WO2024086555A1 - Utilisations d'anticorps anti-c3 - Google Patents

Utilisations d'anticorps anti-c3 Download PDF

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Publication number
WO2024086555A1
WO2024086555A1 PCT/US2023/077057 US2023077057W WO2024086555A1 WO 2024086555 A1 WO2024086555 A1 WO 2024086555A1 US 2023077057 W US2023077057 W US 2023077057W WO 2024086555 A1 WO2024086555 A1 WO 2024086555A1
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seq
amino acid
acid sequence
set forth
sequence set
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PCT/US2023/077057
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English (en)
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Priyamvada Chandra
Chi-Chih Chen
Tatiana Ecoiffier DAVIS
Erin Clark HENRY
Hsiao Lieu
Lulu Ren STERLING
Zhiwu YAN
Husam Sadoon YOUNIS
Kefei ZHOU
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Ngm Biopharmaceuticals, Inc.
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Publication of WO2024086555A1 publication Critical patent/WO2024086555A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • 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
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present disclosure generally relates to methods of treating geographic atrophy (GA), slowing down growth of total GA lesion area, preventing development of choroidal neovascularization (CNV), and/or reducing the development of (conversion to) CNV in an eye of a human subject having GA, the methods comprising administering to the human subject an antibody that specifically binds human complement component C3.
  • the complement cascade is primarily involved in the detection and removal of foreign pathogens such as bacteria.
  • the complement system includes more than 30 cell- associated and circulating proteins (e.g., C1, C1q, C1r, C1s, C2, C3, C3a, C3b, C4, Factor B, Factor D, Factor H, Factor I).
  • C1, C1q, C1r, C1s, C2, C3, C3a, C3b, C4, Factor B, Factor D, Factor H, Factor I There are three main pathways that activate complement, the classical pathway (CP), the lectin pathway (MBL), and the alternative pathway (AP).
  • CP classical pathway
  • MBL lectin pathway
  • AP alternative pathway
  • C4bC2b acts as the C3 convertase of the classical pathway.
  • the lectin complement pathway is activated when mannose-binding lectin (MBL) binds mannose-containing polysaccharides on microorganisms, initiating the cleavage of C4 and C2 by the MBL- MBL-associated serine protease complex.
  • MBL mannose-binding lectin
  • the C4bC2b complex forms the C3 convertase of the lectin pathway.
  • the oldest evolutionary signaling pathway of the three acts both independently of, and as an amplification loop for, the classical and lectin pathways.
  • the alternative complement pathway undergoes low-level self-activation through the slow, spontaneous hydrolysis of C3.
  • C3(H 2 O) binds complement Factor B, which is subsequently cleaved by complement Factor D into C3(H2O)Bb, forming the C3 convertase of the alternative complement pathway.
  • complement Factor B Once hydrolyzed, C3(H 2 O) binds complement Factor B, which is subsequently cleaved by complement Factor D into C3(H2O)Bb, forming the C3 convertase of the alternative complement pathway.
  • complement cascade continues with the cleavage of complement component C5, which triggers cell death via phagocytosis, inflammation, and ultimately membrane attack complex (MAC) activation.
  • MAC membrane attack complex
  • AMD aged-related macular degeneration
  • AMD is the main cause of vision loss among the elderly in developed countries and globally affects approximately 9% of the world’s population.
  • AMD is the main cause of vision loss among the elderly in developed countries and globally affects approximately 9% of the world’s population.
  • Wet AMD occurs when abnormal blood vessels (known as choroidal neovascularization or CNV) grow under the retina and macula. These new blood vessels may bleed and leak fluid, causing the macula to bulge or lift up from its normally flat position, thus distorting or destroying central vision. Under these circumstances, vision loss may be rapid and severe.
  • CNV choroidal neovascularization
  • Dry AMD is characterized by formation of drusen under the retina.
  • GA Geographic atrophy
  • GA is the advanced (late) form of dry AMD.
  • GA is characterized by the progressive loss of areas of the retinal pigment epithelium (RPE), loss of photoreceptors (rods and cones), loss of neuroretina, and loss of choriocapillaris. The loss of one or more of these cells and/or tissues results in permanent central vision loss.
  • the invention provides a method for treating geographic atrophy (GA) in an eye of a human subject identified as having GA, the method comprising (a) identifying the human subject as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 and (b) administering to the human subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from Attorney Docket No.: 47702.0112WO1 the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the method involves treating GA in an eye of a human subject identified as having GA, the method comprising administering to the subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the subject was previously identified as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 .
  • SEQ ID NO:2 human complement component C3
  • the invention provides a method for reducing the growth rate of total GA lesion area in an eye of a human subject identified as having GA, the method comprising (a) identifying the human subject as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 and (b) administering to the human subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the method involves reducing the growth rate of total GA lesion area in an eye of a human subject identified as having GA, the method comprising administering to the subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the subject was previously identified as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 .
  • SEQ ID NO:2 human complement component C3
  • the invention provides a method for reducing the loss of visual acuity in an eye of a human subject identified as having GA, the method comprising (a) identifying the human subject as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 and (b) administering to the human subject, by intravitreal injection, a therapeutically effected dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the method involves reducing the growth rate of total GA lesion area in an eye of a human subject identified as having GA, the method comprising administering to the subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the subject was previously identified as having a total GA lesion area in the eye of about 4.0 mm 2 - about 10.5 mm 2 .
  • SEQ ID NO:2 human complement component C3
  • the invention provides a method for preventing development of choroidal neovascularization in an eye of a human subject identified as having GA, the method comprising administering to the human subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the subject is identified as having a total GA lesion area in the eye of less than about 4.0 mm 2 , about Attorney Docket No.: 47702.0112WO1 4.0 mm 2 – about 10.5 mm 2 , greater than about 10.5 mm 2 , or less than about 9.6 mm 2 (e.g., less than about 9.4 mm 2 , 9.5 mm 2 , 9.6 mm 2 , 9.7 mm 2 , or 9.8 mm 2 ).
  • the invention provides a method for reducing the development of choroidal neovascularization in an eye of a human subject identified as having GA, the method comprising administering to the human subject, by intravitreal injection, a therapeutically effective dose of an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the subject is identified as having a total GA lesion area in the eye of less than about 4.0 mm 2 , about 4.0 mm 2 – about 10.5 mm 2 , greater than about 10.5 mm 2 ,or less than about 9.6 mm 2 (e.g., less than about 9.4 mm 2 , 9.5 mm 2 , 9.6 mm 2 , 9.7 mm 2 , or 9.8 mm 2 ).
  • the dose of the antibody is about 5mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg or more. In one particular embodiment, the dose of the antibody is 15 mg.
  • the interval between successive doses/administrations of the antibody is about every 4 weeks, about every 8 weeks, about every 12 weeks, or about every 16 weeks. In some particular embodiments, the interval is every four weeks or every eight weeks. It is understood that, in practice, nominal variations around the target interval may occur based on practical matters such as subject compliance, scheduling, and other practical issues.
  • the subject is treated for at least about 24 weeks, at least about 52 weeks, at least about 76 weeks, at least about 104 weeks, or even for the lifetime of the patient.
  • the GA is secondary to age-related macular degeneration (AMD).
  • the human subject has a single Attorney Docket No.: 47702.0112WO1 focal GA lesion in the eye prior to administering the anti-C3 antibody.
  • the human subject has multifocal GA lesions in the eye being prior to administering the anti- C3 antibody to the eye, from which at least one lesion area is at least 1.25 mm 2 .
  • the human subject has Best Corrected Visual Acuity (BCVA) score of at least 34 early treatment diabetic retinopathy study (ETDRS) letters (20/200 or better Snellen equivalent) in the eye prior to administering the anti-C3 antibody (i.e., at the initiation of therapy).
  • BCVA Best Corrected Visual Acuity
  • the human subject has a GA lesion in fovea in the eye prior to administering the anti-C3 antibody. [0019] In some embodiments of any of the foregoing aspects, the human subject does not have a GA lesion in fovea in the eye prior to administering the anti-C3 antibody. [0020] In some embodiments of any of the foregoing aspects, the human subject has no current or prior choroidal neovascularization in the eye prior to administering the anti- C3 antibody. [0021] In some embodiments of any of the foregoing aspects, the human subject has banded or diffuse junctional hyperautofluorescence in the eye prior to administering the anti-C3 antibody.
  • the human subject has low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye prior to administering the anti-C3 antibody.
  • LLD luminance deficit
  • the human subject has LLD score of at least 10 ETDRS letters in the eye prior to administering the anti-C3 antibody.
  • the disclosure features a method treating geographic atrophy secondary to age-related macular degeneration in a human subject in need thereof. The method comprises administering to the human subject by intravitreal injection a dose of 15 mg of an anti-C3 antibody once every 4 weeks or once every 8 Attorney Docket No.: 47702.0112WO1 weeks.
  • the dose is administered in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the disclosure provides a method of stabilizing or reducing GA lesion size or lesion growth in a human subject in need thereof. The method comprises administering to the human subject by intravitreal injection a dose of 15 mg of an anti-C3 antibody once every 4 weeks or once every 8 weeks. In some instances the dose is administered in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the disclosure relates to a method for treating geographic atrophy (GA) in a human subject; a method for reducing the growth rate of total GA lesion area in an eye of a human subject; a method for reducing the loss of visual acuity in an eye of a human subject; a method for reducing the development of choroidal neovascularization in an eye of a human subject; or a method for preventing development of, choroidal neovascularization (CNV) in an eye of a human subject.
  • the method comprises administering to the human subject by intravitreal injection a dose of 15 mg of an anti-C3 antibody once every 4 weeks or once every 8 weeks.
  • the dose is administered in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the human subject has a total GA lesion area in the eye of about 4.0 mm 2 to about 10.5 mm 2 .
  • the human subject shows reduced (relative to baseline) or an absence of choroidal neovascularization.
  • the human subject does not have intraocular inflammation, optionally wherein the intraocular inflammation is vitritis, vitreal cells, iridocyclitis, anterior chamber cells, uveitis, ulceris, or anterior chamber flare.
  • the human subject does not have an ocular or periocular infection.
  • the above methods further comprise monitoring for one or more conditions selected from the group consisting of endopthalmitis, retinal detachment, neovascular AMD, intraocular inflammation, and increased intraocular pressure, Attorney Docket No.: 47702.0112WO1 optionally wherein if any of these conditions are present treatment is halted until resolution of the condition.
  • the method further involves administering to the human subject a therapeutically effective amount of a VEGF inhibitor.
  • the VEGF inhibitor can be an anti-VEGF antibody.
  • the anti-VEGF antibody is ranibizumab, bevacizumab, brolucizumab, or faricimab.
  • the VEGF inhibitor is aflibercept or conbercept.
  • the anti-VEGF antibody or a VEGF inhibitor is intravitreally administered to the human subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times a year to the human subject. [0029] In some instances, the above methods involve further administering to the human subject by intravitreal injection a therapeutically effective amount of any one or more of pegcetacoplan, aflibercept, conbercept, ranibizumab, or bevacizumab, brolucizumab, and faricimab.
  • the anti-C3 antibody comprises: a heavy chain variable region (VH) comprising VH complementarity determining region (CDR)1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • VH heavy chain variable region
  • CDR VH complementarity determining region
  • VL light chain variable region
  • the VH CDR1 comprises the amino acid sequence set forth in SEQ ID NO:121
  • the VH CDR2 comprises the amino acid sequence set forth in SEQ ID NO:14
  • the VH CDR3 comprises the amino acid sequence set forth in SEQ ID NO:9
  • the VL CDR1 comprises the amino acid sequence set forth in SEQ ID NO:10
  • the VL CDR2 comprises the amino acid sequence set forth in SEQ ID NO:11
  • the VL CDR3 comprises the amino acid sequence set forth in SEQ ID NO:12.
  • the VH comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:21;
  • the VL comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:25;
  • the VH comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:21 and the VL comprises a sequence that is at least 80%, at least 85%, at least 90%,
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:21 and the VL comprises the amino acid sequence set forth in SEQ ID NO:25.
  • the antibody comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:29; (b) the light chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence set forth in SEQ ID NO:31; (c) the heavy chain comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%
  • the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:29 and the light chain comprises the amino acid sequence set forth in SEQ ID NO:31.
  • the antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of the amino acid sequence set forth in SEQ ID NO:29 and the light chain consists of the amino acid sequence set forth in SEQ ID NO:31.
  • the antibody is formulated as a sterile pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.
  • the antibody is administered at a dose and interval that does not cause an increase in intraocular inflammation and/or does not cause an increase in intraocular pressure that is measurable for more than 48 hours.
  • the disclosure features a pharmaceutical formulation comprising an anti-C3 antibody at a concentration of 75 mg/mL to 175 mg/mL; L- histidine at a concentration of 10 mM to 30 mM; sucrose at a concentration of 5% to 10%; and polysorbate 20 (PS20) at a concentration of 0.01% to 0.05%.
  • the pharmaceutical formulation has a pH of 5.0 to 6.0.
  • the pharmaceutical formulation comprises the anti-C3 antibody at a concentration of 150 mg/mL; L-histidine at a concentration of 20 mM; sucrose at a concentration of 8.2%; and PS20 at a concentration 0.02%.
  • the pharmaceutical composition has a pH of 5.5
  • the anti-C3 antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • the VH CDR1 comprises the amino acid sequence set forth in SEQ ID NO:121
  • the VH CDR2 comprises the amino acid sequence set forth in SEQ ID NO:14
  • the VH CDR3 comprises the amino acid sequence set forth in SEQ ID NO:9
  • the VL CDR1 comprises the amino acid sequence set forth in SEQ ID NO:10
  • the VL CDR2 comprises the amino acid sequence set forth in SEQ ID NO:11
  • the VL CDR3 comprises the amino acid sequence set forth in SEQ ID NO:12.
  • the VH comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:21; the VL comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:25; the VH comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:21 and the VL has at least 80% identical to the amino acid sequence set forth in SEQ ID NO:25; the VH comprises the amino acid sequence set forth in SEQ ID NO:21; or the VL comprises the amino acid sequence set forth in SEQ ID NO: 25.
  • the VH comprises the amino acid sequence set forth in SEQ ID NO:21 and the VL comprises the amino acid sequence set forth in SEQ ID NO:25.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein: (a) the heavy chain comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:29; (b) the light chain comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:31;(c) the heavy chain comprises a sequence that is at least 80% identical to the amino acid Attorney Docket No.: 47702.0112WO1 sequence set forth in SEQ ID NO:29 and the light chain comprises a sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO:31;(d) the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:29; or (e) the light chain comprises the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:29 and the light chain comprises the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of the amino acid sequence set forth in SEQ ID NO:29 and the light chain consists of the amino acid sequence set forth in SEQ ID NO:31.
  • the pharmaceutical formulation is administered with a second agent useful for treating GA or any adverse effects resulting from treatment with the pharmaceutical formulation.
  • the second agent is any one or more of pegcetacoplan, aflibercept, conbercept, ranibizumab, or bevacizumab, brolucizumab, and faricimab.
  • the disclosure provides a method of treating geographic atrophy secondary to age-related macular degeneration in a human subject in need thereof.
  • the method comprises administering the pharmaceutical formulation described herein to the human subject by intravitreal injection.
  • the pharmaceutical formulation is intravitreally administered at a dose of 15 mg once every 4 weeks or once every 8 weeks.
  • the pharmaceutical formulation is administered in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the disclosure features a method of stabilizing or reducing GA lesion size or lesion growth in a human subject in need thereof. The method comprising administering the pharmaceutical formulation described herein to the human subject by intravitreal injection. In some cases, the pharmaceutical formulation is intravitreally administered at a dose of 15 mg once every 4 weeks or once every 8 weeks.
  • the pharmaceutical formulation is administered in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the human subject has a total GA lesion area in the eye of about 4.0 mm 2 to about 10.5 mm 2 .
  • the above methods involve administering the pharmaceutical formulation with a second agent that is useful for treating GA or for treating any adverse effects resulting from treatment with the pharmaceutical formulation.
  • the second agent is any one or more of pegcetacoplan, aflibercept, conbercept, ranibizumab, or bevacizumab, brolucizumab, and faricimab.
  • a delivery device e.g., a syringe or a pump
  • the delivery devices comprises the pharmaceutical formulation in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • FIGS.1A-1C are a series of line graphs demonstrating the effect of anti-C3 therapy on the growth rate of GA lesions.
  • FIG.1A shows the GA lesion growth rate in sham (bottom most line relative to x-axis), Q4W (topmost line from x-axis), and Q8W (middle line) subjects having a total GA lesion area of ⁇ 4 mm 2 at the initiation of treatment.
  • FIG.1B shows the GA lesion growth rate in sham (top most line at week 24), Q4W (lowest line at week 24), and Q8W (middle line at week 24) subjects having a total GA lesion area of >10.5 mm 2 at the initiation of treatment.
  • FIG.1C shows the GA lesion growth rate in sham (top most line at week 52), Q4W (lowest line at week 52), and Q8W (middle line at week 52) subjects having a total GA lesion area of 4 – 10.5 mm 2 at the initiation of treatment.
  • FIGS.2A-2B are a series of line graphs demonstrating the effect of anti-C3 therapy on the GA lesion growth rate using a post-hoc analysis excluding the quartile of patients having the largest lesions (>9.64 mm 2 ) at the initiation of therapy.
  • FIG.2A shows the results of the MMRM analysis of the lower three quartiles.
  • FIG.2B shows the results of a slope analysis.
  • FIGS.3A-3C are a series of line graphs demonstrating the effect of anti-C3 therapy on the growth rate of GA lesions using a post-hoc analysis of regraded FAF images.
  • FIG.3A shows the results of the MMRM analysis of the entire dataset of included patients.
  • FIG.3B shows the results of the MMRM analysis of the middle two quartiles of patients based on initial lesion size.
  • FIG.3C shows the results of a slope analysis on those middle two quartiles.
  • the present disclosure is based on the discovery that anti-C3 therapy, and the IVT administration of an anti-C3 antibody (e.g., Hz38G10(G56A)), slows the growth rate of GA lesions secondary to AMD, reduces the incidence of CNV.
  • the anti-C3 therapy Attorney Docket No.: 47702.0112WO1 was found to be particularly effective in subjects having a moderate GA lesion area of 4 – 10.5 mm 2 at the initiation of therapy.
  • Amino acid (aa) sequences for human C3 (UniProtKB No. P01024), cynomolgus monkey (“cyno”) (NCBI Ref No. XP_005587776.1), and rat C3 (UniProtKB No. P01026) are provided herein as SEQ ID NO:1, SEQ ID NO:32, and SEQ ID NO:37, respectively.
  • SEQ ID NO:1 amino acid positions of C3 refer to the numbering of amino acid sequences including the signal sequence.
  • SEQ ID NO:2 also referred to herein as “anti-C3 antibodies”.
  • the anti-C3 antibody is Hz38G10(G56A).
  • Hz38G10(G56A) is a humanized, IgG1 monoclonal antibody having a molecular weight of approximately 150 kDa.
  • the VH and VL of Hz38G10(G56A) are set forth in SEQ ID NO: 21 and SEQ ID NO:25, respectively.
  • the heavy chain and light chain of Hz38G10(G56A) are set forth in SEQ ID NO:29 and SEQ ID NO:31, respectively.
  • Hz38G10(G56A) binds to human C3 with a KD of approximately 340 pM.
  • the anti-C3 antibody comprises the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2, and the VL CDR3 of Hz38G10(G56A). In some instances, the anti-C3 antibody comprises a VH comprising the VH CDR1, the VH CDR2, and the VH CDR3 of Hz38G10(G56A) and a VL comprising the VL CDR1, the VL CDR2, and the VL CDR3 of Hz38G10(G56A). In some instances, the anti-C3 antibody comprises the VH and the VL of Hz38G10(G56A).
  • the anti-C3 antibody comprises the heavy chain and the light chain of Hz38G10(G56A).
  • the anti-C3 antibody comprises a VH and a VL, wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 based on any one of the CDR definitions set forth in Table 1, and wherein the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 based on any one of the CDR definitions set forth in Table 1.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • CDRs are defined by a variety of methods/systems by those skilled in the art. These systems and/or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM, and Contact.
  • the Kabat definition is based on sequence variability and generally is the most commonly used.
  • the Chothia definition is based on the location of the structural loop regions.
  • the IMGT system is based on sequence variability and location within the structure of the variable domain.
  • the AbM definition is a compromise between Kabat and Chothia.
  • the Contact definition is based on analyses of the available antibody crystal structures.
  • An Exemplary system is a combination of Kabat and Chothia.
  • Software programs e.g., abYsis (www.bioinf.org.uk/abysis/sequence_input/key_annotation/key_annotation.cgi)) are available and known to those of skill in the art for analysis of antibody sequences and determination of CDRs.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9; and (ii) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:120, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:131, and a VH CDR3 Attorney Docket No.: 47702.0112WO1 comprising the amino acid sequence set forth in SEQ ID NO:9; and (ii) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:132, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9; and (ii) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9; and (ii) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:122, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:133, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:126; and (ii) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:127, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:128, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:129.
  • the VH comprises a sequence that is at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:21.
  • Attorney Docket No.: 47702.0112WO1 [0073]
  • the VL comprises a sequence that is at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:25.
  • the VH comprises a sequence that is at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:21 and the VL comprises a sequence that is at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:25.
  • the anti-C3 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:21. In some instances, the anti-C3 antibody comprises a VH consisting of the amino acid sequence set forth in SEQ ID NO:21.
  • the anti-C3 antibody comprises a VL comprising the amino acid sequence set forth in SEQ ID NO:25. In some instances, the anti-C3 antibody comprises a VL consisting of the amino acid sequence set forth in SEQ ID NO:25. [0077] In some instances, the anti-C3 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:21 and a VL comprising the amino acid sequence set forth in SEQ ID NO:25. [0078] In some instances, the anti-C3 antibody comprises a VH consisting of the amino acid sequence set forth in SEQ ID NO:21 and a VL consisting of the amino acid sequence set forth in SEQ ID NO:25.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a sequence that is at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:29.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein the light chain comprises a sequence that is at least 80%, at least 90%, at Attorney Docket No.: 47702.0112WO1 least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody comprises a heavy chain and a light chain, wherein the heavy chain has at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:29 and the light chain has at least 80%, at least 90%, at least 95%, or at least 97% sequence identical to the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:29.
  • the anti-C3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29.
  • the anti-C3 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:31. In some instances, the anti-C3 antibody comprises a light chain consisting of the amino acid sequence set forth in SEQ ID NO:31. [0084] In some instances, the anti-C3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:29 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:31. [0085] In some instances, the anti-C3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody is an antibody described in International Patent Application Publication No. WO 2019/195136, which is incorporated by reference herein in its entirety. In certain instances, the anti-C3 antibody is an antibody described in International Patent Application Publication No.
  • the anti-C3 antibody is an antibody described in International Patent Application Publication No. WO 2023/118312, which is incorporated by reference herein in its entirety. In certain instances, the anti-C3 antibody is an antibody described in International Patent Application Publication No. WO 2004/031240, which is incorporated by reference herein in its entirety. [0087] In some instances, the anti-C3 antibody comprises a human IgG1 heavy chain constant region. In some instances, the anti-C3 antibody comprises a human IgG2 heavy chain constant region. In some instances, the anti-C3 antibody comprises a human IgG4 heavy chain constant region.
  • the anti-C3 antibody comprises a human kappa light chain constant region. In some instances, the anti- C3 antibody comprises a human lambda light chain constant region. [0089] In some instances, the anti-C3 antibody comprises a human IgG1 heavy chain constant region and a human kappa light chain constant region. [0090] In some instances, the anti-C3 antibody comprises a human IgG1 heavy chain constant region and a human lambda light chain constant region. [0091] In some instances, the anti-C3 antibody is a monoclonal antibody. [0092] The anti-C3 antibodies described herein can be produced by any suitable method known in the art.
  • the anti-C3 antibody described herein may be formulated for use as or in a pharmaceutical composition.
  • the pharmaceutical composition may be used in the methods and uses described herein.
  • the pharmaceutical composition comprises an anti-C3 antibody described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for administration to a human subject via intravitreal injection.
  • the pharmaceutical compositions may be sterile.
  • the pharmaceutical composition comprises an anti-C3 antibody and a pharmaceutically acceptable carrier, wherein the anti-C3 antibody comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21 and a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • the pharmaceutical composition comprises an anti-C3 antibody and a pharmaceutically acceptable carrier, wherein the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9, and a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a VH CDR3 comprising the amino acid sequence
  • the pharmaceutical composition comprises an anti-C3 antibody and a pharmaceutically acceptable carrier, wherein the anti-C3 antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:21 and a VL comprising the amino acid sequence set forth in SEQ ID NO:25.
  • the pharmaceutical composition comprises an anti-C3 antibody and a pharmaceutically acceptable carrier, wherein the anti-C3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:29 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:31.
  • the pharmaceutical composition Attorney Docket No.: 47702.0112WO1 comprises an anti-C3 antibody and a pharmaceutically acceptable carrier, wherein the anti-C3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:31.
  • a method of treating GA in an eye of a human subject in need thereof comprising administering to the human subject an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the administering is via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • the dose and interval are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg, administered once every 4 weeks, 8 weeks, 10 weeks, 12 week, or 16 weeks, and the human subject has only extrafoveal GA lesions (i.e., does not have GA lesions in the fovea) or has both foveal and extrafoveal GA lesions at the initiation of therapy.
  • the duration of therapy is at least 26 weeks, 52, weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, or for the lifetime of the patient.
  • the antibody is administered at a dose and an interval that does not cause adverse events in the human subject.
  • the criteria for GA comprises an area of pallor in the fundus with visibility of the underlying choroidal blood vessels and sharply defined borders, occupying (1) a diameter > 175 ⁇ m; (2) a diameter > 250 ⁇ m; or (3) a diameter of at least 433 ⁇ m.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion Attorney Docket No.: 47702.0112WO1 area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. [0096] In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy. [0097] In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • LLD low luminance deficit
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, Attorney Docket No.: 47702.0112WO1 and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy.
  • the adverse event not caused by the intravitreal injection is an increase (e.g., a measurable increase) in intraocular pressure (IOP), an increase in IOP that last longer than 24 hours, 48 hours, or 72 hours after injection, an increase (e.g., a measurable increase) in intraocular inflammation, CNV conversion or the development of neovascular AMD, the likelihood of CNV conversion, or ischemic neuropathy.
  • IOP intraocular pressure
  • imaging modalities used by medical practitioners skilled in the art, including but not limited to, color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA). Imaging modalities allow for the direct measurement and quantification of GA lesion area.
  • CFP color fundus photography
  • FAF fundus autofluorescence
  • OCT optical coherence tomography
  • FA fluorescein angiography
  • ICGA indocyanine green angiography
  • Imaging modalities allow for the direct measurement and quantification of GA lesion area.
  • treating comprises a therapeutic measure that aims to cure, slow down, lessen symptoms of, and/or halt progression of a pathologic condition or disorder.
  • treating comprises reducing the growth rate of the total GA lesion size (e.g., relative to an untreated subject), stopping the growth/increase in the size existing GA lesions, slowing or preventing the development of CNV in a subject that is not diagnosed as having CNV at the initiation of therapy, and/or slowing the progression of CNV in a subject diagnosed as having CNV at the initiation of therapy.
  • Also provided herein is a method of reducing the growth rate of the total GA lesion area in an eye of a human subject in need thereof, the method comprising administering to the human subject an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the administering is via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • the dose and interval are 15 mg and Attorney Docket No.: 47702.0112WO1 once every 4 weeks, respectively, and the human subject does not have GA lesions in the fovea.
  • the dose and interval are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg, administered once every 4 weeks, 8 weeks, 10 weeks, 12 week, or 16 weeks, and the human subject has only extrafoveal GA lesions (i.e., does not have GA lesions in the fovea) or has both foveal and extrafoveal GA lesions at the initiation of therapy.
  • the duration of therapy is at least 26 weeks, 52, weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, or for the lifetime of the patient.
  • the antibody is administered at a dose and an interval that does not cause adverse events in the human subject.
  • an exemplary mean rate of progression of GA area is 1.5 to 2.2 mm 2 /year, with a range of 0.53 to 4.0 mm 2 /year.
  • the method of reducing total GA lesion area reduces the rate of progression of the total GA lesion area to less than 4.0 mm 2 /year, less than 3.75 mm 2 /year, less than 3.5 mm 2 /year, less than 3.25 mm 2 /year, less than 3 mm 2 /year, less than 2.75 mm 2 /year, less than 2.5 mm 2 /year, less than 2.25 mm 2 /year, less than 2 mm 2 /year mm 2 /year, less than 1.9 mm 2 /year, less than 1.8 mm 2 /year, less than 1.7 mm 2 /year, less than 1.6 mm 2 /year, less than 1.5 mm 2 /year, less than 1.4 mm 2 /year, less than 1.3 mm 2 /year, less than 1.2 mm 2 /year, less than 1.1 mm 2 /year, less than 1.0 mm 2 /year, less than 0.9 mm 2 /year, less than 0.8
  • the method of reducing total GA lesion area reduces the rate of progression of the total GA lesion area to 0.3 to 4 mm 2 /year, 0.3 to 3.5 mm 2 /year, 0.3 to 3.0 mm 2 /year, 0.3 to 2.5 mm 2 /year, 0.3 to 2 mm 2 /year, 0.3 to 1.5 mm 2 /year, 0.3 to 1 mm 2 /year, 0.5 to 3.0 mm 2 /year, 0.5 to 2.5 mm 2 /year, 0.5 to 2 mm 2 /year, 0.5 to 1.75 mm 2 /year, 0.5 to 1.5 mm 2 /year, 0.5 to 1.25 mm 2 /year, 0.5 to 1 mm 2 /year, 1 to 1.5 mm 2 /year, or 1 to 2 mm 2 /year.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of less than Attorney Docket No.: 47702.0112WO1 about 4 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. [00104] In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the Attorney Docket No.: 47702.0112WO1 human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy.
  • the total GA lesion area is measured about 6 months after treatment, about 1 year after treatment, about 18 months after treatment, and/or about 2 years after treatment. In some embodiments, the total GA lesion area is measured every time the C3-binding agent is administered. In some embodiments, the total GA lesion area is measured at time points chosen by the medical practitioner.
  • the reduction of the total GA lesion area is measured within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a first dose of the anti-C3 antibody. In some instances, the reduction of the total GA lesion area growth rate is measured after administering two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses) of the anti-C3 antibody.
  • two or more doses e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses
  • the reduction of the total GA lesion area growth rate is measured within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a final dose of the anti-C3 antibody (i.e., after termination of the administering of the anti-C3 antibody at the dose and the interval that does not cause adverse events in the human subject).
  • the adverse event not caused by the intravitreal injection is an increase (e.g., a measurable increase) in intraocular pressure (IOP), an increase in IOP that last longer than 24 hours, 48 hours, or 72 hours after injection, an increase (e.g., a measurable increase) in intraocular inflammation, CNV conversion or the development of neovascular AMD, the likelihood of CNV conversion, or ischemic neuropathy.
  • IOP intraocular pressure
  • Also provided herein is a method of reducing the decline in visual acuity in a human subject having GA (e.g., relative to an untreated subject), the method comprising Attorney Docket No.: 47702.0112WO1 administering to the human subject an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the administering is via intravitreal injection of the eye.
  • the dose and interval are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg, administered once every 4 weeks, 8 weeks, 10 weeks, 12 week, or 16 weeks, and the human subject has only extrafoveal GA lesions or has both foveal and extrafoveal GA lesions at the initiation of therapy.
  • the duration of therapy is at least 26 weeks, 52, weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, or for the lifetime of the patient.
  • the antibody is administered at a dose and an interval that does not cause adverse events in the human subject.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of Attorney Docket No.: 47702.0112WO1 therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject does not have CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has CNV in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy. [00111] In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • LLD low luminance deficit
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy.
  • the adverse event not caused by the intravitreal injection is an increase (e.g., a measurable increase) in intraocular pressure (IOP), an increase in IOP that last longer than 24 hours, 48 hours, or 72 hours after injection, an increase (e.g., a measurable increase) in intraocular inflammation, Attorney Docket No.: 47702.0112WO1 CNV conversion or the development of neovascular AMD, the likelihood of CNV conversion, or ischemic neuropathy.
  • IOP intraocular pressure
  • Also provided herein is a method of preventing development of choroidal neovascularization (CNV) in an eye of a human subject having GA, the method comprising administering to the human subject an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the administering is via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • the eye is monitored for CNV about 6 months after treatment, about 1 year after treatment, about 18 months after treatment, and/or about 2 years after treatment. In some embodiments, the eye is monitored for CNV every time the C3-binding agent is administered. In some embodiments, the eye is monitored for CNV at time points chosen by the medical practitioner. In some instances, the eye does not develop CNV within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a first dose of the anti-C3 antibody.
  • the eye does not develop CNV after being administered one or more doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses) of the anti-C3 antibody. In some instances, the eye does not develop CNV within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of a final dose of the anti-C3 antibody (i.e., after termination of the administering of the anti-C3 antibody at the dose and the interval that does not cause adverse events in the human subject). In some instances, the eye does not develop leakage. In some instances, the eye does not develop severe leakage/ hyperfluorescence.
  • doses e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses
  • the dose and interval are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg, and administered once every 4 weeks, 8 weeks, 10 weeks, 12 week, or 16 weeks.
  • the duration of therapy is at least 26 weeks, 52, weeks, Attorney Docket No.: 47702.0112WO1 78 weeks, 104 weeks, 130 weeks, 156 weeks, or for the lifetime of the patient.
  • the antibody is administered at a dose and an interval that does not cause adverse events in the human subject.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of less than about 4 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of between about 4 mm 2 and 10.5 mm 2 at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a total GA lesion area of greater than about 10.5 mm 2 at the initiation of therapy. [00116] In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • LLD low luminance deficit
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy.
  • CNV is measured using fluorescein angiography (FA) and/or Spectral Domain Optical Coherence Tomography (SD-OCT).
  • FA fluorescein angiography
  • SD-OCT Spectral Domain Optical Coherence Tomography
  • a method of slowing/reducing the development of choroidal neovascularization (CNV) in an eye of a human subject having GA, including GA secondary to AMD comprising administering to the human subject an antibody that specifically binds human complement component C3 (SEQ ID NO:2), wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, wherein the administering is via intravitreal injection of the eye.
  • the eye does not develop vascular leakage.
  • the eye does not develop severe vascular leakage/hyperfluorescence.
  • Methods of measuring CNV are known in the art, see, e.g., Guthrie et al., 2014, Microvasc Res 91:1-7, which is incorporated by reference herein in its entirety.
  • the eye is monitored for CNV about 6 months after treatment, about 1 year after treatment, about 18 months after treatment, and/or about 2 years after treatment.
  • the eye is monitored for CNV every time the C3-binding agent is administered.
  • the eye is monitored for CNV at time points chosen by the medical practitioner.
  • the development of CNV is evaluated within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a first dose of the anti-C3 antibody. In some instances, the development of CNV is evaluated after administering two or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses) of the anti-C3 antibody.
  • two or more doses e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 doses
  • the development of CNV is evaluated within 4 weeks, within 8 weeks, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of a final dose of the anti-C3 antibody (i.e., after termination of the administering of the anti- C3 antibody at the dose and the interval that does not cause adverse events in the human Attorney Docket No.: 47702.0112WO1 subject).
  • the dose and interval are 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg, administered once every 4 weeks, 8 weeks, 10 weeks, 12 week, or 16 weeks.
  • the duration of therapy is at least 26 weeks, 52, weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, or for the lifetime of the patient.
  • the antibody is administered at a dose and an interval that does not cause adverse events in the human subject.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye prior to administering the anti-C3 antibody.
  • the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy.
  • the dose and interval are 15 mg and once every 4 weeks, respectively, and the human subject has a low luminance deficit (LLD) score of at least 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the dose and interval are 15 mg and once every 8 weeks, respectively, and the human subject has a LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy.
  • the human subject has a total GA lesion area of 2.5 mm 2 to 17.5 mm 2 in the eye at the initiation of therapy. In some instances, the human subject has a total GA lesion area of less than 4.0 mm 2 in the eye at the initiation of therapy.
  • the human subject has a total GA lesion area of 4.0 mm 2 to 10.5 mm 2 in the eye at the initiation of therapy. In some instances, the human subject has a total GA lesion area of greater than 10.5 mm 2 in the eye at the initiation of therapy.
  • the human subject has a total GA lesion area of 1 mm 2 to 17.5 mm 2 , 1 mm 2 to 15 mm 2 , 1 mm 2 to 12.5 mm 2 , 1 mm 2 to 10 mm 2 , 1 mm 2 to 7.5 mm 2 , 1 mm 2 to 5 mm 2 , 2.5 mm 2 to 17.5 mm 2 , 2.5 mm 2 to 15 mm 2 , 2.5 mm 2 to 12.5 mm 2 , 2.5 mm 2 to 10 mm 2 , 2.5 mm 2 to 7.5 mm 2 , 2.5 mm 2 to 5 mm 2 , 5 mm 2 to 17.5 mm 2 , 5 mm 2 to 15 mm 2 , 5 mm 2 to 12.5 mm 2 , 5 mm 2 to 10 mm 2 , 5 mm 2 to 7.5 mm 2 , 2.5 mm 2 to 10 mm 2 , 5 mm 2 to 7.5 mm 2 , 2.5 mm 2 to 10 mm 2 , 5 mm 2 to 7.5 mm 2 ,
  • the human subject has a total GA lesion area of at least 0.5 mm 2 , at least 1 mm 2 , at least 1.5 mm 2 , at least 2 mm 2 , at least 2.5 mm 2 , at least 3 mm 2 , at least 4 mm 2 , at least 5 mm 2 , at least 7.5 mm 2 , at least 10 mm 2 , at least 15 mm 2 , at least 20 mm 2 , at least 30 mm 2 , or at least 40 mm 2 in the eye at the initiation of therapy.
  • the human subject has a single focal GA lesion in the eye at the initiation of therapy.
  • the single focal GA lesion area is less than 4.0 mm 2 , 4.0-10.5 mm 2 , or greater than 10.5 mm 2 to 50 mm 2 at the initiation of therapy.
  • the subject has multifocal GA lesions in the eye at the initiation of therapy.
  • the total lesion area in the eye is less than 4.0 mm 2 , 4.0-10.5 mm 2 , or greater than 10.5 mm 2 to 50 mm 2 at the initiation of therapy.
  • the human subject has a Best Corrected Visual Acuity (BCVA) score of at least 4, at least 9, at least 14, at least 19, at least 24, at least 29, at least 34, at least 39, at least 44, at least 49, at least 59, at least 59, or at least 64 early treatment diabetic retinopathy study (ETDRS) letters in the injected eye at the initiation of therapy.
  • BCVA Best Corrected Visual Acuity
  • the human subject has a BCVA score of 4 to 8 (20/800 Snellen equivalent), 9 to 13 (20/640 Snellen equivalent), 14 to 18 (20/500 Snellen equivalent), 19 to 23 (20/400 Snellen equivalent), 24 to 28 (20/320 Snellen equivalent), 29 to 33 (20/250 Snellen equivalent), 34 to 38 (20/200 Snellen equivalent), 39 to 43 (20/160 Snellen equivalent), 44 to 48 (20/125 Snellen equivalent), 49 to 53 (20/100 Snellen equivalent), 54 to 58 (20/80 Snellen equivalent), 59 to 63 (20/63 Snellen equivalent), or 64 to 68 (20/50 Snellen equivalent) ETDRS letters.
  • the human subject has 4 to 68, 4 to 63, 4 to 58, 4 to 53, 4 to 48, 4 to 43, 4 to 38, 4 to 33, 4 to 28, 4 to 23, 4 to 18, 4 to 13, or 4 to 8 ETDRS letters.
  • the human subject has 8 to 68, 8 to 63, 8 to 58, 8 to 53, 8 to 48, 8 to 43, 8 to 38, 8 to 33, 8 to 28, 8 to 23, 8 to 18, or 8 to 13 ETDRS letters.
  • the human subject has 13 to 68, 13 to 63, 13 to 58, 13 to 53, 13 to 48, 13 to 43, 13 to 38, 13 to 33, 13 to 28, 13 Attorney Docket No.: 47702.0112WO1 to 23, or 13 to 18 ETDRS letters.
  • the human subject has 18 to 68, 18 to 63, 18 to 58, 18 to 53, 18 to 48, 18 to 43, 18 to 38, 18 to 33, 18 to 28, or 18 to 23 to 18 ETDRS letters.
  • the human subject has 23 to 68, 23 to 63, 23 to 58, 23 to 53, 23 to 48, 23 to 43, 23 to 38, 23 to 33, or 23 to 28 ETDRS letters.
  • the human subject has 28 to 68, 28 to 63, 28 to 58, 28 to 53, 28 to 48, 28 to 43, 28 to 38, or 28 to 33 ETDRS letters. In some instances, the human subject has 33 to 68, 33 to 63, 33 to 58, 33 to 53, 33 to 48, 33 to 43, or 33 to 38 ETDRS letters.
  • the GA lesion(s) in the eye(s) of the human subject treated in accordance with any one of the foregoing methods may be within or including the fovea, outside of the fovea (extrafoveal), or there may be GA lesion(s) in the fovea and outside of the fovea.
  • the human subject treated in accordance with any one of the foregoing methods is identified as having foveal lesions. In some instances, the subject is identified as having extrafoveal GA lesion(s). In some instances, the human subject treated in accordance with any one of the foregoing methods is identified as having both foveal and extrafoveal lesions. In some instances of the foregoing methods, the human subject is identified as having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) foveal GA lesions at the initiation of therapy. In some instances, the human subject does not have any GA lesions in the fovea of the eye administered the anti-C3 antibody.
  • the human subject has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) extrafoveal GA lesions at the initiation of therapy. In some instances, the human subject has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) foveal GA lesions and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) extrafoveal GA lesions at the initiation of therapy. [00125] In some instances of the foregoing methods, the human subject does not have choroidal neovascularization in the eye at the initiation of therapy.
  • the human subject has never had choroidal neovascularization (e.g., has never been diagnosed as having CNV) in the eye prior to the initiation of therapy.
  • Attorney Docket No.: 47702.0112WO1 [00126]
  • the human subject has CNV in the eye prior to administering the anti-C3 antibody to the eye.
  • the human subject has banded or diffuse junctional hyperautofluorescence in the eye at the initiation of therapy.
  • the human subject has a low luminance deficit (LLD) score of at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, or at least 40 ETDRS letters in the eye at the initiation of therapy.
  • LLD luminance deficit
  • the human subject has an LLD score of 10 to 40, 11 to 40, 12 to 40, 13 to 40, 14 to 40, 15 to 40, 20 to 40, 25 to 40, 30 to 40, 45 to 40, 10 to 35, 11 to 35, 12 to 35, 13 to 35, 14 to 35, 15 to 35, 16 to 35, 17 to 35, 18 to 35, 19 to 35, 20 to 35, 30 to 35, 10 to 30, 11 to 30, 12 to 30, 13 to 30, 14 to 30, 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 30, 20 to 30, 21 to 30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 26 to 30, 27 to 30, 28 to 30, 29 to 30, 10 to 25, 11 to 25, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 15 to 70, 15 to 60, 15 to 50, 15 to 40, 15 to 30, 15 to 30,
  • the human subject has an LLD score of at least 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of at least 20 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of at least 13 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of at least 12 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of at least 11 ETDRS Attorney Docket No.: 47702.0112WO1 letters in the eye at the initiation of therapy.
  • the human subject has an LLD score of at least 10 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of 10 to 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of 13 to 30 ETDRS letters in the eye at the initiation of therapy. In some instances, the human subject has an LLD score of 10 to 40 ETDRS letters in the eye at the initiation of therapy. [00129] In some instances of the foregoing methods, the human subject has bilateral GA at the initiation of therapy. In some instances of the foregoing methods, the human subject has GA in the eye and CNV in a fellow eye at the initiation of therapy.
  • the human subject has GA in the eye and does not have CNV in a fellow eye at the initiation of therapy.
  • an antibody that specifically binds human complement component C3 (SEQ ID NO:2) in the manufacture of a medicament for treating GA in an eye of a human subject in need thereof wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, and wherein the medicament is administered via intravitreal injection of the eye.
  • an antibody that specifically binds human complement component C3 (SEQ ID NO:2) in the manufacture of a medicament for slowing down growth of total GA lesion area in an eye of a human subject in need thereof, wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, and wherein the medicament is administered via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • an antibody that specifically binds human complement component C3 (SEQ ID NO:2) in the manufacture of a medicament for Attorney Docket No.: 47702.0112WO1 improving visual acuity in an eye of a human subject having GA, wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, and wherein the medicament is administered via intravitreal injection of the eye.
  • an antibody that specifically binds human complement component C3 (SEQ ID NO:2) in the manufacture of a medicament for preventing development of choroidal neovascularization in an eye of a human subject having GA, wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, and wherein the medicament is administered via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • an antibody that specifically binds human complement component C3 (SEQ ID NO:2) in the manufacture of a medicament for slowing down development of choroidal neovascularization in an eye of a human subject having GA, wherein the antibody comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25, and wherein the medicament is administered via intravitreal injection of the eye.
  • SEQ ID NO:2 human complement component C3
  • the anti-C3 antibody comprises a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9, and a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH Attorney Docket No.: 47702.0112WO1 comprising the amino acid sequence set forth in SEQ ID NO:21 and a VL comprising the amino acid sequence set forth in SEQ ID NO:25.
  • the anti-C3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:29 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO:29 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO:31.
  • the anti-C3 antibody is formulated as a pharmaceutical composition, wherein the pharmaceutical composition comprises the anti-C3 antibody and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is sterile.
  • the pharmaceutical composition is formulated for intravitreal injection. [00136] In some instances of any of the foregoing methods and uses, the dose of the anti-C3 antibody is 5 to 20 mg.
  • the dose of the anti-C3 antibody is 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 7 to 20 mg, 7 to 15 mg, 7 to 10 mg, 10 to 20 mg, 10 to 15 mg, or 12 to 17 mg. In some instances, the dose of the anti-C3 antibody is about 15 mg. As used herein, “about” in the context of a dose means within 10% of the recited dose (e.g., about 15 mg means 13.5 mg to 16.5 mg). [00137] In some instances of any of the foregoing methods and uses, the dose of the anti-C3 antibody is 15 mg.
  • the interval of administering the anti-C3 antibody is once every 4 to 16 weeks (e.g., once every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, or every 16 weeks). In some instances, the interval of administering the anti-C3 antibody is once every 4 weeks. In some instances, the interval of administering the anti- C3 antibody is once every 8 weeks.
  • the anti-C3 antibody is administered at the dose and interval for a period time, e.g., 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 Attorney Docket No.: 47702.0112WO1 months, or longer than 12 months.
  • the anti-C3 antibody is administered at a dose of 15 mg once every four weeks for a total of 52 weeks (i.e., 15 mg once every four weeks over the course of 52 weeks, totaling 13 doses).
  • the anti-C3 antibody is administered at a dose of 15 mg once every eight weeks for a total of 52 weeks (i.e., 15 mg once every eight weeks over the course of 52 weeks, totaling 6 doses).
  • the dose and interval of administering the anti-C3 antibody is for a period time, e.g., 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, or 80 weeks.
  • the dose and interval of administering the anti-C3 antibody is for a period of 52 weeks (e.g., a dose of 15 mg once every 4 or 8 weeks or a total of 52 weeks).
  • the dose and interval of administering the anti-C3 antibody is 15 mg once every 4 weeks.
  • the dose and interval of administering the anti-C3 antibody is 15 mg once every 8 weeks.
  • the human subject is at least 45 years, at least 50 years, at least 55 years, at least 60 years, at least 65 years, at least 70 years, at least 75 years, at least 80 years, or at least 85 years of age. In some instances, the human subject is at least 55 years of age. In some instances, the human subject is 45 to 100, 45 to 90, 45 to 80, 45 to 70, 45 to 60, or 45-55 years of age. In some instances, the human subject is 55 to 100, 55 to 90, 55 to 80, 55 to 70, or 55 to 65 years of age. In some instances, the human subject is 65 to 100, 65 to 90, 65 to 80, or 65 to 70years of age.
  • the human subject is 70 to 100, 70 to 90, 70 to 80, or 70 to 75 years of age. In some instances, the human subject is 75 to 100, 75 to 95, 75 to 90, 75 to 85, or 75 to 80 years of age. In some instances, the human subject is 80 to 100, 80 to 95, 80 to 90, or 80 to 95 years of age. In some instances, the human subject is 85 to 100, 85 to 95, or 85 to 90 years of age. In some instances, the human subject is 90 to 100 or 90 to 95 years of age.
  • the methods described herein comprise administering to the human subject an anti-C3 antibody at a dose and an interval that does not cause one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) adverse events (e.g., mild, moderate, severe, potentially life threatening) in the human subject.
  • Adverse events may be characterized as mild, moderate, severe, or potentially life threatening. Mild adverse events are minor and do not cause significant discomfort to human subject or change in activities of daily living (ADL); human subject is aware of the symptoms, but the symptoms are easily tolerated.
  • Moderate adverse events are an inconvenience or concern to the human subject and cause interference with ADL, but the human subject is able to continue with ADL. Severe adverse events significantly interfere with ADL and the human subject is incapacitated and/or unable to continue with ADL.
  • Potentially life- threatening adverse events are events/reactions in which the human subject was at risk of death at the time of the event/reaction; it does not refer to events/reactions that hypothetically might have caused death if they were more severe.
  • the dose and interval do not cause one or more adverse events (e.g., mild, moderate, severe, potentially life threatening) within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a first dose of the anti-C3 antibody.
  • adverse events e.g., mild, moderate, severe, potentially life threatening
  • the dose and interval do not cause one or more adverse events (e.g., mild, moderate, severe, potentially life threatening) within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth dose of the anti-C3 antibody.
  • adverse events e.g., mild, moderate, severe, potentially life threatening
  • the dose Attorney Docket No.: 47702.0112WO1 and interval do not cause one or more adverse events (e.g., mild, moderate, severe, potentially life threatening) within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months of administering a last dose of the anti-C3 antibody.
  • adverse events e.g., mild, moderate, severe, potentially life threatening
  • Adverse events may be ocular (e.g., conjunctival, hemorrhage, eye pruritus, endophthalmitis, CNV development, intraocular inflammation, increased intraocular pressure lasting more than 60 minutes after administering the anti-C3 antibody) or non- ocular (e.g., basal cell carcinoma, benign prostatic hyperplasia, diarrhea, diverticulitis, headache, hypoesthesia, pneumonia, sciatica, ventricular extrasystoles).
  • the adverse event is endophthalmitis, CNV development, or intraocular inflammation in either eye.
  • the anti-C3 antibody is administered at a dose (e.g., 15 mg) and an interval (e.g., once every 4 weeks or once every 8 weeks) that does not increase the intraocular pressure (IOP) in the eye administered the anti-C3 antibody by more than 2.5%, more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, or more than 30% relative to the intraocular pressure prior to administering the anti-C3 antibody to the eye (e.g., within 1 hour, within 1 day, within 1 week of prior to administering the anti-C3 antibody), wherein the IOP is measured 1, 2, 3, 4, 5, or more days after said administering.
  • the method does not cause a measurable increase in IOP.
  • compositions comprising any one of the anti-C3antibodies described herein.
  • an anti-C3 Attorney Docket No.: 47702.0112WO1 antibody of this disclosure comprises: a VH comprising VH CDR1, VH CDR2, and VH CDR3 from the amino acid sequence set forth in SEQ ID NO:21, and a VL comprising VL CDR1, VL CDR2, and VL CDR3 from the amino acid sequence set forth in SEQ ID NO:25.
  • the CDRs can be based on any CDR definition known in the art (e.g., Kabat, Chothia, enhanced Chothia, contact, IMGT, etc.).
  • the anti-C3 antibody comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9, a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12.
  • the anti-C3 antibody comprises a VH comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:21 and a VL comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:25.
  • the anti-C3 antibody comprises a heavy chain comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:29 and a light chain comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:31.
  • compositions e.g., pharmaceutical formulations
  • the composition Attorney Docket No.: 47702.0112WO1 e.g., pharmaceutical formulation
  • the composition (e.g., pharmaceutical formulation) is administered to a human subject in need thereof in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the compositions comprise an anti-C3 antibody described herein at a concentration of 75 mg/mL to 175 mg/mL; 0.50 to 1 mg/mL L-Histidine; 2 to 5 mg/mL L-Histidine monohydrochloride monohydrate; 75 to 100 mg/mL sucrose; and 0.1 to 0.5 mg/mL polysorbate 20.
  • the composition (e.g., pharmaceutical formulation) has a pH of 5.0 to 6.0.
  • the composition (e.g., pharmaceutical formulation) is administered to a human subject in need thereof in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the compositions (e.g., pharmaceutical formulations) comprise an anti-C3 antibody described herein at a concentration of 150 mg/mL; histidine at a concentration of 20 mM; sucrose at a concentration of 8.2%; and PS20 at a concentration 0.02%.
  • the composition (e.g., pharmaceutical formulation) has a pH of 5.5.
  • the composition (e.g., pharmaceutical formulation) is administered to a human subject in need thereof in a volume of 50 to 100 ⁇ l (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ l).
  • the compositions (e.g., pharmaceutical formulations) described herein can be used to treat geographic atrophy.
  • the compositions (e.g., pharmaceutical formulations are used in a method treating geographic atrophy secondary to age-related macular degeneration in a human subject in need thereof.
  • the pharmaceutical composition is intravitreally administered to the human subject at a dose of 15 mg once every 4 weeks or once every 8 weeks.
  • compositions e.g., pharmaceutical formulations are used in a method of stabilizing or reducing GA lesion size or lesion growth in a human subject in need thereof.
  • the pharmaceutical composition is intravitreally administered to the human subject at a dose of 15 mg once every 4 weeks or once every 8 weeks.
  • the human subject Attorney Docket No.: 47702.0112WO1 in the above methods has a total GA lesion area in the eye of about 4.0 mm 2 to about 10.5 mm 2 .
  • the compositions (e.g., pharmaceutical formulations) described herein can be provided in any delivery device (e.g. syringe, pump).
  • kits comprising an anti-C3 antibody described herein.
  • the kit comprises (a) a container comprising a composition (e.g., a pharmaceutical composition) comprising an anti-C3 antibody described herein, and optionally (b) informational material.
  • the informational material is descriptive, instructional, marketing or other material that relates to the methods described herein.
  • the composition comprising the anti-C3 antibody in the kit comprises the anti-C3 antibody at a dose that does not cause one or more adverse events (e.g., mild, moderate, severe, potentially life threatening) in the human subject.
  • the composition comprising the anti-C3 antibody in the kit comprises the anti-C3 antibody in an amount sufficient to administer a 15 mg dose to a human subject.
  • the kit further comprises a device suitable for administration of the composition, e.g., a syringe or other suitable delivery device. The device can be provided pre-loaded with the composition comprising the anti-C3 antibody or can be empty, but suitable for loading.
  • Example 1 A randomized, double-masked multicenter study was performed in which subjects with GA secondary to AMD in one or both eyes were administered either the anti-C3 antibody identified as Hz38G10(G56A), as described herein, at a dose of 15 mg in 100 ⁇ l volume by intravitreal (IVT) injection, or a sham control, either every 4 weeks (Q4W; a total of 13 doses) or every 8 weeks (Q8W; a total of 7 doses) over a 52-week period. Only one eye of any given subject was chosen as the study eye. In the event both eyes were eligible, the eye with the worse visual function (lower BCVA value) was used as the study eye.
  • GA lesion area was measured by fundus autofluorescence (FAF).
  • Study inclusion criteria included: (a) male or female (non-pregnant, non-lactating) subjects ⁇ 55 of age; (b) standard luminance BCVA score of 34 letters or better using ETDRS charts at the starting distance of 4 meters (approximately 20/200 Snellen equivalent or better) in study eye; (c) Clinical diagnosis of GA secondary to AMD with the GA lesion meeting the following criteria as determined by the central reading center's assessment of FAF imaging at screening: (i) total GA area must be ⁇ 2.5 and ⁇ 17.5 mm 2 ; (ii) if GA is multifocal, at least one focal lesion must be ⁇ 1.25 mm 2 (0.5 DA), with the overall area of GA ⁇ 2.5 and ⁇ 17.5 mm 2 ; (
  • FIGS.1A-1C Min Lesion Max Size (mm 2 ) Size (mm 2 ) Lesion 2)
  • a further post-hoc quartile analysis was performed using both the MMRM and slope analyses. These analyses excluded only the quartile of patients with the largest lesions at the initiation of therapy (see, Table 5). The initial lesions size cut-off for the upper quartile is 9.64 mm 2 .
  • the middle two quartiles of patients were further assessed using a post-hoc MMRM and slope analysis
  • IOI intraocular inflammation
  • Table 7 Q 4W Q8W Sham Pooled Example 1E – Anti-C3 Therapy Did Not Cause Intraocular Inflammation Or Other Significant Adverse Events.
  • All subjects were assessed for adverse events including intraocular inflammation (IOI) in the study eye.
  • IOI is defined as inflammation, anterior chamber cells, vitreous cells, endophthalmitis, vitritis, retinal vasculitis, and retinal vein occlusion.
  • Attorney Docket No.: 47702.0112WO1 As shown in Table 8, the current anti-C3 therapies did not result in elevated IOI relative to the sham group.
  • the anti-C3 antibody comprises a VH and VL, wherein the VH comprises the three VH-CDRs of Hz38G10(G56A) and the VL comprises the three VL-CDRs of Hz38G10(G56A). See, Table 1. [00169] Provided below are exemplary sequences.

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Abstract

La présente divulgation propose de manière générale des procédés de traitement de l'atrophie géographique (GA), de réduction du taux de croissance de la zone de lésion GA totale, de ralentissement de la perte d'acuité visuelle, et de prévention ou de ralentissement du développement et/ou de la progression de la néovascularisation choroïdienne (CNV) dans un œil d'un sujet humain atteint de GA par administration intravitréenne au sujet d'un anticorps qui se lie spécifiquement au composant du complément humain C3. Dans certains modes de réalisation, le sujet est identifié comme présentant une zone de lésion GA totale dans l'œil inférieure à environ 4,0 mm2, environ 4,0 mm2 – environ 10,5 mm2, ou supérieure à environ 10,5 mm2. Dans certains cas, l'anticorps est administré à une dose et à un intervalle qui ne provoque pas une augmentation de l'inflammation intraoculaire et/ou qui ne provoque pas une augmentation de la pression intraoculaire qui est mesurable pendant plus de 48 heures.
PCT/US2023/077057 2022-10-17 2023-10-17 Utilisations d'anticorps anti-c3 WO2024086555A1 (fr)

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