the subject selected from eye pain, eye pressure, headaches, rainbow-colored halos around lights, low vision, blurred vision, narrowed vision, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes.
  • the disease is glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells, optionally wherein said glaucoma is primary or glucocorticoid-induced glaucoma.
  • Embodiments of the present disclosure include antibodies against Angiopoietin-Like Protein 7 (ANGPTL7) peptides, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3.
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • VL light chain variable region
  • the HCDR1 comprises one of the following amino acid sequences: (a) X1YX2IX3 (SEQ ID NO: 1), wherein Xi is S or D; X2 is G or Y; Xs is S or H; (b) TSGVGVG (SEQ ID NO: 18); (c) XiX 2X3MX4 (SEQ ID NO: 27), wherein Xi is V, S, D, or T; X2 is Y, H, or F; X3 is D, G, S, or A; X4 is H, S, or N; or (d) SX1SX2YWX3 (SEQ ID NO: 74), wherein Xi is S or G; X2 is S or Y; X?
  • the HCDR2 comprises one of the following ammo acid sequences: (a) WIXiX2X 3 X4GX 5 TX6YAQX7XkX9G(SEQ ID NO: 7), wherein Xi is S, I, or N; X 2 is A or P; X 3 is Y or N; X4 is N or T; X5 is N or A; Xg is N or K; X7 is N or K; Xg is L or F; X9 is R or Q; (b) LmVNDDKXiYSPSLKS (SEQ ID NO: 21), wherein Xi is R or Q; (c) X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15G (SEQ ID NO: 43), wherein Xi is G, T, S, A, V, H, or I; X2 is I or M; X3 is D, N, T, T, T, S, A,
  • the HCDR3 comprises one of the following ammo acid sequences: (a) SEQ ID NOs: 13-17; (b) X1X2X3X4X5X6FFDX7 (SEQ ID NO: 24) wherein Xi is S, D, or N; X2 is Y or P; X3 is G or D; X4 is D or Y; X5 is Y or G; Xg is W or D; X7 is L or Y; (c) SEQ ID NOs: 59-73, or (d) X1X2X 3X4GX5X6X7X8X9Y (SEQ ID NO: 82) wherein Xi is Q or A; X2 is Y or K; X 3 is I or W; X4 is S or E; X5 is T or D; Xg is E or Y; X7 is Y or F; Xs is F or D; X9 is Q or Y.
  • the LCDRl of the anti-ANGPTL7 antibodies of the present disclosure includes an amino acid sequences of any of SEQ ID NOs: 87- 97, SEQ ID NOs: 123-127, or SEQ ID NOs: 141-149;
  • the LCDR2 comprises an ammo acid sequence of any of SEQ ID NOs: 99-109, SEQ ID NOs: 129-133, or SEQ ID NOs 151-159;
  • the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 111-121, SEQ ID NOs: 135-139, or SEQ ID NOs: 161-169.
  • the present disclosure provides antibodies directed against ANGPTL7 peptides, or an antigen-binding fragment thereof, that include a VH comprising complementarity determining regions HCDR1, FICDR2, and HCDR3, and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein the LCDRl comprises one of the following ammo acid sequences: (a) RASQX1IX2X3X4LX5 (SEQ ID NO: 86), wherein Xj is G or S; X2 is S, R, or Y; X3 is S, N, or I; X4 is W, D, or Y; Xs is A, G, or N; (b) RSSQSLX1X2SX3X4X5X6YLX7 (SEQ ID NO: 122), wherein Xi is L or V; X 2 is H, Y, or F; X3 is N or D: X 4 is R or
  • RASQSVSX1X2X3X4A (SEQ ID NO: 140), wherein Xj is S, N, or R: X 2 is Y or S; Xs is L or Y; Xr is A or L.
  • the LCDR2 comprises one of the following amino acid sequences: (a) AX1SSLX2S (SEQ ID NO: 98), wherein Xi is A or T; X 2 is Q or P; (b) X1X2SNRX3S (SEQ ID NO: 12.8), wherein Xi is L, K, or E; X2 is G or V; X3 is A or D; or (c) X1ASX2RAT (SEQ ID NO: 150), wherein Xi is D or G; X2 is N, S, or T.
  • the LCDR3 comprises one of the following ammo acid sequences: (a) X1QX2X3X4X5PX6X7 (SEQ ID NO: 110), wherein Xi is L or Q; X2 is A, H, S, or D; X3 is N, F, or Y; X 4 is S, T, or N; X5 is F, Y, or T; Xe is W, L, I, P, or Y; X?
  • the HCDR1 of the anti-ANGPTL7 antibodies of the present disclosure includes an ammo acid sequences of any of SEQ ID NOs: 2- 6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42, or SEQ ID NOs: 75-77
  • the HCDR2 comprises an ammo acid sequence of any of SEQ ID NOs: 8-12, SEQ ID NOs: 22-23, SEQ ID NOs 44-58, or SEQ ID NOs: 79-81
  • the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73, or SEQ ID NOs: 83-85.
  • the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the FICDR2 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 ammo acid sequence of SEQ ID NO: 3; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 9; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 14.
  • the IICDRl 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 HCDRl comprises the ammo acid sequence of SEQ ID NO: 5; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 11; and the HCDR3 comprises the amino acid sequence of SEQ) ID NO: 16.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 6; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 12; and the HCDR3 comprises the ammo acid sequence of SEQ ID NO: 17.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 20.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 19; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 2.2; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 25.
  • the HCDR1 comprises the ammo acid sequence of SEQ ID NO: 20; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 23; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 26.
  • the HCDRl 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 ammo acid sequence of SEQ ID NO: 59.
  • the HCDR1 comprises the amino acid sequence of SEQ ID NO: 29; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 45; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 60.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 30; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 46; and the IICDR3 comprises the amino acid sequence of SEQ ID NO: 61.
  • the HCDRl 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 HCDRl comprises the amino acid sequence of SEQ ID NO: 32
  • the HCDR2 comprises the amino acid sequence of SEQ ID NO: 48
  • the HCDR3 comprises the amino acid sequence of SEQ ID NO: 63.
  • the HCDR1 comprises the amino acid sequence of SEQ ID NO: 33; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 49; and the HCDR3 comprises the ammo acid sequence of SEQ) ID NO: 64.
  • the HCDR1 comprises the ammo 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 HCDRl comprises the ammo acid sequence of SEQ ID NO: 35; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 51; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 66.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 36; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 52; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 67.
  • the HCDRl 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 HCDRl 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 ammo acid sequence of SEQ ID NO: 69.
  • the HCDRl 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 HCDRl comprises the ammo acid sequence of SEQ ID NO: 40; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 56; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 71.
  • the HCDRl 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 HCDRl comprises the ammo acid sequence of SEQ ID NO: 42; the HCDR2 comprises the ammo acid sequence of SEQ ID NO: 58; and the HCDR3 comprises the ammo acid sequence of SEQ ID NO: 73.
  • the HCDRl comprises the ammo 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. In some embodiments, the HCDRl comprises the amino acid sequence of SEQ ID NO; 76; the IICDR2 comprises the ammo acid sequence of SEQ ID NO: 80, and the TICDR3 comprises the ammo acid sequence of SEQ ID NO: 84.
  • the HCDRl comprises the amino acid sequence of SEQ ID NO: 77; the HCDR2 comprises the amino acid sequence of SEQ) ID NO: 81 , and the TICDR3 comprises the amino acid sequence of SEQ ID NO: 85.
  • the LCDRl 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 LCDRl comprises the amino acid sequence of SEQ ID NO: 88; the LCDR2 comprises the ammo 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 ammo acid sequence of SEQ ID NO: 101; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 113.
  • the LCDRl 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 LCDRl 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 LCDRl comprises the ammo 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 LCDRl 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 ammo acid sequence of SEQ ID NO: 117.
  • the LCDRl comprises the amino acid sequence of SEQ ID NO: 94; the LCDR2. comprises the ammo acid sequence of SEQ ID NO: 106; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 118.
  • the LCDRl 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, In some embodiments, the LCDRl comprises the amino acid sequence of SEQ ID NO: 96; the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 108; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, the LCDRl 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 LCDRl 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 LCDRl comprises the amino acid sequence of SEQ ID NO: 124, the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 130; and the LCDR3 comprises the ammo acid sequence of SEQ ID NO: 136.
  • the LCDRl comprises the ammo acid sequence of SEQ ID NO: 125; the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 131; and the LCDR3 comprises the ammo acid sequence of SEQ ID NO: 137.
  • the LCDRl 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 LCDRl 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 ammo acid sequence of SEQ ID NO: 141; the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 151; and the LCDR3 comprises the ammo acid sequence of SEQ ID NO: 161.
  • the LCDRl comprises the ammo acid sequence of SEQ ID NO: 142; the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 152; and the LCDR3 comprises the ammo acid sequence of SEQ ID NO: 162.
  • the LCDRl 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 LCDRl 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 LCDRl 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 LCDRl 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 LCDRl 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 ammo acid sequence of SEQ ID NO: 167.
  • the LCDRl comprises the ammo acid sequence of SEQ ID NO: 148; the LCDR2 comprises the ammo acid sequence of SEQ ID NO: 158, and the LCDR3 comprises the ammo acid sequence of SEQ ID NO: 168. In some embodiments, the LCDRl comprises the amino acid sequence of SEQ ID NO: 149; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 169.
  • the VII of the anti-ANGPTL7 antibodies of the present disclosure includes an ammo acid sequence that is at least 90% identical to any of: (a) SEQ ID NOs: 170-174; (b) SEQ ID NOs: 190-191; (c) SEQ ID NOs: 198-212; or (d) SEQ ID NOs: 258- 260.
  • the VL of the anti-ANGPTL7 antibodies of the present disclosure includes an amino acid sequence that is at least 90% identical to any of: (a) SEQ ID NOs: ISO- 184; (b) SEQ ID NOs: 194-195; (c) SEQ ID NOs: 228-242; or (d) SEQ ID NOs: 264-266.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 170 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 180. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 171 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 181. In some embodiments, the VH comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 172 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 182.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 173 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 183. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 174 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 184. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 190 and the VI., comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 194.
  • 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. In some embodiments, 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. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 199 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 229.
  • the VH comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 200 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 230. In some embodiments, the VH comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 201 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 231.
  • the VH comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 202 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 232, In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 203 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 233. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 204 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 234.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 205 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 235. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 206 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 236. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 207 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 237.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 208 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 238. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 209 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 239.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 210 and the NT comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 240, In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 211 and the VI, comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 241 . In some embodiments, 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.
  • the VH comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 259 and the NT comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 265.
  • the VH comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 260 and the VL comprises an ammo acid sequence that is at least 90% identical to SEQ ID NO: 266.
  • the present disclosure provides anti- ANGPTL7 antibodies comprising various functional characteristics.
  • the anti-ANGPTL7 antibodies described herein bind ANGPTL7 (or a fragment thereof) and increase outflow facility compared to a control.
  • the control is selected from the group consisting of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and ANGPTL7 protein with an isotype control antibody treatment.
  • the anti- ANGPTL7 antibody comprises: (a) a VH comprising an ammo 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 ammo 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 ammo 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 ammo 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 ammo acid sequence that is at least 90%
  • the anti-ANGPTL7 antibody comprises: (a) a VH comprising an ammo 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 ammo 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 ammo 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.
  • 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 ammo 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 ammo 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 ammo 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 ammo acid sequence that is an ammo acid sequence that is
  • 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 ammo 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 ammo 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 ammo acid sequence that is at least 90% identical to SEQ ID NO: 229.
  • the anti-ANGPTL7 antibodies of the present disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and/or a chimeric antibody.
  • the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')2 fragments.
  • the anti-ANGPTL7 antibody is a monospecific antibody.
  • the anti-ANGPTL7 antibody is a bispecific antibody.
  • the anti-ANGPTL7 antibody comprises two or more single-domain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.
  • 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 ammo 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-termmus of the antibody.
  • the anti-A.NGPTL7 antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat an eye disease (e.g., glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells).
  • the composition is suitable for ocular administration.
  • ocular administration comprises injection into vitreous fluid.
  • ocular administration comprises delivering the antibody using a conjunctival insert, a contact lens, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and/or an implant.
  • Embodiments of the present disclosure also include methods of treating glaucoma and/or a disease affecting the optic nerve and/or retinal ganglion cells.
  • the methods include administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure.
  • the pharmaceutical composition is administered ocularly and treats at least one symptom associated with glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells.
  • the at least one symptom associated with glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells comprises eye pain, eye pressure, headaches, rainbow-colored halos around lights, low vision, blurred vision, narrowed vision, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes.
  • administering the pharmaceutical composition attenuates intraocular pressure and/or increases outflow facility in the subject’s eye.
  • the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg/dose to about 100 mg/dose. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg/ml to about 100 mg/ml.
  • Embodiments of the present disclosure also include a polynucleotide encoding any of the anti-ANGPTL7 antibodies of the present disclosure.
  • 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.
  • 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.
  • 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.
  • the polynucleotide encoding an 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
  • the polynucleotide encoding an 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.
  • the polynucleotide encoding an 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.
  • 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
  • the polynucleotide encoding an 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.
  • the present disclosure includes an expression vector comprising any of the polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure.
  • the expression vector is suitable for manufacturing an anti- ANGPTL7 antibody of the present disclosure for delivery of the antibody to a subject.
  • 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 to a subject).
  • the expression vector is an adeno-associated virus (AAV) vector, or comprises an AAV backbone.
  • the expression vector is a lentiviral vector (LV), or comprises an LV backbone.
  • the expression vector is a herpes simplex virus (HSV) vector, or a retrovirus vector.
  • HSV herpes simplex virus
  • the present disclosure also provides a method of administering ocular gene therapy to a subject in need thereof comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-ANGPTL.7 antibody of the present disclosure).
  • the present disclosure also provides a method of treating glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells comprising administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure).
  • administering the pharmaceutical composition treats at least one symptom of glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells.
  • the anti-ANGPTL7 antibodies of the present disclosure bind an epitope from an ANGPTL7 polypeptide having any amino acid sequence of SEQ ID NOs: 370-374, or a variant thereof. In some embodiments, the anti-ANGPTL7 antibodies of the present disclosure bind an epitope from an ANGPTL7 polypeptide with a KD of about 100 nM or lower.
  • FIG. I Representative data demonstrating the levels of ANGTPL7 gene expression relative to control following treatment with dexamethasone for 5 days.
  • FIG 2 Representative data of treatment-induced gene changes from 3 days of ANGPTL7 (50 mg/ml) treatment in human TM and SC cells using an RNAseq panel.
  • FIGS. 3A-3C Representative schematic diagram of 3D-HTM scaffolding technology (Glauconix) used as an ex-vivo human eye tissue model to assess the effects of ANGPTL7 on outflow' facility (FIG. 3A).
  • FIG. 4B includes representative data demonstrating outflow facility for donor 2 treated with vehicle (DMSO), 500nM Dexamethasone, or 25, 50, 150 ng/mL of ANGPTL7.
  • FIGS. 5A-5D Representative ELISA results used to determine antigen positive serum titers of mice immunized with ANGPTL7, according to four different immunization protocols/ cohorts (FIG. 5 A - Cohort 1 ; FIG. 5B - Cohort 2; FIG. 5C - Cohort 3; FIG. 5D - Cohort 4).
  • FIGS. 6A-6I Representative results of ANGPTL7 antibody cross-blocking experiments, including data from a representative heatmap analyzing the ability of the antibodies to block one another for binding to the antigen (FIG. 6A), and representative dendrograms, which progressively group antibodies with similar competition profiles.
  • FIG. 6B includes data from a granular binning network.
  • FIG. 6C includes data from a combined binary dendrogram (color indicates bins in the Community binning network).
  • FIG. 6D includes data from a community binning network.
  • FIG. 6E includes binning data based on affinity for huANGPTL7-his (P62).
  • FIG. 6F includes binning data based on antibody source (hybridoma or phage).
  • FIG. 6G includes binning data based on fibrinogen domain (P60P) binding.
  • FIG. 6H includes binning data based on rabbit ANGPTL7 (p66) binding.
  • FIG. 61 includes binning data based on mouse ANGPTL7 binding.
  • FIGA. 7 Representative results of the effects of anti-ANGPTL7 antibodies on conventional outflow facility using a 3D HTM/HSC Tissue Model (see FIG. 3A).
  • FIGS. 8A-8C Representative data of the effects of dexamethasone-induced ocular hypertension in ANGPTL7 knockout mice.
  • FIG. 8A includes body weight data of mice postimplantation surgery: dexamethasone impaired weight gain in male mice compared to PBS-treated mice, thereby confirming the proper functioning of the dexamethasone osmotic pumps.
  • FIG. 8B includes intraocular pressure (TOP) data of ANGPTL7 WT and ANGPTL7 KO mice dosed with PBS control or Dexamethasone (4 mg/kg/day); osmotic pumps were implanted on day 0.
  • TOP intraocular pressure
  • 8C includes representative data of the changes in IOP of ANGPTL7 WT and ANGPTL7 KO mice implanted with osmotic pumps containing PBS vehicle or dexamethasone (4 mg/kg/day) over 2.8 days. All IOP values were normalized to baseline (day 0) readings.
  • FIGS. 9A-9R Representative data demonstrating the in vivo tolerability of anti- ANGPTL7 antibodies using single intravitreal (IVT) injections in New' Zealand White Rabbits.
  • the anti-ANGPTL7 antibodies indicated were injected at either a 0.5 mg dose (FIGS. 9C, 9D, 9G, 9H, 9K, 91.., 90, 9P) or a 2.0 mg dose (FIGS. 9E, 9F, 91, 9J, 9M, 9N, 9Q, 9R) in the right eye (OD), or with a corresponding vehicle dose in the left eye (OS).
  • FIGS. 9A and 9B include data from controls at 2 mg doses).
  • Intraocular pressure (TOP) measurements FIGS.
  • FIGS. 10A-10C Representative pharmacokinetic (PK) data for ANGPTL7 antibody, ATX-P-424, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle ( FIG 10A), changes in IOP compared to baseline (FIG. 10B); and total ocular examination scores (OE) (FIG. 10C).
  • IOP intraocular pressure
  • FIGS. 11A-11C Representative pharmacokinetic (PK) data for ANGPTL7 antibody, ATX-P-439, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle (FIG 1 1 A), changes in IOP compared to baseline (FIG. 1 IB); and total ocular examination scores (OE) (FIG. 11 C).
  • IOP intraocular pressure
  • OE total ocular examination scores
  • FIGS. 12A-12C Representative pharmacokinetic (PK) data for ANGPTL7 antibody, ATX-P-448, including intraocular pressure (IOP) measurements at 0.5 mg or 2.0 mg (OU) doses compared to vehicle (FIG. 12A); changes in IOP compared to baseline (FIG. 12B); and total ocular examination scores (OE) (FIG. 12C).
  • FIGS. 13A-13 Representative data demonstrating the in vivo tolerability of anti- ANGPTL7 antibodies using single intravitreal (IVT) injections in African Green Monkeys. Data includes absolute IOP values at baseline (day 3) and on day 10, 6 hours post topical administration of saline and Latanoprost (FIG.
  • FIGS. 14A-14H Representative IOP measurements (FIGS. 14A, 14C, 14E, and 14G) and changes in IOP (FIGS. 14B, 14D, 14F, and 14H) in African Green Monkeys dosed with 2 mg of the indicated anti-ANGPTL7 antibody compared to an isotype control (BTX-330) and a single vehicle eye.
  • FIG. 15 Representative clinical scores of ocular examinations (OE) across all the dosed groups in FIGS. 14A-14H.
  • Embodiments of the present disclosure relate to the treatment and/or prevention of glaucoma and other ocular diseases affecting the optic nerve and retinal ganglion cells.
  • the present disclosure provides novel therapeutic antibodies that target angiopoietin- related protein 7 (ANGPTL7) as a means for reducing intraocular pressure (IOP) and/or increasing outflow facility’, thereby’ preventing optic nerve damage and/or restoring vision.
  • IOP intraocular pressure
  • Angiopoietin-like proteins are a family’ of proteins that have structural similarity to angiopoietin proteins. Seven proteins have been initially’ grouped into this family’ (ANGPTL 1-7), and more recently, another protein called ANGPTL8 has been identified. ANGPTL proteins have an amino-terminal coiled-coil domain as well as a carboxyl-terminal fibrinogen-like domain, except ANGPTL8, which lacks the later domain.
  • ANGPTL proteins are not known to bind tyrosine kinase receptors such as Tie 1 and Tie 2, distinguishing them from angiopoietin proteins, ANGPTL proteins have been shown to play different physiological roles in metabolism, inflammation and cancer. Increasing evidence is connecting these proteins to obesity and insulin resistance.
  • ANGPTL2 for example, has been shown to associate with adiposity and insulin resistance as well as the development of type 2 diabetes.
  • ANGPTL3, 4, and 8 have been shown to play a major role in regulating lipid metabolism through their inhibition of lipoprotein lipase.
  • ANGPTL6 has been shown to be higher in subjects with metabolic syndrome and to positively associate with HDL level.
  • the levels of ANGPTL8 has been shown to be higher in obese and diabetic subjects and to positively associate with insulin resistance and fasting blood glucose in non-diabetic subjects.
  • ANGPTL7 is a poorly studied member of the ANGPTL protein family that has been initially discovered in the stromal layer of the cornea. Levels of ANGPTL7 have been shown to be elevated in glaucoma and its overexpression increases the collagen expression level while, its induction by glucocorticoids caused the up-regulation of important glaucoma- related proteins including fibronectin, niyocilin and MMP1. These data suggest that ANGPTL7 may coordinate the trabecular meshwork’s extracellular matrix and its response to steroids. Additionally, ANGPTL7 has been associated with various cancers potentially through its interaction with the WNTAbeta-catenin signaling pathway. Currently, there are no therapeutic approaches that target ANGPTL7.
  • Glaucoma is a leading cause of worldwide irreversible vision loss, characterized by progressive optic neuropathy.
  • POAG primary open-angle glaucoma
  • IOP intraocular pressure
  • DEX dexamethasone
  • the pathogenesis of POAG can be deduced from the mechanisms underlying DEX-induced ocular hypertension. Understanding the DEX-induced molecular mechanisms may assist in developing therapies for glucocorticoid-induced glaucoma and POAG.
  • aqueous humor AH
  • actin cytoskeletal rearrangement of the trabecular meshwork (TM) forming cross-linked actin networks is a crucial contributor to this increased resistance.
  • TM trabecular meshwork
  • ECM extracellular matrix
  • ANGPTL7 protein-altering variants exert a strong protective effect on glaucoma and suggested ANGPTL7 as a therapeutic target for glaucoma.
  • ANGPTL7 may play a vital role in modulating TM’s ECM and regulating IOP.
  • composition “consisting essentially of’ recited elements may contain an unrecited contaminant at a level such that, though present, the contaminant does not alter the function of the recited composition as compared to a pure composition, i.e., a composition “consisting of’ the recited components.
  • one or more refers to a number higher than one.
  • the term “one or more” encompasses 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, 100 or more, or an even greater number.
  • the higher number can be 10,000, 1,000, 100, 50, etc.
  • the higher number can be approximately 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).
  • immunoglobulin refers to a protein that is found in blood or other bodily fluids of vertebrates, which is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
  • an immunoglobulin or antibody is a protein that comprises at least one complementarity determining region (CDR).
  • CDRs form the “hypervariable region” of an antibody, which is responsible for antigen binding (discussed further below).
  • a whole 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 of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CHI, CH?., and CH?) regions, and each light chain contains one N-terminal variable (Vr.) region and one C -terminal constant (CL) region.
  • the light chains of antibodies can be assigned to one of two distinct types, either kappa (K) or lambda (X), based upon the amino acid sequences of their constant domains.
  • K kappa
  • X lambda
  • each light chain is linked to a heavy chain by disulfide bonds, and the two heavy chains are linked to each other by disulfide bonds.
  • the light chain variable region is aligned with the variable region of the heavy chain
  • the light chain constant region is aligned with the first constant region of the heavy chain.
  • the remaining constant regions of the heavy chains are aligned with each other.
  • variable regions of each pair of light and heavy chains form the antigen binding site of an antibody.
  • the VH and Vi. regions have the same general structure, with each region comprising four framework (FW or FR) regions.
  • framework region refers to the relatively conserved amino acid sequences within the variable region which are located between the CDRs.
  • the framework regions form the p sheets that provide the structural framework of the variable region (see, e.g., C. A. Janeway et al. (eds.), Immunobiology-, 5th Ed., Garland Publishing, New York, N.Y. (2001)).
  • the framework regions are connected by three CDRs.
  • the three CDRs known as CDR1 , CDR2, and CDR3, form the “hypervariable region” of an antibody, which is responsible for antigen binding.
  • the CDRs form loops connecting, and in some cases comprising part of, the beta-sheet structure formed by the framework regions.
  • the constant regions of the light and heavy chains are not directly involved in binding of the antibody to an antigen, the constant regions can influence the orientation of the variable regions.
  • the constant regions also exhibit various effector functions, such as participation in antibody-dependent complement- mediated lysis or antibody-dependent cellular toxicity via interactions with effector molecules and cells.
  • an antibody or other entity e.g., antigen binding domain
  • affinity which is substantially higher means affinity that is high enough to enable detection of an antigen or epitope which is distinguished from entities using a desired assay or measurement apparatus.
  • affinity having a binding constant (Ka) of at least 10 7 M -1 , etc.).
  • an antibody is capable of binding different antigens so long as the different antigens comprise that particular epitope.
  • homologous proteins from different species may comprise the same epitope.
  • fragment of an antibody refers 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 the antibody described herein is within the scope of the present disclosure.
  • the antibody fragment desirably comprises, for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof.
  • antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a domain antibody (dAb), which is an antibody single variable region domain (VH or VL) polypeptide that specifically binds antigen.
  • a Fab fragment which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains
  • the term “monoclonal antibody,” as used herein, refers to an antibody produced by a single clone of B lymphocytes that is directed against a single epitope on an antigen.
  • Monoclonal antibodies typically are produced using hybridoma. technology, as first described in Kohler and Milstein, Eur. J. Immunol., 5: 511-519 (1976).
  • Monoclonal antibodies may also be produced using recombinant DNA methods (see, e.g., U.S. Patent 4,816,567), isolated from phage display antibody libraries (see, e.g., Clackson et al. Nature, 352: 624-628 (1991 )); and Marks et al., J. Mol.
  • polyclonal antibodies are antibodies that are secreted by different B cell lineages within an animal. Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen.
  • nucleic acid refers to a polymer or oligomer 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)).
  • the 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 polymers or oligomers may be heterogenous or homogenous in composition, may be isolated from naturally occurring sources, or may be artificially or synthetically produced.
  • the nucleic acids may be DNA or RNA, or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states.
  • a nucleic acid or nucleic acid sequence comprises other kinds of nucleic acid structures such as, for instance, a DNA'RNA helix, peptide nucleic acid (PNA), morpholino nucleic acid (see, e.g., Braasch and Corey, Biochemistry, 4503-4510 (2002) and U.S. Patent 5,034,506), locked nucleic acid (LNA; see Wahlestedt et al., Proc. Natl. Acad. Set. U.S.A., 97: 5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, J. Am. Chem.
  • nucleic acid and “nucleic acid sequence” may also encompass a chain comprising nonnatural nucleotides, modified nucleotides, and/or non-nucleotide building blocks that can exhibit the same function as natural nucleotides (e.g., “nucleotide analogs”).
  • peptide refers to a polymeric form of ammo acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones.
  • 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, without limitation, single- and double-stranded nucleic acids.
  • nucleic acid also includes DNA as described above that contains one or more modified bases.
  • nucleic acid DNA with a backbone modified for stability or for other reasons is a “nucleic acid.”
  • nucleic acid as it is used herein embraces such chemically, enzymatically, or metabolically modified forms of nucleic acids, as well as the chemical forms of DNA characteristic of viruses and cells, including for example, simple and complex cells.
  • oligonucleotide or “polynucleotide” or “nucleotide” or “nucleic acid” refer to a molecule having two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and usually more than ten. The exact size will depend on many factors, which in turn depends on the ultimate function or use of the oligonucleotide.
  • the oligonucleotide may be generated in any manner, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof.
  • Typical deoxyribonucleotides for DNA are thymine, adenine, cytosine, and guanine.
  • Typical ribonucleotides for RNA are uracil, adenine, cytosine, and guanine.
  • complementarity refers to nucleotides (e.g., 1 nucleotide) or polynucleotides (e.g., a sequence of nucleotides) related by the base-pairing rules.
  • sequence 5’-A-G-T-3’ is complementary to the sequence 3'-T-C-A-5'.
  • Complementarity may be “partial,” in which only some of the nucleic acids’ bases are matched according to the base pairing rules. Or, there may be “complete” or “total” complementarity between the nucleic acids.
  • the degree of complementarity between nucleic acid strands affects the efficiency and strength of hybridization between nucleic acid strands. This is of particular importance in amplification reactions and in detection methods that depend upon binding between nucleic acids.
  • the term “gene” refers to a nucleic acid (e.g., DNA or RNA) sequence that comprises coding sequences necessary for the production of an RNA, or of a polypeptide or its precursor, A functional polypeptide can be encoded by a full-length coding sequence or by any portion of the coding sequence as long as the desired activity or functional properties (e.g., enzymatic activity, ligand binding, signal transduction, etc.) of the polypeptide are retained.
  • portion when used in reference to a gene refers to fragments of that gene. The fragments may range in size from a few nucleotides to the entire gene sequence minus one nucleotide. Thus, “a nucleotide comprising at least a portion of a “gene” may comprise fragments of the gene or the entire gene.
  • the term “gene” also encompasses the coding regions of a structural gene and includes sequences located adjacent to the coding region on both the 5’ and 3‘ ends, e.g., for a distance of about 1 kb on either end, such that the gene corresponds to the length of the full-length mRNA (e.g., comprising coding, regulatory', structural and other sequences).
  • the sequences that are located 5' of the coding region and that are present on the mRNA are referred to as 5’ non- translated or untranslated sequences.
  • the sequences that are located 3' or downstream of the coding region and that are present on the mRN A are referred to as 3' non-translated or 3' untranslated sequences.
  • genomic form or clone of a gene contains the coding region interrupted with noncoding sequences termed “introns” or “intervening regions” or “intervening sequences.”
  • Introns are segments of a gene that are transcribed into nuclear RNA (hnRNA); introns may contain regulator ⁇ ' elements such as enhancers. Introns are removed or “spliced out” from the nuclear or primary transcript: introns therefore are absent in the messenger RNA (mRNA) transcript.
  • mRNA messenger RNA
  • genomic forms of a gene may also include sequences located on both the 5' and 3' ends of the sequences that are present on the RNA transcript. These sequences are referred to as “flanking” sequences or regions (these flanking sequences are located 5' or 3' to the non-translated sequences present on the mRNA transcript).
  • the 5' flanking region may contain regulator ⁇ ' sequences such as promoters and enhancers that control or influence the transcription of the gene.
  • the 3* flanking region may contain sequences that direct the termination of transcription, posttranscriptional cleavage, and polyadenylation.
  • wild-type when made in reference to a gene refers to a gene that has the characteristics of a gene isolated from a naturally occurring source.
  • wild-type when made in reference to a gene product refers to a gene product that has the characteristics of a gene product isolated from a naturally occurring source.
  • wild-type when made in reference to a protein refers to a protein that has the characteristics of a naturally occurring protein.
  • naturally-occurring as applied to an object refers to the fact that an object can be found in nature.
  • a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature, and which has not been intentionally modified by the hand of a person in the laboratory is naturally-occurring.
  • a wild-type gene is often that gene or allele that is most frequently observed in a population and is thus arbitrarily designated the “normal” or “wild-type” form of the gene.
  • the term “modified” or “mutant” when made in reference to a gene or to a gene product refers, respectively, to a gene or to a gene product that displays modifications in sequence and/or functional properties (e.g., altered characteristics) when compared to the wild-type gene or gene product.
  • naturally-occurring mutants can be isolated; these are identified by the fact that they have altered characteristics when compared to the wild-type gene or gene product.
  • allele refers to a variation of a gene; the variations include but are not limited to variants and mutants, polymorphic loci, and single nucleotide polymorphic loci, frameshift, and splice mutations. An allele may occur naturally in a population, or it might arise during the lifetime of any particular individual of the population.
  • variant and mutant when used in reference to a nucleotide sequence refer to a nucleic acid sequence that differs by one or more nucleotides from another, usually related, nucleotide acid sequence.
  • a “variation” is a difference between two different nucleotide sequences; typically, one sequence is a reference sequence.
  • 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 entail, for example, antibody production and/or the activation of immune effector cells.
  • An antigen in the context of the disclosure can comprise any subunit, fragment, or epitope of any proteinaceous or non-proteinaceous (e.g., carbohydrate or lipid) molecule that provokes an immune response in a mammal.
  • epitope refers to a sequence of an antigen that is recognized by an antibody or an antigen receptor.
  • an epitope is a region of an antigen that is specifically bound by an antibody.
  • an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups.
  • an epitope may have specific three- dimensional structural characteristics (e.g,, a “conformational” epitope) and/or specific charge characteristics.
  • the antigen can be a protein or peptide of viral, bacterial, parasitic, fungal, protozoan, prion, cellular, or extracellular origin, which provokes an immune response in a mammal, preferably leading to protective immunity.
  • a “pharmaceutically acceptable carrier” as used herein generally refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • composition generally refers to a preparation which is in such form as to permit the biological activity of an active ingredient (e.g., an anti- ANGPTL7 antibody, an antibody conjugate, a fusion protein, or a polymeric formulation) contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • an active ingredient e.g., an anti- ANGPTL7 antibody, an antibody conjugate, a fusion protein, or a polymeric formulation
  • treatment and grammatical variations thereof such as “treat” or “treating” generally refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • anti-ANGPTL7 antibodies of the present disclosure or other compositions that include an anti-ANGPTL7 antibody of the present disclosure are used to delay development of a disease or to slow the progression of a disease.
  • 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., in the eye (e.g., the vitreous)) or in vitro.
  • a substance e.g., an anti-ANGPTL7 antibody, an antibody conjugate, a fusion protein (e.g., a Fab fusion protein), or a polymeric formulation
  • an “effective amount” of an agent e.g., a pharmaceutical formulation, as used herein generally refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • An “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human. A “subject” may be a “patient.” Anti-ANGPTL7 Antibodies
  • Embodiments of the present disclosure relate to the treatment and/or prevention of glaucoma and other ocular diseases affecting the optic nerve and retinal ganglion cells.
  • the present disclosure provides novel therapeutic antibodies that target angiopoietin- related protein 7 (ANGPTL7) as a means for reducing intraocular pressure (IOP) and/or increasing outflow facility, thereby preventing optic nerve damage and/or restoring vision.
  • ANGPTL7 angiopoietin- related protein 7
  • embodiments of the present disclosure include an antibody, or an antigen binding fragment thereof, which specifically binds human Angiopoietin-Like Protein 7 (ANGPTL7), optionally wherein said human ANGPTL7 is a polypeptide which comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 370 to 374.
  • ANGPTL7 is a polypeptide which comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 370 to 374.
  • the antibody, or an antigen binding fragment thereof exhibits any one or more the following functional characteristics: increases outflow facility compared to a control when administered to the eye of a subject, optionally wherein the control is vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, or ANGPTL7 protein with an isotype control antibody treatment; and/or binds to ANGPTL7 with a KD of about I OOnM or lower; 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 the sequences of which are provided in Table 11; and/or competes for binding to ANGPTL7 with an antibody comprising the VH and VL sequences of any one of the exemplary’ antibodies the sequences of which are provided in Table 11.
  • the antibody, or an antigen binding fragment thereof is monoclonal, optionally recombinant. In some embodiments, the antibody, or an antigen binding fragment thereof, is human, humanized, or chimeric,
  • the antibody, or an antigen binding fragment thereof is a full length antibody, a single chain antibody, a single chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), a Fab-C, a Fab’-SH, a (Fab’)2, a singledomain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.
  • an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.
  • the antibody, or an antigen binding fragment thereof is conjugated to at least one additional moiety, optionally selected from: an antigen binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human ANGPTL7, preferably wherein said target is expressed in the human eye; a therapeutic or cytotoxic moiety; a detection moiety; a purification moiety; a half-life extension moiety, optionally a polypeptide that is at least 20 ammo acids in length and comprises any combination of G, A, S T, E, and P residue, which polypeptide is conjugated to the C- or N- terminus of the antibody.
  • an antigen binding moiety such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human ANGPTL7, preferably wherein said target is expressed in the human eye
  • a therapeutic or cytotoxic moiety such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target
  • the antibody, or an antigen binding fragment thereof is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided in Table I I, 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 the sequences of which are provided in Table 11, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably wherein variation is not permitted in the HCDRs or LCDRs; and/or all six CDRs of any of the exemplary’ antibodies exemplary antibodies the sequences of which are provided in Table 11; and/or the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 11; and/or the full length heavy chain (VH + constant) sequence of any one of the exemplary antibodies the sequences of which are provided in Table
  • Embodiments of the present disclosure also include a polynucleotide encoding an antibody, or an antigen binding fragment thereof, of any of the preceding paragraphs, optionally wherein said polynucleotide comprises or consists of a nucleic acid sequence having at least 70%, 80%, 90% or 100% identity to a nucleic acid sequence of any one of the exemplary? antibodies the sequences of which are provided in Table 11.
  • Embodiments of the present disclosure also include an expression vector comprising the polynucleotide of the preceding paragraph, which is optionally an adeno-associated virus (AAV) vector, a lenti viral (LV) vector, a herpes simplex virus (HSV) vector, or a retrovirus vector.
  • AAV adeno-associated virus
  • LV lenti viral
  • HSV herpes simplex virus
  • 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: at least one pharmaceutically acceptable carrier, diluent or preservative; and/or at least one additional active ingredient.
  • the pharmaceutical composition is suitable for ocular administration to a subject, optionally by delivery using a conjunctival insert, a contact lens, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and/or an implant, preferably by injection into the vitreous fluid.
  • Embodiments of the present disclosure also include the antibody, or an antigen binding fragment thereof, the polynucleotide, the vector, or the compositions of any of the preceding paragraphs, for use as a medicament, optionally for use in a method of treating a disease of the eye in a subject.
  • the disease is characterized by increased intraocular pressure and/or reduced outflow facility in the eye of the subject.
  • the method comprises ocular administration of the antibody, preferably by injection into the vitreous fluid, and wherein said administration preferably relieves at least one symptom in the subject selected from eye pain, eye pressure, headaches, rainbow-colored halos around lights, low vision, blurred vision, narrowed vision, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes.
  • the disease is glaucoma and/or a disease affecting the optic nerve or retinal ganglion cells, optionally wherein said glaucoma is primary or glucocorticoid-induced glaucoma.
  • anti-ANGPTL7 antibodies were generated, and their structural and functional properties were elucidated. Based on these data, embodiments of the present disclosure include anti-ANGPTL7 antibodies, or antigen-binding fragments thereof, that are comprised of a heavy chain variable region (VH) comprising complementarity' determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3.
  • VH heavy chain variable region
  • CDRs complementarity' determining regions
  • VL light chain variable region
  • the HCDR1 comprises one of the following amino acid sequences: (a) X1YX2IX3 (SEQ ID NO: 1), wlierem Xi is S or D; X 2 is G or Y; Xs is S or H; (b) TSGVGVG (SEQ ID NO: 18); (c) X1X2X3MX4 (SEQ ID NO: 27), wherein Xi is V, S, D, or T; X2 is Y, H, or F; X3 is D, G, S, or A; X 4 is H, S, or N; or (d) SX1SX2YWX3 (SEQ ID NO: 74), wherein Xi is S or G; X 2 is S or Y; X3 is G or S.
  • the HCDR2 comprises one of the following amino acid sequences: (a) WIXiX2X3X4GX5TX6YAQX7XsX9G(SEQ ID NO: 7), wherein Xi is S, I, or N; X2 is A or P; X3 is Y or N; X4 is N or T; X5 is N or A, Xe is N or K; X7 is N or K; Xg is L or F; X9 is R or Q; (b) LIYWNDDKXiYSPSLKS (SEQ ID NO: 21), wherein Xi is R or Q; (c) X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15G (SEQ ID NO: 43), wherein Xi is G, T, S, A, V, H, or I, X2 is I or M; X3 is D, N, T, S, or G; X 4
  • the HCDR3 comprises one of the following ammo acid sequences: (a) SEQ ID NOs: 13-17; (b) X1X2X3X4X5X6FFDX7 (SEQ ID NO: 24) wherein Xi is S, D, or N; X2 is Y or P; X3 is G or D; X 4 is D or Y; Xs is Y or G; X 6 is W or D; X7 is L or Y; (c) SEQ ID NOs: 59-73; or (d) X1X2X3X4GX5X6X7X8X9Y (SEQ ID NO: 82) wherein Xi is Q or A; X 2 is Y or K; X3 is I or W; X4 is S or E; X5 is T or D; Xg is E or Y; X7 is Y or F; Xg is F or D; X9 is Q or Y.
  • anti-ANGPTL7 antibodies of the present disclosure include an LCDRl comprising an amino acid sequence of any of SEQ ID NOs: 87-97, SEQ ID NOs: 123-127, or SEQ ID NOs: 141 -149; the LCDR2 comprises an ammo acid sequence of any of SEQ ID NOs: 99-109, SEQ ID NOs: 129-133, or SEQ ID NOs 151-159; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 111-121, SEQ ID NOs: 135-139, or SEQ ID NOs: 161-169.
  • the present disclosure provides anti-ANGPTL7 antibodies, or antigen-binding fragments thereof, that include a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementarity determining regions LCDRl, LCDR2, and LCDR3.
  • the LCDRl comprises one of the following amino acid sequences: (a) RASQX1IX2X3X4LX5 (SEQ ID NO: 86), wherein Xi is G or S; X2 is S, R, or Y; X3 is S, N, or I; X4 is W, D, or Y; X5 is A, G, or N; (b) RSSQSLX 1X2SX: cXrX.vXA’LX" (SEQ ID NO: 122), wherein Xi is L or V; X2 is H, Y, or F; X 3 is N or D; X4 is R or G; X5 is Y or N; Xg is N or T; X7 is D or N; or (c) RASQSVSX1X2X3X4A (SEQ ID NO: 140), wherein Xi is S, N, or R; X 2 is Y or S; X3 is L or
  • the LCDR2 comprises one of the following amino acid sequences: (a) AX1SSLX2S (SEQ ID NO: 98), wherein Xi is A or T; X 2 is Q or P; (b) X1X2SNRX3S (SEQ ID NO: 128), wherein Xi is L, K, or E; X2 is G or V; X3 is A or D; or (c) X1ASX2RAT (SEQ ID NO: 150), wherein Xi is D or G; X 2 is N, S, or T.
  • the LCDR3 comprises one of the following amino acid sequences: (a) X1QX2X3X4X5PX6X7 (SEQ ID NO: 1 10), wherein Xi is L or Q; X 2 is A, H, S, or D; X3 is N, F, or Y; X4 is S, T, or N; X5 is F, Y, or T; Xg is W, L, I, P, or Y; X7 is T or Y; (b) MQXi X 2X3X4PX5T (SEQ ID NO: 134), wherein Xi is T or G; X 2 is L or T, X3 is Q or H; X4 is T or W, X5 is Y or W; or (c) QQX1X2X3X4X5X6T (SEQ ID NO: 160), wherein Xi is R, Y, or G; X2 is S, G, or Q, X
  • anti-ANGPTL7 antibodies of the present disclosure include an 1ICDR1 comprising an ammo acid sequence of any of SEQ ID NOs: 2-6, SEQ ID NOs: 19-20, SEQ ID NOs: 28-42, or SEQ ID NOs: 75-77;
  • the HCDR2 comprises an ammo acid sequence of any of SEQ ID NOs: 8-12, SEQ ID NOs: 22-23, SEQ ID NOs 44-58, or SEQ ID NOs: 79-81;
  • the HCDR3 comprises an ammo acid sequence of any of SEQ ID NOs: 13-17, SEQ ID NOs: 25-26, SEQ ID NOs: 59-73, or SEQ ID NOs: 83-85.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 2, the IICDR2 of SEQ ID NO: 8, and the HCDR3 of SEQ ID NO: 13.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 3, the HCDR2 of SEQ ID NO: 9, and the HCDR3 of SEQ ID NO: 14.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 10, and the HCDR3 of SEQ ID NO: 15.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 5, the HCDR2 of SEQ ID NO: 11, and the HCDR3 of SEQ ID NO: 16. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 6, the HCDR2 of SEQ ID NO: 12, and the HCDR3 of SEQ ID NO: 17. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 7, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, and the HCDR3 of SEQ ID NO: 20.
  • an anti-ANGPTL7 antibody comprises the HCDR1 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.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 20, the HCDR2 of SEQ ID NO: 23, and the HCDR3 of SEQ ID NO: 26.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 28, the HCDR2 of SEQ ID NO: 44, and the HCDR3 of SEQ ID NO: 59.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 29, the I ICDR2 of SEQ ID NO: 45, and the HCDR3 of SEQ ID NO: 60. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 30, the HCDR2 of SEQ ID NO: 46, and the HCDR3 of SEQ ID NO: 61. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 31 , the IICDR2 of SEQ ID NO: 47, and the HCDR3 of SEQ ID NO: 62.
  • an anti- ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 32, the HCDR2 of SEQ ID NO: 48, and the HCDR3 of SEQ ID NO: 63.
  • an anti-ANGPTL7 antibody comprises the HCDR 1 of SEQ ID NO: 33, the I1CDR2 of SEQ ID NO: 49, and the IICDR3 of SEQ ID NO: 64.
  • an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 34, the HCDR2 of SEQ ID NO: 50, and the HCDR3 of SEQ ID NO: 65.
  • an anti- ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 35, the HCDR2 of SEQ ID NO: 51, and the HCDR3 of SEQ ID NO: 66. In some embodiments, an anti- ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 36, the HCDR2 of SEQ ID NO: 52, and the HCDR3 of SEQ ID NO: 67. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 37, the HCDR2 of SEQ ID NO: 53, and the HCDR3 of SEQ ID NO: 68.
  • an anti-ANGPTL7 antibody comprises the HCDR 1 of SEQ ID NO: 38, the HCDR2 of SEQ ID NO: 54, and the HCDR3 of SEQ ID NO: 69. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDR1 of SEQ ID NO: 39, the HCDR2 of SEQ ID NO: 55, and the HCDR3 of SEQ ID NO: 70. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 40, the HCDR2 of SEQ ID NO: 56, and the HCDR3 of SEQ ID NO: 71.
  • an anti-ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 41, the HCDR2 of SEQ ID NO: 57, and the HCDR3 of SEQ ID NO: 72. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 42, the HCDR2 of SEQ ID NO: 58, and the HCDR3 of SEQ ID NO: 73. In some embodiments, an anti-ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 75, the HCDR2 of SEQ ID NO: 79, and the HCDR3 of SEQ ID NO: 83.
  • an anti-ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 76, the HCDR2 of SEQ ID NO: 80, and the HCDR3 of SEQ ID NO: 84. In some embodiments, an anti- ANGPTL7 antibody comprises the HCDRl of SEQ ID NO: 77, the HCDR2 of SEQ ID NO: 81 and the HCDR3 of SEQ ID NO: 85.
  • an anti-ANGPTE7 antibody comprises the LCDR1 of SEQ ID NO: 87, the LCDR2 of SEQ ID NO: 99, and the LCDR3 of SEQ ID NO: 111.
  • an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 88, the LCDR2 of SEQ ID NO: 100, and the LCDR3 of SEQ ID NO: 112.
  • an anti- ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 89, the LCDR2 of SEQ ID NO: 101 , and the LCDR3 of SEQ ID NO: 113.
  • an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 90, the LCDR2 of SEQ ID NO: 102, and the LCDR3 of SEQ ID NO: 114. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 91 , the LCDR2 of SEQ ID NO: 103, and the LCDR3 of SEQ ID NO: 115. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 92, the LCDR2 of SEQ ID NO: 104, and the LCDR3 of SEQ ID NO: 116.
  • an anti- ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 93, the LCDR2 of SEQ ID NO: 105, and the LCDR3 of SEQ ID NO: 117. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 94, the LCDR2 of SEQ ID NO: 106, and the LCDR3 of SEQ ID NO: 118. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 95, the LCDR2 of SEQ ID NO: 107, and the LCDR3 of SEQ ID NO: 119.
  • an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 96, the LCDR2 of SEQ ID NO: 108, and the LCDR3 of SEQ ID NO: 120. In some embodiments, an anti- ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 97, the LCDR2 of SEQ ID NO: 109, and the LCDR3 of SEQ ID NO: 121. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 123, the LCDR2 of SEQ ID NO: 129, and the LCDR3 of SEQ ID NO: 135.
  • an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 124, the LCDR2 of SEQ ID NO: 130, and the LCDR3 of SEQ ID NO: 136. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 125, the HCDR2 of SEQ ID NO: 131, and the LCDR3 of SEQ ID NO: 137. In some embodiments, an anti- ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 126, the LCDR2 of SEQ ID NO: 132, and the LCDR3 of SEQ ID NO: 138.
  • an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 127, the LCDR2 of SEQ ID NO: 133, and the LCDR3 of SEQ ID NO: 139. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 141 , the LCDR2 of SEQ ID NO: 151 , and the LCDR3 of SEQ ID NO: 161 . In some embodiments, an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 142, the LCDR2 of SEQ ID NO: 152, and the LCDR3 of SEQ ID NO: 162.
  • an anti- ANGPTL7 antibody comprises the LCDR 1 of SEQ ID NO: 143, the LCDR2 of SEQ ID NO: 153, and the LCDR3 of SEQ ID NO: 163.
  • an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 144, the LCDR2 of SEQ ID NO: 154, and the LCDR3 of SEQ ID NO: 164.
  • an anti-ANGPTL7 antibody comprises the LCDR1 of SEQ ID NO: 145, the LCDR2 of SEQ ID NO: 155, and the LCDR3 SEQ ID NO: 165.
  • an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 146, the LCDR2 of SEQ ID NO: 156, and the LCDR3 of SEQ ID NO: 166. In some embodiments, an anti- ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 147, the LCDR2 of SEQ ID NO: 157, and the LCDR3 of SEQ ID NO: 167. In some embodiments, an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 148, the LCDR2 of SEQ ID NO: 158, and the LCDR3 of SEQ ID NO: 168.
  • an anti-ANGPTL7 antibody comprises the LCDRl of SEQ ID NO: 149, the LCDR2 of SEQ ID NO: 159, and the LCDR3 of SEQ ID NO: 169.
  • the VH of the anti-ANGPTL7 antibodies of the present disclosure includes an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any of: (a) SEQ ID NOs: 170-174; (b) SEQ ID NOs: 190-191; (c) SEQ ID NOs: 198-212; or (d) SEQ ID NOs: 258-260.
  • the VL of the anti-ANGPTL7 antibodies of the present disclosure includes an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any of: (a) SEQ ID NOs: 180-184; (b) SEQ ID NOs: 194-195; (c) SEQ ID NOs: 228-242; or (d) SEQ ID NOs: 264-266.
  • ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any of: (a) SEQ ID NOs: 180-184; (b) SEQ ID NOs: 194-195; (c) SEQ ID NOs: 228
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 170 and the VL comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 171 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 181.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 172 and the VL comprises an ammo 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,
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 173 and the VL comprises an amino
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 174 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 184.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 190 and the VL comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 191 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 195.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 198 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 228.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least. 98%, at least 99%, or 100% identical) to SEQ ID NO: 199 and the VL comprises an ammo 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.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 200 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 230.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 201 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 231.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 202 and the VL comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 203 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 233.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 204 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 234.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least. 98%, at least 99%, or 100% identical) to SEQ ID NO: 205 and the VL comprises an ammo 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.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 206 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 236.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 207 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 237.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 208 and the VL comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 209 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 239.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 210 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 240.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least. 98%, at least 99%, or 100% identical) to SEQ ID NO: 211 and the VL comprises an ammo 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 .
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 212 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 242.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 258 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 264.
  • the VH comprises an ammo acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 259 and the VL comprises an ammo 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.
  • the VH comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 260 and the VL comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 266.
  • Nucleic acid or amino acid sequence “identity,” as described herein, can be determined by comparing a nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence.
  • a number of mathematical algorithms for obtaining the optimal alignment and calculating identity between two or more sequences are known and incorporated into a number of available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and ammo acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, and later versions thereof) and FASTA programs (e.g., FASTA3x, FASTM, and SSEARCH) (for sequence alignment and sequence similarity searches).
  • Sequence alignment algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990), Beigert. et al., Proc. Nail. Acad. Set. 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(1'1): 3389-3402 (1997), and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).
  • one or more ammo acids of the aforementioned anti-ANGPTL7 antibodies, or antigen fragments thereof can be replaced or substituted with a different ammo acid.
  • An amino acid “replacement” or “substitution” refers to the replacement of one amino acid at a given position or residue by another ammo acid at the same position or residue within a polypeptide sequence.
  • Ammo acids are broadly grouped as “aromatic” or “aliphatic.”
  • An aromatic amino acid includes an aromatic ring.
  • 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 grouped as “aliphatic.”
  • Examples of “aliphatic” ammo acids include glycine (G or Gly), alanine (A or Ala), valine (V or Vai), leucine (L or Leu), isoleucine (I or He), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine (C or Cys), proline (P or Pro), glutamic acid (E or Giu), aspartic acid (A or Asp), asparagine (N or Asn), glutamine (Q or Gin), lysine (K or Lys), and arginine (R or Arg).
  • Aliphatic amino acids may be sub-divided into four sub-groups.
  • the “large aliphatic non-polar sub-group” consists of valine, leucine, and isoleucme.
  • the “aliphatic slightly- polar sub-group” consists of methionine, serine, threonine, and cysteine.
  • the “aliphatic polar/charged sub-group” consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine.
  • the “small-residue sub-group” consists of glycine and alanine.
  • the group of charged/polar amino acids may be sub-divided into three sub-groups: the “positively-charged subgroup” consisting of lysine and arginine, the “negatively-charged sub-group” consisting of glutamic acid and aspartic acid, and the “polar sub-group” consisting of asparagine and glutamine.
  • Aromatic amino acids may be sub-divided into two sub-groups: the “nitrogen ring sub-group” consisting of histidine and tryptophan and the “phenyl sub-group” consisting of phenylalanine and tyrosine.
  • ammo acid replacement or substitution can be conservative, semi-conservative, or non-conservative.
  • conservative amino acid substitution or “conservative mutation” refers to the replacement of one ammo acid by another amino acid with a common property.
  • a functional way to define common properties between individual amino acids is to analyze the normalized frequencies of ammo acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Springer- Verlag, New York (1979)). According to such analyses, groups of amino acids may be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure.
  • conservative ammo acid substitutions include substitutions of ammo acids within the sub-groups described above, for example, lysine for arginine and vice versa such that a positive charge may be maintained, glutamic acid for aspartic acid and vice versa such that a negative charge may be maintained, serine for threonine such that a free -OH can be maintained, and glutamine for asparagine such that a free -NHz can be maintained.
  • “Semi-conservative mutations” include ammo acid substitutions of ammo acids within the same groups listed above, but not within the same sub-group.
  • substitution of aspartic acid for asparagine, or asparagine for lysine involves amino acids within the same group, but different sub-groups.
  • “Non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc.
  • one or more ammo acids can be inserted into the anti-ANGPTL7 antibodies, or antigen-binding fragments thereof (e.g., insertion into the heavy and/or light chain variable region amino acid sequence). Any number of suitable ammo acids can be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof. In this respect, at least one ammo acid (e.g., 2 or more, 5 or more, or 10 or more ammo acids), but not more than 2.0 amino acids (e.g., 18 or less, 15 or less, or 12 or less ammo acids), can be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof.
  • at least one ammo acid e.g., 2 or more, 5 or more, or 10 or more ammo acids
  • 2.0 amino acids e.g., 18 or less, 15 or less, or 12 or less ammo acids
  • 1-10 ammo acids may be inserted into the ammo acid sequence of the monoclonal antibody or antigen-binding fragment thereof.
  • the amino acid(s) can be inserted into an antibody or antigen-binding fragment thereof in any suitable location.
  • the amino acid(s) are inserted into a CDR (e.g,, CDR1, CDR2, or CDR3) of the antibody or antigen-binding fragment thereof.
  • an anti-ANGPTL7 antibody or antigen-binding fragment thereof can comprise any heavy chain polypeptide or light chain polypeptide that competes with the anti-ANGPTL7 antibodies or antigen-binding fragments thereof for conformational binding to ANGPTL7.
  • Antibody competition can be assayed using routine peptide competition assays such as, for example, ELISA, Western blot, or immunohistochemistry methods (see, e.g., U.S. Patents 4,828,981 and 8,568,992; and Braitbard et al., Proteome Sci., 4'. ⁇ 2 (2006)).
  • An anti-ANGPTL7 antibody of the present disclosure may be a whole antibody, or an antigen-binding fragment of a whole antibody.
  • antigen-binding antibody fragments encompassed by the present disclosure include, but are not limited to, F(ab’)?, Fab’, Fab, Fv, scFv, dsFv, dAb, and single chain binding polypeptides.
  • Antibody fragments and their therapeutic utility are further described in, e.g., Nelson, A.L., MAbs.
  • 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 (VH) and light chains (VL) of immunoglobulins through a short polypeptide linker.
  • scFv single-chain variable fragment
  • Single chain variable domain (Fv) fragments are used in the art in a variety of clinical and therapeutic applications, primarily due to their improved pharmacokinetic properties as compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org/10.3390/antib2020193; Safdan etal., MolMed. 2.016; 2.2: 2.58-270; 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/sl2929-019-0592-z).
  • An anti-ANGPTL7 antibody of the present disclosure may be a diabody.
  • Diabodies are antibody fragments with two antigen-binding sites that may 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 tetrabodies are also described in Hudson et al., Nat. Med. 9: 129-134 (2003).
  • An anti-ANGPTL7 antibody of the present disclosure may be a single-domain antibody (also referred to as a nanobody).
  • Singledomain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
  • a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 Bl).
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coh' or phage), as described herein.
  • the anti-ANGPTL7 antibody is a whole antibody.
  • a whole antibody comprises two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide.
  • Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CHI, CHZ, and Cm) regions, and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL).
  • the heavy chain C-terminal constant region contains the fragment crystallizable (Fc) domain, which determines antibody class and is responsible for humoral and cellular effector functions.
  • Antibodies are divided into five major classes (or “isotypes”), IgG, IgM, IgA, IgD and IgE, which differ in their function in the immune system.
  • IgGs are the most abundant immunoglobulins in the blood, representing 60% of total serum antibodies in humans.
  • IgG antibodies may be subclassified as IgGl, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgGl being the most abundant) (Vidarsson et al., Frontiers in Immunology. 5: 520 (2014)).
  • a whole anti-ANGPTL7 monoclonal antibody described herein may be of any suitable class and/or subclass.
  • the monoclonal antibody is of class IgG (e.g., IgGl, IgG2, IgG3, or IgG4).
  • the monoclonal antibody may be an IgGl antibody.
  • the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (triggering effector functions that eliminate the antigen).
  • the Fc domain may be modified or engineered to alter its effector functions.
  • Fc domains may be modified to improve antibodydependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and to control serum half-life.
  • the Fc domain of the anti-ANGPTL7 antibody may be engineered to modulate affinity for an Fc receptor, such as Fey receptors (FcyRs) and the neonatal Fc receptor (FcRn).
  • the Fc domain also may be modified to improve serum half-life, e.g., by engineering IgG Fc for higher FcRn binding (Zalevsky et al ., Nat. Biotechnol. 28, 157-159 (2010); and DalFAcqua et al., J. Immunol. 169, 5171-5180 (2002)).
  • the Fc domain may be modified to create monovalency or antibody bispecificity for improving therapeutic potency.
  • an Fc domain may be generated that does not form a homodimer but remains as a soluble monomer, mFc, that exhibits high affinity for FcyRI but no detectable binding to FcyRIIIa.
  • a heterodimeric Fc domain may be generated to obtain bispecific properties for antigen binding to circumvent homodimer formation.
  • Engineered Fc domains may be generated by inducing point mutations or by modifying 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).
  • the anti-ANGPTL7 antibodies of the present disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and/or a chimeric antibody.
  • the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')z fragments.
  • the anti-ANGPTL7 antibody is a monospecific antibody.
  • the anti-ANGPTL7 antibody is a bispecific antibody.
  • the anti-ANGPTL7 antibody comprises two or more singledomain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.
  • an anti-ANGPTL7 antibody provided herein is a chimeric antibody.
  • Certain chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567; and Morrison et al.. Proc. Natl. Acad. Sci. USA. 81 :6851-6855 (1984),
  • a chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant domain.
  • a chimeric antibody is a “class switched” antibody m which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, for example, CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs for example, CDRs, (or portions thereof) are derived from a non-human antibody
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.
  • a non-human antibody e.g., the antibody from which the HVR residues are derived
  • an anti-ANGPTL7 antibody of the present disclosure can be made into bivalent, trivalent, or tetravalent formats.
  • an anti- ANGPTL7 antibody of the present disclosure can be a bivalent, bispecific antibody with heteromeric heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc).
  • An anti- ANGPTL7 antibody of the present disclosure can be a tetravalent multispecific antibody comprised of IgGs with other binding domains fused to either the N- or C-termini of either the heavy or light chains (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG with non-antibody binding scaffold “centyrin” fused to C-terminal end of heavy chains).
  • An anti- ANGPTL7 antibody of the present disclosure can be comprised of IgGs to which additional antigen combining sites have been added within the structure (e.g., two-in-one antibodies, MAT “Modular Antibody Technology” platform from F-Star).
  • An anti-ANGPTL7 antibody of the present disclosure can be an engineered antibody fragment linked by short peptide linkers which can be made into bivalent, trivalent, or tetravalent formats addressing two to three targets (e.g., bispecific T-cell engager (Bi IE), Nanobody platform, dual- affinity re-targeting (DART) antibodies, “tandem antibody” structures (TandAbs)).
  • targets e.g., bispecific T-cell engager (Bi IE), Nanobody platform, dual- affinity re-targeting (DART) antibodies, “tandem antibody” structures (TandAbs)
  • an anti-ANGPTL7 antibody of the present disclosure can be comprised of chemically coupled IgGs.
  • an anti-ANGPTL7 antibody of the present disclosure is a multispecific antibody, such as a bispecific antibody, which have binding specificities for at least two different antigens.
  • the anti-ANGPTL7 antibodies of the present disclosure, or antigen-binding fragments thereof can be used to form one arm (e.g., antigenbinding portion) of a bispecific antibody, whereas the other arm of the bispecific antibody can be specific for a different antigen.
  • the other antigen includes, but is not limited to, interleukin- 1 beta (IL- Ip), 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; SIP: integrins avp3, avp5, and a5pl ; betacellulin; apelin/APJ; erythropoietin; complement factor D; TNFa; HtrAl; a VEGF receptor (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF-receptor (mbVEGFR), or soluble VEGF receptor (sVEGFR)); ST-2 receptor; and proteins genetically linked to age-related macular degeneration (AMD) risk, such as complement pathway components C2,
  • a bispecific antibody of the present disclosure includes 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 benefits.
  • the anti-ANGPTL7 arm can be any of the anti-ANGPTL7 antibodies of the present disclosure
  • the anti-VEGF arm can be any VEGF antagonist, including but not limited to, anti-VEGF antibodies (e.g., bevacizumab, sevacizumab, and ranibizumab), anti-VEGFR2 antibodies and related molecules (e.g., ramucirumab, tambirumab, aflibercept), anti-VEGFRl antibodies and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye; EYLEA®), and ziv-aflibercept (VEGF Trap; ZALTRAP®)), anti-VEGF arms of VEGF bispecific antibodies (e.g., MP-0250, vanucizumab (VEGF-ANG2)), including anti-VEGF, anti-VEGFRl, and anti-VEGFR2 arms.
  • VEGF antibodies e.g., bevacizumab,
  • the present disclosure provides anti- ANGPTL7 antibodies comprising various functional characteristics.
  • the anti-ANGPTL7 antibodies described herein bind an antigen on ANGPTL7 (SEQ ID NO: 370), or a variant or isoform thereof, via interaction with its antigenic determinants (epitopes).
  • the anti-ANGPTL7 antibodies described herein bind an antigen/epitope from a human ANGPTL7 fibrinogen domain (e.g., ATX-P-60; SEQ ID NO: 373), an antigen/epitope from a full length human ANGPTL7 monomeric variant L59P_L84P (ATX-P-62; SEQ ID NO: 371), an antigen/epitope from a full length human ANGPTL7 monomeric variant L59 GGPGG (ATX- P-63; SEQ ID NO: 372), an antigen/epitope from a human wild type ANGPTL7 multimer (PExt- 1; SEQ ID NO: 374).
  • a human ANGPTL7 fibrinogen domain e.g., ATX-P-60; SEQ ID NO: 373
  • an antigen/epitope from a full length human ANGPTL7 monomeric variant L59P_L84P ATX-P-62; SEQ ID NO:
  • binding of an anti-ANGPTL7 antibody to an ANGPTL7 polypeptide reduces intraocular pressure and/or increases outflow facility (see, e.g., Example 9 and FIG. 7).
  • the anti-ANGPTL7 antibody binds an epitope on human ANGPTL7 with a KD of about 100 nM or lower (see, e.g., Example 10).
  • the anti-ANGPTL7 antibodies described herein bind ANGPTL7 (or a fragment thereof) and increase outflow facility compared to a control.
  • control is selected from the group consisting of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and treatment with an ANGPTL7 protein/polypeptide and an isotype control antibody (see, e.g., FIG. 7).
  • 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.
  • 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: 240.
  • the anti- ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • VH comprising an ammo 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:
  • 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.
  • 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 ammo 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.
  • 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.
  • 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.
  • 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.
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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 ammo 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.
  • VH comprising an ammo 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)
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • VH comprising an ammo 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
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • VH comprising an ammo 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.
  • the anti- ANGPTL7 antibody comprises a VH comprising an ammo 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 ammo 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.
  • 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.
  • 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.
  • 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 ammo 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.
  • 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: 232.
  • 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.
  • 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.
  • the anti-ANGPTL7 antibodies described herein bind ANGPTL7 (or a fragment thereof) and increase outflow facility compared to a control.
  • the control is any of vehicle treatment, dexamethasone treatment, ANGPTL7 protein treatment, and/or treatment with an ANGPTL7 protein/polypeptide and an isotype control antibody.
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • VH comprising an ammo 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.
  • 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 at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 200 and a VL comprising an ammo 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.
  • 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.
  • the anti-ANGPTL7 antibodies described herein bind ANGPTL7 (or a fragment thereof) and increase outflow facility compared to a control.
  • the control is any of dexamethasone treatment, ANGPTL7 protein treatment, and/or treatment with an ANGPTL7 protein/polypeptide and an isotype control antibody.
  • 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.
  • 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 ammo 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.
  • 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.
  • 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.
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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 ammo 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.
  • the anti- ANGPTL7 antibody comprises a VH comprising an ammo 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 ammo 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.
  • VH comprising an ammo 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: 2
  • 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.
  • the anti-ANGPTL7 antibody comprises a VH comprising an ammo 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.
  • VH comprising an ammo 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.
  • 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 ammo 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.
  • 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: 242.
  • 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.
  • 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.
  • the anti-ANGPTL7 antibodies described herein bind ANGPTL7 (or a fragment thereof) and increase outflow facility compared to a control.
  • the control is any of dexamethasone treatment and/or ANGPTL7 protein treatment.
  • 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: 2.02.
  • 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.
  • 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.
  • 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 ammo 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.
  • 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
  • Embodiments of the present disclosure also include a polynucleotide encoding any of the anti-A.NGPTL7 antibodies of the present, disclosure.
  • the polynucleotide comprises a 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 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.
  • the polynucleotide comprises a 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 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.
  • the polynucleotide comprises a sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227; or (d) SEQ ID NOs: 261-263.
  • the polynucleotide comprises a sequence that is at least 80% identical (e.g., at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257; or (d) SEQ ID NOs: 267-269.
  • 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 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.
  • 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 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.
  • the polynucleotide comprises a sequence that is at least 90% identical (e.g., at least 90%, at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227; or (d) SEQ ID NOs: 261-263.
  • the polynucleotide comprises a sequence that is at least 90% identical (e.g., at least 90%, at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257; or (d) SEQ ID NOs: 267-269.
  • the polynucleotide comprises a sequence that is at least 95% identical (e.g., at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 175-179; (b) SEQ ID NOs: 192-193; (c) SEQ ID NOs: 213-227; or (d) SEQ ID NOs: 261-263.
  • the polynucleotide comprises a sequence that is at least 95% identical (e.g., at least 95%, or 100% identical) to any of the following nucleic acid sequences: (a) SEQ ID NOs: 185-189; (b) SEQ ID NOs: 196-197; (c) SEQ ID NOs: 243-257; or (d) SEQ ID NOs: 267-269.
  • the polynucleotide encoding an 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: 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
  • the polynucleotide encoding an 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: 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.
  • 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
  • SEQ ID NO: 214 a nucleic acid sequence that is at least.
  • 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
  • SEQ ID NO: 222 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
  • nucleic acid sequence that is at least 70% identical e.g., at. least 70%, at least.
  • 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
  • SEQ ID NO: 253 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; (1) a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 224 and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to SEQ ID NO: 254; or (m) a nucleic acid sequence that is at least 70%
  • the polynucleotide encoding an 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.
  • 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.
  • 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: 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: 26
  • the present disclosure includes an expression vector comprising any of the polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure.
  • the expression vector is suitable for manufacturing an anti- ANGPTL7 antibody of the present disclosure for delivery of the antibody to a subject.
  • 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., retroviral or adenoviral), or phage.
  • Suitable vectors and methods of vector preparation are well known in the art (see, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 4 th 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)).
  • the vector desirably comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the antibody-encoding nucleic sequence in a host cell.
  • expression control sequences such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the antibody-encoding nucleic sequence in a host cell.
  • Exemplary’ expression control sequences are known in the art and described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).
  • a vector comprising a nucleic acid sequence encoding an anti-ANGPTL7 antibody or antigen-binding fragment thereof may be introduced into a host cell that is capable of expressing the polypeptides encoded thereby, including any suitable prokaryotic or eukaryotic cell.
  • suitable prokaryotic cells include, but are not limited to, cells from the genera Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coif), Pseudomonas, Streptomyces, Salmonella, and Erwinia.
  • Particularly useful prokaryotic cells include the various strains of Escherichia coli (e.g., K12, HB101 (ATCC No.
  • Suitable eukaryotic cells include, for example, yeast cells, insect cells, and mammalian cells.
  • yeast cells include those from the genera Hansenula, Kluyveromyces, Pichia, Bhinosporidium, Saccharomyces, and Schizosaccharomyces.
  • suitable insect cells include Sf-9 and HIS cells (Invitrogen, Carlsbad, Calif.) and are described in, for example, Kitts et al., Biotechniques, 14: 810-817 (1993); Lucklow, Curr. Opin.
  • suitable mammalian cells include, but are not limited to, Chinese hamster ovary cells (CHO) (ATCC No. CCL61 ), CHO DHFR-cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC No. CRLI 573), and 3T3 cells (ATCC No. CCL92).
  • CHO Chinese hamster ovary cells
  • CHO DHFR-cells Urlaub et al., Proc. Natl. Acad. Sci. USA, 97: 4216-4220 (1980)
  • human embryonic kidney (HEK) 293 or 293T cells ATCC No. CRLI 573
  • 3T3 cells ATCC No. CCL92.
  • Other suitable mammalian cell lines are the monkey COS-1 (ATCC No.
  • CRL1650 and COS-7 cell lines (ATCC No. CRL1651), as well as the CV-1 cell hne (ATCC No. CCL70).
  • Further exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines. Normal diploid cells, cell strains derived from in vitro culture of primary tissue, as well as primary explants also are 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 of which are available from the ATCC.
  • the mammalian cell is a human cell.
  • the vector can include means for attaching a detection moiety to an anti-ANGPTL7 antibody of the present disclosure. In some embodiments, the vector can include means for attaching a purification moiety to an anti-ANGPTL7 antibody of the present disclosure.
  • Exemplary detection and/or purification moieties/tags that can be coupled to an anti- ANGPTL7 antibody of the present disclosure includes, but is not limited to, hemagglutinin (HA), c-Myc, V5, DYKDDDDK, His tag (e.g., 6x-HIS), Glutathione S-Transferase (GST), Maltose Binding Protein (MBP), a fluorophore (e.g., Green Fluorescent Protein (GFP), Red Fluorescent Protein (RFP), mCherry, a chromophore, and/or a luminescent peptide (e.g., luciferase).
  • HA hemagglutinin
  • c-Myc V5
  • His tag e.g., 6x-HIS
  • GST Glutathione S-Transferase
  • MBP Maltose Binding Protein
  • a fluorophore e.g., Green Flu
  • 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 to a subject).
  • the expression vector is a herpes simplex virus (HSV) vector, or a retrovirus vector.
  • the expression vector is an adeno-associated virus (AAV) vector, or comprises an AAV backbone.
  • AAV vectors have been designed, produced and used to mediate gene delivery in human subjects, including for therapeutic purposes.
  • AAV vectors for use in gene transfer comprise a replication defective AAV genome lacking functional Rep and Cap coding viral sequences.
  • Such replication defective 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 in a viral particle, to form a defective, recombined AAV virus, also termed “AAV vector.”
  • Methods of producing such AAV vectors have been disclosed in the literature, including using packaging cells, auxiliary 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.
  • AAV vectors may be prepared or derived from various serotypes of AAVs, which may be even mixed together or with other types of viruses to produce chimeric (e.g., pseudotyped) AAV viruses.
  • tAAVs are human AAV4 vectors, human AAV7 vectors, human AAV9 vectors, human AAV10 vectors, or bovine AAV vectors.
  • the AAV vector may be derived from a single AAV serotype or comprise sequences or components originating from at least two distinct AAV serotypes (pseudotyped AAV vector), e.g., an AAV vector comprising an AAV genome derived from one AAV serotype (for example AAV9), and a capsid derived at least in part from a distinct AAV serotype.
  • An AAV vector, as used herein, is a vector winch comprises at least one component part derivable from an adeno-associated virus.
  • the expression vector is a lentiviral vector (LV), or comprises an LV backbone.
  • Lentiviruses are part of a larger group of retroviruses. A detailed list of lentiviruses may 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 divided into primate and non-primate groups.
  • primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV).
  • the non- primate lentiviral group includes the prototype “slow virus” visna/maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (El AV), feline immunodeficiency virus (FIV), Maedi visna virus (MW) and bovine immunodeficiency virus (BIV).
  • 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 capability to infect both dividing and non-dividing cells (Lewis et al (1992) EM BO J 1 1 (8): 3053-3058 and Lewis and Emerman (1994) J Virol 68 (1): 510-516).
  • retroviruses such as MLV, are unable to infect non-dividing or slowly dividing cells such as those that make up, for example, muscle, brain, lung and liver tissue.
  • a lentiviral vector is a vector which comprises at least one component part derivable from a lentivirus.
  • that component part is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses an anti-ANGPTL7 antibody of the present disclosure (e.g., ocular delivery/expression).
  • gene therapy platforms, methods, and compositions that can be used to deliver an anti-ANGPTL7 antibody of the present disclosure to a subject includes the platforms, methods, and compositions disclosed in US20220025396, US20220011308, US20210371877, US20210363192, US20190078099, US20190038724, and US 10494646B2, which are incorporated herein by reference.
  • gene therapy platforms, methods, and compositions that can be used to deliver an anti-ANGPTL7 antibody of the present disclosure to a subject includes the platforms, methods, and compositions based on HMR59 (Hemera Biosciences), which through its protein product soluble CD59, blocks the membrane attack complex that forms during the terminal step in the complement cascade, HMR59 is designed to be administered as a single intraocular injection.
  • HMR59 Hemera Biosciences
  • the present disclosure also provides a method of administering ocular gene therapy to a subject in need thereof comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure).
  • a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure).
  • the method comprises administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-ANGPTL7 antibody of the present disclosure).
  • administering the pharmaceutical composition treats at least one symptom of glaucoma or other ocular diseases affecting the optic nerve and retinal ganglion cells.
  • the anti-ANGPTL7 antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat an eye disease (e.g., glaucoma).
  • the composition is suitable for ocular administration.
  • ocular administration comprises injection into vitreous fluid.
  • ocular administration comprises delivering the antibody using a conjunctival insert, a contact lens, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, eye drops, and/or an implant (e.g., SusvimoTM).
  • Recent methods and formulations for ocular administration can be found in, e.g., 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).
  • the methods include administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure.
  • the pharmaceutical composition is administered ocularly and treats at least one symptom of glaucoma or other ocular diseases affecting the optic nerve and retinal ganglion cells.
  • the at least one symptom comprises eye pain, eye pressure, headaches, rainbow-colored halos around lights, low vision, blurred vision, narrowed vision, impaired peripheral vision, blind spots, nausea, vomiting, and red eyes.
  • administering the pharmaceutical composition reduces or atenuates intraocular pressure and/or increases or enhances outflow facility in the subject’s eye.
  • the pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is administered at a dose ranging from about 0.0001 mg/dose to about 100 mg/dose.
  • the anti- ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg/dose to about. 100 mg/dose.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg/dose to about 100 mg/dose.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg/dose to about. 100 mg/dose.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 1.0 mg/dose to about 100 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about. 10 mg/dose to about. 100 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/dose to about 10 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/dose to about 1.0 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/dose to about 0.1 mg/dose.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/dose to about 0.001 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg/dose to about 10 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg/dose to about 1.0 mg/dose. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg/dose to about 10 mg/dose.
  • the pharmaceutical composition comprising a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is administered at a dose ranging from about 0.0001 mg/ml to about 100 mg/ml.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg/ml to about 100 mg/ml.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg/ml to about 100 mg/ml.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg/ml to about 100 mg/ml.
  • the anti- ANGPTL7 antibody is administered at a dose ranging from about 1.0 mg/ml to about 100 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 10 mg/ml to about 100 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/ml to about 10 mg/ml. In some embodiments, the anti- ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/ml to about 1,0 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/ml to about 0.1 mg/ml.
  • the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/ml to about. 0.01 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.0001 mg/ml to about 0.001 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.01 mg/ml to about 10 mg/ml. In some embodiments, the anti- ANGPTL7 antibody is administered at a dose ranging from about 0.001 mg/ml to about 1.0 mg/ml. In some embodiments, the anti-ANGPTL7 antibody is administered at a dose ranging from about 0.1 mg/ml to about 10 mg/ml.
  • the terms “treatment,” “treating,” and the like refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect is therapeutic, i.e., the effect partially or completely cures a disease and/or adverse symptom attributable to the disease.
  • the methods of the present disclosure comprise administering a “therapeutically effective amount” of an anti-ANGPTL7 antibody , or composition comprising an anti-ANGPTL7 antibody.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • the therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the monoclonal antibody to elicit a desired response in the individual.
  • a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure is an amount that treats at least one symptom of glaucoma or other ocular diseases affecting the optic nerve and retinal ganglion cells in a subject.
  • the pharmacologic and/or physiologic effect may be prophylactic, i.e., the effect completely or partially prevents a disease or symptom thereof.
  • the methods of the present disclosure comprise administering a “prophylactically effective amount” of an anti-ANGPTL7 antibody or composition comprising an anti-ANGPTL7 antibody.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary’, to achieve a desired prophylactic result (e.g., prevention of glaucoma or at least one symptom associated with glaucoma).
  • a typical dose of a therapeutically effective amount of an anti-ANGPTL7 antibody of the present disclosure can range from, for example, about 0.0001 mg/dose to about 100 mg/dose for each eye to be treated.
  • a therapeutically effective amount of an anti- ANGPTL7 antibody of the present disclosure 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/dose to about 50 mg/dose, from about 0.1 mg/dose to about 10 mg/dose, from about 0.5 mg/dose to about 5 mg/dose, and from about 1 mg/dose to about 10 mg/dose.
  • a therapeutically effective concentration of an anti-ANGPTL7 antibody of the present disclosure can range from, for example, about 0.0001 mg to about 100 mg of the antibody per milliliter of solution. In some embodiments, a therapeutically effective concentration of an anti-ANGPTL7 antibody of the present disclosure 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 and about 100 mg/ml, from about 0.001 mg/ml and about 50 mg/ml, from about 0.01 mg/ml and about 50 mg/ml, from about 0.1 mg/ml and about 50 mg/ml, from about 0.1 mg/ml and about 25 mg/ml, from about 0.1 mg/ml and about 10 mg/ml, and from about 1.0 mg/ml and about 10 mg/ml.
  • a therapeutically effective dose of an anti-ANGPTL7 antibody of the present disclosure 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.
  • a sustained release formulation (e.g., an ocular implant) can be, exactly or approximately, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 nig, 0.35 mg, 0.4 mg, 0.45 nig, 0.5 mg, 0.55 mg, 0.6 nig, 0.65 mg, 0.7 mg, 0.75 nig, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 nig, 2.0 mg, 3.0 mg, 4.0 nig, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg of an anti-ANGPTL7 antibody, or an amount that falls within a range delimited by any two of the foregoing values.
  • Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs.
  • other dosage regimens may be useful and are within the scope of the present disclosure.
  • the desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.
  • composition comprising an anti-ANGPTL7 antibody, or antigen-binding fragment thereof, can be administered to a mammal using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.
  • the composition preferably is suitable for ocular administration.
  • embodiments of the present disclosure include anti-ANGPTL7 antibodies that have enhanced halflife (e.g., after ocular administration), such that the anti-ANGPTL7 antibody can be administered less often to a subject.
  • the antibody comprises a half-life extension moiety.
  • the half-life extension moiety comprises a polypeptide that can be coupled to an anti-ANGPTL7 antibody of the present disclosure by any means known in the art (e.g., generation of a fusion protein).
  • the polypeptide that can be coupled to an anti-ANGPTL7 antibody of the present disclosure is at least 20 amino acids in length and comprises any combination of G, A, S T, E, and P residues.
  • the half-life extension polypeptide is attached to the C-terminus or N-terminus of the antibody. In some embodiments, this is referred to as “XTENylation,” as described further in US8933197, US7846445, US7855279, US8492530, US993833I, US8673860, US9371369, US9926351, USI0961287, US10172953, and US10953073.
  • the present disclosure also provides a composition comprising any of the anti- ANGPTL7 antibodies or antigen-binding fragments thereof described herein.
  • the composition desirably is a pharmaceutically acceptable (e.g., physiologically acceptable) composition, which comprises a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and the anti-ANGPTL7 antibody or antigen-binding fragment thereof.
  • a pharmaceutically acceptable composition which comprises a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and the anti-ANGPTL7 antibody or antigen-binding fragment thereof.
  • a carrier preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier
  • the anti-ANGPTL7 antibody or antigen-binding fragment thereof e.g., 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.
  • the composition may contain preservatives, such as, for example, methyl
  • buffering agents may be included in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffering agents optionally may be used. Methods for preparing compositions for pharmaceutical use are known to those skilled in the art and are described in, for example, Remington: The Science and Practice of Pharmacy , Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).
  • the biological activity of the anti- ANGPTL7 antibody, or antigen-binding fragment thereof can be measured by any suitable method known in the art.
  • the biological activity can be assessed by determining the stability of the anti-ANGPTL7 antibody.
  • the biological activity of the anti-ANGPTL7 antibody also can be assessed by determining its binding affinity to ANGPTL7 peptides and/or by assessing its binding affinity to peptides with which it may cross-react.
  • affinity refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (Ko).
  • Affinity of a binding agent to a ligand can be, for example, from about 1 femtomolar (fM) to about 1 millimolar (rnM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (pM)).
  • the affinity of an anti-ANGPTL7 antibody may be from about 1 nm to about 20 nm, and desirably from about 5 nm to about 10 nm.
  • Antibody affinity for an antigen or epitope of interest can be measured using any art- recognized assay.
  • Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and/or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, Sth ed., Garland Publishing, New York, N.Y., 2001).
  • FACS fluorescence activated cell sorting
  • separable beads e.g., magnetic beads
  • antigen panning e.g., antigen panning
  • ELISA see, e.g., Janeway et al. (eds.), Immunobiology, Sth ed., Garland Publishing, New York, N.Y., 2001).
  • an anti- ANGPTL7 antibody may be administered alone or in combination with other drugs/therapeutic agents.
  • the anti-ANGPTL7 antibody can be administered in combination with other agents for the treatment or prevention of glaucoma or other ocular disease affecting the optic nerve or retinal ganglion cells, as disclosed herein.
  • anti-ANGPTL7 antibodies of the present disclosure, or antibody conjugates, fusion proteins, or polymeric formulations thereof, can be used either alone or in combination with other agents in a therapy.
  • an anti- ANGPTL7 antibody may be co-administered with at least one additional therapeutic agent.
  • an additional therapeutic agent is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, an anti-emetic, a cancer vaccine, an analgesic, a growth-inhibitory agent, or combinations thereof.
  • an anti-ANGPTL7 antibody of the present disclosure is administered with a drug/therapeutic agent that treats/prevents glaucoma or other ocular disease that affects the optic nerve or retinal ganglion cells.
  • a drug/therapeutic agent that treats/prevents glaucoma or other ocular disease that affects the optic nerve or retinal ganglion cells.
  • Any suitable glaucoma therapeutic agent can be administered as an additional therapeutic agent in combination with an anti-ANGPTL7 antibody of the present disclosure, or an antibody conjugate, fusion protein, and/or polymeric formulation thereof, for treatment of an ocular disorder (e.g., e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells).
  • an anti-ANGPTL7 antibody of the present disclosure can be administered with an agent that lowers intraocular pressure by promoting the drainage of fluid from the eye, including but not limited to, prostaglandins (e.g., Xalatan (latanoprost), Travatan Z (travoprost), Zioptan (tafluprost), and Lumigan (bimatoprost)), Rho kinase inhibitors (e.g., Rhopressa (netarsudil)), nitric oxides (e.g., Vyzulta (latanoprostene bunod), and miotic or cholinergic agents (e.g., Isopto Carpine (pilocarpine)).
  • prostaglandins e.g., Xalatan (latanoprost), Travatan Z (travoprost), Zioptan (tafluprost), and Lumigan (bimatoprost)
  • an anti-ANGPTL7 antibody of the present disclosure can be administered with an agent that lowers intraocular pressure by reducing the amount of fluid produced in the eye, including but not limited to, alpha-adrenergic agonists (e.g., lopidine (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 (dorzoiamide) and Azopt (brinzoiamide)).
  • alpha-adrenergic agonists e.g., lopidine (apraclonidine) and Alphagan P or Qoliana (brimonidine)
  • beta blockers e.g., Betoptic (betaxolol) and Betimol, Istalol, or Timoptic (timolol)
  • one or more of these therapeutic agents can be administered with an anti-ANGPTL7 antibody of the present disclosure, in conjunction with other treatments, such as laser treatment (e.g., trabeculoplasty) and surgery (e.g., glaucoma implant surgery, and minimally invasive glaucoma surgery (MIGS)).
  • laser treatment e.g., trabeculoplasty
  • surgery e.g., glaucoma implant surgery, and minimally invasive glaucoma surgery (MIGS)
  • an anti-ANGPTL7 antibody, antibody conjugate, fusion protein, or polymeric formulation of the present disclosure is administered simultaneously with an additional therapeutic agent. In some embodiments, an anti-ANGPTL7 antibody, antibody conjugate, fusion protein, or polymeric formulation of the present disclosure is administered before or after an additional therapeutic agent.
  • the additional therapeutic agent(s) binds to a second biological molecule selected from the group consisting of VEGF, IL-1J3; IL-6; IL-6R; IL-13; IL-13R; PDGF; angiopoietin; Ang2; Tie2; SIP; integrins av
  • a second biological molecule selected from the group consisting of VEGF, IL-1J3
  • the ocular disorder is an intraocular neovascular disease selected from the group consisting of proliferative retinopathies, choroidal neovascularization (CNV), glaucoma, diseases affecting the optic nerve, diseases affecting the retinal ganglion cells, diabetic and other ischemia-related retinopathies, diabetic macular edema, pathological myopia, von Hippel-Lmdau disease, histoplasmosis of the eye, retinal vein occlusion (RVO), including CRVO and BRVO, corneal neovascularization, retinal neovascularization, and retinopathy of prematurity (ROP).
  • CNV choroidal neovascularization
  • RVO retinal vein occlusion
  • ROP retinal neovascularization
  • ROP retinopathy of prematurity
  • an anti-ANGPTL7 antibody of the present disclosure may be administered in combination with at least one additional therapeutic agent for treatment of an ocular disorder, for example, an ocular disorder described herein (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells).
  • an ocular disorder described herein e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells.
  • VEGF antagonists include, without limitation, anti-angiogenic agents, such as VEGF antagonists, including, for example, anti-VEGF antibodies (e.g., the anti- VEGF Fab LUCENTIS® (ranibizumab)), soluble receptor fusion proteins (e.g., the recombinant soluble receptor fusion protein EYLEA® (aflibercept, also known as VEGF Trap Eye: Regeneron/ ’Aventis)), aptamers (e.g., the 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-(l-methylpiperidin-4- ylmethoxyjquinazoline (ZD6474), 4-(4-fluor
  • additional therapeutic agents that can be used in combination with an anti-ANGPTL7 antibody of the present disclosure, or an antibody conjugate, fusion protein, and/or polymeric formulation thereof, for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells), include, but are not limited to, VISUDYNE® (verteporfin; a light-activated drug that is typically used in conjunction with photodynamic therapy with a non-thermal laser), PKC412, Endovion (NS 3728; NeuroSearch A/S), neurotrophic factors (e.g., glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF)), diltiazem, dorzolamide, PHOTOTROP®, 9-cis-retinal, eye medication (e.g., phospholine iodide, echothiophate, or carbonic anhydrase inhibitors), veovastat (
  • An anti-ANGPTL7 antibody of the present disclosure may be administered in combination with a therapy or surgical procedure for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells), including, for example, laser photocoagulation (e.g., panr etinal photocoagulation (PRP)), drusen lasenng, macular hole surgery, macular translocation surgery, implantable miniature telescopes, 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 rheopheresis (also known as membrane differential filtration and rheotherapy), microchip implantation, stem cell therapy,
  • RNA interference RNA interference
  • extracorporeal rheopheresis
  • an anti-ANGPTL7 antibody of the present disclosure can be administered in combination with an anti-angiogenic agent for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells).
  • an anti-angiogenic agent for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells).
  • Any suitable anti-angiogenic agent can be used in combination with an antibody of the present disclosure, including, but not limited to, those listed by Carmeliet et al. Nature 407:249-257, 2000.
  • the anti-angiogenic agent is a VEGF antagonist, including, but not limited to, an anti-VEGF antibody (e.g., the 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 such as RG-7716; Roche)), a soluble recombinant receptor fusion protein (e.g., EYLEA® (aflibercept)), a VEGF variant, a soluble VEGFR fragment, an aptamer capable of blocking VEGF (e.g., pegaptanib) or VEGFR, a neutralizing anti- VEGFR antibody, a small molecule inhibitor of VEGFR tyrosine kinases, an anti- VEGF DARPin® (e.g.
  • Suitable anti-angiogenic agents that may be administered in combination with an antibody of the present disclosure, or an antibody conjugate, fusion protein, and/or polymeric formulation thereof, for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells) include corticosteroids, angiostatic steroids, anecortave acetate, angiostatin, endostatin, tyrosine kinase inhibitors, matrix metalloproteinase (MMP) inhibitors, insulin-like growth factor-binding protein 3 (IGFBP3), stromal derived factor (SDF-1) antagonists (e.g., anti-SDF-1 antibodies), pigment epithelium- derived factor (PEDF), gamma-secretase, Delta-like ligand 4, mtegrin antagonists, hypoxiainducible factor (HIF)- la antagonists, protein kinase CK2 antagonists, agents that inhibit stem cell (
  • an anti-ANGPTL7 antibody of the present disclosure can be administered in combination with an agent that has activity against neovascularization for treatment of an ocular disorder (e.g., glaucoma or other disease associated with or affecting the optic nerve or retinal ganglion cells), such as an anti-inflammatory drug, a mammalian target of rapamycin (mTOR) inhibitor (e.g., rapamycin, AFINITOR® (everolimus), and TORISEL® (temsirolimus)), cyclosporine, a tumor necrosis factor (INF) antagonist (e.g., an anti-TNFa antibody or antigenbinding fragment thereof (e.g., infliximab, adalimumab, certolizumab pegol, and golimumab) or a soluble receptor fusion protein (e.g., etanercept)), an anti-inflammatory drug, a mammalian target of rapamycin (mTOR) inhibitor (e.g.
  • an anti-ANGPTL7 antibody or antigen-binding fragment described herein can be used in diagnostic or research applications.
  • Research applications include, for example, methods that utilize the anti-ANGPTL7 antibody and a label to detect an ANGPTL7 polypeptide or protein in a sample (e.g., in a human body fluid or in a cell or tissue extract).
  • the anti-ANGPTL7 antibody or antigen- binding fragment thereof may be employed 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, Forster resonance energy transfer (FRET), one-step antibody detection assays, single molecule detection assays, radioimmunoassays (RIA), and FACS.
  • sandwich immunoassays enzyme immunoassays (EIA), enzyme-linked immunosorbent assays (ELISA), lateral flow assays, competitive inhibition immunoassays (e.g., forward and reverse), competitive binding assays, Forster resonance energy transfer (FRET), one-step antibody detection assays, single molecule detection assays, radioimmunoassays (RIA), and FACS.
  • EIA enzyme immunoassays
  • ELISA enzyme-linked immunosorbent assays
  • lateral flow assays e
  • the anti-ANGPTL7 antibody or antigen -binding fragment thereof can be provided in a kit, e.g., a packaged combination of reagents in predetermined amounts with instructions for performing an assay using the antibody (e.g., an assay that detects ANGPTL7).
  • a kit comprising the antibody or antigen-binding fragment described herein and instructions for use thereof
  • the instructions can be in paper form or computer-readable form, such as a disk, CD, DVD, etc.
  • the kit can comprise a calibrator or control, and/or at.
  • the kit comprises all components, i.e., reagents, standards, buffers, diluents, etc., which are necessary to perform the assay.
  • Other additives may be included in the kit, such as stabilizers, buffers (e.g., a blocking buffer or lysis buffer), and the like.
  • the relative amounts of the various reagents can be varied to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay.
  • the reagents may be provided as dry powders (typically lyophilized), including excipients which on dissolution will provide a reagent solution having the appropriate concentration.
  • This example describes dexamethasone-induced changes in gene expression in primary human trabecular meshwork cells.
  • Primary trabecular meshwork cells isolated from post-mortem human donors were treated with dexamethasone (DEX). Changes in ANGTPL7 gene expression relative to vehicle were quantified using qPCR, as shown in FIG. 1. Using these data, strong DEX responders were selected for future studies, such as RNAseq.
  • DEX dexamethasone
  • media were removed and replaced with media containing 100 nM DEX or 0.1% ethanol (EtOH, vehicle).
  • EtOH 0.1% ethanol
  • Media was refreshed after 2-3 days, and cells were harvested for qPCR on day 5 using the Cells to Ct kit.
  • qPCR was run using an 4NGPTL7 TaqMan assay from Life Technologies on a Quantstudio6 qPCR machine. Gene expression was normalized to the EtOH control.
  • RNAseq of ANGPTL7 treatment-induced changes in gene expression of human trabecular meshwork (TM) and Schlemm’s Canal (SC) cells (FIG, 2). Briefly, primary human trabecular meshwork and Schlemm’s canal cells were passed in DMEM with 10% fetal bovine serum (PBS) with 1% penicillin/streptomycin. Cells were seeded at 200k cells/well in 6-well formats. Cells were differentiated in low serum for a week with media changes 3 times a week. For ANGPTL7 treatment, media were removed and replaced with media containing 50 ng/mL of ANGPTL7 protein made from BIORTUS. Treatment media was refreshed daily for three days. After three days, cells were spun down and frozen into a pellet and then stored into a -80C freezer until shipment to SeqMatic for processing.
  • PBS fetal bovine serum
  • Treatment media was refreshed daily for three days. After three days, cells were spun down and frozen into a pellet and then stored into a -
  • Glauconix developed a proprietary technology allowing multi-layer growth of bioengineered 3D human trabecular mesh work (HTM) cells cocultured with human Schlemms’ canal (HSC) cells, thereby mimicking the architecture of the tissues responsible for pressure build-up in the human eye (FIG. 3A). This allows endpoint analyses relevant to lOP-modulation.
  • HTM human trabecular mesh work
  • HSC human Schlemms’ canal
  • This scaffolding of cells is used to compare treatment effects of vehicle (DMSO), dexamethasone (a steroid known to elevate I OP), and human ANGPTL7 protein on outflow facility.
  • HTM cells were thawed and allowed to grow' for about 7 days (media changes ever ⁇ ' 2 days).
  • the HTM cells were seeded onto scaffolds and HSC cells were thawed on the same day; the HTM ceils were aliowed to grow for 7 days on the scaffolds with media changes every 2. days.
  • HSCs were co-cultured on the back side of the HTM scaffolds and grown for 10-12 days with media changes every 2 days.
  • HTMZHSC constructs were serum starved the in a 1% medium the day before treatment. The first day of treatment was called Day 0. On Day 3, supernatants were collected, re-treated, and this process was repeated on Days 6 and 9. Perfusion was done on Day 10.
  • FIG. 3C includes representative data demonstrating outflow facility for 3D-HTM donor 3 treated with vehicle (DMSO), 500nM Dexamethasone, 50 ng/mL of ANGPTL7.
  • Glauconix developed a proprietary technology allowing multi-layer growth of bioengineered 3D human trabecular meshwork (HTM) cells co-cultured with human Schlemms’ canal (HSC) cells, thereby mimicking the architecture of the tissues responsible for pressure build-up in the human eye (FIG. 3A; see also exemplary protocol in Example 3). This allows endpoint analyses relevant to lOP-modulation.
  • HTM human trabecular meshwork
  • HSC human Schlemms’ canal
  • This experiment compared three different doses (25, 50, and 150 ug/ml) of ANGPTL7 protein on outflow facility in three different donor HTM cell lines (FIGS. 4A-4C).
  • experiments were focused on the reproducibility of ANGPTL7 effects on outflow facility (from SOW1) and dose response effects in three different HTM donors.
  • the human and African green monkey sequences were engineered to favor the production of monomeric material, while the rabbit protein was a mixture of monomer, trimer, and hexamer. When finished, all protein preparations exceeded 90% purity by analytical methods and were less than ⁇ 1 endotoxin unit per milliliter.
  • ANGPTL7 consists of two domains, a small N-terminal coiled coil domain and a larger C-terminal fibrinogen like domain.
  • Coiled coil domains follow a well-defined heptad repeat of hydrophobic and charged amino acids. This repeat, in conjugation with the property of approximately seven amino acids per two turns of an alpha helix, and the aqueous environment of either the extra or intracellular space, favor packing of the hydrophobic side chains into the interior of the coil while the charged amino acids face the aqueous environment. Dimerization, trimerization or other higher order mul timers result as each linear alpha helix is dependent on others to reach the energetically favorable “packed” state.
  • AH Sequences were examined for liabilities and modified to add further ammo acid sequence which encoded for “tags” to facilitate purification, lower immunogenicity, or simplify analytical screening.
  • tags used in this work include the HIS tag and the Avi tag. Tags were separated from each other and from the ANGPTL7 sequences with short linker sequences. All tags were added to the C -terminal end of the sequences. Additionally, the native signal peptide was removed and replaced with a signal peptide conducive to recombinant expression.
  • the sequence verified plasmid was transfected into human embryonic kidney cells adapted for recombinant expression.
  • the cells were supplemented with chemicals and nutrients designed to increase recombinant protein expression. These supplements include sodium propionate, valproic acid, glucose, glutamine, and a variety of yeast lysates.
  • the expressing cell cultures were harvested. As the recombinant protein is secreted into the growth medium, the cells, cell fragments, and cell debris, were removed via centrifugation and filtration through a membrane with pores no greater than 0.22 microns. The clarified culture medium, conditioned with the recombinant protein, was now ready for purification.
  • the protein of interest was purified from the cell culture medium and immobilized on the chromatography column.
  • a Ni-NTA agarose column was used for HIS tagged proteins. Multiple column washes followed, each specific for the type of column/tag/chromatography.
  • the protein of interest was eluted from the column with 300 mM of imidazole for HIS tagged proteins. [00179] Protein quality and quantity were assessed using a combination of SDS-PAGE gel electrophoresis, spectrophotometry, and analytical-SEC (size exclusion chromatography). Most proteins for this project required further purification.
  • the FPLC and a second chromatography column were employed. Separation by size, accomplished with a size exclusion column, enabled increased protein purities up to >90%. SEC also enabled buffer exchange out of the affinity chromatography elution buffer and into the final buffer of choice (PBS). The protein sample then moved onto quality control. If, at any point during purification, protein concentration needed to be increased, Amicon Ultra molecular weight cutoff (MWCO) filtration units were used to concentrate protein by separating protein from buffer. MWCO was chosen to ensure compatibility with the size of the protein of interest. Before moving to final quality control, all final samples were concentrated to > 1 milligram per milliliter.
  • MWCO Amicon Ultra molecular weight cutoff
  • Endotoxin contamination in the final protein sample was assayed using Charles River’s Endosafe PTS system. Spectrophotometry’ determined the final protein concentration. Three micrograms of the final sample were injected onto an analytical SEC column (YMC Diol 300) to determine its final purity. Additionally, sometimes SDS-PAGE electrophoresis was performed to determine final quality. Once all final metrics passed, the protein was sterilized in a biosafety cabinet using a sterile 0.22 micron filter. This was followed by sterile aliquoting and flash freezing in liquid nitrogen before storage at -80°C.
  • ANGPTL7 Immunization' Four cohorts of Alloy Therapeutic transgenic humanized mice, ATX-GK, were immunized with various human ANGPTL7 antigens using a standard 5-week RIMMS protocol: 10 gg subcutaneous dosing of antigen emulsified in complete Freund’s adjuvant followed by 5 weekly subcutaneous dosing of antigen emulsified in incomplete Freund’s adjuvant.
  • Cohort 1 Three ATX-GK mice immunized with human ANGPTL7 fibrinogen domain (ATX-P-60; SEQ ID NO: 373).
  • Cohort 2 Three ATX-GK mice immunized with full length human ANGPTL7 monomeric variant L59P_L84P (ATX-P-62; SEQ ID NO: 371).
  • Cohort 3 Three ATX- GK mice immunized with full length human ANGPTL7 monomeric variant L59 GGPGG (ATX- P-63; SEQ ID NO: 372).
  • Cohort 4 Three ATX-GK mice immunized with human wild type ANGPTL7 multimer (PExt-1; SEQ ID NO: 374).
  • Hybridoma Immune tissues from high titer mice were harvested and preserved for antibody discovery.
  • Hybridoma cell lines producing ANGPTL7 antibodies were produced by fusion of single B Cells from spleen and lymph nodes of titer positive mice with myeloma cells. Twenty 96 well plates of hybridoma fusions were generated and expanded. Hy bridomas expressing ANGPTL7 specific antibodies were detected by antigen binding by ELISA. Affinity of antibodies in the hybridoma supernatants were measured by SPR using the Octet instrument. ANGPTL7 antibodies in hybridoma supernatant were loaded on a biosensor.
  • Phage Display Variable heavy and light chains were amplified from the spleen of high titer immunized mice by reverse transcription using gene specific primers followed by PCR amplification with variable chain gene specific primers. Variable regions were cloned into a phage display vector designed to express Fabs on phage g3p protein. Libraries of phage expressing unique Fabs were amplified and purified. Phage were allowed to bind to biotinylated ANGPTL7 antigens captured on streptavidin magnetic beads. Phage remaining bound to antigen beads after several stringent washes was eluted using a basic triethylamine solution and neutralized with Tris buffer pH 8.0.
  • Eluted phages were reinfected into TGI bacterial cells, amplified by coinfection with Ml 3 helper phage, and purified by PEG precipitation. Purified phages expressing Fabs were selected for antigen binding as described. Phage from the second round were diluted and infected into TGI cells. Polyclonal pools of phage output from two rounds of panning were tested by ELISA to confirm that the pools contained ANGPTL7-specific phage. Variable heavy and light chain regions were sequenced from single infected bacterial colonies using a rolling circle amplification and standard Sanger sequencing.
  • Antibody Sequencing' Unique variable heavy and light chain pairs from hybridoma and phage display campaigns were cloned into vectors designed to express full length antibodies as IgGs in HEK293 cells under the control of a CMV promoter. Antibody expression vectors were complexed with poly ethylenimme and transfected into HEK293 cultures. After 5 days of shaking at 37 °C in 2.93 cell culture media, antibodies were captured on agarose- based protein A resin. After several stringent washes, antibodies were eluted in glycine solution, pH 3, neutralized with Hepes, pH 9, and buffer exchanged into PBS.
  • DSF Human ANGPTL7 monoclonal antibody differential scanning fluorimetry
  • Table 1 DSF analysis of human anti-Al ⁇ GPTL7 monoclonal antibodies.
  • ANGPTL7 Antibody Cross-Blocking High-throughput epitope binning experiments were conducted on real-time label-free biosensors (Carterra LSA) to sort large panels of mAbs into bins based on their ability to block one another for binding to the antigen.
  • antigen and antibody 2 analyte antibody
  • H200M sensor chip covalently pre-loaded with antibody 1 (ligand antibody).
  • An increase in response upon exposure to the analyte antibody indicates non-competition between the two antibodies, whereas a lack of change in the signal indicates competition.
  • Antibodies having the same blocking profiles towards others in the test set are grouped into one bin.
  • FIG. 6B includes data from a granular binning network.
  • FIG. 6C includes data from a combined binary dendrogram (color indicates bins in the Community binning network).
  • FIG. 61 includes data from a community binning network.
  • FIG. 6E includes binning data based on affinity for huANGPTL7-liis (P62).
  • FIG. 6F includes binning data based on antibody source (hybridoma or phage).
  • FIG. 6G includes binning data based on fibrinogen domain (P60P) binding.
  • FIG. 6H includes binning data based on rabbit ANGPTL7 (p66) binding.
  • FIG. 61 includes binning data based on mouse ANGPTL7 binding.
  • ANGPTL7 Functional Evaluation Experiments were conducted to test the effects of anti-ANGPTL7 antibodies on conventional outflow facility using a 3D HTM/HSC Tissue Model (see FIG. 3A/Example 3). The purpose of this study is to screen antibodies that bind ANGPTL7 to determine whether they are able to block ANGPTL7’s depression of outflow facility in an organoid model of the aqueous outflow tract. Antibodies that are capable of increasing outflow facility by blocking ANGPTL7’s activity are drug candidates for further study.
  • ANGPTL7 Antibody Kinetics Experiments were conducted to determine the reactivity and dissociation constants (KD) of anti-ANGPTL7 antibodies with the human fibrinogen domain of the ANGPTL7 protein. Binding experiments were performed on Octet HTX (ForteBio) in lx 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 on pre-hydrated AHC biosensors for 5 min. The loaded sensors were dipped into monovalent P60 (huANGPTL7-Fibrinogen-his) at a concentration of 200 nM for 5 min association, followed by 10 mm dissociation. Results were analyzed with ForteBio
  • the loaded sensors were dipped into monovalent P62 (huANGPTL7-his) at a range of concentration from 0.343-250 nM (a serial 3-fold dilution) for 5 min association, followed by 10 min dissociation. Results were analyzed with ForteBio Data Analysis 11.1 and fit globally to a 1 : 1 binding model to determine the monovalent KD (Table 3).
  • KD anti-ANGPTL7 antibodies with the rabbit ANGPTL7 protein. Binding experiments were performed on Octet HTX (ForteBio) in lx 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 on pre-hydrated AHC biosensors for 5 min. The loaded sensors were dipped into monovalent P66 (rabbit ANGPTL7- his) at a concentration of 200 nM for 5 min of association, followed by 10 min of dissociation. Results were analyzed with ForteBio Data Analysis 11.1 and fit to a 1:1 binding model to determine the monovalent KD. Responses (nm) at the end of association were also determined
  • Table 7 Reactivity of anti-ANGPTL7 antibodies with the human ANGPTL7 multimer protein.
  • ANGPTL7 is a member of the ANGPTL family though its function is poorly characterized. Previous studies have shown that loss-of-function variants in the ANGPTL7 gene are associated with protection from glaucoma and reduced 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 therapeutics.
  • IOP intraocular pressure
  • ANGPTL7 knockout model was generated by Lexicon therapeutics in 129SvEv-C57BL/6 mixed genetic background.
  • Alzet osmotic pumps (Model 1004) were sterile-fill ed with PBS or 45.45 mg/mL, of dexamethasone- cyclodextrin solution to provide a dose of 4 mgs/kg/day for the average 30g mouse.
  • PBS or dexamethasone pumps were subcutaneously implanted into the mouse. IOP and body weight were taken weekly on days 7, 14, 21, and 28. On day 28, final body weight and IOP measurements were taken. OS/OD v/ere enucleated and snap frozen in liquid nitrogen. Mice were euthanized following humane IACUC procedures.
  • FIGS. 8A-8C Representative results of the effects of dexamethasone-induced ocular hypertension in ANGPTL7 knockout mice are provided in FIGS. 8A-8C.
  • FIG. 8A includes body weight data of mice post-implantation surgery; dexamethasone impaired weight gam in male mice compared to PBS-treated mice, thereby confirming the proper functioning of the dexamethasone osmotic pumps.
  • FIG. 8B includes intraocular pressure (IOP) data of ANGPTL7 WT and ANGPTL7 KO mice dosed with PBS control or Dexamethasone (4 mg/kg/day); osmotic pumps were implanted on day 0.
  • IOP intraocular pressure
  • 8C includes representative data of the changes in IOP of ANGPTL7 WT and ANGPTL7 KO mice implanted with osmotic pumps containing PBS vehicle or dexamethasone (4 mg/kg/day) over 28 days. All IOP values were normalized to baseline (day 0) readings.
  • FIGS. 9A-9R Representative data is provided in FIGS. 9A-9R.
  • the anti-ANGPTL7 antibodies indicated (“BTX” labels are interchangeable with “ATX-P‘ labels) were injected at either a 0.5 mg dose (FIGS. 9C, 9D, 9G, 9H, 9K, 9L, 90, 9P) or a 2.0 mg dose (FIGS. 9E, 9F, 91, 9J, 9M, 9N, 9Q, 9R) in the right eye (OD), or with a corresponding vehicle dose in the left eye (OS).
  • FIGS. 9C, 9D, 9G, 9H, 9K, 9L, 90, 9P a 2.0 mg dose
  • OD right eye
  • OS left eye
  • IOP Intraocular pressure
  • OD experimental eyes
  • OS vehicle eyes
  • Rabbits were sedated using a ketamine/xylazine cocktail (4-10/20-50 mg/kg) IM and the eyes were aseptically prepared using topical 5% betadine solution, followed by rinsing with sterile eye wash, and application of one drop of 0.5% proparacame HC1.
  • Intraocular pressure was measured in both eyes of all animals at the timepoints indicated. The measurements were taken using a Tonovet probe (iCare Tonometer, Espoo, Finland) without use of topical anesthetic. The tip of the Tonovet probe was directed to gently contact the central cornea. Six consecutive measurements were obtained. After the sixth measurement, the average IOP shown w'as recorded. Animals did not require tranquilization for the procedure.
  • PK Pharmacokinetic evaluation. Previous studies (described above) demonstrated that both 0.5 mg and 2.0 mg doses of several novel anti-ANGPTL7 antibodies were well tolerated in rabbits over a 21 -day period. Thus, experiments were conducted to evaluate the pharmacokinetics (PK) of several of the well tolerated anti-ANGPTL7 antibodies. New Zealand White Rabbits received a single bilateral (OU) injection of each of ATX-P-424 (FIGS. 10A-10C), ATX-P-439 (FIGS. 11A-11C), and ATX-P-448 (FIGS. 12A-12C).
  • f‘BTX” labels are interchangeable with “ATX-P“ labels.)
  • IOP intraocular pressure
  • OE total ocular examination score
  • the whole blood samples were centrifuged at 4°C for 10 minutes at 2,000 x g in a refrigerated centrifuge. Immediately after centrifugation, the clear serum was aliquoted into four (4) 200 pL samples and stored frozen at-80°C until shipment for analysis. Additionally, a veterinary ophthalmologist performed complete ocular examinations using a slit lamp biomicroscope and indirect ophthalmoscope to evaluate ocular surface morphology and anterior and posterior segment inflammation on all animals prior to dosing to serve as a baseline and at the timepoints indicated. All animals received normal ocular examinations to be considered for this study. The modified Hackett and McDonald ocular grading system, with additional scoring parameters for the ocular posterior segment were used for scoring.
  • FIGS. 13A-13C include representative data of absolute TOP values at baseline (day 3) and on day 10, 6 hours post topical administration of saline and Latanoprost (FIG. 13 A); changes in IOP 6 hours post topical administration of either saline (day 3) or Latanoprost (day 10) (FIG. 13B); and changes in TOP between vehicle and Latanoprost administration (FIG 13C).
  • FIGS. 13A-13C include representative data of absolute TOP values at baseline (day 3) and on day 10, 6 hours post topical administration of saline and Latanoprost (FIG. 13 A); changes in IOP 6 hours post topical administration of either saline (day 3) or Latanoprost (day 10) (FIG. 13B); and changes in TOP between vehicle and Latanoprost administration (FIG 13C).
  • FIG. 14A-14H include representative IOP measurements (FIGS. 14A, 14C, 14E, and 14G) and changes in IOP (FIGS. 14B, 14D, 14F, and 14H) in African Green Monkeys dosed with 2 nig of the indicated anti-ANGPTL7 antibody compared to an isotype control (BTX-330) and a single vehicle eye.
  • FIG. 15 includes representative clinical scores of ocular examinations (OE) across all the dosed groups.
  • monkeys underwent prescreening to identify animals with basal IOP values greater than 16 mmHg and below 26 mmHg.
  • IVT dosing topical proparacaine 0.5% was administered, allowing 30 seconds to take effect, and an eye speculum placed, then the ocular surface was rinsed with 5% Betadme solution followed by sterile 0.9% saline.
  • IVT injections were performed in both eyes (OU) according to the treatment assignment using a 31 -gauge 5/16- inch needle/ syringe (Ulticare VetRx U-100, or equivalent) inserted inferotemporally at the level of the ora serrata ⁇ 2 mm posterior to the limbus.
  • a topical antibiotic ophthalmic ointment (neomycin, polymyxin, bacitracin or equivalent) was administered.
  • I OP intraocular pressure
  • both eyes were examined by slit lamp biomicroscopy. Scoring was applied to qualitative clinical ophthalmic findings using a nonhuman primate ophthalmic scoring system and summary score derived from exam components.
  • bilateral color fundus images of the retina were captured with 50° of view centered on the fovea using a Topcon TRC-50EX retinal camera with Canon 6D digital imaging hardware and New' Vision Fundus Image Analysis Sy stem software.
  • blood samples 0.5-1 mL
  • Aqueous humor (50 gL) was sampled with a 0.3 mL insulin syringe with a 31 -gauge needle advance into the anterior chamber '-2 mm anterior to the temporal limbus. Aqueous samples were transferred to cryotubes, flash frozen and stored and shipped below' -70°C to the Sponsor, or to a Sponsor designated laboratory’ for analysis. Subjects were additionally assessed at cage-side twice daily for general w'ellbeing and evidence of ocular pathology. Data generated from protocol-defined endpoints were collated, summarized, and analyzed. Specified statistical analyses were performed where data meets required assumptions. If data failed to meet assumptions for defined statistical methods alternative methods were employed where possible. P values ⁇ 0.05 will be considered statistically significant.
  • Human Angiopoietin-related protein 7 (UniProt Accession No. 043827): MLKKPLSAVTWLC1FIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVAN LSSLLSELNKKQERDWVSVVMQVMELESNSKRMESRLTDAESKYSEMNNQIDIMQLQA AQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWniQR RKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAE YSHF'VLGNELNSYRLFLGNYTGNVGNDALQYHNNTAF'STKDKDNDNCLDKCAQLRKG GYWYNCCTDSNLNGVYYRLGEHNKHLDGITWYGU'HGSTYSLKRVEMKIRPEDFKP (SEQ ID NO: 370).
  • Human Angiopoietin-related protein 7 L59P L84P variant (ATX-P-62): MLKKPLSAVTWLC1FIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEVKELKAQVAN PSSLLSELNKKQERDWVSVVMQVMEPESNSKRMESRLTDAESKYSEMNNQIDIMQLQA AQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWniQR RKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEGNLRYAE YSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKG GYWYNCCTDSNLNGVYYRLGEHNKHLDGIl'WYGWHGSTYSLKRVEMKIRI’EDFKI’ (SEQ ID NO: 371).
  • Human Angiopoietin-related protein 7 L59 GGPGG variant (ATX-P-63): MLKKPLSAVTWLCIFIVAFVSHPAWLQKLSKHKTPAQPQLKAANCCEEXTCELKAQVAN GOPGGSSLLSELNKKQERDWV'SYA ⁇ MQVMELESNSKRMESRLTDAESKYSEMNNQIDI MQLQAAQTVTQTSADAIYDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGG WTnQRRKSGLVSFYRDWKQYKQGFGSIRGDFWLGNEHIHRLSRQPTRLRVEMEDWEG NLRYAEYSHFVLGNELNSYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKC AQLRKGGYWYNCCTDSNI,NGV ⁇ r YRLGEHNKHI,DGITWYGWHGSTYSLKRVEMKIRPE DFKP (SEQ
  • Human Angiopoietin-related protein 7 fibrinogen domain (ATX-P-60): YDCSSLYQKNYRISGVYKLPPDDFLGSPELEVFCDMETSGGGWTTIQRRKSGLVSFYRD WKQYKQGFGSIRGDFWI.GNEHIEIRLSRQPTRI.RX T.WDW.GNI.,RYAEYSHFV’I.GNE.I,N SYRLFLGNYTGNVGNDALQYHNNTAFSTKDKDNDNCLDKCAQLRKGGYWYNCCTOS NLNC rVYYRLGEHNKI ILDGI1 AVYC 1WHGS1 YSLKR ⁇ a 3MKIRPED (SEQ ID NO: 373).
  • aa amino acid
  • HCDR 1, 2, 3 heavy chain CDRs 1, 2, and 3 (in numerical order)
  • LCDRs 1 , 2, 3 light chain CDRs 1 , 2, and 3 (in numerical order)
  • VH heavy chain variable region
  • VL light chain variable region
  • VH + constant heavy chain variable region sequence with an exemplary human heavy chain constant region sequence (typically IgGl)
  • VL + constant light chain variable region sequence with an exemplary human light chain constant region sequence (typically kappa). All numbers except in “Antibody Name’’ correspond to SEQ ID NOs in the sequence listing and Tables 8, 9, and 10.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2023/020354 2022-04-29 2023-04-28 Angiopoietin-related protein 7-specific antibodies and uses thereof Ceased WO2023212294A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP23726246.4A EP4514470A1 (en) 2022-04-29 2023-04-28 Angiopoietin-related protein 7-specific antibodies and uses thereof
CN202380047683.3A CN119630698A (zh) 2022-04-29 2023-04-28 血管生成素相关蛋白7特异性抗体及其用途
PE2024002370A PE20250560A1 (es) 2022-04-29 2023-04-28 Anticuerpos especificos contra la proteina 7 relacionada con la angiopoyetina y usos de estos
JP2024564495A JP2025517111A (ja) 2022-04-29 2023-04-28 アンジオポエチン関連タンパク質７特異的抗体及びその使用
KR1020247039794A KR20250021399A (ko) 2022-04-29 2023-04-28 안지오포이에틴-관련 단백질 7-특이적 항체 및 그의 용도
US18/860,128 US20250296996A1 (en) 2022-04-29 2023-04-28 Angiopoietin-related protein 7-specific antibodies and uses thereof
CA3250430A CA3250430A1 (en) 2022-04-29 2023-04-28 SPECIFIC ANTIBODIES OF ANGIOPOETIN-BINDED PROTEIN 7 AND THEIR USES
AU2023259251A AU2023259251A1 (en) 2022-04-29 2023-04-28 Angiopoietin-related protein 7-specific antibodies and uses thereof
IL316603A IL316603A (en) 2022-04-29 2023-04-28 Antibodies specific for angiopoietin-related protein 7 and uses thereof
MX2024013138A MX2024013138A (es) 2022-04-29 2024-10-24 Anticuerpos específicos contra la proteína 7 relacionada con la angiopoyetina y usos de estos
CONC2024/0016093A CO2024016093A2 (es) 2022-04-29 2024-11-27 Anticuerpos específicos contra la proteína 7 relacionada con la angiopoyetina y usos de estos

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263336747P 2022-04-29 2022-04-29
US63/336,747 2022-04-29

Publications (1)

Publication Number Publication Date
WO2023212294A1 true WO2023212294A1 (en) 2023-11-02

Family

ID=86558903

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/020354 Ceased WO2023212294A1 (en) 2022-04-29 2023-04-28 Angiopoietin-related protein 7-specific antibodies and uses thereof

Country Status (13)

Country Link
US (1) US20250296996A1 (enExample)
EP (1) EP4514470A1 (enExample)
JP (1) JP2025517111A (enExample)
KR (1) KR20250021399A (enExample)
CN (1) CN119630698A (enExample)
AU (1) AU2023259251A1 (enExample)
CA (1) CA3250430A1 (enExample)
CL (1) CL2024003281A1 (enExample)
CO (1) CO2024016093A2 (enExample)
IL (1) IL316603A (enExample)
MX (1) MX2024013138A (enExample)
PE (1) PE20250560A1 (enExample)
WO (1) WO2023212294A1 (enExample)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240043520A1 (en) * 2022-08-03 2024-02-08 Fred Hutchinson Cancer Center Targeting of peri-necrotic tumor cells

Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4828981A (en) 1983-08-24 1989-05-09 Synbiotics Corporation Immunoassays for determining Dirofilaria immitis infection using antiidiotype monoclonal antibody reagents
EP0404097A2 (de) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Bispezifische und oligospezifische, mono- und oligovalente Rezeptoren, ihre Herstellung und Verwendung
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
WO1993001161A1 (en) 1991-07-11 1993-01-21 Pfizer Limited Process for preparing sertraline intermediates
US5480792A (en) 1990-09-14 1996-01-02 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5525524A (en) 1991-04-10 1996-06-11 Biosite Diagnostics, Inc. Crosstalk inhibitors and their uses
US5679526A (en) 1989-01-10 1997-10-21 Biosite Diagnostics Incorporated Threshold ligand-receptor assay
WO1998022607A1 (fr) 1996-11-22 1998-05-28 Rhone-Poulenc Rorer S.A. Procede de production de virus recombinants
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
US5824799A (en) 1993-09-24 1998-10-20 Biosite Diagnostics Incorporated Hybrid phthalocyanine derivatives and their uses
US5851776A (en) 1991-04-12 1998-12-22 Biosite Diagnostics, Inc. Conjugates and assays for simultaneous detection of multiple ligands
WO1999006562A1 (en) 1997-07-31 1999-02-11 Chiron Corporation Method enabling readministration of aav vector via immunosuppression of host
US5885527A (en) 1992-05-21 1999-03-23 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membrances
US5922615A (en) 1990-03-12 1999-07-13 Biosite Diagnostics Incorporated Assay devices comprising a porous capture membrane in fluid-withdrawing contact with a nonabsorbent capillary network
US5939272A (en) 1989-01-10 1999-08-17 Biosite Diagnostics Incorporated Non-competitive threshold ligand-receptor assays
US5947124A (en) 1997-03-11 1999-09-07 Biosite Diagnostics Incorporated Diagnostic for determining the time of a heart attack
WO2000028004A1 (en) 1998-11-10 2000-05-18 The University Of North Carolina At Chapel Hill Virus vectors and methods of making and administering the same
US6113855A (en) 1996-11-15 2000-09-05 Biosite Diagnostics, Inc. Devices comprising multiple capillarity inducing surfaces
US6143576A (en) 1992-05-21 2000-11-07 Biosite Diagnostics, Inc. Non-porous diagnostic devices for the controlled movement of reagents
WO2000073316A2 (en) 1999-05-28 2000-12-07 Cell Genesys, Inc. Virus immunologic determinants
WO2001023001A2 (en) 1999-09-29 2001-04-05 The Trustees Of The University Of Pennsylvania Rapid peg-modification
US6248516B1 (en) 1988-11-11 2001-06-19 Medical Research Council Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors
WO2004112727A2 (en) 2003-06-19 2004-12-29 Avigen, Inc. Aav virions with decreased immunoreactivity and uses therefor
WO2005005610A2 (en) 2003-06-30 2005-01-20 The Regents Of The University Of California Mutant adeno-associated virus virions and methods of use thereof
WO2005072364A2 (en) 2004-01-27 2005-08-11 University Of Florida A modified baculovirus expression system for production of pseudotyped raav vector
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
US7527791B2 (en) 2004-03-31 2009-05-05 Genentech, Inc. Humanized anti-TGF-beta antibodies
US7846445B2 (en) 2005-09-27 2010-12-07 Amunix Operating, Inc. Methods for production of unstructured recombinant polymers and uses thereof
US7855279B2 (en) 2005-09-27 2010-12-21 Amunix Operating, Inc. Unstructured recombinant polymers and uses thereof
WO2011051276A1 (en) * 2009-10-26 2011-05-05 Externautics S.P.A. Colon and rectal tumor markers and methods of use thereof
US8568992B2 (en) 2001-12-03 2013-10-29 Amgen Fremont Inc. Antibody categorization based on binding characteristics
US8673860B2 (en) 2009-02-03 2014-03-18 Amunix Operating Inc. Extended recombinant polypeptides and compositions comprising same
US8933197B2 (en) 2007-08-15 2015-01-13 Amunix Operating Inc. Compositions comprising modified biologically active polypeptides
US10172953B2 (en) 2012-02-27 2019-01-08 Amunix Operating Inc. XTEN conjugate compositions and methods of making same
US20190038724A1 (en) 2015-05-01 2019-02-07 Spark Therapeutics, Inc. Adeno-Associated Virus-Mediated CRISPR-Cas9 Treatment of Ocular Disease
US20190078099A1 (en) 2016-03-30 2019-03-14 Spark Therapeutics, Inc. Cell line for recombinant protein and/or viral vector production
US20210363192A1 (en) 2018-04-27 2021-11-25 Spark Therapeutics, Inc. Engineered aav capsids with increased tropism and aav vectors comprising the engineered capsids and methods of making and using same
US20210371877A1 (en) 2017-12-18 2021-12-02 Spark Therapeutics, Inc. Adeno-associated virus (aav) vector lipid nanoparticle compositions and methods of use
US20220011308A1 (en) 2018-11-16 2022-01-13 Spark Therapeutics, Inc. In vitro assay for detecting enhancers and inhibitors of adeno associated virus (aav) vector transduction and/or detecting or quantitating anti-aav binding antibodies
US20220025396A1 (en) 2018-05-07 2022-01-27 Spark Therapeutics, Inc. Plasmid free aav vector producing cell lines

Patent Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4828981A (en) 1983-08-24 1989-05-09 Synbiotics Corporation Immunoassays for determining Dirofilaria immitis infection using antiidiotype monoclonal antibody reagents
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
US6248516B1 (en) 1988-11-11 2001-06-19 Medical Research Council Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors
US5939272A (en) 1989-01-10 1999-08-17 Biosite Diagnostics Incorporated Non-competitive threshold ligand-receptor assays
US5679526A (en) 1989-01-10 1997-10-21 Biosite Diagnostics Incorporated Threshold ligand-receptor assay
EP0404097A2 (de) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Bispezifische und oligospezifische, mono- und oligovalente Rezeptoren, ihre Herstellung und Verwendung
US5922615A (en) 1990-03-12 1999-07-13 Biosite Diagnostics Incorporated Assay devices comprising a porous capture membrane in fluid-withdrawing contact with a nonabsorbent capillary network
US5480792A (en) 1990-09-14 1996-01-02 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5985579A (en) 1990-09-14 1999-11-16 Biosite Diagnostics, Inc. Antibodies to complexes of ligand receptors and ligands and their utility in ligand-receptor assays
US5525524A (en) 1991-04-10 1996-06-11 Biosite Diagnostics, Inc. Crosstalk inhibitors and their uses
US5851776A (en) 1991-04-12 1998-12-22 Biosite Diagnostics, Inc. Conjugates and assays for simultaneous detection of multiple ligands
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1993001161A1 (en) 1991-07-11 1993-01-21 Pfizer Limited Process for preparing sertraline intermediates
US6019944A (en) 1992-05-21 2000-02-01 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membranes
US5885527A (en) 1992-05-21 1999-03-23 Biosite Diagnostics, Inc. Diagnostic devices and apparatus for the controlled movement of reagents without membrances
US6143576A (en) 1992-05-21 2000-11-07 Biosite Diagnostics, Inc. Non-porous diagnostic devices for the controlled movement of reagents
US5824799A (en) 1993-09-24 1998-10-20 Biosite Diagnostics Incorporated Hybrid phthalocyanine derivatives and their uses
US6113855A (en) 1996-11-15 2000-09-05 Biosite Diagnostics, Inc. Devices comprising multiple capillarity inducing surfaces
WO1998022607A1 (fr) 1996-11-22 1998-05-28 Rhone-Poulenc Rorer S.A. Procede de production de virus recombinants
US5947124A (en) 1997-03-11 1999-09-07 Biosite Diagnostics Incorporated Diagnostic for determining the time of a heart attack
WO1999006562A1 (en) 1997-07-31 1999-02-11 Chiron Corporation Method enabling readministration of aav vector via immunosuppression of host
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
WO2000028004A1 (en) 1998-11-10 2000-05-18 The University Of North Carolina At Chapel Hill Virus vectors and methods of making and administering the same
WO2000073316A2 (en) 1999-05-28 2000-12-07 Cell Genesys, Inc. Virus immunologic determinants
WO2001023001A2 (en) 1999-09-29 2001-04-05 The Trustees Of The University Of Pennsylvania Rapid peg-modification
US8568992B2 (en) 2001-12-03 2013-10-29 Amgen Fremont Inc. Antibody categorization based on binding characteristics
WO2004112727A2 (en) 2003-06-19 2004-12-29 Avigen, Inc. Aav virions with decreased immunoreactivity and uses therefor
WO2005005610A2 (en) 2003-06-30 2005-01-20 The Regents Of The University Of California Mutant adeno-associated virus virions and methods of use thereof
WO2005072364A2 (en) 2004-01-27 2005-08-11 University Of Florida A modified baculovirus expression system for production of pseudotyped raav vector
US7527791B2 (en) 2004-03-31 2009-05-05 Genentech, Inc. Humanized anti-TGF-beta antibodies
US7846445B2 (en) 2005-09-27 2010-12-07 Amunix Operating, Inc. Methods for production of unstructured recombinant polymers and uses thereof
US7855279B2 (en) 2005-09-27 2010-12-21 Amunix Operating, Inc. Unstructured recombinant polymers and uses thereof
US9938331B2 (en) 2005-09-27 2018-04-10 Amunix Operating Inc. Biologically active proteins having increased in vivo and/or in vitro stability
US8492530B2 (en) 2005-09-27 2013-07-23 Amunix Operating Inc. Unstructured recombinant polymers and compositions comprising same
US8933197B2 (en) 2007-08-15 2015-01-13 Amunix Operating Inc. Compositions comprising modified biologically active polypeptides
US10961287B2 (en) 2009-02-03 2021-03-30 Amunix Pharmaceuticals, Inc Extended recombinant polypeptides and compositions comprising same
US9371369B2 (en) 2009-02-03 2016-06-21 Amunix Operating Inc. Extended recombinant polypeptides and compositions comprising same
US9926351B2 (en) 2009-02-03 2018-03-27 Amunix Operating Inc. Extended recombinant polypeptides and compositions comprising same
US8673860B2 (en) 2009-02-03 2014-03-18 Amunix Operating Inc. Extended recombinant polypeptides and compositions comprising same
WO2011051276A1 (en) * 2009-10-26 2011-05-05 Externautics S.P.A. Colon and rectal tumor markers and methods of use thereof
US10172953B2 (en) 2012-02-27 2019-01-08 Amunix Operating Inc. XTEN conjugate compositions and methods of making same
US10953073B2 (en) 2012-02-27 2021-03-23 Amunix Pharmaceuticals, Inc. XTEN conjugate compositions and methods of making same
US20190038724A1 (en) 2015-05-01 2019-02-07 Spark Therapeutics, Inc. Adeno-Associated Virus-Mediated CRISPR-Cas9 Treatment of Ocular Disease
US20190078099A1 (en) 2016-03-30 2019-03-14 Spark Therapeutics, Inc. Cell line for recombinant protein and/or viral vector production
US20210371877A1 (en) 2017-12-18 2021-12-02 Spark Therapeutics, Inc. Adeno-associated virus (aav) vector lipid nanoparticle compositions and methods of use
US20210363192A1 (en) 2018-04-27 2021-11-25 Spark Therapeutics, Inc. Engineered aav capsids with increased tropism and aav vectors comprising the engineered capsids and methods of making and using same
US20220025396A1 (en) 2018-05-07 2022-01-27 Spark Therapeutics, Inc. Plasmid free aav vector producing cell lines
US20220011308A1 (en) 2018-11-16 2022-01-13 Spark Therapeutics, Inc. In vitro assay for detecting enhancers and inhibitors of adeno associated virus (aav) vector transduction and/or detecting or quantitating anti-aav binding antibodies

Non-Patent Citations (68)

* Cited by examiner, † Cited by third party
Title
"Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids", 2009, CAMBRIDGE UNIVERSITY PRESS
"Immunobiology", 2001, CIARLAND PUBLISHING
"Remington: The Science and Practice of Pharmacy", 1 May 2005, LIPPINCOTT WILLIAMS & WILKINS
ADAMCZYK ET AL., ANAL. CHIM. ACTA, vol. 579, no. 1, 2006, pages 61 - 67
ALBERT L. LEHNINGER: "Principles of Biochemistry", 1982, WORTH PUB, pages: 793 - 800
ALMAGROFRANSSON, FRONT. BIOSCI., vol. 13, 2008, pages 1619 - 1633
ALTSCHUL ET AL., J. MOLECULAR BIOL., vol. 215, no. 3, 1990, pages 403 - 410
ALTSCHUL ET AL., NUCLEIC ACIDS RES., vol. 25, no. 17, 1997, pages 3389 - 3402
ANONYMOUS: "Mouse Angiopoietin-like Protein 7/ANGPTL7 Antibody", 18 November 2021 (2021-11-18), XP093072452, Retrieved from the Internet <URL:https://www.bio-techne.com/datasheet-pdf?src=rnd&pdf=mab4960.pdf> [retrieved on 20230809] *
AUSUBEL ET AL.: "Short Protocols in Molecular Biology", 2002, JOHN WILEY & SONS
BATES A: "Power CA.", ANTIBODIES (BASEL, vol. 8, no. 2, 2019, pages 28
BEIGERT ET AL., PROC. NATL. ACAD. SCI. USA, vol. 10, 2009, pages 3770 - 3775
BORDET, 'Γ.BEHAR-COHEN, F.: "Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives", DRUG DISCOVERY TODAY, vol. 24, no. 8, August 2019 (2019-08-01), pages 1685 - 1693, XP085782111, DOI: 10.1016/j.drudis.2019.05.038
BRAASCHCOREY, BIOCHEMISTRY, vol. 11, no. 14, 2002, pages 4503 - 4510
BRAITBARD ET AL., PROTEOME SCI., vol. 4, 2006, pages 12
CARMELIET ET AL., NATURE, vol. 407, 2000, pages 249 - 257
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
COFFIN ET AL.: "Algorithms on Strings, Trees and Sequences", 1997, COLD SPRING HARBOUR LABORATORY PRESS, pages: 758 - 763
DALL'ACQUA ET AL., J. IMMUNOL., vol. 169, 2002, pages 5171 - 5180
DALL'ACQUA ET AL., METHODS, vol. 36, 2005, pages 61 - 68
GOEDDEL: "Gene Expression Technology: Methods in Enzymology", vol. 185, 1990, ACADEMIC PRESS
HOLLIGER ET AL., NAT. BIOTECH., vol. 23, no. 9, 2005, pages 1126 - 1129
HOLLINGER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448
HUDSON ET AL., NAT. MED., vol. 9, 2003, pages 129 - 134
INOUE ET AL., J. VIROL., vol. 72, 1998, pages 7024
JOOSTEN ET AL., MICROBIAL CELL FACTORIES, vol. 2, no. 1, 2003
KANG, T.Σ-I.JUNG, S.T, EXP MOL MED, vol. 51, 2019, pages 1 - 9
KELLEY, RF.MENG, Y.G.LIU ET AL., J BIOL CHEM., vol. 289, 2014, pages 3571 - 90
KITTS ET AL., BIOTECHNIQUES, vol. 14, 1993, pages 810 - 817
KLIMKA ET AL., BR. J. CANCER., vol. 83, 2000, pages 252 - 260
KOHLERMILSTEIN, EUR. J. IMMUNOL., vol. 5, 1976, pages 511 - 519
KUCHTEY JOHN ET AL: "Angiopoietin-like 7 secretion is induced by glaucoma stimuli and its concentration is elevated in glaucomatous aqueous humor", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 49, no. 8, 1 August 2008 (2008-08-01), pages 3438 - 3448, XP002618242, ISSN: 0146-0404, DOI: 10.1167/IOVS.07-1347 *
LAZAR ET AL., PROC. NATL ACAD. SCI. USA, vol. 103, 2006, pages 4005 - 4010
LEWIS ET AL., EM BO J, vol. 11, no. 8, 1992, pages 3053 - 3058
LEWISEMERMAN, J VIROL, vol. 68, no. 1, 1994, pages 510 - 516
LI ET AL., PROC NATL ACAD SCI U S A., vol. 114, 2017, pages 3485 - 90
LIN ET AL., PROC NATL ACAD SCI USA., vol. 112, 2015, pages 10611 - 6
LONBERG, HANDH. EXP. PHARMACOL., vol. 181, 2008, pages 69 - 97
LONBERG, NAT. BIOTECHNOL., vol. 23, no. 9, 2005, pages 1117 - 25
LU, R.HWANG, Y.LIU, I. ET AL.: "Development of therapeutic antibodies for the treatment of diseases", J BIOMED SCI, vol. 27, no. 1, 2020, XP009528498, DOI: 10.1186/s12929-019-0592-z
LUCKLOW ET AL., J. VIROL., vol. 67, 1993, pages 4566 - 4579
LUCKLOW, CURR. OPIN. BIOTECHNOL., vol. 4, 1993, pages 564 - 572
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
MIMOTO ET AL., CURR. PHARM. BIOTECHNOL ., vol. 17, 2016, pages 1298 - 1314
MONNET ET AL., MABS, vol. 6, 2014, pages 422 - 36
MONNIER ET AL., ANTIBODIES, vol. 2, no. 2, 2013, pages 193 - 208
MORRISON ET AL., PROC. NATL. ACAD. SCI. TISA., vol. 81, 1984, pages 6851 - 6855
NELSON, A.L., MABS, vol. 2, no. 1, January 2010 (2010-01-01), pages 77 - 83
NORDSTROM ET AL., BREAST CANCER RES., vol. 13, 2011, pages R123
PADLAN, MOL. IMMUNOL., vol. 28, 1991, pages 489 - 498
PRAVEEN KAVITA ET AL: "Genetic and Functional Characterization of ANGPTL7 as a Therapeutic Target for Glaucoma", RESEARCH SQUARE, 8 September 2021 (2021-09-08), XP055935846, Retrieved from the Internet <URL:https://assets.researchsquare.com/files/rs-858876/v1_covered.pdf?c=1631878681> [retrieved on 20220627], DOI: 10.21203/rs.3.rs-858876/v1 *
QUEEN ET AL., PROC. NAT'L ACAD. SCI. U, vol. 86, 1989, pages 10029 - 10033
RENATA GRIFANTINI ET AL: "A novel polyclonal antibody library for expression profiling of poorly characterized, membrane and secreted human proteins", JOURNAL OF PROTEOMICS, ELSEVIER, AMSTERDAM, NL, vol. 75, no. 2, 23 August 2011 (2011-08-23), pages 532 - 547, XP028124879, ISSN: 1874-3919, [retrieved on 20110905], DOI: 10.1016/J.JPROT.2011.08.018 *
RICHARDS ET AL., MOL. CANCER THER., vol. 7, 2008, pages 2517 - 2527
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329
SAFDARI ET AL., MOL MED., vol. 22, 2016, pages 258 - 270
SAMBROOK ET AL.: "Molecular Cloning, a Laboratory Manual", 2012, COLD SPRING HARBOR PRESS
SAMULSKI ET AL., J. VIROLOGY, vol. 63, 1989, pages 3822
SAUNDERS, K.O., FRONT IMMUNOL., vol. 10, 2019, pages 1296
SODING, BIOINFORMATICS, vol. 21, no. 7, 2005, pages 951 - 960
SOUTO, E.B. ET AL.: "Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents", PHARMACEUTICS, vol. 11, no. 9, September 2019 (2019-09-01), pages 460
URLAUB ET AL., PROC. NATL. ACAD. SCI. USA, vol. 97, 1980, pages 4216 - 4220
VIDARSSON ET AL., FRONTIERS IN IMMUNOLOGY, vol. 5, 2014, pages 520
WAHLESTEDT ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 97, 2000, pages 5633 - 5638
WANG, J. AM. CHEM. SOC., vol. 122, 2000, pages 8595 - 8602
XIAO ET AL., J. VIROLOGY, vol. 72, 1998, pages 2224
XU TONG ET AL: "Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation", THE FASEB JOURNAL, vol. 34, no. 10, 12 October 2020 (2020-10-12), US, pages 13548 - 13560, XP093072478, ISSN: 0892-6638, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.202000246RR> DOI: 10.1096/fj.202000246RR *
ZALEVSKY ET AL., NAT. BIOTECHNOL, vol. 28, 2010, pages 157 - 159

Also Published As

Publication number Publication date
JP2025517111A (ja) 2025-06-03
EP4514470A1 (en) 2025-03-05
AU2023259251A1 (en) 2024-11-14
KR20250021399A (ko) 2025-02-12
MX2024013138A (es) 2025-02-10
CL2024003281A1 (es) 2025-05-02
CN119630698A (zh) 2025-03-14
US20250296996A1 (en) 2025-09-25
IL316603A (en) 2024-12-01
CO2024016093A2 (es) 2025-02-13
PE20250560A1 (es) 2025-02-24
CA3250430A1 (en) 2023-11-02

Similar Documents

Publication Publication Date Title
US20250346653A1 (en) Bispecific antibodies and method of treating ocular disease
JP6480338B2 (ja) Ｉｌ−６アンタゴニストおよびその使用
US11807680B2 (en) Gremlin-1 crystal structure and inhibitory antibody
CN104936614B (zh) 抗-PDGFR-β抗体及其使用
EP3215530B9 (en) Improved il-6 antibodies
US20250296996A1 (en) Angiopoietin-related protein 7-specific antibodies and uses thereof
JP2025013590A (ja) ネコＭｃＤｏｎｏｕｇｈ肉腫（ＦＭＳ）様チロシンキナーゼ３受容体リガンド（ＦＬＴ３Ｌ）に対する抗体並びに自己免疫疾患及び炎症性疾患を治療するためのそれらの使用
US20250289873A1 (en) Complement factor h related 4-specific antibodies and uses thereof
OA21947A (en) Angiopoietin-related protein 7-specific antibodies and uses thereof.
WO2024227154A1 (en) Complement component 3 (c3)-specific antibodies and uses thereof
CA3250574A1 (en) Bispecific antibodies and methods of treating ocular disease
TW202246319A (zh) 補體c3抗原結合蛋白
AU2024304442A1 (en) Mhc class i chain-related protein a (mica)-specific antibodies and uses thereof
HK40102410A (en) Improved il-6 antibodies
HK40041682A (en) Antibodies to feline mcdonough sarcoma (fms)-like tyrosine kinase 3 receptor ligand (flt3l) and uses thereof for treating autoimmune and inflammatory diseases
HK1244008B (en) Improved il-6 antibodies

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23726246

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: MX/A/2024/013138

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 202492488

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 316603

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2024564495

Country of ref document: JP

Ref document number: 12024552593

Country of ref document: PH

Ref document number: P2024-02885

Country of ref document: AE

Ref document number: 815883

Country of ref document: NZ

Ref document number: AU2023259251

Country of ref document: AU

Ref document number: 002370-2024

Country of ref document: PE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024022462

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2023259251

Country of ref document: AU

Date of ref document: 20230428

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202417091175

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: NC2024/0016093

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: DZP2024001499

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 11202407489R

Country of ref document: SG

Ref document number: 2023726246

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2023726246

Country of ref document: EP

Effective date: 20241129

WWE Wipo information: entry into national phase

Ref document number: 202380047683.3

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: MX/A/2024/013138

Country of ref document: MX

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112024022462

Country of ref document: BR

Free format text: APRESENTE NOVAS FOLHAS DE RELATORIO DESCRITIVO E RESUMO COM TITULO ADAPTADO A PORTARIA/INPI/NO 14/2024, UMA VEZ QUE O TITULO NAO ESTA CENTRALIZADO NA PAGINA. A EXIGENCIA DEVE SER RESPONDIDA EM ATE 60 (SESSENTA) DIAS DE SUA PUBLICACAO E DEVE SER REALIZADA POR MEIO DA PETICAO GRU CODIGO DE SERVICO 207.

WWP Wipo information: published in national office

Ref document number: 1020247039794

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: NC2024/0016093

Country of ref document: CO

WWP Wipo information: published in national office

Ref document number: 202380047683.3

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 112024022462

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20241029

WWP Wipo information: published in national office

Ref document number: 202492488

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 18860128

Country of ref document: US