Methods for treating eye diseases using lipid-binding protein-based complexes

Abstract

Disclosed herein are methods for treating ocular diseases, e.g., ocular diseases associated with lipid accumulation, using lipid-binding protein-based conjugates, such as CER-001; compositions comprising the lipid-binding protein-based conjugates as carriers for one or more ophthalmic drugs, and uses thereof.

Description

[Technical field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 328,088, filed April 6, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] 2. Sequence Listing This application contains a Sequence Listing that has been submitted electronically and is hereby incorporated by reference in its entirety. Said electronic copy, created on Mar. 28, 2023, is an XML file entitled CRN-041B-WO_ST26 and is 3,216 bytes in size. [Background technology]

[0003] 3.Background 3.1. Eye diseases The vertebrate eye is a complex sensory organ composed of multiple individual tissues, each with its own unique biochemical composition, structure, and physiological function. Chief among these are the retina, lens, and cornea, which work in concert to direct quanta of light into the eye, focus them correctly on the retina, and convert their energy into electrochemical signals that are transmitted to the brain, where they are finally processed into a coherent visual image. Defects in any or all of these tissues, whether congenital or acquired, through disease processes, or by trauma, can impair vision and ultimately result in complete and irreversible blindness. Lipids and lipid-soluble compounds are essential components of cells and tissues, including the eye, and defects in their synthesis, intracellular and extracellular transport, and turnover underlie a variety of significant, common, and often severely debilitating eye diseases.

[0004] Eye diseases can have various causes, such as genetics, infections, and aging. Some eye diseases, such as fish eye disease, dry eye disease associated with meibomian gland dysfunction or lacrimal gland dysfunction, corneal diseases such as blepharitis, uveitis, lipokeratopathy, dry macular degeneration (dry AMD), Stargardt's disease, and Leber's idiopathic stellate neuroretinitis, are associated with lipid accumulation in or near the eye.

[0005] 3.2. Lecithin cholesterol acyltransferase Lecithin cholesterol acyltransferase (LCAT) is an enzyme produced by the liver and is a key enzyme in the reverse cholesterol transport (RCT) pathway. The RCT pathway functions to eliminate cholesterol from most extrahepatic tissues and is essential to maintain the structure and function of most cells in the body. RCT consists mainly of three steps: (a) cholesterol efflux, i.e., the initial removal of cholesterol from various pools in peripheral cells; (b) cholesterol esterification by the action of lecithin:cholesterol acyltransferase (LCAT), which blocks the re-entry of the effluxed cholesterol into the cell; and (c) uptake of high-density lipoprotein (HDL)-cholesterol and cholesteryl esters into hepatocytes for hydrolysis, followed by recycling, storage, excretion into the bile, or catabolism to bile acids.

[0006] LCAT circulates in plasma associated with the HDL fraction. LCAT converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL and destined for elimination (see Jonas 2000, Biochim. Biophys. Acta 1529(1-3):245-56). Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) contribute to further remodeling of the circulating HDL population. CETP transfers cholesteryl esters made by LCAT to other lipoproteins, particularly those containing ApoB, such as very low density lipoproteins (VLDL) and low density lipoproteins (LDL). PLTP provides lecithin to HDL. HDL triglycerides are catabolized by extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.

[0007] LCAT deficiency causes the accumulation of non-esterified cholesterol in certain body tissues. Cholesterol is exported from cells as free cholesterol and transported in HDL as esterified cholesterol. LCAT is an enzyme that esterifies free cholesterol on HDL and allows HDL maturation. LCAT deficiency does not allow HDL maturation, resulting in its rapid catabolism of circulating apoA-1 and apoA-2. The remaining form of HDL resembles pristine HDL. Subjects with LCAT deficiency (both complete and partial) have low HDL cholesterol.

[0008] Familial LCAT deficiency is a rare genetic disorder that suffers from insufficient LCAT activity and is at risk for progressive chronic kidney disease and, in some cases, kidney failure. Fish eye disease is a partial LCAT deficiency in which LCAT cannot esterify cholesterol or convert acids to alkyl in HDL particles. However, LCAT remains active on cholesterol particles in VLDL and LDL.

[0009] 3.3.Fish eye disease Fish eye disease, also known as partial LCAT deficiency, is a disorder that gradually clouds the clear front surface of the eye (the cornea). The clouding, which typically first appears during adolescence or early adulthood, consists of small grayish dots (opacities) of cholesterol dispersed across the cornea.

[0010] Fish eye disease is characterized by abnormalities such as visual impairment, plaques of fatty material, and deep opacification. Fish eye disease is an autosomal recessive disorder caused by mutations in the LCAT gene, located on chromosome 16q22.1.

[0011] LCAT gene mutations that cause fish eye disease impair alpha-LCAT activity, reducing the enzyme's ability to attach cholesterol to HDL. Dysfunction of this mechanism for lowering cholesterol in the body leads to cholesterol-containing opacities in the cornea. It is unclear why cholesterol deposits only affect the cornea in this disorder. Mutations that affect both alpha-LCAT activity and beta-LCAT activity lead to a related disorder called complete LCAT deficiency, which involves corneal opacities in combination with traits that affect other parts of the body.

[0012] Currently, there is no specific treatment to correct LCAT deficiency, so therapy focuses on alleviating symptoms. In severe cases of fish eye disease, corneal transplants may be recommended.

[0013] New methods for treating subjects with ocular diseases, such as ocular diseases associated with lipid accumulation, are needed. Summary of the Invention

[0014] 4. Overview In one embodiment, the present disclosure provides a method for treating eye disease, such as eye disease associated with lipid accumulation (e.g., in subjects with ocular lipid deposits), using lipid-binding protein-based complexes, such as CER-001.Other lipid-binding protein-based complexes that can be used in the methods of the present disclosure include Apomer, Cargomer, and HDL-based complexes such as CSL-111, CSL-112, ETC-216, or delipidated HDL or HDL mimic-based complexes.In some eye diseases, lipids can accumulate in or near the eye (e.g., lipids can accumulate in the meibomian or lacrimal glands of a subject). Exemplary eye diseases associated with lipid accumulation that may be treated by the method of the present disclosure include dry eye disease, such as dry eye disease associated with meibomian gland dysfunction or lacrimal gland dysfunction, corneal diseases, such as blepharitis, uveitis, and lipokeratopathy, eye diseases associated with LCAT deficiency, such as dry macular degeneration (dry AMD), Stargardt's disease, Leber's idiopathic stellate neuroretinopathy, and fish eye disease. In some embodiments, the use of lipid-binding protein complexes may reduce the severity of eye diseases. In some embodiments, the use of lipid-binding protein complexes may slow the progression of eye diseases. Without being bound by theory, it is believed that lipid-binding protein complexes may reduce ocular lipid deposits, for example, by solubilizing lipids accumulated in ocular deposits, leading to their elimination.

[0015] In another aspect, the present disclosure provides a method for delivering an ophthalmic drug to the eye of a subject having an ocular disease using a lipid-binding protein-based conjugate (e.g., CER-001) as a drug carrier, thereby treating the ocular disease. For example, the subject may be a subject suffering from an anterior or posterior ocular pathology, such as uveitis, macular edema (e.g., diabetic macular edema), macular degeneration, retinal detachment, ocular tumor, fungal or viral infection, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, or glaucoma.

[0016] In another embodiment, the disclosure provides a composition comprising a lipid-binding protein-based conjugate (eg, CER-001) and one or more ophthalmic drugs conjugated thereto.

[0017] In the methods described herein, the lipid-binding protein-based complex (e.g., CER-001) can be administered systemically (e.g., by injection). Alternatively, the lipid-binding protein-based complex (e.g., CER-001) can be administered locally (e.g., by intraocular or local administration). Intraocular administration can be, for example, by intraocular injection, for example, intravitreal injection, sub-conjuctival injection, parabulbar injection, peribulbar injection, or retrobulbar injection. For local administration, the lipid-binding protein-based complex (e.g., CER-001) can be administered, for example, as eye drops. Additional means of delivery can also be used, for example, suprachoroidal injection, suprascleral injection, implant (e.g., disk, sheet, wand, rod, or pellet), iontophoresis, or delivery by electroporation.

[0018] In one embodiment, the present disclosure provides a dosing regimen for lipid-binding protein-based complex (e.g., CER-001) for treating subjects with eye diseases associated with lipid accumulation.The dosing regimen described herein can also be applied to deliver ophthalmic drugs to the eye using lipid-binding protein-based complex (e.g., CER-001) as a drug carrier.

[0019] The dosing regimen of the present disclosure, in some embodiments, involves administering a lipid-binding protein-based complex (e.g., CER-001) to a subject according to an initial "induction" regimen, followed by administering a lipid-binding protein-based complex (e.g., CER-001) to the subject according to an "intensification" regimen, followed by administering a lipid-binding protein-based complex (e.g., CER-001) to the subject according to a "maintenance" regimen. Alternatively, the dosing regimen may involve administering a lipid-binding protein-based complex (e.g., CER-001) to a subject according to a "maintenance" regimen without a preceding "induction" or "intensification" regimen. As another alternative, the dosing regimen may involve administering a lipid-binding protein-based complex (e.g., CER-001) to a subject according to an "induction" regimen followed by a "maintenance" regimen, without an intervening "intensification" regimen.

[0020] The induction regimen typically comprises administering to the subject multiple doses of lipid-binding protein-based complex (e.g., CER-001), with one or more days between each dose. In some embodiments, the induction regimen comprises three or more doses of lipid-binding protein-based complex (e.g., CER-001). In some embodiments, the induction regimen comprises three doses of lipid-binding protein-based complex (e.g., CER-001) per week. In some embodiments, the induction regimen comprises three doses of lipid-binding protein-based complex (e.g., CER-001) per week for a period of more than one week, for example, two or more weeks. In some embodiments, the induction regimen comprises three doses of lipid-binding protein-based complex (e.g., CER-001) per week for a period of three weeks.

[0021] The intensive regimen typically comprises administering to the subject multiple doses of lipid-binding protein-based complex (e.g., CER-001) less frequently than during the induction regimen. The intensive regimen typically comprises administering to the subject multiple doses of lipid-binding protein-based complex (e.g., CER-001), with one or more days between each dose, for example, two or more days between each dose. In some embodiments, the intensive regimen comprises two or more doses of lipid-binding protein-based complex (e.g., CER-001). In some embodiments, the intensive regimen comprises two doses of lipid-binding protein-based complex (e.g., CER-001) per week. In some embodiments, the intensive regimen comprises two doses of lipid-binding protein-based complex (e.g., CER-001) per week for more than one week, for example, two or more weeks. In some embodiments, the intensive regimen comprises two weekly doses of a lipid-binding protein-based conjugate (eg, CER-001) for a period of three weeks.

[0022] A maintenance regimen typically comprises administering one or more doses of lipid-binding protein-based complex (e.g., CER-001) to a subject less frequently than during a consolidation regimen, with a period of, for example, 5 days or more, e.g., 1 week, between doses. In certain embodiments, multiple doses of lipid-binding protein-based complex (e.g., CER-001) are administered once a week during a maintenance regimen.

[0023] In certain embodiments, the present disclosure provides a method of treating a subject with a lipid-binding protein-based complex (e.g., CER-001) using an induction regimen comprising administering to the subject three doses of the lipid-binding protein-based complex (e.g., CER-001) within one week for three weeks with at least one day between each dose, followed by a consolidation regimen comprising administering to the subject two doses of the lipid-binding protein-based complex (e.g., CER-001) within one week for three weeks with at least two days between each dose, followed by a maintenance regimen comprising administering to the subject one dose of the lipid-binding protein-based complex (e.g., CER-001) every week.

[0024] In certain aspects, the present disclosure provides a method of treating a subject with lipid-binding protein-based complex (e.g., CER-001) according to the dosing regimen described herein.In some embodiments, lipid-binding protein-based complex (e.g., CER-001) is diluted with saline before intravenous administration, such as intravenous infusion using an infusion pump.In certain embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) for infusion is based on subject weight, for example, 10mg / kg on protein weight basis.

[0025] In certain aspects, the present disclosure provides: - Three doses per week for three weeks (induction regimen), followed by - 2 doses per week for 3 weeks (intensive regimen), followed by - One dose per week until the end of treatment (maintenance regimen) The present invention provides a method of treating a subject having an ocular disease (e.g., associated with lipid accumulation) with a lipid-binding protein-based conjugate (e.g., CER-001) according to a dosing regimen comprising:

[0026] In certain embodiments, for example, when lipid-binding protein-based complex is administered by IV infusion, antihistamine (e.g., dexchlorpheniramine, hydroxyzine, diphenhydramine, cetirizine, fexofenadine, or lorantadine) can be administered before administration of lipid-binding protein-based complex (e.g., CER-001).Antihistamine can reduce the possibility of allergic reaction.

[0027] The subject treated according to the dosage regimen of the present disclosure can be any subject suffering from eye disease associated with lipid accumulation, such as the subject with LCAT deficiency.LCAT deficiency can be complete LCAT deficiency or partial LCAT deficiency.In some embodiments, the subject treated according to the dosage regimen of the present disclosure has fish eye disease.Alternatively, the subject treated according to the dosage regimen of the present disclosure can be any subject that requires treatment with ophthalmic drugs, and the drug is delivered to the eye using lipid-binding protein-based complex (e.g., CER-001) as drug carrier. [Brief description of the drawings]

[0028] 5. Brief description of the drawings [Figure 1-1] Ophthalmic drugs Azithromycin (Figure 1A), Spironolactone (Figure 1B) [Figure 1-2] FIG. 1C shows the ability of CER-001 to act as a drug carrier for dexamethasone palmitate (FIG. 1C) and cyclosporine (FIG. 1D). [Figure 2-1] 2A-2C are graphs showing tolerability scores from rabbits administered CER-001 with or without conjugated dexamethasone palmitate (Example 4). Figure 2A: Plot of tolerability at 6 and 24 hour time points; [Figure 2-2] Figure 2B: Tolerability at 6 hours; [Figure 2-3] Figure 2C: Tolerability at 24 hours. [Figure 3-1]Cellular infiltration in the aqueous humor of rabbits administered CER-001 with or without combined dexamethasone palmitate (Figure 3A) and [Figure 3-2] 3B is a graph showing the protein (FIG. 3B) (Example 4). [Figure 4] 1 is a graph showing haze in the eyes of rabbits administered CER-001 and a soft corticoid (CER-S Cort) at 0, 6, and 24 hours post-dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] 6. Detailed Description In some aspects, the present disclosure provides a method for treating ocular diseases (e.g., ocular diseases associated with lipid accumulation) using lipid-binding protein-based complexes (e.g., CER-001). The method of the present disclosure can reduce the severity of ocular diseases in a subject. In some embodiments, the lipid-binding protein-based complex is an Apomer, a Cargomer, an HDL-based complex, or an HDL mimic-based complex. In some embodiments, the lipid-binding protein-based complex can be used as a drug carrier to deliver one or more ophthalmic drugs, such as one or more ophthalmic drugs that are hydrophobic and / or poorly water-soluble or water-insoluble, to the eye.

[0030] In some embodiments, the lipid-binding protein-based complex (e.g., CER-001) (e.g., when used as a drug carrier or not used as a drug carrier) does not contain or is not administered with a cell-penetrating peptide (CPP) (e.g., a CPP described in WO 2019 / 018350), a chemical penetration enhancer (CPE) (e.g., a CPE described in WO 2019 / 018350), or a cell affinity peptide (e.g., a cell affinity peptide described in EP 3238746). The contents of WO 2019 / 018350 and EP 3238746 are incorporated herein by reference in their entirety.

[0031] In additional embodiments, the present disclosure provides lipid-binding protein-based complexes, such as CER-001, for use as carriers for one or more ophthalmic drugs. Thus, in some embodiments, the present disclosure provides compositions comprising lipid-binding protein-based complexes (e.g., CER-001) having one or more ophthalmic drugs (e.g., as described in Section 6.1.8) conjugated thereto. Such compositions can be used in the methods of the present disclosure.

[0032] Exemplary characteristics of lipid-binding protein-based complexes that can be used in the methods and compositions of the present disclosure are described in Section 6.1. Exemplary subject populations that can be treated by the methods and with the compositions of the present disclosure are described in Section 6.2.

[0033] The lipid-binding protein-based complex can be administered peripherally or locally. In some embodiments, the lipid-binding protein-based complex is administered peripherally, for example by injection. In other embodiments, the lipid-binding protein-based complex is administered locally (for example by intraocular or topical administration).

[0034] In some embodiments, the method of the present disclosure comprises administering lipid-binding protein-based complexes (e.g., CER-001) to a subject in three phases. First, lipid-binding protein-based complexes (e.g., CER-001) are administered in an initial strong "induction" regimen. The induction regimen is followed by a less strong "consolidation" regimen. The consolidation regimen is followed by a "maintenance" regimen. In other methods of the present disclosure, lipid-binding protein-based complexes (e.g., CER-001) are administered in two phases (e.g., induction regimen followed by maintenance regimen) or in a single phase (e.g., maintenance regimen). Induction regimens that can be used in the methods of the present disclosure are described in Section 6.3, consolidation regimens that can be used in the methods of the present disclosure are described in Section 6.4, and maintenance regimens that can be used in the methods of the present disclosure are described in Section 6.5. The dosing regimens of the present disclosure include administering a lipid-binding protein-based conjugate (e.g., CER-001) as a monotherapy or as part of a combination therapy with one or more pharmaceutical agents. Combination therapy is described in Section 6.6.

[0035] 6.1. Lipid-binding protein-based complexes 6.1.1. HDL and HDL-mimetic-based complexes In one embodiment, the lipid-binding protein-based complex comprises HDL or HDL mimic-based complex.For example, the complex may comprise the lipoprotein complex described in U.S. Pat. No. 8,206,750, WO 2012 / 109162, WO 2015 / 173633 (e.g., CER-001), WO 2004 / 073684, or U.S. Patent Application Publication No. 2004 / 0229794, the contents of each of which are incorporated herein by reference in their entirety.The terms "lipoprotein" and "apolipoprotein" are used interchangeably herein, and unless otherwise required by context, the term "lipoprotein" encompasses lipoprotein mimics.The terms "lipid-binding protein" and "lipid-binding polypeptide" are also used interchangeably herein, and unless otherwise required by context, the terms do not imply a specific length of amino acid sequence.

[0036] The lipoprotein complex may include a protein fraction (e.g., an apolipoprotein fraction) and a lipid fraction (e.g., a phospholipid fraction). The protein fraction includes one or more lipid-binding protein molecules, such as an apolipoprotein, a peptide, or an apolipoprotein peptide analog or mimetic, for example, one or more lipid-binding protein molecules described in Section 6.1.4. In some embodiments, the lipid-binding protein molecule includes an apolipoprotein molecule (e.g., an ApoA-I molecule), but does not include an apolipoprotein mimetic molecule.

[0037] The lipid fraction typically contains one or more phospholipids, which may be neutral, negatively charged, positively charged, or a combination thereof. Exemplary phospholipids and other amphipathic molecules that may be included in the lipid fraction are described in Section 6.1.6.

[0038] In certain embodiments, the lipid fraction contains at least one neutral phospholipid (e.g., sphingomyelin (SM)), and optionally one or more negatively charged phospholipids. In lipoprotein complexes that contain both neutral and negatively charged phospholipids, the neutral and negatively charged phospholipids may have fatty acid chains with the same or different numbers of carbons, and the same or different degrees of saturation. In some cases, the neutral and negatively charged phospholipids will have the same acyl tail, e.g., C16:0, or polymitoyl, acyl chains. In specific embodiments, particularly those in which egg SM is used as the neutral lipid, the weight ratio of apolipoprotein fraction:lipid fraction ranges from about 1:2.7 to about 1:3 (e.g., 1:2.7).

[0039] Any phospholipid that has at least a partial negative charge at physiological pH can be used as the negatively charged phospholipid.Non-limiting examples include phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, and the negatively charged forms, such as salts, of phosphatidic acid.In a specific embodiment, the negatively charged phospholipid is phosphatidylglycerol 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], i.e. DPPG.Preferred salts include potassium and sodium salts.

[0040] In some embodiments, the lipoprotein complexes used in the compositions and methods of the present disclosure are lipoprotein complexes described in U.S. Pat. No. 8,206,750 or WO 2012 / 109162 (and its U.S. counterpart, U.S. Patent Application Publication No. 2012 / 0232005), the contents of each of which are incorporated herein by reference in their entireties. In certain embodiments, the protein components of the lipoprotein complex are as described in Section 6.1 and preferably Section 6.1.1 of WO 2012 / 109162 (and US 2012 / 0232005), and the lipid components are as described in Section 6.2 of WO 2012 / 109162 (and US 2012 / 0232005), which may optionally be complexed together in amounts as described in Section 6.3 of WO 2012 / 109162 (and US 2012 / 0232005). The contents of each of these sections are incorporated by reference herein. In certain embodiments, the lipoprotein complexes of the present disclosure are in a population of complexes that is at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% homogeneous, as described in Section 6.4 of WO 2012 / 109162 (and U.S. Patent Application Publication No. 2012 / 0232005), the contents of which are incorporated by reference herein.

[0041] In a specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure contains 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 50-80 molecules of lecithin, and 20-50 molecules of SM.

[0042] In another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure contains 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 50 molecules of lecithin, and 50 molecules of SM.

[0043] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure contains 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 80 molecules of lecithin, and 20 molecules of SM.

[0044] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure contains 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 70 molecules of lecithin, and 30 molecules of SM.

[0045] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure contains 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 60 molecules of lecithin, and 40 molecules of SM.

[0046] In a specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure consists essentially of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 50-80 molecules of lecithin, and 20-50 molecules of SM.

[0047] In another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure consists essentially of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 50 molecules of lecithin, and 50 molecules of SM.

[0048] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure consists essentially of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 80 molecules of lecithin, and 20 molecules of SM.

[0049] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure consists essentially of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 70 molecules of lecithin, and 30 molecules of SM.

[0050] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure consists essentially of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipid, 60 molecules of lecithin, and 40 molecules of SM.

[0051] In specific embodiments, lipoprotein complexes that can be used in the compositions and methods of the present disclosure comprise a lipid component that includes about 90-99.8 wt% SM and about 0.2-10 wt% negatively charged phospholipids, such as about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids. In another specific embodiment, a lipoprotein complex that can be used in the methods of the present disclosure comprises about 90-99.8 wt% lecithin and about 0.2-10 wt% negatively charged phospholipids, such as about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids.

[0052] In specific embodiments, lipoprotein complexes that can be used in the compositions and methods of the present disclosure include a lipid component consisting essentially of about 90-99.8 wt% SM, and about 0.2-10 wt% negatively charged phospholipids, e.g., about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids. In another specific embodiment, a lipoprotein complex that can be used in the methods of the present disclosure consists essentially of about 90-99.8 wt% lecithin and about 0.2-10 wt% negatively charged phospholipids, such as about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids.

[0053] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure comprises a lipid fraction containing about 9.8-90 wt% SM, about 9.8-90 wt% lecithin, and about 0.2-10 wt% negatively charged phospholipids, for example, from about 0.2-1 wt%, to 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% negatively charged total phospholipids.

[0054] In yet another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure comprises a lipid fraction consisting essentially of about 9.8-90 wt% SM, about 9.8-90 wt% lecithin, and about 0.2-10 wt% negatively charged phospholipids, for example, from about 0.2-1 wt%, to 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% negatively charged total phospholipids.

[0055] In another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure comprises an ApoA-I apolipoprotein and a lipid fraction, the lipid fraction comprising sphingomyelin and about 3 wt. % negatively charged phospholipids, the molar ratio of lipid fraction to ApoA-I apolipoprotein is about 2:1 to 200:1, and the complex is a small or large discoid particle containing 2 to 4 ApoA-I equivalents.

[0056] In another specific embodiment, a lipoprotein complex that can be used in the compositions and methods of the present disclosure comprises an ApoA-I apolipoprotein and a lipid fraction, the lipid fraction consisting essentially of sphingomyelin and about 3 wt. % negatively charged phospholipids, the molar ratio of lipid fraction to ApoA-I apolipoprotein is about 2:1 to 200:1, and the complex is a small or large discoid particle containing 2 to 4 ApoA-I equivalents.

[0057] HDL-based or HDL-mimetic-based complexes may contain a single type of lipid-binding protein or a mixture of two or more different lipid-binding proteins, which may be derived from the same or different species.Although not required, the complexes will preferably contain lipid-binding proteins that are derived from or correspond in amino acid sequence to the animal species being treated, in order to avoid inducing immune response to therapy.Therefore, for the treatment of human patients, lipid-binding proteins of human origin are preferably used.The use of peptidomimetic apolipoproteins can also reduce or avoid immune response.

[0058] In some embodiments, the lipid component comprises two types of phospholipids: sphingomyelin (SM) and negatively charged phospholipids. Exemplary SM and negatively charged lipids are described in Section 6.1.6.1.

[0059] The lipid component comprising the SM may optionally contain small amounts of additional lipids. Virtually any type of lipid may be used, including, but not limited to, lysophospholipids, galactocerebrosides, gangliosides, cerebrosides, glycerides, triglycerides, and cholesterol and its derivatives.

[0060] If included, such optional lipids will typically comprise less than about 15 wt% of the lipid fraction, although in some cases more optional lipids may be included.In some embodiments, optional lipids comprise less than about 10 wt%, less than about 5 wt%, or less than about 2 wt%.In some embodiments, the lipid fraction does not comprise optional lipids.

[0061] In a specific embodiment, the phospholipid fraction contains egg SM or palmitoyl SM or phytosphingomyelin and DPPG in a weight ratio (SM:negatively charged phospholipid) ranging from 90:10 to 99:1, more preferably ranging from 95:5 to 98:2. In one embodiment, the weight ratio is 97:3.

[0062] The molar ratio of lipid to protein components of the complexes of the present disclosure may vary and will depend, among other factors, on the identity of the apolipoproteins that make up the protein component, the identity and amount of the lipids that make up the lipid component, and the desired size of the complex. Because the biological activity of apolipoproteins such as ApoA-I is believed to be mediated by the amphipathic helices that make up the apolipoprotein, it is advantageous to use ApoA-I protein equivalents to express the apolipoprotein fraction of the lipid:apolipoprotein molar ratio. Depending on the method used to calculate the helices, it is generally accepted that ApoA-I contains between 6 and 10 amphipathic helices. Other apolipoproteins can be expressed in terms of ApoA-I equivalents based on the number of amphipathic helices they contain. For example, ApoA-I, which typically exists as a disulfide-bridged dimer, is a soluble form of ApoA-I.M can be expressed as two ApoA-I equivalents, because ApoA-I M Each molecule of apoA-I contains twice as many amphipathic helices as a molecule of ApoA-I. Conversely, a peptide apolipoprotein containing a single amphipathic helix may be expressed as 1 / 10 to 1 / 6 of an ApoA-I equivalent, since each molecule contains 1 / 10 to 1 / 6 of an ApoA-I equivalent. In general, the lipid:ApoA-I equivalent molar ratio (defined herein as "Ri") of the lipoprotein complex will range from about 105:1 to 110:1. In some embodiments, Ri is about 108:1. Weight ratios may be achieved using a MW of approximately 650 to 800 for the phospholipid.

[0063] In some embodiments, the lipid:ApoA-I equivalent molar ratio ("RSM") ranges from about 80:1 to about 110:1, such as from about 80:1 to about 100:1. In a specific example, the RSM for the complex can be about 82:1.

[0064] In some embodiments, the lipoprotein complex used in the methods of the present disclosure is a negatively charged complex comprising a protein fraction, preferably mature full-length ApoA-I, and a lipid fraction comprising neutral phospholipids, sphingomyelin (SM), and negatively charged phospholipids.

[0065] In a specific embodiment, the lipid component contains SM (e.g., egg SM, palmitoyl SM, phyto SM, or a combination thereof) and a negatively charged phospholipid (e.g., DPPG) in a weight ratio (SM:negatively charged phospholipid) ranging from 90:10 to 99:1, more preferably from 95:5 to 98:2, for example, ranging from 97:3.

[0066] In specific embodiments, the ratio of protein components to lipid components can range from about 1:2.7 to about 1:3, with 1:2.7 being preferred. This corresponds to a molar ratio of ApoA-I protein to lipid ranging from approximately 1:90 to 1:140. In some embodiments, the molar ratio of protein to lipid in the complex is from about 1:90 to about 1:120, from about 1:100 to about 1:140, or from about 1:95 to about 1:125.

[0067] In certain embodiments, the conjugate comprises CER-001, CSL-111, CSL-112, CER-522, or ETC-216. In a preferred embodiment, the conjugate is CER-001.

[0068] CER-001 as used herein and in the examples below refers to the complex described in Example 4 of WO 2012 / 109162. WO 2012 / 109162 refers to CER-001 as a complex having a lipoprotein weight:total phospholipid weight ratio of 1:2.7, with a SM:DPPG weight:weight ratio of 97:3. Example 4 of WO 2012 / 109162 also describes a method of its preparation.

[0069] When used in the context of the CER-001 dosing regimen or composition of the present disclosure, CER-001 refers to a lipoprotein complex whose individual components may differ by up to 20% from CER-001 described in Example 4 of WO 2012 / 109162. In certain embodiments, the components of the lipoprotein complex differ by up to 10% from CER-001 described in Example 4 of WO 2012 / 109162. Preferably, the components of the lipoprotein complex are those described in Example 4 of WO 2012 / 109162 (plus / minus allowed manufacturing tolerance variations). The SM in CER-001 can be natural or synthetic. In some embodiments, the SM is a natural SM, such as a natural SM described in WO 2012 / 109162, such as chicken egg SM. In some embodiments, the SM is a synthetic SM, such as the synthetic SM described in WO 2012 / 109162, such as the synthetic palmitoyl sphingomyelin described in WO 2012 / 109162. Methods for synthesizing palmitoyl sphingomyelin are known in the art, for example as described in WO 2014 / 140787. The lipoprotein in CER-001, apolipoprotein AI (ApoA-I), preferably has an amino acid sequence corresponding to amino acids 25-267 of SEQ ID NO: 1 of WO 2012 / 109162 (SEQ ID NO: 1 of WO 2012 / 109162, disclosed herein as SEQ ID NO: 2). ApoA-I can be purified from an animal source (particularly from a human source) or can be recombinantly produced. In a preferred embodiment, the ApoA-I in CER-001 is recombinant ApoA-I. CER-001 used in the dosing regimens of the present disclosure is preferably highly homogenous, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% homogenous, as reflected by a single peak in gel permeation chromatography.See, for example, Section 6.4 of WO 2012 / 109162.

[0070] CSL-111 is reconstituted human ApoA-I purified from plasma in complex with soybean phosphatidylcholine (SBPC) (Tardif et al., 2007, JAMA 297:1675-1682).

[0071] CSL-112 is a formulation of ApoA-I purified from plasma and reconstituted to form HDL suitable for intravenous infusion (Diditchenko et al., 2013, DOI 10.1161 / ATVBAHA.113.301981).

[0072] ETC-216 (also known as MDCO-216) is a recombinant ApoA-I ミラノ It is a lipid-depleted form of HDL that contains. See Nicholls et al., 2011, Expert Opin Biol Ther. 11(3):387-94. doi: 10.1517 / 14712598.2011.557061.

[0073] In another embodiment, a complex that can be used in the methods of the present disclosure is CER-522. CER-522 is a lipoprotein complex that contains a combination of three phospholipids and the 22 amino acid peptide CT80522.

[0074] [ka]

[0075] The phospholipid component of CER-522 consists of egg sphingomyelin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (dipalmitoylphosphatidylcholine, DPPC), and 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (dipalmitoylphosphatidyl-glycerol, DPPG) in a weight ratio of 48.5:48.5:3. The peptide to total phospholipid ratio in the CER-522 complex is 1:2.5 (w / w).

[0076] In some embodiments, the lipoprotein complex is delipidated HDL. Most HDL in plasma is rich in cholesterol. Lipids in HDL can be depleted, for example partially and / or selectively depleted, for example to reduce its cholesterol content. In some embodiments, delipidated HDL can resemble small alpha, pre-beta-1, and other pre-beta forms of HDL. The process for selective depletion of HDL is described in Sacks et al., 2009, J Lipid Res. 50(5): 894-907.

[0077] In certain embodiments, the lipoprotein complexes comprise bioactive agent delivery particles as described in US Patent Application Publication No. 2004 / 0229794.

[0078] The bioactive agent delivery particle can include a lipid-binding polypeptide (e.g., an apolipoprotein as described herein or previously in Section 6.1.4), a lipid bilayer (e.g., including one or more phospholipids as described herein or previously in Section 6.1.6.1), and a bioactive agent (e.g., an anti-cancer agent), wherein the interior of the lipid bilayer includes a hydrophobic region, and the bioactive agent associates with the hydrophobic region of the lipid bilayer. In some embodiments, the bioactive agent delivery particle is described in U.S. Patent Application Publication No. 2004 / 0229794.

[0079] In some embodiments, the bioactive agent delivery particles do not include a hydrophilic core.

[0080] In some embodiments, the bioactive agent delivery particles are disc-shaped (eg, having a diameter of about 7 to about 29 nm).

[0081] The bioactive agent delivery particle comprises a bilayer-forming lipid, such as a phospholipid (e.g., as described previously in this section or in Section 6.1.6.1). In some embodiments, the bioactive agent delivery particle comprises both bilayer-forming and non-bilayer-forming lipids. In some embodiments, the lipid bilayer of the bioactive agent delivery particle comprises a phospholipid. In one embodiment, the phospholipid incorporated into the delivery particle comprises dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG). In one embodiment, the lipid bilayer comprises DMPC and DMPG in a molar ratio of 7:3.

[0082] In some embodiments, the lipid-binding polypeptide is an apolipoprotein (e.g., as described in this section or previously in Section 6.1.4). The primary interaction between lipid-binding polypeptide, e.g., apolipoprotein molecule, and lipid bilayer is generally hydrophobic interaction between residues on the hydrophobic face of amphipathic structure, e.g., α-helix of lipid-binding polypeptide, and fatty acyl chains of lipids on the outer surface at the periphery of the particle. Bioactive agent delivery particles can include exchangeable and / or non-exchangeable apolipoproteins. In one embodiment, the lipid-binding polypeptide is ApoA-I.

[0083] In some embodiments, the bioactive agent delivery particles include lipid-binding polypeptide molecules, such as apolipoprotein molecules, that have been modified to increase the stability of the particles. In one embodiment, the modification includes the introduction of cysteine ​​residues that form intra- and / or intermolecular disulfide bonds.

[0084] In another embodiment, the bioactive agent delivery particle comprises a chimeric lipid-binding polypeptide molecule, e.g., a chimeric apolipoprotein molecule, with one or more associated functional moieties, e.g., one or more targeting moieties and / or one or more moieties having a desired biological activity, e.g., antimicrobial activity, that may enhance or act in synergy with the activity of the bioactive agent incorporated within the delivery particle.

[0085] 6.1.2.Apomer-based complexes In one embodiment, the lipid-binding protein-based complex that can be used in the method and composition of the present disclosure comprises Apomer.The characteristics of Apomer that can be included in Apomer-based complex are described in International Publication No. WO2019 / 030575, the contents of which are incorporated herein by reference in their entirety.

[0086] Apomers generally comprise apolipoproteins in monomeric or multimeric form complexed with amphiphilic molecules. Generally, apomers comprise one or more apolipoprotein molecules, each of which is complexed with one or more amphiphilic molecules. In certain embodiments, the amphiphilic molecules together contribute at least +1 or -1 net charge per apolipoprotein molecule in the apomer. Exemplary apolipoproteins that can be used in apomers are described in Section 6.1.5.1. Exemplary amphiphilic molecules are described in Section 6.1.6.

[0087] Cargomer-based Complexes In one embodiment, the lipid-binding protein-based complex that can be used in the methods and compositions of the present disclosure comprises Cargomer, which is a lipid-binding protein-based complex having one or more cargo moieties.The characteristics of Cargomer that can be included in Cargomer-based complex are described in WO2019 / 030574, the contents of which are incorporated herein by reference in their entirety.

[0088] Cargomers generally comprise apolipoproteins in monomeric or multimeric form (e.g., 2, 4, or 8 apolipoprotein molecules) and one or more cargo moieties. The cargo moieties may be amphipathic or non-amphipathic. Amphipathic cargo moieties may solubilize apolipoproteins and prevent them from aggregating. If the cargo moiety is not amphipathic or insufficient to solubilize apolipoprotein molecules, the Cargomer may also comprise one or more additional amphipathic molecules that solubilize apolipoproteins. Thus, reference to an amphipathic molecule in the context of a Cargomer encompasses amphipathic molecules that are cargo moieties, amphipathic molecules that are not cargo moieties, or combinations of parts thereof. Preferably, the Cargomer is not discotic, for example, as determined using NMR spectroscopy.

[0089] The cargo moiety may include biologically active molecules (e.g., drugs, biologics, and / or immunogens) or other agents, such as agents used in diagnosis. As used herein, the terms "molecule" and "agent" also include complexes and conjugates (e.g., antibody-drug conjugates). Terms such as "biologically active", "diagnostically useful" are not limited to substances with direct pharmacological or biological activity, but may include substances that become active after administration, for example, due to metabolism of a prodrug or cleavage of a linker. Thus, the terms "biologically active" and "diagnostically useful" also include substances that become biologically active or diagnostically useful after administration through the creation of metabolites or other cleavage products that exert a pharmacological or biological effect and / or are detectable in a diagnostic test.

[0090] The amphipathic molecule in the Cargomer may solubilize the apolipoprotein and / or reduce or minimize apolipoprotein aggregation, and may have other functions in the Cargomer. For example, the amphipathic molecule may have therapeutic utility and thus may be the cargo moiety intended for delivery by the Cargomer upon administration to a subject. Additionally, as discussed in Section 6.1.6 below, the amphipathic molecule may be used to anchor a non-amphipathic cargo moiety to the apolipoprotein in the Cargomer. Thus, in some embodiments, the cargo moiety and the amphipathic molecule in the Cargomer are the same. In other embodiments, the anchor moiety and the amphipathic molecule in the Cargomer are the same. In still other embodiments, the cargo moiety, anchor moiety, and amphipathic molecule in the Cargomer are the same (e.g., when the amphipathic molecule has therapeutic activity and also anchors another biologically active molecule to the apolipoprotein molecule).

[0091] The anchor and / or linker moieties are particularly useful for Cargomers that have cargo moieties that are not amphipathic molecules.

[0092] In some embodiments, at least one of the cargo moieties, a majority of the cargo moieties, or all of the cargo moieties in a Cargomer of the present disclosure are conjugated to the Cargomer via an anchor. In some embodiments, at least one of the cargo moieties in a Cargomer is conjugated to the Cargomer via an anchor. In some embodiments, a majority of the cargo moieties in a Cargomer are conjugated to the Cargomer via an anchor. In some embodiments, all of the cargo moieties in a Cargomer are conjugated to the Cargomer via an anchor. Each anchor in a Cargomer can be the same, or alternatively, different types of anchors can be included in a single Cargomer (e.g., one type of cargo moiety can be conjugated to the Cargomer via one type of anchor and a second type of cargo moiety can be conjugated to the Cargomer via a second type of anchor).

[0093] In certain embodiments, the amphipathic molecule, the cargo, and, if present, the anchor and / or linker together contribute at least +1 or -1 net charge (e.g., +1, +2, +3, -1, -2, or -3) per apolipoprotein molecule in the Cargomer. In some embodiments, the net charge is a negative charge. In other embodiments, the net charge is a positive charge. Unless otherwise required by context, the charge is measured at physiological pH.

[0094] The molar ratio of apolipoprotein molecules to amphipathic molecules in a Cargomer can be, but need not be, an integer, or can reflect a one-to-one relationship between apolipoproteins and amphipathic molecules. By way of example and not limitation, a Cargomer can have an apolipoprotein to amphipathic molecule molar ratio of 2:5, 8:7, 3:2, or 4:7.

[0095] In some embodiments, the Cargomer is 8:1 to 1:15 (e.g., 8:1 to 1:15, 7:1 to 1:15, 6:1 to 1:15, 5:1 to 1:15, 4:1 to 1:15, 3:1 to 1:15, 2:1 to 1:15, 1:1 to 1:15, 8:1 to 1:14, 7:1 to 1:14, 6:1 to 1:14, 5:1 to 1:14, 4:1 to 1:14, 3:1 to 1:14, 2:1 to 1:14, 1:1 to 1:14, 8:1 to 1:13, 7:1 to 1:13, 6:1 to 1:13, 5:1 to 1:13, 4:1 to 1:13, 3:1 to 1:13, 2:1 to 1:13, 1:1 to 1: 13, 8:1~1:12, 7:1~1:12, 6:1~1:12, 5:1~1:12, 4:1~1:12, 3:1~1:12, 2:1~1:12, 1:1~1:12, 8:1~1:11, 7:1~1:11, 6:1~1:11, 5:1~1:11, 4:1~1:11, 3:1~ 1:11, 2:1~1:11, 1:1~1:11, 8:1~1:10, 7:1~1:10, 6:1~1:10, 5:1~1:10, 4:1~1:10, 3:1~1:10, 2:1~1:10, 1:1~1:10, 8:1~1:9, 7:1~1:9, 6:1~1:9, 5:1~1: 9, 4:1~1:9, 3:1~1:9, 2:1~1:9, 1:1~1:9, 8:1~1:8, 7:1~1:8, 6:1~1:8, 5:1~1:8, 4:1~1:8, 3:1~1:8, 2:1~1:8, 1:1~1:8, 8:1~1:7, 7:1~1:7, 6:1~1:7, 5: 1~1:7, 4:1~1:7, 3:1~1:7, 2:1~1:7, 1:1~1:7, 8:1~1:6, 7:1~1:6, 6:1~1:6, 5:1~1:6, 4:1~1:6, 3:1~1:6, 2:1~1:6, 1:1~1:6, 8:1~1:5, 7:1~1:5, 6:1~1:5 , 5:1~1:5, 4:1~1:5, 3:1~1:5, 2:1~1:5, 1:1~1:5, 8:1~1:4, 7:1~1:4, 6:1~1:4, 5:1~1:4, 4:1~1:4, 3:1~1:4, 2:1~1:4, 1:1~1:4, 8:1~1:3, 7:1~1:3, 6:1 ~1:3, 5:1~1:3, 4:1~1:3, 3:1~1:3, 2:1~1:3, 1:1~1:3, 8:1~1:2, 7:1~1:2, 6:1~1:2, 5:1~1:2, 4:1~1:2, 3:1~1:2, 2:1~1:2, 1:1~1:2, 8:1~1:1, 7:1~1:1,The amphipathic molecule in the apolipoprotein complex includes an apolipoprotein molecule:amphipathic molecule molar ratio ranging from 6:1 to 1:1, 5:1 to 1:1, 4:1 to 1:1, 3:1 to 1:1, or 2:1 to 1:1.

[0096] In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio in the Cargomer ranges from 6:1 to 1:6. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 5:1 to 1:6. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 4:1 to 1:6. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 3:1 to 1:6. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 2:1 to 1:6. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 5:1 to 1:5. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 4:1 to 1:5. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 3:1 to 1:5. In some embodiments, the apolipoprotein to amphiphilic molecule molar ratio ranges from 2:1 to 1:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:1 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 4:1 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 3:1 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 2:1 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:1 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 4:1 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 3:1 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 2:1 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 4:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 3:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 2:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:1 to 1:1.In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 4:1 to 1:1. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 3:1 to 1:1. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 2:1 to 1:1. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:1 to 1:6. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:1 to 1:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:1 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:1 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:2 to 1:6. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:2 to 1:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:2 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:2 to 1:3. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:3 to 1:6. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:3 to 1:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:3 to 1:4. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:4 to 1:6. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:4 to 1:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1:5 to 1:6. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 1.5:1 to 1:2. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:4 to 4:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:3 to 3:5. In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 5:2 to 2:5.In some embodiments, the apolipoprotein to amphipathic molecule molar ratio ranges from 3:2 to 2:3.

[0097] In some embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:1. In other embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:2. In yet other embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:3. In yet other embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:4. In yet other embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:5. In yet other embodiments, the ratio of apolipoprotein molecules to amphipathic molecules is about 1:6.

[0098] In some embodiments, the Cargomer comprises one apolipoprotein molecule.

[0099] In other embodiments, Cargomer comprises two apolipoprotein molecules. Cargomer comprising two apolipoprotein molecules preferably has a Stokes radius of 3 nm or less. In some embodiments, Cargomer may comprise two apolipoprotein molecules and one, two, or three negatively charged amphiphilic molecules (e.g., negatively charged phospholipid molecules) per apolipoprotein molecule.

[0100] In other embodiments, Cargomer comprises four apolipoprotein molecules. Cargomer comprising four apolipoprotein molecules preferably has a Stokes radius of 4 nm or less. In some embodiments, Cargomer may comprise four apolipoprotein molecules and one, two, or three negatively charged amphiphilic molecules (e.g., negatively charged phospholipid molecules) per apolipoprotein molecule.

[0101] In other embodiments, Cargomer comprises 8 apolipoprotein molecules. Cargomer comprising 8 apolipoprotein molecules preferably has a Stokes radius of 5 nm or less. In some embodiments, Cargomer may comprise 8 apolipoprotein molecules and 1, 2, or 3 negatively charged amphiphilic molecules (e.g., negatively charged phospholipid molecules) per apolipoprotein molecule. In certain embodiments, Cargomer of the present disclosure does not contain cholesterol and / or cholesterol derivatives (e.g., cholesteryl esters).

[0102] In some embodiments, the Cargomer comprises an apolipoprotein to phospholipid ratio in the range of about 1:2 to about 1:3 by weight.

[0103] In some embodiments, the Cargomer comprises an apolipoprotein to phospholipid ratio of 1:2.7 by weight.

[0104] The Cargomer may be soluble in one or more of biological fluids, such as lymphatic fluid, cerebrospinal fluid, vitreous fluid, aqueous humor, and blood or blood fractions (eg, serum or plasma).

[0105] Cargomers may include targeting functionality, for example, targeting Cargomers to specific cell or tissue types. In some embodiments, Cargomers include targeting moieties attached to apolipoprotein molecules or amphiphilic molecules. In some embodiments, one or more cargo moieties incorporated into Cargomers have targeting capabilities.

[0106] ApoA-I Preparations In one embodiment, the disclosure relates to an ApoA-I formulation comprising ApoA-I and one or more lipids, wherein the ApoA-I and the lipids are in the form of a lipoprotein complex.

[0107] The ApoA-I can be any such apolipoprotein described in Section 6.1.5.1, including, among others, ApoA-I having the amino acid sequence of amino acids 25-267 of SEQ ID NO:2, and / or recombinantly expressed ApoA-I.

[0108] The lipid may be any one or more of those described in Section 6.1.6.1. The lipid may include neutral lipids and / or negatively charged lipids. The neutral lipid may include or consist of sphingomyelin, such as natural sphingomyelin (e.g., chicken egg sphingomyelin) and / or synthetic sphingomyelin (e.g., palmitoyl sphingomyelin). The negatively charged lipid may include or consist of 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof.

[0109] The lipids may comprise neutral phospholipids and negatively charged phospholipids in any weight or molar ratio described herein. The lipids may consist of 95-99% neutral phospholipids and 1-5% negatively charged phospholipids, such as 96-98% neutral phospholipids and 2-4% negatively charged phospholipids, or 97% neutral phospholipids and 3% negatively charged phospholipids.

[0110] The formulation may include any weight or molar ratio of ApoA-I and lipid described herein.For example, the molar ratio of negatively charged lipid to neutral lipid to ApoA-I components in the formulation is 2-6:90-120:1.Exemplary formulations may include ApoA-I to lipid ratios ranging from 1:2 to 1:3 by weight, such as about 1:2.7 by weight.

[0111] Optionally, the formulation may further comprise one or more ophthalmic drugs as described in Section 6.1.9.

[0112] The formulations may be used in methods of treating ocular diseases, such as those described in Sections 6.2-6.6. The formulations may also be for use in treating ocular diseases. The formulations may also be for use in the manufacture of medicaments for treating ocular diseases.

[0113] Examples of ApoA-I formulations and uses thereof include those set forth in numbered embodiments 357-458 of group 1.

[0114] 6.1.5. Lipid-binding protein molecules The lipid-binding protein molecules that can be used in the complexes described herein include apolipoproteins, such as those described in Section 6.1.5.1, and apolipoprotein mimetic peptides, such as those described in Section 6.1.5.2. In some embodiments, the complexes include a mixture of lipid-binding protein molecules. In some embodiments, the complexes include a mixture of one or more lipid-binding protein molecules and one or more apolipoprotein mimetic peptides. In some embodiments, the complexes include one or more apolipoprotein molecules (e.g., ApoA-I molecules) and do not include one or more apolipoprotein mimetic peptides.

[0115] In some embodiments, the complex comprises 1-8 equivalents of ApoA-I (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-8, 2-6, 2-4, 4-6, or 4-8 equivalents of ApoA-I). Lipid binding proteins can be expressed in terms of ApoA-I equivalents based on the number of amphipathic helices they contain. For example, ApoA-I, which typically exists as a disulfide-bridged dimer, can be expressed in terms of ApoA-I equivalents based on the number of amphipathic helices they contain. M can be expressed as two ApoA-I equivalents, because ApoA-I MA peptidomimetic containing a single amphipathic helix can be expressed as 1 / 10 to 1 / 6 the equivalent of ApoA-I, because each molecule contains twice as many amphipathic helices as a molecule of ApoA-I. Conversely, a peptidomimetic containing a single amphipathic helix can be expressed as 1 / 10 to 1 / 6 the equivalent of ApoA-I, because each molecule contains 1 / 10 to 1 / 6 the number of amphipathic helices as a molecule of ApoA-I.

[0116] Apolipoproteins Suitable apolipoproteins that may be included in the lipid-binding protein-based complex include apolipoproteins ApoA-I, ApoA-II, ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoJ, ApoH, and any combination of two or more of the foregoing. Polymorphic forms, isoforms, variants, and mutants, as well as truncated forms, of the foregoing apolipoproteins, the most common of which is apolipoprotein AI. ミラノ (ApoA-I M ), apolipoprotein AI パリ (ApoA-I P ), and apolipoprotein AI サラゴサ (ApoA-I Z ) may also be used. Apolipoprotein variants containing cysteine ​​residues are also known and may be used (see, e.g., U.S. Patent Application Publication No. 2003 / 0181372). Apolipoproteins may be in the form of monomers or dimers, which may be homodimers or heterodimers. For example, ApoA-I (Duverger et al., 1996, Arterioscler. Thromb. Vasc. Biol. 16(12):1424-29), ApoA-I M (Franceschini et al., 1985, J. Biol. Chem. 260:1632-35), ApoA-I P(Daum et al., 1999, J. Mol. Med. 77:614-22), ApoA-II (Shelness et al., 1985, J. Biol. Chem. 260(14):8637-46;Shelness et al., 1984, J. Biol. Chem. 259(15):9929-35), ApoA-IV (Duverger et al., 1991, Euro. J. Biochem. 201(2):373-83), ApoE (McLean et al., 1983, J. Biol. Chem. 258(14):8993-9000), ApoJ, and homodimers and heterodimers (where feasible) of ApoH may be used.

[0117] Apolipoproteins can be modified in their primary sequence to make them less susceptible to oxidation, for example as described in US Patent Application Publication Nos. 2008 / 0234192 and 2013 / 0137628, and US Patent Nos. 8,143,224 and 8,541,236. Apolipoproteins can contain residues that correspond to elements that facilitate their isolation, such as His tags, or other elements designed for other purposes. Preferably, the apolipoproteins in the complex are soluble in biological fluids, such as lymph, cerebrospinal fluid, vitreous humor, aqueous humor, blood, or blood fractions, such as serum or plasma.

[0118] In some embodiments, the complex comprises a covalently linked lipid-binding protein monomer, such as dimeric apolipoprotein AI, which is a cysteine-containing mutant form of ApoA-I. ミラノ The cysteines allow the formation of disulfide bridges that can lead to the formation of homodimers or heterodimers (e.g., ApoA-I Milano-ApoA-II).

[0119] In some embodiments, the apolipoprotein molecule includes an ApoA-I, ApoA-II, ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoJ, or ApoH molecule, or a combination thereof.

[0120] In some embodiments, the apolipoprotein molecule comprises or consists of an ApoA-I molecule. In some embodiments, the ApoA-I molecule is a human ApoA-I molecule. In some embodiments, the ApoA-I molecule is recombinant. In some embodiments, the ApoA-I molecule is ApoA-I. ミラノ isn't it.

[0121] In some embodiments, the ApoA-I molecule is apolipoprotein AI. ミラノ (ApoA-IM), apolipoprotein AI パリ (ApoA-IP), or apolipoprotein AI サラゴサ (ApoA-IZ) molecule.

[0122] Apolipoproteins can be purified from animal sources (particularly from human sources) or recombinantly produced, as is well known in the art, see e.g., Chung et al., 1980, J. Lipid Res. 21(3):284-91; Cheung et al., 1987, J. Lipid Res. 28(8):913-29. See also U.S. Patent Nos. 5,059,528, 5,128,318, 6,617,134; U.S. Patent Application Publication Nos. 2002 / 0156007, 2004 / 0067873, 2004 / 0077541, and 2004 / 0266660; and WO 2008 / 104890 and WO 2007 / 023476. Other methods of purification are possible, for example as described in WO 2012 / 109162, the disclosure of which is incorporated herein by reference in its entirety.

[0123] Apolipoproteins can be in prepro, pro, or mature forms. For example, the complex can include ApoA-I (e.g., human ApoA-I) where ApoA-I is preproApoA-I, proApoA-I, or mature ApoA-I. In some embodiments, the complex includes ApoA-I having at least 90% sequence identity with SEQ ID NO:1.

[0124] [ka]

[0125] In another embodiment, the complex comprises an ApoA-I having at least 95% sequence identity to SEQ ID NO: 1. In another embodiment, the complex comprises an ApoA-I having at least 98% sequence identity to SEQ ID NO: 1. In another embodiment, the complex comprises an ApoA-I having at least 99% sequence identity to SEQ ID NO: 1. In another embodiment, the complex comprises an ApoA-I having 100% sequence identity to SEQ ID NO: 1.

[0126] In another embodiment, the complex comprises an ApoA-I having at least 95% sequence identity to amino acids 25-267 of SEQ ID NO:2. In another embodiment, the complex comprises an ApoA-I having at least 98% sequence identity to amino acids 25-267 of SEQ ID NO:2. In another embodiment, the complex comprises an ApoA-I having at least 99% sequence identity to amino acids 25-267 of SEQ ID NO:2. In another embodiment, the complex comprises an ApoA-I having 100% sequence identity to amino acids 25-267 of SEQ ID NO:2.

[0127] In some embodiments, the complex comprises 1-8 apolipoprotein molecules (e.g., 1-6, 1-4, 1-2, 2-8, 2-6, 2-4, 4-8, 4-6, or 6-8 apolipoprotein molecules). In some embodiments, the complex comprises 1 apolipoprotein molecule. In some embodiments, the complex comprises 2 apolipoprotein molecules. In some embodiments, the complex comprises 3 apolipoprotein molecules. In some embodiments, the complex comprises 4 apolipoprotein molecules. In some embodiments, the complex comprises 5 apolipoprotein molecules. In some embodiments, the complex comprises 6 apolipoprotein molecules. In some embodiments, the complex comprises 7 apolipoprotein molecules. In some embodiments, the complex comprises 8 apolipoprotein molecules.

[0128] The apolipoprotein molecule may include a chimeric apolipoprotein comprising an apolipoprotein and one or more attached functional moieties, such as, for example, one or more CRN-001 complexes, one or more targeting moieties, a moiety with a desired biological activity, an affinity tag to aid in purification, and / or a reporter molecule for characterization or localization. The attached moiety with biological activity may have an activity that may enhance and / or synergize with the biological activity of the compound or cargo moiety incorporated in the complex of the present disclosure. For example, the moiety with biological activity may have antimicrobial (e.g., antifungal, antibacterial, antiprotozoan, bacteriostatic, fungistatic, or antiviral) activity. In one embodiment, the attached functional moiety of the chimeric apolipoprotein is not in contact with a hydrophobic surface of the complex. In another embodiment, the attached functional moiety is in contact with a hydrophobic surface of the complex. In some embodiments, the functional moiety of the chimeric apolipoprotein may be inherent to the natural protein. In some embodiments, the chimeric apolipoprotein comprises a ligand or sequence that can be recognized by or interact with a cell surface receptor or other cell surface moiety.

[0129] In one embodiment, the chimeric apolipoprotein includes a targeting moiety that is not native to the native apolipoprotein, such as, for example, S. cerevisiae α-mating factor peptide, folic acid, transferrin, or lactoferrin. In another embodiment, the chimeric apolipoprotein includes a moiety that has a desired biological activity that enhances and / or synergizes with the activity of the compound or cargo moiety incorporated in the complex of the present disclosure. In one embodiment, the chimeric apolipoprotein can include an apolipoprotein-specific functional moiety. One example of an apolipoprotein-specific functional moiety is the unique targeting moiety formed by approximately amino acids 130-150 of human ApoE, which includes a receptor binding region recognized by members of the low density lipoprotein receptor family. Other examples of apolipoprotein-specific functional moieties include the region of ApoB-100 that interacts with the low density lipoprotein receptor, and the region of ApoA-I that interacts with the scavenger receptor type B1. In other embodiments, functional parts can be synthetically or recombinantly added to produce chimeric apolipoproteins. Another example is an apolipoprotein that has a prepro or pro sequence from another preproapolipoprotein (e.g., a prepro sequence from preproapoA-II that is substituted for the prepro sequence of preproapoA-I). Another example is an apolipoprotein in which some of the amphipathic sequence segments are replaced by other amphipathic sequence segments from another apolipoprotein.

[0130] As used herein, "chimera" refers to two or more molecules that can exist separately and are joined together to form a single molecule that has all the desired functionality of its component molecules. The component molecules of a chimeric molecule can be synthetically joined by chemical conjugation, or, if the component molecules are all polypeptides or analogs thereof, the polynucleotides encoding the polypeptides can be recombinantly fused to each other so that a single continuous polypeptide is expressed. Such chimeric molecules are referred to as fusion proteins. A "fusion protein" is a chimeric molecule in which the component molecules are all polypeptides and the chimeric molecule is attached (fused) to each other to form a continuous single chain. The various components can be directly attached to each other or conjugated through one or more linkers. One or more segments of the various components can be inserted into the sequence of the apolipoprotein, for example, or can be added to the sequence of the apolipoprotein at the N-terminus or C-terminus. For example, the fusion protein can include an antibody light chain, an antibody fragment, a heavy chain antibody, or a single domain antibody.

[0131] In some embodiments, the chimeric apolipoprotein is prepared by chemically conjugating the apolipoprotein with the functional moiety to be attached. Means for chemically conjugating molecules are well known to those skilled in the art. Such means will vary according to the structure of the moiety to be attached, but will be easily ascertainable to those skilled in the art. Polypeptides typically contain a variety of functional groups, such as carboxylic acid (--COOH), free amino (--NH2), or sulfhydryl (--SH) groups, that are available for reaction with the appropriate functional group on the functional moiety or on the linker that binds the moiety thereto. The functional moiety can be attached to a functional group at the N-terminus, C-terminus, or on an internal residue (i.e., a residue at a position intermediate between the N-terminus and the C-terminus) of the apolipoprotein molecule. Alternatively, the apolipoprotein and / or the moiety to be tagged can be derivatized to expose or attach additional reactive functional groups.

[0132] In some embodiments, fusion protein comprising polypeptide functional part is synthesized using recombinant expression system.Typically, this involves creating the nucleic acid (e.g., DNA) sequence that codes for apolipoprotein and functional part, such that the two polypeptides will be in frame when expressed, placing the DNA under the control of a promoter, expressing the protein in a host cell, and isolating the expressed protein.

[0133] The nucleic acid encoding the chimeric apolipoprotein can be incorporated into a recombinant expression vector in a suitable form for expression in a host cell. As used herein, an "expression vector" is a nucleic acid that can be transcribed and translated into a polypeptide when introduced into a suitable host cell. The vector can also include regulatory sequences such as promoters, enhancers, or other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are known to those skilled in the art (see, for example, Goeddel, 1990, Gene Expression Technology: Meth. Enzymol. 185, Academic Press, San Diego, Calif.; Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology 152 Academic Press, Inc., San Diego, Calif.; Sambrook et al., 1989, Molecular Cloning--A Laboratory Manual (2nd ed.) Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, NY, etc.).

[0134] In some embodiments, the apolipoprotein is modified such that when the apolipoprotein is incorporated into the complex of the present disclosure, the modification will increase the stability of the complex, confer targeting ability, or increase the capacity. In one embodiment, the modification includes the introduction of a cysteine ​​residue into the apolipoprotein molecule to allow the formation of intramolecular or intermolecular disulfide bonds, for example, by site-directed mutagenesis. In another embodiment, a chemical crosslinker is used to form an intermolecular link between apolipoprotein molecules to enhance the stability of the complex. The intermolecular crosslink prevents or reduces the dissociation of the apolipoprotein molecule from the complex and / or prevents replacement by endogenous apolipoprotein molecules in the individual to whom the complex is administered. In other embodiments, the apolipoprotein is modified by chemical derivatization or by site-directed mutagenesis of one or more amino acid residues to confer targeting ability to or recognition by cell surface receptors.

[0135] The complex can be targeted to a specific cell surface receptor by engineering receptor recognition properties into the apolipoprotein. For example, the complex can be targeted to a particular cell type known to carry a particular type of infectious agent, for example by modifying the apolipoprotein to render it capable of interacting with a receptor on the surface of the cell type being targeted. For example, the complex can be targeted to macrophages by modifying the apolipoprotein to confer recognition by macrophage endocytic class A scavenger receptor (SR-A). SR-A binding ability can be conferred to the complex by modifying the apolipoprotein by site-directed mutagenesis to replace one or more positively charged amino acids with neutral or negatively charged amino acids. SR-A recognition can also be conferred by preparing chimeric apolipoproteins that contain N- or C-terminal extensions with ligands recognized by SR-A, or amino acid sequences with a high concentration of negatively charged residues. Complexes containing apolipoproteins can also interact with apolipoprotein receptors, such as, but not limited to, the ABCA1 receptor, the ABCG1 receptor, Megalin, Cubilin, and HDL receptors such as SR-B1.

[0136] The complex may include a lipid-binding protein (e.g., an apolipoprotein molecule) that anchors the cargo moiety to the Cargomer. In some embodiments, the apolipoprotein molecule is conjugated to the cargo moiety by a direct bond. In other embodiments, the apolipoprotein molecule is conjugated to the cargo moiety by a linker, e.g., as described in Section 6.1.8.

[0137] Apolipoprotein Mimetics Peptides, peptide analogs, and agonists that mimic the activity of apolipoproteins (collectively referred to herein as "apolipoprotein peptidomimetics") may also be used in the conjugates described herein, alone or in combination with one or more other lipid-binding proteins. Peptides and peptide analogs corresponding to apolipoproteins, as well as ApoA-I, ApoA-I, and ApoA-II that are suitable for inclusion in the conjugates and compositions described herein, may also be used in the conjugates described herein. M Non-limiting examples of agonists that mimic the activity of ApoA-II, ApoA-IV, and ApoE are described in U.S. Pat. Nos. 6,004,925, 6,037,323, and 6,046,166 (issued to Dasseux et al.), U.S. Pat. No. 5,840,688 (issued to Tso), U.S. Pat. No. 6,743,778 (issued to Kohno), U.S. Patent Application Publication No. 2004 / 0266671, the disclosures of which are incorporated by reference in their entireties. Nos. 2004 / 0254120, 2003 / 0171277, and 2003 / 0045460 (to Fogelman), U.S. Patent Application Publication No. 2006 / 0069030 (to Bachovchin), U.S. Patent Application Publication No. 2003 / 0087819 (to Bielicki), U.S. Patent Application Publication No. 2009 / 0081293 (to Murase et al.), and WO 2010 / 093918 (to Dasseux et al.). These peptides and peptide analogs may be composed of L- or D-amino acids, or mixtures of L- and D-amino acids. They may also include one or more non-peptide or amide linkages, such as one or more of the well-known peptide / amide isosteres. Such apolipoprotein peptidomimetics may be synthesized or produced using any technique for peptide synthesis known in the art, including, for example, the techniques described in U.S. Pat. Nos. 6,004,925, 6,037,323, and 6,046,166.

[0138] In some embodiments, the lipid binding protein molecule comprises an apolipoprotein peptidomimetic molecule, and optionally one or more apolipoprotein molecules, such as those described above.

[0139] In some embodiments, the apolipoprotein peptidomimetic molecule comprises an ApoA-I peptidomimetic, an ApoA-II peptidomimetic, an ApoA-IV peptidomimetic, or an ApoE peptidomimetic, or a combination thereof.

[0140] The complex of the present disclosure may include an apolipoprotein peptidomimetic molecule that fixes the cargo moiety to the complex.In some embodiments, the apolipoprotein peptidomimetic molecule is conjugated to the cargo moiety by direct bond.In other embodiments, the apolipoprotein peptidomimetic molecule is conjugated to the cargo moiety by a linker, for example as described in Section 6.1.8.

[0141] 6.1.6. Amphiphilic molecules An amphipathic molecule is a molecule that possesses both hydrophobic (non-polar) and hydrophilic (polar) elements. Amphipathic molecules that may be used in the complexes described herein include lipids (e.g., as described in Section 6.1.6.1), surfactants (e.g., as described in Section 6.1.6.2), fatty acids (e.g., as described in Section 6.1.6.3), and non-polar molecules covalently attached to polar molecules such as, but not limited to, sugars or nucleic acids, and sterols (e.g., as described in Section 6.1.6.4).

[0142] The complex may contain a single class of amphiphilic molecules (e.g., a single type of phospholipid or a mixture of phospholipids) or may contain a combination of classes of amphiphilic molecules (e.g., phospholipids and surfactants). The complex may contain one type of amphiphilic molecule or a combination of amphiphilic molecules that are configured to facilitate solubilization of lipid-binding protein molecules.

[0143] In some embodiments, the Apomer and / or Cargomer-based complexes contain only a sufficient amount of amphipathic molecules to solubilize the lipid-binding protein molecule. In other words, the Apomer and / or Cargomer-based complexes may contain the minimum amount of one or more amphipathic molecules necessary to solubilize the lipid-binding protein molecule.

[0144] In some embodiments, the amphipathic molecules included include phospholipids, surfactants, fatty acids, nonpolar moieties covalently attached to sugars or sterols, or combinations thereof (e.g., selected from the types of amphipathic molecules discussed above).

[0145] In some embodiments, the amphipathic molecules comprise or consist of phospholipid molecules. In some embodiments, the phospholipid molecules comprise negatively charged phospholipids, neutral phospholipids, positively charged phospholipids, or a combination thereof. In some embodiments, the phospholipid molecules contribute 1-3 net charges per apolipoprotein molecule in the complex. In some embodiments, the net charge is a negative net charge. In some embodiments, the net charge is a positive net charge. In some embodiments, the net charge is a positive net charge. In some embodiments, the phospholipid molecules consist of a combination of negatively charged and neutral phospholipids. In some embodiments, the molar ratio of negatively charged phospholipids to neutral phospholipids ranges from 1:1 to 1:3, such as about 1:1, about 1:2, or about 1:3. In some embodiments, the molar ratio of negatively charged phospholipids to neutral phospholipids is about 1:1 or about 1:2. In some embodiments, the weight ratio of neutral phospholipids to negatively charged phospholipids ranges from 95:5 to 99:1.

[0146] In some embodiments, the complex includes at least one amphipathic molecule that is an anchor.

[0147] In some embodiments, the amphipathic molecules comprise neutral phospholipids and negatively charged phospholipids in a weight ratio of 95:5 to 99:1.

[0148] Lipids A lipid-binding protein-based complex may include one or more lipids. In various embodiments, the one or more lipids may be saturated and / or unsaturated, natural and / or synthetic, charged or uncharged, zwitterionic or non-zwitterionic. In some embodiments, lipid molecules (e.g., phospholipid molecules) may, taken together, contribute 1-3 (e.g., 1-3, 1-2, 2-3, 1, 2, or 3) net charges per lipid-binding protein molecule in the complex. In some embodiments, the net charge is negative. In other embodiments, the net charge is positive.

[0149] In some embodiments, lipid comprises phospholipid.Phospholipid can have two acyl chains that are the same or different (e.g., chains with different number of carbon atoms, different degree of saturation between acyl chains, different branching of acyl chains, or combinations thereof).Lipid can also be modified to contain fluorescent probe (e.g., as described at avantilipids.com / product-category / products / fluorescent-lipids / ).Preferably, lipid comprises at least one phospholipid.

[0150] Phospholipids can have unsaturated or saturated acyl chains ranging from about 6 to about 24 carbon atoms (e.g., 6-20, 6-16, 6-12, 12-24, 12-20, 12-16, 16-24, 16-20, or 20-24). In some embodiments, phospholipids used in the conjugates of the present disclosure have one or two acyl chains of 12, 14, 16, 18, 20, 22, or 24 carbons (e.g., two acyl chains of the same length or two acyl chains of different lengths).

[0151] Non-limiting examples of acyl chains present in common fatty acids that may be included in phospholipids are provided in Table 1 below.

[0152] [Table 1]

[0153] Lipids that may be present in the complexes of the present disclosure include small alkyl chain phospholipids, egg phosphatidylcholine, soy phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearoyl phosphatidylcholine, 1-myristoyl-2-palmitoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-palmitoyl-2-stearoyl phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, di-stearo ... Oleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, dilauroylphosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, e.g. dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid, dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine, dipalmitoylphosphatidylserine, brain phosphatidylserine, brain sphingomyelin, palmitoyl sphingomyelin, dipalmitoyl sphingomyelin, egg sphingomyelin, milk sphingomyelin These include, but are not limited to, angiomyelin, phytosphingomyelin, distearoyl sphingomyelin, dipalmitoyl phosphatidylglycerol salts, phosphatidic acid, galactocerebrosides, gangliosides, cerebrosides, dilauryl phosphatidylcholine, (1,3)-D-mannosyl-(1,3) diglyceride, aminophenyl glycosides, 3-cholesteryl-6'-(glycosylthio)hexyl ether glycolipids, and cholesterol and its derivatives. Synthetic lipids, such as synthetic palmitoyl sphingomyelin or N-palmitoyl-4-hydroxysphinganine-1-phosphocholine (a form of phytosphingomyelin), may be used to minimize lipid oxidation.

[0154] In some embodiments, the lipid-binding protein-based complex comprises two types of phospholipids: neutral lipids, such as lecithin and / or sphingomyelin (abbreviated as SM), and charged phospholipids (e.g., negatively charged phospholipids). A "neutral" phospholipid has a net charge of about zero at physiological pH. In many embodiments, the neutral phospholipid is zwitterionic, although other types of net neutral phospholipids are known and can be used. In some embodiments, the molar ratio of charged phospholipids (e.g., negatively charged phospholipids) to neutral phospholipids ranges from 1:1 to 1:3, such as about 1:1, about 1:2, or about 1:3.

[0155] The neutral phospholipid may, for example, comprise one or both of lecithin and / or SM, and may optionally comprise other neutral phospholipids. In some embodiments, the neutral phospholipid comprises lecithin but does not comprise SM. In other embodiments, the neutral phospholipid comprises SM but does not comprise lecithin. In still other embodiments, the neutral phospholipid comprises both lecithin and SM. All of these specific exemplary embodiments may comprise neutral phospholipids in addition to lecithin and / or SM, although many embodiments do not comprise such additional neutral phospholipids.

[0156] As used herein, the term "SM" includes sphingomyelin derived from or obtained from natural sources, as well as analogs and derivatives of naturally occurring SM that are not susceptible to hydrolysis by LCAT, as naturally occurring SM is.SM is a phospholipid that is very similar in structure to lecithin, but unlike lecithin, it does not have a glycerol backbone and therefore does not have ester linkages attached to the acyl chains.Rather, SM has a ceramide backbone, with amide linkages connecting the acyl chains.SM can be obtained, for example, from milk, eggs, or brain.SM analogs or derivatives can also be used. Non-limiting examples of useful SM analogs and derivatives include, but are not limited to, palmitoyl sphingomyelin, N-palmitoyl-4-hydroxysphinganine-1-phosphocholine (a form of phytosphingomyelin), palmitoyl sphingomyelin, stearoyl sphingomyelin, D-erythro-N-16:0-sphingomyelin and its dihydro isomer D-erythro-N-16:0-dihydro-sphingomyelin. Synthetic SMs such as synthetic palmitoyl sphingomyelin or N-palmitoyl-4-hydroxysphinganine-1-phosphocholine (phytosphingomyelin) can be used to produce more homogenous complexes, with fewer contaminants and / or oxidation products than sphingolipids of animal origin. Methods for synthesizing SMs are described in US Patent Application Publication No. 2016 / 0075634.

[0157] Sphingomyelin isolated from natural sources can be artificially enriched with one particular saturated or unsaturated acyl chain. For example, milk sphingomyelin (Avanti Phospholipid, Alabaster, Ala.) is characterized by long saturated acyl chains (i.e., acyl chains with 20 or more carbon atoms). In contrast, egg sphingomyelin is characterized by short saturated acyl chains (i.e., acyl chains with fewer than 20 carbon atoms). For example, only about 20% of milk sphingomyelin contains C16:0 (16 carbons, saturated) acyl chains, whereas about 80% of egg sphingomyelin contains C16:0 acyl chains. Solvent extraction can be used to enrich the composition of milk sphingomyelin to have an acyl chain composition comparable to that of egg sphingomyelin, or vice versa.

[0158] SM can be semi-synthetic, such that it has a specific acyl chain. For example, milk sphingomyelin can be first purified from milk, and then one specific acyl chain, such as the C16:0 acyl chain, can be cleaved and replaced by another acyl chain. SM can also be fully synthesized, for example, by large-scale synthesis. See, for example, U.S. Patent No. 5,220,043, issued June 15, 1993, to Dong et al., entitled Synthesis of D-erythro-sphingomyelins; Weis, 1999, Chem. Phys. Lipids 102 (1-2):3-12. SM can be entirely synthetic, for example, as described in U.S. Patent Application Publication No. 2014 / 0275590.

[0159] The length and saturation level of the acyl chains comprising the semi-synthetic or synthetic SM can be selectively varied. The acyl chains can be saturated or unsaturated and can contain from about 6 to about 24 carbon atoms. Each chain can contain the same number of carbon atoms, or alternatively, each chain can contain a different number of carbon atoms. In some embodiments, the semi-synthetic or synthetic SM comprises mixed acyl chains, such that one chain is saturated and one chain is unsaturated. In such mixed acyl chain SM, the chain lengths can be the same or different. In other embodiments, the acyl chains of the semi-synthetic or synthetic SM are either both saturated or both unsaturated. Again, the chains can contain the same or different numbers of carbon atoms. In some embodiments, both acyl chains comprising the semi-synthetic or synthetic SM are identical. In a specific embodiment, the chains correspond to the acyl chains of naturally occurring fatty acids, such as oleic acid, palmitic acid, or stearic acid. In another embodiment, SM with saturated or unsaturated functionalized chains is used. In another specific embodiment, both acyl chains are saturated and contain from 6 to 24 carbon atoms. Non-limiting examples of acyl chains present in commonly found fatty acids that can be included in semi-synthetic and synthetic SMs are provided in Table 1 above.

[0160] In some embodiments, the SM is palmitoyl SM, such as synthetic palmitoyl SM having a C16:0 acyl chain, or egg SM that contains palmitoyl SM as a major component.

[0161] In a specific embodiment, a functionalized SM, such as phytosphingomyelin, is used.

[0162] Lecithin can be derived or isolated from natural sources, or it can be obtained synthetically. Examples of suitable lecithin isolated from natural sources include, but are not limited to, egg phosphatidylcholine and soybean phosphatidylcholine. Additional non-limiting examples of suitable lecithins include dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1-palmitoyl-2-stearoylphosphatidylcholine, 1-stearoyl-2-palmitoylphosphatidylcholine, 1-palmitoyl-2-oleylphosphatidylcholine, 1-oleoyl-2-palmitoylphosphatidylcholine, dioleoylphosphatidylcholine, and ether derivatives or analogs thereof.

[0163] Lecithin derived from or isolated from natural sources can be enriched to contain designated acyl chains. In embodiments employing semi-synthetic or synthetic lecithin, the identity of the acyl chains can be selectively varied as discussed above in relation to SM. In some embodiments of the complexes described herein, both acyl chains on the lecithin are the same. In some embodiments of the complexes containing both SM and lecithin, the acyl chains of the SM and lecithin are all the same. In specific embodiments, the acyl chains correspond to the acyl chains of myristic, palmitic, oleic, or stearic acid.

[0164] The complex of the present disclosure may include one or more negatively charged phospholipids (e.g., alone or in combination with one or more neutral phospholipids). As used herein, a "negatively charged phospholipid" is a phospholipid that has a net negative charge at physiological pH. A negatively charged phospholipid may include a single type of negatively charged phospholipid or a mixture of two or more different negatively charged phospholipids. In some embodiments, the charged phospholipid is a negatively charged glycerophospholipid. Specific examples of suitable negatively charged phospholipids include, but are not limited to, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and its salts (e.g., sodium or potassium salts). In some embodiments, the negatively charged phospholipid comprises one or more of phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, and / or phosphatidic acid.In a specific embodiment, the negatively charged phospholipid comprises or consists of a salt of phosphatidylglycerol or a salt of phosphatidylinositol.In another specific embodiment, the negatively charged phospholipid comprises or consists of 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], i.e. DPPG, or its salt.

[0165] Negatively charged phospholipids may be obtained from natural sources or prepared by chemical synthesis. In embodiments employing synthetic negatively charged phospholipids, the identity of the acyl chains may be selectively varied as discussed above in connection with SM. In some embodiments of the complexes of the present disclosure, both acyl chains on the negatively charged phospholipid are the same. In some embodiments, the acyl chains of all types of phospholipids included in the complexes of the present disclosure are all the same. In a specific embodiment, the complexes include negatively charged phospholipids and / or SMs that all have C16:0 or C16:1 acyl chains. In a specific embodiment, the fatty acid moiety of the SM is predominantly C16:1 palmitoyl. In one specific embodiment, the acyl chains of the charged phospholipids, lecithin, and / or SM correspond to the acyl chains of palmitic acid. In yet another specific embodiment, the acyl chains of the charged phospholipids, lecithin, and / or SM correspond to the acyl chains of oleic acid.

[0166] Examples of positively charged phospholipids that can be included in the complexes of the present disclosure include N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2-di-O-octadecenyl-3-trimethylammonium propane, 1,2-dimyristoleoyl-sn-glycero-3-ethylphosphocholine, 1-palmitoyl-2-oleoyl-sn- Glycerol-3-ethylphosphocholine, 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine, 1,2-distearoyl-sn-glycero-3-ethylphosphocholine, 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine, 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine, 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine, 1,2-dioleoyl-3-di Methylammonium-propane, 1,2-dimyristoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-3-dimethylammonium-propane, N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium, 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-stearoyl-3-trimethylammonium-propane, 1 ,2-dipalmitoyl-3-trimethylammonium-propane, 1,2-dimyristoyl-3-trimethylammonium-propane, N-[1-(2,3-dimyristyloxy)propyl]-N,N-dimethyl-N-(2-hydroxyethyl)ammonium bromide, N,N,N-trimethyl-2-bis[(1-oxo-9-octadecenyl)oxy]-(Z,Z)-1propanaminium methylsulfate, and salts thereof (e.g., chloride or bromide salts).

[0167] The lipids used are preferably at least 95% pure and / or have reduced levels of oxidizing agents, such as but not limited to peroxides. Lipids obtained from natural sources preferably have less polyunsaturated fatty acid moieties and / or fatty acid moieties that are less susceptible to oxidation. The level of oxidation in a sample can be determined using iodometric titration methods, which provide a peroxide value expressed in milliequivalents of isolated iodine per kg sample, abbreviated as meq O / kg. See, for example, Gray, 1978, Measurement of Lipid Oxidation: A Review, Journal of the American Oil Chemists Society 55:539-545;Heaton, FW and Ur, Improved Iodometric Methods for the Determination of Lipid Peroxides, 1958, Journal of the Science of Food and Agriculture 9:781-786. Preferably, the level of oxidation, ie, peroxide levels, is low, for example, less than 5 meq O / kg, less than 4 meq O / kg, less than 3 meq O / kg, or less than 2 meq O / kg.

[0168] The complex may, in some embodiments, contain a small amount of additional lipid. Virtually any type of lipid may be used, including but not limited to lysophospholipids, galactocerebrosides, gangliosides, cerebrosides, glycerides, triglycerides, and sterols and sterol derivatives (e.g., plant sterols, animal sterols such as cholesterol, or sterol derivatives such as cholesterol derivatives). For example, the complex of the present disclosure may contain cholesterol or cholesterol derivatives, such as cholesterol esters. The cholesterol derivatives may also be substituted cholesterol or substituted cholesterol esters. The complex of the present disclosure may also contain oxidized sterols, such as but not limited to oxidized cholesterol or oxidized sterol derivatives (such as but not limited to oxidized cholesterol esters). In some embodiments, the complex does not contain cholesterol and / or its derivatives (such as cholesterol esters or oxidized cholesterol esters).

[0169] Surfactants The complex may contain one or more surfactants. The surfactants may be zwitterionic, nonionic, cationic, anionic, or a combination thereof. Exemplary zwitterionic surfactants include 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO), and N,N-dimethyldodecylamine N-oxide (LDAO). Exemplary nonionic surfactants include D-(+)-trehalose 6-monooleate, N-octanoyl-N-methylglucamine, N-nonanoyl-N-methylglucamine, N-decanoyl-N-methylglucamine, 1-(7Z-hexadecenoyl)-rac-glycerol, 1-(8Z-hexadecenoyl)-rac-glycerol, 1-(8Z-heptadecenoyl)-rac-glycerol, 1-(9Z-hexadecenoyl)-rac-glycerol, 1-decanoyl-rac-glycerol. Exemplary cationic surfactants include (S)-O-methyl-serine dodecylamide hydrochloride, dodecylammonium chloride, decyltrimethylammonium bromide, and cetyltrimethylammonium sulfate. Exemplary anionic surfactants include cholesteryl hemisuccinate, cholate salts, alkyl sulfates, and alkyl sulfonates.

[0170] 6.1.6.3.Fatty acids The complex may contain one or more fatty acids. The one or more fatty acids may include short chain fatty acids having an aliphatic tail of 5 or fewer carbons (e.g., butyric acid, isobutyric acid, valeric acid, or isovaleric acid), medium chain fatty acids having a fatty acid tail of 6 to 12 carbons (e.g., caproic acid, caprylic acid, capric acid, or lauric acid), long chain fatty acids having a fatty acid tail of 13 to 21 carbons (e.g., myristic acid, palmitic acid, stearic acid, or arachidic acid), very long chain fatty acids having a fatty acid tail of 22 or more carbons (e.g., behenic acid, lignoceric acid, or cerotic acid), or combinations thereof. The one or more fatty acids may be saturated (e.g., caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, or cerotic acid), unsaturated (e.g., myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, or docosahexaenoic acid), or a combination thereof. The unsaturated fatty acid may be a cis or trans fatty acid. In some embodiments, the unsaturated fatty acid used in the complexes of the present disclosure is a cis fatty acid.

[0171] 6.1.6.4. Nonpolar molecules and sterols attached to sugars The complex may contain one or more amphipathic molecules, including a nonpolar molecule or moiety (e.g., a hydrocarbon chain, an acyl or diacyl chain) or a sterol (e.g., cholesterol) attached to a saccharide (e.g., a monosaccharide such as glucose or galactose, or a disaccharide such as maltose or trehalose). The saccharide may be a modified or substituted sugar. Exemplary amphiphilic molecules comprising apolar molecules attached to a saccharide include dodecan-2-yloxy-β-D-maltoside, tridecan-3-yloxy-β-D-maltoside, tridecan-2-yloxy-β-D-maltoside, n-dodecyl-β-D-maltoside (DDM), n-octyl-β-D-glucoside, n-nonyl-β-D-glucoside, n-decyl-β-D-maltoside, n-dodecyl-β-D-maltopyranoside, 4-n-dodecyl-α,α-trehalose, 6-n-dodecyl-α,α-trehalose, and 3-n-dodecyl-α,α-trehalose.

[0172] In some embodiments, the non-polar moiety is an acyl or diacyl chain.

[0173] In some embodiments, the sugar is a modified or substituted sugar.

[0174] Anchor The cargo moiety may be covalently attached to the amphipathic or apolar moiety to facilitate conjugation of the cargo moiety to the lipid-binding protein-based complex. The amphipathic and apolar moieties may interact with apolar regions in the lipid-binding protein-based complex, thereby anchoring the cargo moiety attached to the amphipathic and apolar moiety to the complex.

[0175] Amphiphilic moieties that can be used as anchors include lipids (e.g., as described in Section 6.1.6.1) and fatty acids (e.g., as described in Section 6.1.6.3). In some embodiments, the anchor comprises a sterol or a sterol derivative, such as a plant sterol, an animal sterol, or a sterol derivative, such as a vitamin. For example, a sterol, such as cholesterol, can be covalently attached to a cargo moiety (e.g., via a hydroxyl group at the 3-position of the A ring of the sterol) and used to anchor the cargo moiety to the complex. Nonpolar moieties that can be used as anchors include alkyl chains, acyl chains, and diacyl chains. The cargo moiety can be covalently attached to the anchor moiety directly or indirectly through a linker (e.g., via a bifunctional peptide or other linker as described in Section 6.1.8). Biologically active cargo moieties may retain their biological activity while covalently bound to the anchor (or to a linker attached to the anchor), while others may require cleavage (e.g., by hydrolysis) of the covalent bond attaching the cargo moiety to the anchor (or to a linker attached to the anchor) to regain biological activity.

[0176] In some embodiments, at least one cargo moiety is conjugated to the anchor. In some embodiments, the anchor comprises an amphiphilic and / or apolar moiety. In some embodiments, the anchor comprises an amphiphilic moiety. In some embodiments, the amphiphilic moiety comprises one of the amphiphilic molecules in the complex. In some embodiments, the amphiphilic moiety comprises a lipid, a surfactant, a fatty acid, an apolar molecule attached to a sugar, or a sterol attached to a sugar.

[0177] In some embodiments, the amphiphilic moiety comprises a sterol. In some embodiments, the sterol comprises an animal sterol or a plant sterol. In some embodiments, the sterol comprises cholesterol.

[0178] In other embodiments, the anchor comprises a non-polar moiety, hi some embodiments, the non-polar moiety comprises an alkyl chain, an acyl chain, or a diacyl chain.

[0179] In some embodiments, the cargo moiety is conjugated to the anchor by a direct bond.

[0180] In some embodiments, the cargo moiety is conjugated to the anchor by a linker.

[0181] Linker A linker comprises a chain of atoms that covalently attaches a cargo moiety to other moieties in a cargo-carrying complex, such as a Cargomer, for example, an apolipoprotein molecule, an amphiphilic molecule, and an anchor. Several linker molecules are commercially available, for example, from ThermoFisher Scientific. Suitable linkers are well known to those skilled in the art, and include, but are not limited to, linear or branched carbon linkers, heterocyclic carbon linkers, and peptide linkers. A linker can be a bifunctional linker, which is either homobifunctional or heterobifunctional.

[0182] Suitable linkers include cleavable and non-cleavable linkers.

[0183] The linker may be a cleavable linker, facilitating the release of the cargo moiety in vivo. Cleavable linkers include acid-labile linkers (e.g., including hydrazine or cis-aconityl), protease-sensitive (e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers (Chari et al., 1992, Cancer Research 52:127-131; U.S. Pat. No. 5,208,020). Cleavable linkers are typically susceptible to cleavage under intracellular conditions. Suitable cleavable linkers include, for example, peptide linkers that are cleavable by intracellular proteases, such as lysosomal or endosomal proteases. In an exemplary embodiment, the linker may be a dipeptide linker, such as a valine-citrulline (val-cit) or phenylalanine-lysine (phe-lys) linker.

[0184] The cleavable linker can be pH sensitive, i.e. sensitive to hydrolysis at a certain pH value. Typically, pH sensitive linkers are hydrolyzable under acidic conditions. For example, acid labile linkers (e.g., hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, etc.) that are hydrolyzable in lysosomes can be used. (See, for example, U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661). Such linkers are relatively stable under neutral pH conditions, such as those in blood, but are unstable below pH 5.5 or 5.0, which is the approximate pH of lysosomes. In certain embodiments, the hydrolyzable linker is a thioether linker, such as a thioether attached to a cargo moiety via an acylhydrazone bond (see, eg, US Pat. No. 5,622,929).

[0185] In some embodiments, the linker is cleavable under reducing conditions (eg, a disulfide linker). A variety of disulfide linkers are known in the art, including, for example, SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), which can be formed using SPDB and SMPT (see, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (CW Vogel ed., Oxford U. Press, 1987)). See also U.S. Pat. No. 4,880,935.

[0186] In some embodiments, the linker is cleavable by a cleavage agent, e.g., an enzyme, present in the intracellular environment (e.g., in lysosomes or endosomes or caveolae). The linker can be, for example, a peptidyl linker that is cleaved by intracellular peptidases or protease enzymes, including but not limited to lysosomal or endosomal proteases. In some embodiments, the peptidyl linker is at least 2 amino acids long or at least 3 amino acids long. The cleavage agent can include cathepsin B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives and cause the release of active drugs inside target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). In some embodiments, the peptidyl linker that is cleavable by intracellular proteases is a Val-Cit linker or a Phe-Lys linker.

[0187] In some embodiments, the linker is a malonate linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304), or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1305-12).

[0188] In other embodiments, the linker unit is non-cleavable and the cargo moiety is released, for example, by complex degradation. Exemplary non-cleavable linkers include maleimidocaproyl, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), and N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB).

[0189] In some embodiments, the cargo moiety is coupled to the anchor by a linker (e.g., as described in Section 6.1.7). In some embodiments, the linker coupling the cargo moiety to the anchor is a bifunctional linker. In some embodiments, the linker coupling the cargo moiety to the anchor is a cleavable linker. In some embodiments, the cleavable linker is a dipeptide linker, such as a valine-citrulline (val-cit) or phenylalanine-lysine (phe-lys) linker. In some embodiments, the linker coupling the cargo moiety to the anchor is a non-cleavable linker. Exemplary non-cleavable linkers include maleimidocaproyl, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), and N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB).

[0190] Ophthalmic drugs In some embodiments of the methods described herein, the lipid-binding protein-based complex (e.g., CER-001) may be used as a carrier to deliver one or more ophthalmic drugs to the eye of a subject. In some embodiments, the one or more ophthalmic drugs may be considered as cargo moieties and may be non-covalently or covalently (e.g., via an anchor or linker) conjugated to the lipid-binding protein-based complex (e.g., CER-001) to the components of the complex. In some embodiments, the one or more ophthalmic drugs are not covalently linked to the complex. One or more ophthalmic drugs may be added to a preformed complex, such as preformed CER-001, to create a complex further comprising one or more ophthalmic drugs. The conjugation between the one or more ophthalmic drugs and the preformed complex may be facilitated by performing one or more heating and cooling cycles, for example, as described in Example 1. Alternatively, the one or more ophthalmic drugs may be included during the process used to create the complex, for example, included in a starting suspension comprising lipid-binding protein and lipid components that is subjected to thermal cycling. Thermal cycling processes for making lipid-linked protein-based complexes are described in WO2012 / 109162 and WO2019 / 030574.

[0191] In some embodiments, the one or more ophthalmic drugs include a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, a prostaglandin analog, or a combination thereof.

[0192] Exemplary ophthalmic drugs that may be used include steroids such as dexamethasone, dexamethasone palmitate, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, and spironolactone; axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, and cyclosporine; Zantinib (carbozantinib), cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, sorafenib, tofacitinib, and ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro- kinase inhibitors such as 2-methylphenol; angiotensin II receptor antagonists such as candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan; aldose reductase inhibitors such as 2-methylsorbinol; immunosuppressants such as sirolimus, cyclosporine, and tacrolimus; carbonic anhydrase inhibitors such as acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, and methazolamide; azithromycin, acyclovir, chloramphenicol, chlortetracycline, and chlortetracycline. Antimicrobial, antifungal, and antiviral agents such as tracycline, ciprofloxacin, fusidic acid, gancyclovir, norfloxacin, ofloxacin, tetracycline, and zidovudine; antihistamines such as levocabastine; nonsteroidal anti-inflammatory drugs such as bromfenac, diclofenac, indomethacin, and nepafenac; and prostaglandin analogs such as latanoprost, travaprost, bimatoprost, and tafluprost.

[0193] In some embodiments, the lipid-binding protein-based complex comprises a prostaglandin analogue, such as latanoprost, travoprost, bimatoprost, tafluprost, or a combination thereof. In a specific embodiment, the lipid-binding protein-based complex comprises latanoprost. In another embodiment, the lipid-binding protein-based complex comprises travoprost. In another embodiment, the lipid-binding protein-based complex comprises bimatoprost. In another embodiment, the lipid-binding protein-based complex comprises tafluprost.

[0194] In some embodiments, the lipid binding protein-based conjugate comprises dexamethasone, axitinib, cediranib, dovitinib, motesanib, pazopanib, regorafenib, losartan, olmesartan, dorzolamide, diclofenac, nepafenac, or a combination thereof.

[0195] In another embodiment, the lipid binding protein-based conjugate comprises azithromycin.

[0196] In another embodiment, the lipid binding protein-based conjugate comprises spironolactone.

[0197] In another embodiment, the lipid binding protein-based complex comprises dexamethasone palmitate.

[0198] In another embodiment, the lipid binding protein-based conjugate comprises a cyclosporine.

[0199] In another embodiment, the lipid binding protein-based conjugate comprises dexamethasone.

[0200] In another embodiment, the lipid binding protein-based conjugate comprises loteprednol etabonate.

[0201] In other embodiments, the lipid binding protein-based conjugate comprises triamcinolone.

[0202] In another embodiment, the lipid binding protein-based conjugate comprises acyclovir.

[0203] In other embodiments, the lipid binding protein-based conjugate comprises pazopanib.

[0204] In other embodiments, the lipid binding protein-based conjugate comprises sirolimus.

[0205] In other embodiments, the lipid binding protein-based conjugate comprises tacrolimus.

[0206] In another embodiment, the lipid binding protein-based conjugate comprises nepafenac.

[0207] CER-001 and Ophthalmic Drug Combinations As disclosed herein, CER-001 can be used as a drug carrier to deliver one or more ophthalmic drugs to the eye of a subject.Thus, the present disclosure provides a composition comprising CER-001 and one or more ophthalmic drugs, such as one or more drugs that are hydrophobic and / or poorly water-soluble or water-insoluble.

[0208] In one embodiment, the composition comprises CER-001 and a steroid. In some embodiments, the composition comprises CER-001 and dexamethasone. In some embodiments, the composition comprises CER-001 and dexamethasone palmitate. In some embodiments, the composition comprises CER-001 and loteprednol etabonate. In some embodiments, the composition comprises CER-001 and triamcinolone.

[0209] In another embodiment, the composition comprises CER-001 and an antimicrobial, antifungal, or antiviral agent. In some embodiments, the composition comprises CER-001 and azithromycin. In some embodiments, the composition comprises CER-001 and acyclovir.

[0210] In another embodiment, the composition comprises CER-001 and a prostaglandin analog. In some embodiments, the composition comprises CER-001 and latanoprost. In some embodiments, the composition comprises CER-001 and travoprost. In some embodiments, the composition comprises CER-001 and bimatoprost. In some embodiments, the composition comprises CER-001 and tafluprost.

[0211] In another embodiment, the composition comprises CER-001 and a kinase inhibitor. In some embodiments, the composition comprises CER-001 and pazopanib.

[0212] In another embodiment, the composition comprises CER-001 and an immunosuppressant. In some embodiments, the composition comprises CER-001 and sirolimus. In some embodiments, the composition comprises CER-001 and tacrolimus.

[0213] In another embodiment, the composition comprises CER-001 and a nonsteroidal anti-inflammatory drug. In some embodiments, the composition comprises CER-001 and nepafenac.

[0214] In a further embodiment, the composition comprises CER-001 and spironolactone.

[0215] In another embodiment, the composition comprises CER-001 and cyclosporine.

[0216] The compositions described in this section 6.1.9.1 may be prepared by any suitable means, such as those described in section 6.1.10, for example, by thermocycling a mixture containing CER-001 and an ophthalmic drug. The compositions may be appropriately formulated for the intended route of administration, such as local administration, for example, topical administration or intraocular administration. Compositions for intraocular administration may be formulated for administration, for example, by intraocular injection, for example, intravitreal injection, subconjunctival injection, parabulbar injection, peribulbar injection, retrobulbar injection, suprachoroidal injection, or episcleral injection. For local administration, the compositions may be formulated for administration, for example, as eye drops. The compositions may also be formulated as implants, formulated for administration by iontophoresis, or formulated for administration by electroporation. In some embodiments, the compositions are formulated for suprachoroidal injection. In other embodiments, the compositions are formulated for suprascleral injection. In other embodiments, the composition is formulated as an implant (e.g., a disk, sheet, wand, rod, or pellet). In other embodiments, the composition is formulated for administration by iontophoresis. In other embodiments, the composition is formulated for administration by electroporation.

[0217] Preparations The lipid-binding protein-based conjugates can be formulated for the intended route of administration according to techniques known in the art (e.g., as described in Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK; or as described in Davis et al., 2004, Curr Opin Mol Ther. 6(2):195-205). In some embodiments, the formulation comprises a lipid-binding protein-based conjugate, such as CER-001, and one or more ophthalmic drugs, such as one or more ophthalmic drugs described in Section 6.1.9.

[0218] In some embodiments, the formulation of a lipid-binding protein-based conjugate, such as CER-001, and optionally one or more ophthalmic drugs, is formulated for delivery by intraocular injection, such as intravitreal, subconjunctival, parabulbar, peribulbar, retrobulbar, suprachoroidal, or episcleral injection.

[0219] In some embodiments, the formulation is formulated for suprachoroidal injection. Using suprachoroidal injection, it is possible to achieve higher chorioretinal drug concentrations than can be achieved by traditional intravitreal injection. In other embodiments, the formulation is formulated for suprascleral injection.

[0220] In some embodiments, the lipid-binding protein-based complex such as CER-001 and optionally one or more ophthalmic drug formulations are formulated for delivery as implants.The implants of the present disclosure can have various shapes, such as disks, sheets, stuffing, rods, or spheres.The implants can be biodegradable.The biodegradable implants can be formulated with materials such as polylactic acid and / or poly-lactic-co-glycolic acid that degrade over time.Alternatively, the implants can be non-biodegradable.The non-biodegradable implants can be formulated with materials such as silicon, or polymers such as ethylene vinyl acetate or polyvinyl alcohol.

[0221] Implants may be implanted, for example, in the episcleral or intrascleral space, in the sclera, in the vitreous cavity, or in the anterior chamber. Subconjunctival, intrascleral, and anterior chamber implants may be used, for example, in treating anterior segment disease, while intravitreal, suprachoroidal, and intrascleral implants may be used, for example, to treat posterior segment disease.

[0222] In some embodiments, the formulation of a lipid-binding protein-based conjugate, such as CER-001, and optionally one or more ophthalmic drugs, is formulated for delivery by iontophoresis, for example, transcorneal or transscleral iontophoresis.

[0223] In other embodiments, the formulation of a lipid-binding protein-based complex, such as CER-001, and optionally one or more ophthalmic drugs, is formulated for delivery by electroporation.

[0224] CER-001 intended for administration by injection can be formulated in phosphate buffer with sucrose and mannitol excipients, for example, as described in WO 2012 / 109162. Formulations of lipid-binding protein-based complexes intended for topical administration can include, for example, carriers, stabilizers, excipients, and combinations thereof. Topical formulations (e.g., eye drops) can include buffers such as phosphate, citrate, or other inorganic acid buffers, antioxidants such as ascorbic acid and / or methionine, preservatives, proteins such as low molecular weight polypeptides, gelatin, serum albumin, or immunoglobulins, hydrophilic polymers such as PVP, amino acids, mono- or disaccharides or other carbohydrates, chelating agents, sugars, non-ionic surfactants, and the like.

[0225] In some embodiments, the topical formulation comprises an osmolality adjusting agent, hi some embodiments, the osmolality adjusting agent is sodium chloride.

[0226] In some embodiments, the topical formulation comprises a preservative, which in some embodiments is benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium, polyhexamethylene biguanide, or a combination thereof.

[0227] In some embodiments, the topical formulation comprises a buffering agent, hi some embodiments, the buffering agent is selected from borate, borate-polyol complex, succinate, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, and combinations thereof.

[0228] In some embodiments, the topical formulation comprises a tonicity adjusting agent, which in some embodiments is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, trehalose, and combinations thereof.

[0229] Formulations of lipid-binding protein-based complexes, such as CER-001, intended for intraocular administration may include, for example, carriers, stabilizers, viscosifiers, osmolality adjusters, buffers, and combinations thereof. In some embodiments, intraocular formulations include osmolality adjusters. An example of an osmolality adjuster is sodium chloride. In some embodiments, intraocular formulations include buffers. Examples of buffers include borate, borate-polyol complexes, succinate, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, and combinations thereof.

[0230] In some embodiments, a formulation comprising CER-001 (optionally using CER-001 as a carrier for one or more ophthalmic drugs) may contain CER-001 at a concentration of 0.5 mg / ml to 8 mg / ml (e.g., 0.5 mg / ml, 0.8 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, any range bounded by any two of the foregoing values) on a protein weight basis. In some embodiments, a formulation comprising CER-001 may contain CER-001 at a concentration of at least 1 mg / ml, at least 2 mg / ml, at least 3 mg / ml, at least 4 mg / ml, at least 5 mg / ml, at least 6 mg / ml, at least 7 mg / ml, or at least 8 mg / ml (on a protein weight basis).

[0231] Formulations of lipid-binding protein-based complexes (e.g., CER-001) and one or more ophthalmic drugs can be produced, for example, by thermocycling a mixture containing lipid-binding protein-based complexes and one or more ophthalmic drugs. For example, the mixture can be (a) heated from a temperature in a first temperature range to a temperature in a second temperature range, then (b) cooled from a temperature in the second temperature range to a temperature in the first temperature range, and then (c) optionally subjected to one or more additional heating and cooling cycles, for example, a total of 2, 3, 4, 5, or 6 heating and cooling cycles. Alternatively, the mixture can be (a) cooled from a temperature in a second temperature range to a temperature in a first temperature range, then (b) heated from a temperature in the first temperature range to a temperature in the second temperature range, and then (c) optionally subjected to one or more additional cooling and heating cycles, for example, a total of 2, 3, 4, 5, or 6 cooling and heating cycles. The first temperature range, in some embodiments, can include a temperature between 30°C and 45°C (e.g., 35°C and 45°C, 30°C and 35°C, 35°C and 40°C, or 40°C and 45°C). The second temperature range, in some embodiments, can include a temperature between 50°C and 65°C (e.g., 50°C and 60°C, 50°C and 55°C, or 55°C and 60°C). In some embodiments, thermal cycling includes thermal cycling between 37°C and 55°C, for example, as described in Example 1. Thus, in some aspects, the present disclosure provides a composition comprising a lipid-binding protein-based complex, such as CER-001, and one or more ophthalmic drugs, produced by a process including a step of thermal cycling a mixture comprising the lipid-binding protein-based complex and one or more ophthalmic drugs.

[0232] Target population The subjects which can be treated according to the methods described herein are preferably mammals, most preferably human.

[0233] In some embodiments, the subject may be a subject who needs therapy for eye disease, for example eye disease associated with lipid accumulation, for example eye lipid deposition.In some cases, lipid may accumulate in or near the eye.The exemplary eye disease associated with lipid accumulation that can be treated by the method of the present disclosure includes dry eye disease, such as cataract, dry eye disease associated with meibomian gland dysfunction or lacrimal gland dysfunction, blepharitis, uveitis, corneal disease, such as lipokeratopathy (e.g., secondary lipokeratopathy, e.g., lipokeratopathy secondary to previous eye disease or injury) and corneal dystrophy (e.g., hereditary corneal dystrophy, anterior or superficial corneal dystrophy, stromal corneal dystrophy, or posterior corneal dystrophy), eye disease associated with LCAT deficiency, such as fish eye disease, dry macular degeneration (dry AMD), Stargardt's disease, and Leber's idiopathic stellate neuroretinopathy. For example, lipid deposits in the cornea in subjects with LCAT deficiency can cause impaired function, such as blurred vision.

[0234] In some embodiments, the subject has a cataract. For clarity, treatment of a subject with a cataract includes treatment of subjects with a cataract in one eye, as well as subjects with cataracts in both eyes.

[0235] In some embodiments, the subject has an inflammatory eye disease, such as uveitis (e.g., anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis) or scleritis. In some embodiments, the subject has acute anterior uveitis.

[0236] In some embodiments, the subject treated according to the method and / or dosing regimen of the present disclosure has LCAT deficiency, and optionally, the lipid-binding protein-based complex used to treat the subject is CER-001.The subject can be homozygous or heterozygous for LCAT mutation.In some embodiments, the subject treated according to the method and / or dosing regimen of the present disclosure has fish eye disease.Subjects with fish eye disease typically develop bilateral corneal opacity and may have visual impairment, such as reduced contrast sensitivity compared to normal, and / or blurred vision.Corneal opacity and its progression or regression (e.g., in response to the treatment described herein) can be qualitatively evaluated, for example, by comparing slit lamp images of the subject's eye taken at various time points. Corneal opacity can also be quantitatively evaluated, for example, by anterior segment optical coherence tomography (OCT) (see Kanai et al., 2018, American Journal of Ophthalmology Case Reports, 10:137-141, incorporated herein by reference in its entirety). Visual function can be assessed, for example, by measuring the subject's contrast sensitivity using a standard test chart (e.g., CSV-1000E chart; Vector Vision Co., Greenville, Ohio). Straylight measurement can be used to quantify light scattering resulting in straylight covering over the retinal image, which can lead to hazy vision or increased glare obstructions. Straylight can be measured using a straylight meter (e.g., C-Quant, manufactured by Oculus GmbH, Wetzlar, Germany). In certain embodiments, the methods of the present disclosure can reduce the severity of fish eye disease in a subject, as measured, for example, by corneal opacity, contrast sensitivity, straylight value, or a combination thereof.

[0237] In some embodiments, the subject does not have an LCAT deficiency.

[0238] In some embodiments, the subject has an eye disease that is other than fish eye disease, such as an eye disease described herein other than fish eye disease, and optionally the lipid-binding protein-based complex used to treat the subject is CER-001.

[0239] In some embodiments, the subject has a genetic disease, such as Stargardt's disease, and optionally the lipid binding protein-based conjugate used to treat the subject is CER-001.

[0240] In some embodiments, the subject has macular degeneration, such as dry AMD or wet AMD, and optionally the lipid-binding protein-based complex used to treat the subject is CER-001. In other embodiments, the subject has an eye disease other than macular degeneration, such as an eye disease described herein other than macular degeneration.

[0241] In some embodiments, the subject has diabetic retinopathy, and optionally the lipid-binding protein-based complex used to treat the subject is CER-001. In some embodiments, the subject with diabetic retinopathy has diabetic macular edema.

[0242] In some embodiments, the subject has a retinal vein occlusion.

[0243] In some embodiments, the subject has dry eye disease (e.g., severe dry eye disease). In some embodiments, the subject has meibomian gland dysfunction (MBD), e.g., obstructive MGD. In other embodiments, the subject has lacrimal gland dysfunction. In some embodiments, the subject has blepharitis. In some embodiments, the subject has uveitis (e.g., caused by bacterial infection). In some embodiments, the subject has lipokeratopathy. In some embodiments, the lipid-binding protein-based complex used to treat a subject with one of the eye diseases described in this paragraph is CER-001.

[0244] In some embodiments, the subject has ocular lipid deposits, including lipid deposits present in and / or near the eye.In one embodiment, lipid deposits are corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or combinations thereof.In some embodiments, the lipid-binding protein-based complex used for treating the subject with one of the eye diseases described in this paragraph is CER-001.

[0245] In some embodiments, the subject has lipid deposits in the cornea and / or in the retina.The lipid deposits in the cornea can cause visual impairment, such as blurred vision.The lipid deposits in the retina, such as drusen in dry AMD or lipofuscin in Stargardt's disease, can lead to retinal degeneration.In some embodiments, the lipid-binding protein-based complex used to treat the subject with one of the eye diseases described in this paragraph is CER-001.

[0246] In some embodiments, the subject has eyelid lipid deposits, which are lipid deposits on the eyelid.

[0247] In some embodiments, the lipid deposits are within the drusen deposits. Drusen are focal deposits of extracellular debris located between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagen layer of Bruch's membrane. Most drusen are of the hard type, which may be dome-shaped with a solid interior and homogenous content, and a median diameter of 47 μm. Hard drusen contain lipid particles of about 60-90 nm in diameter, containing abundant esterified cholesterol, non-esterified cholesterol, phosphatidylcholine, and apolipoprotein B. The presence of a few hard drusen is normal as people age. The presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD).

[0248] In one embodiment, the lipid deposits are lipofuscin granules. Lipofuscin granules accumulate in the RPE lysosomal compartment after mitosis. Lipofuscin granules contain primarily N-retinylidene-N-retinyl-ethanolamine (A2E). The presence of lipofuscin granules is an indication of Stargardt's disease.

[0249] In one embodiment, the lipid deposits are cholesterol deposits, particularly in the cornea. In individuals with a genetic deficiency of LCAT, cholesterol accumulates within the extracellular connective tissue matrix of the corneal stroma. Typically, such cholesterol deposits have a diameter of 0.2 to 2.5 μm.

[0250] In one embodiment, the ocular lipid deposits are non-calcified.

[0251] The presence of ocular lipid deposits can be determined by one or more of retinal slit lamp photography, Heidelberg retinal tomography (HRT) scan, optical coherence tomography (OCT), fundus autofluorescence imaging, and fundus by slit lamp. In particular, drusen can be observed by retinal slit lamp photography, HRT scan, and / or OCT; lipofuscin granules can be observed by fundus autofluorescence imaging; cholesterol pools in the cornea can be observed by slit lamp.

[0252] The use of the lipid-binding protein complexes described herein can reduce the severity of eye diseases in subjects.Without being bound by theory, it is believed that the lipid-binding protein complexes can solubilize lipids accumulated in ocular deposits, leading to their elimination.

[0253] In some embodiments, the use of the lipid binding protein complexes described herein can reduce the number of ocular lipid deposits. In some embodiments, the use of the lipid binding protein complexes described herein can reduce the size of ocular lipid deposits.

[0254] The reduction in the number and / or size of lipid deposits can be assessed qualitatively by comparing the results of examinations performed before, during or after administration of the lipid-binding protein complex, such as, for example, slit-lamp photography of the retina, Heidelberg retinal tomography (HRT) scans, optical coherence tomography (OCT), fundus autofluorescence imaging, slit-lamp fundus, etc. The reduction in the number and / or size of lipid deposits can also be assessed quantitatively by the methods described above.

[0255] Alternatively, the reduction in the number and / or size of lipid deposits may be determined indirectly by comparing results or measurements of corneal opacity, contrast sensitivity, stray light values, or combinations thereof, obtained before, and during or after administration of the lipoprotein complex.

[0256] In certain embodiments, a reduction in the severity of an ocular disease may be measured, for example, by assessment of corneal opacity, contrast sensitivity, stray light value, or a combination thereof.

[0257] In one embodiment, the subject has impaired vision, including blurred vision, due to ocular lipid deposits, and the amount of lipoprotein complex is an amount that improves the subject's vision.

[0258] In one embodiment, the subject has corneal opacity due to lipid deposition in the cornea. Treatment with the lipid-binding protein complex described herein can reduce the opacity of the subject's cornea. Corneal opacity and its progression or regression (e.g., in response to treatment described herein) can be qualitatively evaluated, for example, by comparing slit lamp images of the subject's eye taken at various time points. Corneal opacity can also be quantitatively evaluated, for example, by anterior optical coherence tomography (OCT) (see Kanai et al., 2018, American Journal of Ophthalmology Case Reports, 10:137-141, which is incorporated herein by reference in its entirety). Visual function can be assessed by measuring the patient's contrast sensitivity, for example, using a standard test chart (e.g., CSV-1000E chart; Vector Vision Co., Greenville, OH). Stray light measurement can be used to quantify the light scattering that results in stray light covering over the retinal image, which can lead to hazy vision or increased glare. Stray light can be measured using a stray light meter (e.g., C-Quant, manufactured by Oculus GmbH, Wetzlar, Germany).

[0259] In one embodiment, the amount of lipid binding protein complex administered is an amount effective to reduce corneal opacity in a patient.

[0260] In one embodiment, the amount of lipid binding protein complex administered is effective to improve the contrast sensitivity of the patient.

[0261] In one embodiment, the amount of lipid binding protein complex administered is effective to reduce stray light levels in the patient.

[0262] In other embodiments, the subject has an ocular disease (which may be, but is not necessarily, a disease associated with lipid accumulation), and the lipid-binding protein-based complex is used as a drug carrier to deliver one or more ophthalmic drugs to the subject's eye.For example, the subject may have an anterior or posterior ocular pathology, such as uveitis (e.g., caused by bacterial infection), macular edema (e.g., diabetic macular edema), macular degeneration, retinal detachment, ocular tumor, fungal infection, viral infection, bacterial infection such as bacterial conjunctivitis or trachoma, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, or glaucoma.

[0263] 6.2.1. CER-001 for use in treating uveitis Inflammatory eye diseases such as uveitis (e.g., anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis), which may or may not be caused by bacterial infection, may be treated by administration of CER-001. Use of CER-001 to treat uveitis may be accomplished by administering to a subject in need thereof a therapeutically effective amount of CER-001, for example, an amount that reduces the severity of uveitis (e.g., by alleviating one or more symptoms of uveitis). CER-001 may be formulated appropriately for the intended route of administration. Exemplary formulations are described in Section 6.1.10. For the treatment of uveitis, local administration of CER-001 to a subject in need thereof, such as topical or intraocular administration, is preferred. Intraocular administration can be, for example, by intraocular injection, for example, intravitreal injection, subconjunctival injection, parabulbar injection, peribulbar injection, retrobulbar injection, suprachoroidal injection, or episcleral injection. Implants can also be used to deliver CER-001. For local administration, CER-001 can be administered, for example, as eye drops. As shown in Examples 3 and 4, good ocular tolerability of CER-001 has been observed, even with repeated administration.

[0264] In some embodiments, CER-001 may be used to treat uveitis in a subject in need thereof according to the dosing regimen described in one or more of Sections 6.3, 6.4, and 6.5. For example, CER-001 may be used to treat uveitis in a subject in need thereof according to the induction regimen described in Section 6.3. Alternatively or in addition, CER-001 may be used to treat uveitis in a subject in need thereof according to the consolidation regimen described in Section 6.4. Alternatively or in addition, CER-001 may be used to treat uveitis in a subject in need thereof according to the maintenance regimen described in Section 6.5. In some embodiments, CER-001 may be used to treat uveitis in a subject in need thereof according to the induction regimen described in Section 6.3; and / or the consolidation regimen described in Section 6.4; and / or the maintenance regimen described in Section 6.5.

[0265] 6.2.2. CER-001 with Ophthalmic Drugs for Use in Treating Eye Disease In some embodiments, inflammatory eye diseases such as uveitis (e.g., anterior uveitis (e.g., acute anterior uveitis), intermediate uveitis, posterior uveitis, or panuveitis), which may or may not be caused by bacterial infection, may be treated by administration of a composition comprising CER-001 and dexamethasone, a composition comprising CER-001 and dexamethasone palmitate, or a composition comprising CER-001 and tacrolimus. Use of such compositions to treat uveitis may be accomplished by administering to a subject in need thereof a therapeutically effective amount of the composition, for example an amount that reduces the severity of uveitis (e.g., by alleviating one or more symptoms of uveitis). The composition may be formulated appropriately for the intended route of administration. Exemplary formulations are described in Section 6.1.10. For the treatment of uveitis, local administration of the composition to a subject in need thereof, such as topical or intraocular administration, is preferred. Intraocular administration can be, for example, by intraocular injection, for example, intravitreal injection, subconjunctival injection, parabulbar injection, peribulbar injection, retrobulbar injection, suprachoroidal injection, or episcleral injection. Implants can also be used. For local administration, the composition can be administered, for example, as eye drops. As shown in Examples 3 and 4, good ocular tolerability of such compositions has been observed, even with repeated administration.

[0266] In some embodiments, a composition comprising CER-001 and dexamethasone, a composition comprising CER-001 and dexamethasone palmitate, or a composition comprising CER-001 and tacrolimus may be used to treat uveitis in a subject in need thereof according to a dosing regimen described in one or more of Sections 6.3, 6.4, and 6.5. For example, the composition may be used to treat uveitis in a subject in need thereof according to an induction regimen described in Section 6.3. Alternatively or in addition, the composition may be used to treat uveitis in a subject in need thereof according to a consolidation regimen described in Section 6.4. Alternatively or in addition, the composition may be used to treat uveitis in a subject in need thereof according to a maintenance regimen described in Section 6.5. In some embodiments, the compositions may be used to treat uveitis in a subject in need thereof according to an induction regimen described in Section 6.3; and / or a consolidation regimen described in Section 6.4; and / or a maintenance regimen described in Section 6.5.

[0267] Compositions comprising CER-001 and dexamethasone, and compositions comprising CER-001 and dexamethasone palmitate, may also be used to treat other ocular diseases, such as macular degeneration and dry macular edema (e.g., by alleviating one or more symptoms of the disease). Compositions comprising CER-001 and tacrolimus may also be used to treat other ocular diseases, such as dry eye disease, such as severe dry eye disease (e.g., by alleviating one or more symptoms of the disease).

[0268] Compositions comprising CER-001 and dexamethasone, compositions comprising CER-001 and dexamethasone palmitate, and compositions comprising CER-001 and tacrolimus may be made, in some embodiments, by thermal cycling a mixture comprising CER-001 and the respective drug, e.g., as described in Section 6.1.10.

[0269] 6.3. Induction regimen Suitable induction regimens for use in the methods of the present disclosure involve administering multiple doses of a lipid-binding protein-based conjugate (e.g., CER-001), separated by one or more days between each administration.

[0270] The induction regimen typically includes at least three doses of the lipid-binding protein-based complex (e.g., CER-001), but may include four or more doses of the lipid-binding protein-based complex (e.g., CER-001), for example, 5, 6, 7, 8, 9, 10, 11, or 12 doses.

[0271] The induction regimen may last for one or more weeks, two or more weeks, three or more weeks, four or more weeks, five or more weeks, six or more weeks, seven or more weeks, eight or more weeks, nine or more weeks, or ten or more weeks.

[0272] For example, the induction regimen may include: three doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of one week; three doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; three doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a three-week period; four doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; four doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 2 weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 3 weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 4 weeks; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a four-week period; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a four-week period; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over four weeks; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a three-week period; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over four weeks; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over six weeks; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a 4-week period; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 5 weeks; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 6 weeks; or Ten doses of lipid-binding protein-based conjugates (e.g., CER-001) over a period of seven weeks The method may include administering

[0273] In one embodiment, the induction regimen comprises 2 doses of a lipid-binding protein-based conjugate (eg, CER-001) per week to 5 doses per week.

[0274] In one embodiment, the induction regimen comprises administering nine doses of a lipid binding protein-based conjugate (eg, CER-001) over a three week period, for example on days 1, 2, 4, 7, 9, 11, 14, 16, and 18.

[0275] In practice, a dosing window may be provided to accommodate minor variations in dosing schedules, for example, multiple dosing per week, e.g., a window of ±2 days or ±1 day around the dosing date may be used.

[0276] The therapeutic dose of lipid-binding protein-based complex (e.g., CER-001) administered by infusion in the induction regimen can range from 4 to 30 mg / kg on a protein weight basis (e.g., 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, or 30 mg / kg, or any range bounded by any two of the aforementioned values, e.g., 5 to 15 mg / kg, 10 to 20 mg / kg, or 15 to 25 mg / kg). As used herein, the term "protein weight basis" means that the dose of lipid-binding protein-based complex (e.g., CER-001) to be administered to a subject is calculated based on the amount of lipid-binding protein (e.g., ApoA-I) in the lipid-binding protein-based complex (e.g., CER-001) to be administered and the weight of the subject. For example, a subject weighing 70 kg and who should receive a 10 mg / kg dose of CER-001 will receive an amount of CER-001 that provides 700 mg of ApoA-I (70 kg x 10 mg / kg). In some embodiments, the dose of the lipid-binding protein-based complex (e.g., CER-001) used in the induction regimen is 8 mg / kg. In some embodiments, the induction regimen includes 9 doses of lipid-binding protein-based complex (e.g., CER-001) administered at a dose of 8 mg / kg over a period of 3 weeks. In some embodiments, the dose of the lipid-binding protein-based complex (e.g., CER-001) used in the induction regimen is 10 mg / kg. In some embodiments, the dose of the lipid-binding protein-based complex (e.g., CER-001) used in the induction regimen is 15 mg / kg. In some embodiments, the dose of the lipid-binding protein-based complex (e.g., CER-001) used in the induction regimen is 20 mg / kg. In some embodiments, the induction regimen includes 9 doses of lipid-binding protein-based complex (e.g., CER-001) at a dose of 10 mg / kg administered over a period of 3 weeks. The dose of lipid-binding protein-based complex used to deliver an ophthalmic drug can be a dose that delivers a therapeutically effective amount of the drug.

[0277] In yet other embodiments, the lipid-binding protein-based complex (e.g., CER-001) may be administered on a unit dosage basis. The unit dosage used in the induction phase may range from 300 mg to 3000 mg per administration by injection.

[0278] In certain embodiments, the dosage of lipid-binding protein-based conjugate (e.g., CER-001) used during the induction phase is 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg per administration by injection.

[0279] In certain embodiments, the lipid-binding protein-based complex (e.g., CER-001) is administered as an IV infusion. For example, a stock solution of CER-001 can be diluted to a total volume of 125-250 ml in normal saline, such as physiological saline (0.9% NaCl). In a preferred embodiment, subjects weighing less than 80 kg will have a total volume of 125 ml, while subjects weighing at least 80 kg will have a total volume of 250 ml. The lipid-binding protein-based complex (e.g., CER-001) can be administered over a period of 1 hour using an infusion pump at a fixed rate of 250 ml / hour. Depending on the needs of the subject, administration can be by slow infusion with a duration of more than 1 hour (e.g., up to 2 hours), by rapid infusion for 1 hour or less, or by a single bolus injection.

[0280] In an alternative embodiment, the lipid-binding protein-based complex (e.g., CER-001) is administered locally to the eye, for example by intraocular injection or topical administration. A stock solution of the lipid-binding protein-based complex (e.g., CER-001) can be diluted in a suitable diluent prior to administration. Suitable diluents include normal saline, such as physiological saline (0.9% NaCl). In some embodiments, the lipid-binding protein-based complex is formulated as an eye drop.

[0281] 6.4. Intensive regimen Suitable intensification regimens for use in the methods of the present disclosure involve administering multiple doses of a lipid-binding protein-based complex (e.g., CER-001), separated by one or more days between each dose, e.g., two or more days between each administration.

[0282] The intensification regimen typically includes at least two doses of a lipid-binding protein-based complex (e.g., CER-001), but may include three or more doses of a lipid-binding protein-based complex (e.g., CER-001), e.g., 4, 5, 6, 7, 8, 9, or 10 doses.

[0283] The intensive regimen may last for one or more weeks, two or more weeks, three or more weeks, four or more weeks, five or more weeks, six or more weeks, seven or more weeks, eight or more weeks, nine or more weeks, or ten or more weeks.

[0284] For example, the intensive regimen may include: two doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of one week; two doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; three doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; three doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a three-week period; four doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a two-week period; four doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 3 weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 4 weeks; Five doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of five weeks; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of three weeks; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a four-week period; six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a four-week period; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; seven doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a six-week period; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over four weeks; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; eight doses of a lipid-binding protein-based conjugate (e.g., CER-001) over six weeks; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over four weeks; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a five-week period; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over six weeks; nine doses of a lipid-binding protein-based conjugate (e.g., CER-001) over six weeks; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a 4-week period; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 5 weeks; 10 doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a period of 6 weeks; or Ten doses of lipid-binding protein-based conjugates (e.g., CER-001) over a period of seven weeks The method may include administering

[0285] In one embodiment, the intensive regimen comprises 2 doses of a lipid-binding protein-based conjugate (eg, CER-001) per week to 5 doses per week.

[0286] In one embodiment, the consolidation regimen comprises administering six doses of a lipid-binding protein-based conjugate (e.g., CER-001) over a three week period, e.g., on days 21, 24, 28, 31, 35, and 38 of the treatment regimen beginning with an induction regimen on day 1.

[0287] In practice, a dosing window may be provided to accommodate minor variations in dosing schedules, for example, multiple dosing per week, e.g., a window of ±2 days or ±1 day around the dosing date may be used.

[0288] The therapeutic dose of lipid-binding protein-based complex (e.g., CER-001) administered by infusion in the intensive regimen can range from 4 to 30 mg / kg on a protein weight basis (e.g., 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, or 30 mg / kg, or any range bounded by any two of the aforementioned values, e.g., 5 to 15 mg / kg, 10 to 20 mg / kg, or 15 to 25 mg / kg). In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) used in the intensive regimen is 8 mg / kg. In some embodiments, the intensive regimen includes six doses of lipid-binding protein-based complex (e.g., CER-001) administered at a dose of 8 mg / kg over a period of three weeks. In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) used in the intensive regimen is 10 mg / kg. In some embodiments, the lipid-binding protein-based complex (e.g., CER-001) dose in the intensive regimen is 15 mg / kg. In some embodiments, the lipid-binding protein-based complex (e.g., CER-001) dose used in the intensive regimen is 20 mg / kg. In some embodiments, the intensive regimen includes 6 doses of lipid-binding protein-based complex (e.g., CER-001) administered at a dose of 10 mg / kg over 3 weeks. The dose of lipid-binding protein-based complex used to deliver ophthalmic drugs can be a dose that delivers a therapeutically effective amount of the drug.

[0289] In yet other embodiments, the lipid-binding protein-based complex (e.g., CER-001) may be administered on a unit dosage basis. The unit dosage used in the consolidation phase may range from 300 mg to 3000 mg per administration by injection.

[0290] In certain embodiments, the dosage of lipid-binding protein-based conjugate (e.g., CER-001) used during the consolidation phase is 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg per administration by injection.

[0291] In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the consolidation phase is higher than the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the induction phase. For example, the dose administered in the consolidation phase can be 1.5 to 3 times the dose administered in the induction phase. In a specific embodiment, the dose of lipid-binding protein-based complex (e.g., CER-001) administered in the consolidation phase is twice the dose of lipid-binding protein-based complex (e.g., CER-001) administered in the consolidation phase. Increasing the dose in the consolidation phase can compensate for a reduced frequency of dosing. In other embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the consolidation phase is the same as the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the induction phase.

[0292] The lipid-binding protein-based complex (e.g., CER-001) may be administered during the consolidation phase in the same manner as described in Section 6.3, for example, as an IV infusion over a period of one hour, or may be administered locally, such as intraocularly or topically. If the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the consolidation phase is greater than the dose administered in the induction phase, the lipid-binding protein-based complex (e.g., CER-001) may optionally be administered in a larger volume and / or infused and / or administered over a longer period. For example, if the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the consolidation phase is twice the dose administered during the induction phase, the administration volume may be increased (e.g., doubled) and / or the infusion time may be increased (e.g., doubled).

[0293] 6.5. Maintenance regimen The method of the present disclosure may include a maintenance regimen, which may follow induction regimen and optionally reinforcement regimen, but does not necessarily follow.In some embodiments, the maintenance regimen includes administering lipid-binding protein-based complex (e.g., CER-001) to the subject less frequently than during induction phase and / or reinforcement phase.Typically, lipid-binding protein-based complex (e.g., CER-001) is administered once every 3 days or more, for example once a week or twice a week, during the maintenance regimen.

[0294] A maintenance regimen may involve administering a lipid-binding protein-based conjugate (e.g., CER-001) for one month or more, two months or more, three months or more, six months or more, nine months or more, one year or more, eighteen months or more, two years or more, or indefinitely.

[0295] In some embodiments, the maintenance regimen comprises administering a lipid-binding protein-based complex (e.g., CER-001) once every 5 days to 1 week for at least 16 weeks, in other embodiments, the maintenance regimen comprises administering a lipid-binding protein-based complex (e.g., CER-001) once a week for at least 20 weeks, at least 30 weeks, or at least 40 weeks.

[0296] Similar to the dosing windows described in Section 6.3 above, dosing windows can also be used in maintenance regimens to accommodate minor variations in the weekly dosing schedule. For example, a window of ±2 days or ±1 day around a weekly date can be used.

[0297] The therapeutic dose of lipid-binding protein-based complex (e.g., CER-001) administered by infusion in a maintenance regimen can range from 4 to 30 mg / kg on a protein weight basis (e.g., 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, or 30 mg / kg, or any range bounded by any two of the foregoing values, e.g., 5 to 15 mg / kg, 10 to 20 mg / kg, or 15 to 25 mg / kg). For example, a subject weighing 70 kg and who should receive a 10 mg / kg dose of CER-001 would receive an amount of CER-001 that provides 700 mg of ApoA-I (70 kg x 10 mg / kg). In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) used in a maintenance regimen is 8 mg / kg. In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) used in a maintenance regimen is 10 mg / kg. In some embodiments, the lipid-binding protein-based complex (e.g., CER-001) used in the intensive regimen is administered at a dose of 15 mg / kg. In some embodiments, the lipid-binding protein-based complex (e.g., CER-001) used in the intensive regimen is administered at a dose of 20 mg / kg. The lipid-binding protein-based complex used to deliver ophthalmic drugs can be administered at a dose that delivers a therapeutically effective amount of the drug.

[0298] In yet other embodiments, the lipid-binding protein-based complex (e.g., CER-001) may be administered on a unit dosage basis. The unit dosage used in the maintenance phase may vary from 300 mg to 3000 mg per administration by injection.

[0299] In certain embodiments, the dosage of lipid-binding protein-based conjugate (e.g., CER-001) used during the maintenance phase is 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg per administration by infusion.

[0300] In some embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the maintenance phase is higher than the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the induction phase and / or consolidation phase. For example, the dose administered in the maintenance phase may be 1.5 to 3 times the dose administered in the consolidation phase. In a specific embodiment, the dose of lipid-binding protein-based complex (e.g., CER-001) administered in the maintenance phase is twice the dose of lipid-binding protein-based complex (e.g., CER-001) administered in the consolidation phase. Increasing the dose in the maintenance phase may compensate for a reduced frequency of dosing. In other embodiments, the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the maintenance phase is the same as the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the induction phase and / or consolidation phase. In some embodiments, the dose administered in the maintenance phase can be adjusted, e.g., increased or decreased, to reach a dose that stabilizes a clinical parameter (e.g., corneal opacity). Alternatively or in addition, the frequency of administration in the maintenance phase can be adjusted, e.g., increased or decreased, to achieve stabilization of a clinical parameter (e.g., corneal opacity).

[0301] The lipid-binding protein-based complex (e.g., CER-001) may be administered during the maintenance phase in the same manner as described in Section 6.3, for example, as an IV infusion, or may be administered locally, such as intraocularly or topically. If the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the maintenance phase is greater than the dose administered in the consolidation phase, the lipid-binding protein-based complex (e.g., CER-001) may optionally be administered in a larger volume and / or infused and / or administered over a longer period of time. For example, if the dose of lipid-binding protein-based complex (e.g., CER-001) administered during the maintenance phase is twice the dose administered during the consolidation phase, the administration volume may be increased (e.g., doubled) and / or the infusion time may be increased (e.g., doubled).

[0302] Combination Therapy Subjects are treated with a combination of chemotherapy, either as monotherapy or as a treatment with other anti-cancer drugs, such as statins (e.g., atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, pravastatin), cholesterol absorption inhibitors (e.g., ezetimibe), niacin, aspirin, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors (e.g., alirocumab, bococizumab, evolocumab, antibodies such as 1D05-IgG2 (Ni et al., 2011, J Lipid Res. 52(1):78-86), and LY3015014 (Kastelein et al., 2016, Eur Heart J 37(17):1360-9), or ALN-PCSSC (the Medicines The lipid-binding protein-based complex (e.g., CER-001) may be used as part of a combination therapy regimen with one or more lipid-regulating medications, such as RNAi therapeutics (e.g., erythropoietin ...

[0303] The combination therapy regimen may involve administering a lipid-binding protein-based complex (e.g., CER-001) in combination with one or more of the aforementioned drugs and / or one or more of the aforementioned classes of pharmaceuticals. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with atorvastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with ezetimibe. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with niacin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with rosuvastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with simvastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with aspirin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with fluvastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with lovastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with pravastatin. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with alirocumab. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with evolocumab. In some embodiments, the subject is treated with a lipid-binding protein-based complex (e.g., CER-001) in combination with ALN-PCSsc.In each of the foregoing embodiments, the lipid regulating drug may be the only lipid regulating drug that the subject receives in combination with the lipid binding protein-based complex therapy, or may be part of a combination of lipid regulating drugs administered in combination with the lipid binding protein-based complex.

[0304] In some embodiments, lipid-binding protein-based complex (e.g., CER-001) is administered in combination with one, two, or all three of antihypertensive drugs, such as amlodipine, urapidil, and furosemide. In some embodiments, lipid-binding protein-based complex (e.g., CER-001) is administered in combination with amlodipine, urapidil, and furosemide. In some embodiments, the combination further comprises a statin, such as atorvastatin.

[0305] Therapy with a lipid-binding protein-based conjugate (e.g., CER-001) can be added to a lipid-lowering background therapy initiated prior to therapy with a lipid-binding protein-based conjugate (e.g., CER-001).

[0306] In some embodiments, the subject is treated with a stable dose of lipid-regulating medicament for at least 6 weeks (e.g., 6 weeks, 8 weeks, 2 months, 6 months, 1 year, or more than 1 year) before starting therapy with lipid-binding protein-based complex (e.g., CER-001) according to the dosage regimen of the present disclosure. Alternatively, lipid-binding protein-based complex (e.g., CER-001) therapy can be started before or in parallel with treatment with one or more lipid-regulating medicaments. EXAMPLES

[0307] 7. Working Example 7.1. Example 1: CER-001 as a Carrier for Ophthalmic Drugs 7.1.1. Azithromycin and spironolactone Azithromycin is an antibiotic used to treat bacterial infections of the eye, such as bacterial conjunctivitis and trachoma (www.mayoclinic.org / drugs-supplements / azithromycin-ophthalmic-route / description / drg-20070979). Spironolactone is a steroid being investigated for the treatment of meibomian gland dysfunction and associated dry eye (Yee et al., 2016, Investigative Ophthalmology & Visual Science 57(12):5664). A study was conducted to evaluate the suitability of CER-001 to act as a drug carrier for the delivery of azithromycin and spironolactone.

[0308] A solution of CER-001 was mixed with azithromycin to provide a final azithromycin concentration of 10 mg / ml and subjected to five heating and cooling cycles from 37° C. to 55° C. to promote the complexation of azithromycin to CER-001. For controls, a sample of CER-001 without added azithromycin and a sample of azithromycin at a concentration of 10 mg / ml in phosphate buffered saline (PBS) were similarly subjected to five heating and cooling cycles from 37° C. to 55° C. As shown in FIG. 1A, the sample of CER-001 without azithromycin (left tube) remained clear after the heating and cooling cycles, while the sample of azithromycin in PBS (right tube) contained numerous crystals in the liquid and on the glass tube. The sample of CER-001 with azithromycin (middle tube) was cloudier than the pure CER-001 sample, but contained significantly fewer azithromycin crystals than the sample of azithromycin in PBS.

[0309] A solution of CER-001 was mixed with spironolactone to provide a final spironolactone concentration of 1.5 mg / ml and subjected to five heating and cooling cycles from 37° C. to 55° C. to promote the complexation of spironolactone to CER-001. For controls, a sample of CER-001 without added spironolactone and a sample of spironolactone at a concentration of 1.5 mg / ml in phosphate buffered saline (PBS) were similarly subjected to five heating and cooling cycles from 37° C. to 55° C. As shown in FIG. 1B, the sample of CER-001 without spironolactone (left tube) remained clear after the heating and cooling cycles, while the sample of spironolactone in PBS (right tube) contained numerous crystals in the liquid, on the glass tube, and above the meniscus. The sample of CER-001 with spironolactone (middle tube) was cloudier than CER-001 alone, but contained significantly fewer spironolactone crystals than the sample of spironolactone in PBS.

[0310] Dexamethasone palmitate Dexamethasone palmitate is a lipophilic prodrug of dexamethasone and can be used to treat macular edema (Daull et al., 2013, J. Ocul Pharmacol Ther. 29(2):258-69). Studies were conducted to evaluate the suitability of CER-001 to act as a drug carrier for the delivery of dexamethasone palmitate.

[0311] A solution of CER-001 was mixed with dexamethasone palmitate to provide a final dexamethasone palmitate concentration of 1 mg / ml and subjected to five heating and cooling cycles from 37° C. to 55° C. to promote conjugation of dexamethasone palmitate to CER-001. For controls, a sample of CER-001 without the addition of dexamethasone palmitate, and a sample of dexamethasone palmitate at a concentration of 1 mg / ml in phosphate buffered saline (PBS) were similarly subjected to five heating and cooling cycles from 37° C. to 55° C. As shown in FIG. 1C, the sample of CER-001 without dexamethasone palmitate (left tube) remained clear after the heating and cooling cycles, while the sample of dexamethasone palmitate in PBS (right tube) contained a lipid film on the glass above the meniscus and was very cloudy or "milky." The sample of CER-001 with dexamethasone palmitate (middle tube) was cloudier than CER-001 alone, but contained no precipitate or crystals.

[0312] Cyclosporine Cyclosporine is an immunomodulatory agent used to increase tear production in subjects with dry eye (Ames and Galor, 2015, Clin Investig (Longd.) 5(3):267-285). A study was conducted to evaluate the suitability of CER-001 to act as a drug carrier for the delivery of cyclosporine.

[0313] A solution of CER-001 was mixed with cyclosporine to provide a final cyclosporine concentration of 1 mg / ml and subjected to five heating and cooling cycles from 37°C to 55°C to promote the conjugation of cyclosporine to CER-001. For controls, a sample of CER-001 without added cyclosporine and a sample of cyclosporine at a concentration of 1 mg / ml in phosphate buffered saline (PBS) were similarly subjected to five heating and cooling cycles from 37°C to 55°C. As shown in Figure 1D, the sample of CER-001 without cyclosporine (left tube) remained clear after the heating and cooling cycles, while the sample of cyclosporine in PBS (right tube) contained crystals in the glass and in the liquid. The sample of CER-001 with cyclosporine (middle tube) was cloudier than CER-001 alone but did not contain precipitate or crystals even after overnight storage at 4°C.

[0314] This example shows that CER-001 can be complexed with azithromycin, spironolactone, dexamethasone palmitate, and cyclosporine, indicating that CER-001 is a suitable carrier for ophthalmic drugs.

[0315] 7.2. Example 2: Intraocular distribution of CER-001 in rabbits after intravenous administration A study was conducted to evaluate the distribution of CER-001 in the aqueous humor, vitreous humor, retina, and choroid of both eyes, and in plasma, following multiple intravenous (IV) administration in albino rabbits. Briefly, on days 1, 3, and 5, each rabbit received a single IV injection of 2 mL / kg of CER-001 at 8.1 mg / mL (16.2 mg / kg). On day 7, rabbits received two IV injections of 1.25 mL / kg of CER-001 at 8.1 mg / mL (10.13 mg / kg per injection). Sampling for bioanalysis was performed 1 hour after the last IV administration.

[0316] The greatest amount of CER-001 was detected in plasma (454 μg / mL). Smaller amounts of CER-001 were found in the choroid (16.4 μg / g), retina, and aqueous humor (2.1 μg / g and 2.7 μg / mL, respectively). CER-001 was not detected in the vitreous humor at the time of sampling.

[0317] The results of this example demonstrate that IV administration of CER-001 is associated with localization of CER-001 to ocular structures.

[0318] 7.3. Example 3: Intraocular distribution of CER-001 in rabbits after intravitreal administration A study was conducted to evaluate the distribution of CER-001 in the aqueous humor, vitreous humor, retina, and choroid of both eyes, as well as in plasma, following intravitreal (IVT) administration in albino rabbits. Briefly, a single 50 μL IVT injection of 8.1 mg / mL CER-001 was administered to the right eye of six albino rabbits on day 1, followed by a single 50 μL IVT injection of 8.1 mg / mL CER-001 to the left eye on day 2 (two animals) or day 3 (remaining four animals). Sampling for bioanalysis was performed at 24, 48, or 120 hours after the last injection.

[0319] CER-001 was detected in all ocular tissues analyzed. The highest amount of CER-001 was found in the vitreous humor (approximately 140 μg / mL), which remained constant for up to 144 hours after injection. The amount of CER-001 was relatively low in the aqueous humor (approximately 20 μg / mL), retina (approximately 40 μg / mL), and choroid (approximately 30 μg / g), but remained constant at all sampling time points. No systemic exposure was observed, as CER-001 was not detected in any of the plasma samples. Full results are shown in Table 2:

[0320] [Table 2]

[0321] The results of this example show that this mode of administration is effective in localizing the CER-001 formulation in the analyzed ocular structures, primarily in the vitreous humor. Given the IVT administration route, it was expected that the highest levels would be found in the vitreous humor. Distribution to all ocular tissues was consistent at all time points. No systemic exposure was observed.

[0322] 7.4. Example 4: CER-001 Therapy for Visual Impairment Associated with LCAT Deficiency Subjects with LCAT deficiency and visual impairment associated with their LCAT deficiency (visual impairment resulting from ocular lipid deposits) were administered CER-001 according to a treatment regimen including an induction regimen, a consolidation regimen, and a maintenance regimen.

[0323] Prior to treatment with CER-001, the subject had ocular lipid deposits manifesting as white corneal limbal opacities. The subject had normal visual acuity but blurred vision, especially at night. Slit-lamp examination and optical computed tomography showed hyperreflective corneal opacification (data not shown). Next generation sequencing confirmed that the subject was compound heterozygous for two LCAT gene variations, none in the ABCA1 or APOA1 genes. The first allele of maternal inheritance is an exon-5 (c.605T>C) missense mutation p.(Ile202Thr), previously well established as causing familial LCAT deficiency (FLD) in Europe. The paternal allele (c.154+5G>C) was novel and not found in the general referral population database. It alters a highly evolutionarily conserved residue in the intron-1 donor splice site, thereby potentially altering exon-1 mRNA splicing and creating a cryptic acceptor splice site at position c.154+15. As a result, RNA incorporation of the intron sequence may generate an aberrant / truncated protein if it does not abrogate LCAT expression.

[0324] The induction regimen included nine doses of CER-001 administered over a three week period. The dose of CER-001 administered in the induction regimen was 10 mg / kg, calculated based on the amount of ApoA-I in the CER-001 administered and the weight of the subject.

[0325] After the induction regimen, subjects were administered CER-001 according to a consolidation regimen that included seven doses of CER-001 administered over a four week period. The dose of CER-001 administered in the induction regimen was 10 mg / kg, calculated based on the amount of ApoA-I in the administered CER-001 and the weight of the subject.

[0326] After the intensification regimen, the subjects were administered CER-001 according to a maintenance regimen, which included administration of CER-001 once a week for three weeks. The dose of CER-001 administered in the maintenance regimen was 10 mg / kg, calculated based on the amount of ApoA-I in CER-001 to be administered and the weight of the subjects. The dose was then increased to 20 mg / kg once a week for six weeks. The treatment period was five months, followed by a three-month treatment-free follow-up period.

[0327] In the induction, consolidation, and maintenance regimens, CER-001 was administered as an IV infusion after premedication with hydroxyzine. The stock solution of CER-001 was diluted in physiological saline (0.9% NaCl) prior to administration, and all doses of CER-001 were administered using an infusion pump at a fixed rate of 250 ml / hour over 1 hour.

[0328] The subject's vision improved over the course of treatment with CER-001. Notably, administration of CER-001 was accompanied by a normalization of vision. At the end of the follow-up period, there was no recurrence of blurred vision.

[0329] CER-001 administered by injection appeared to reach the anterior portion of the subject's eye, including the cornea, where it exerted its therapeutic effect. Without being bound by theory, it is believed that the observed effect on the subject's vision is due to the ability of CER-001, even when administered peripherally, to mobilize (e.g., directly or indirectly) accumulated lipids in and / or around the eye. Additionally, and again without being bound by theory, it is believed that the anti-inflammatory properties of CER-001 may contribute to the observed effect on the subject's vision.

[0330] Again without being bound by theory, it is further believed that subjects suffering from other ocular diseases, particularly those associated with lipid accumulation, may similarly benefit from treatment with CER-001 or another lipid-binding protein-based complex.Furthermore, again without being bound by theory, it is believed that the ability of CER-001 to reach the anterior segment of the eye when administered peripherally may be exploited to deliver ophthalmic drugs to the eye (e.g., the anterior segment of the eye).

[0331] 7.5. Example 5: Ocular Tolerance of CER-001 in Rabbits The ocular tolerability of CER-001 was assessed in albino rabbits. In the first assessment, CER-001 was administered topically or by a single IVT injection at 8 mg / mL (protein weight basis) with or without conjugated dexamethasone palmitate to the eyes of albino rabbits. No tolerability problems were observed with repeated topical administration of up to 8 drops or with a single intravitreal administration.

[0332] In a second assessment, the ocular tolerability of CER-001 with or without soft corticoids (S-Cort) was evaluated following repeated daily 50 μL instillations or a single 50 μL IVT injection into the right eye. As in the first assessment, no tolerability issues of concern were observed in any of the groups tested, indicating that CER-001 as well as CER-001 with S-Cort were macroscopically well tolerated.

[0333] 7.6. Example 6: CER-001 Treatment of Endotoxin-Induced Uveitis (Severe Inflammation) in Rabbits A study was conducted to assess the ability of CER-001 to treat endotoxin-induced uveitis (severe inflammation) when administered locally or by a single intravitreal injection (IVT) with or without conjugated dexamethasone palmitate (DXP). CER-001 vehicle and Solu-Medrol®, an injectable formulation containing the anti-inflammatory glucocorticoid methylprednisolone sodium succinate, were included as controls. Tolerability was assessed by the McDonald-Shadduck scoring system 6 and 24 hours after administration (see Eaton et al., Journal of Ocular Pharmacology and Therapeutics 33(10):718-734). Cell infiltration and protein content in aqueous humor were measured 24 hours after administration.

[0334] Briefly, five groups of 10 animals were used in the first study: Group 1: Vehicle administered topically in the right eye Group 2: CER-001 8mg / ml administered topically in the right eye (3 doses of 50μl) Group 3: Vehicle for IVT administration in the right eye Group 4: CER-001 0.8mg / ml in 50μl IVT in the right eye Group 5: Solu-Medrol 20mg / ml in 250μl subconjunctival administration in the right eye (as a positive control)

[0335] One group was added at one-month intervals from the previous in-life stage. Group 6: CER-001 at 8mg / ml in 50μl IVT in the right eye

[0336] Another group was added at one-month intervals from the previous in-life stage. Group 7: 8mg / ml CER-S Cort in 50μl IVT in the right eye. CER-S Cort (a soft corticoid) was prepared using 8mg / ml CER-001.

[0337] 7.6.1. Method The right eye of each rabbit was examined using a slit lamp.

[0338] Observations were scored using a modified McDonald-Shadduck for the conjunctiva (redness and edema), aqueous humor flare, and iris as follows:

[0339] Modified scale by McDonald and Shadduck conjunctiva

[0340] [Table 3]

[0341] [Table 4]

[0342] Aqueous humor flare The intensity of the Tyndall phenomenon is scored by comparing the normal Tyndall effect observed when the slit lamp beam passes through the lens with that seen in the anterior chamber. The presence of aqueous humor flare is presumptive evidence of a breakdown of the blood-aqueous humor barrier.

[0343] [Table 5]

[0344] iris In the following definition, the primary, secondary, and tertiary vessels are used as aids in determining the subjective ocular score of iris involvement. It is hypothesized that the more vascular engorgement and the greater the involvement of secondary and tertiary vessels, the greater the intensity of iris involvement. The score ranges from 0 to +4.

[0345] [Table 6]

[0346] The tolerability for the different treatment groups is shown in Figures 2A-2C. Data are expressed as mean ± SEM. One-way ANOVA test results: * :p<0.05; ** :p<0.01; **** :p<0.0001.

[0347] Histological observation was performed to determine the number of infiltrating cells in the aqueous humor (AH) after Giemsa staining under a microscope. AH cell infiltration is shown in Figure 3A. Data are expressed as mean ± SEM. One-way ANOVA test results: * :p<0.05; ** :p<0.01; **** :p<0.0001.

[0348] Protein concentration in the AH was measured by protein-dye binding assay (Bradford test). AH protein content is shown in Figure 3B. Data are expressed as mean ± SEM. One-way ANOVA test results: * :p<0.05; ** :p<0.01; **** :p<0.0001.

[0349] For ocular examination, the overall grade consisted of the sum of the scores in each of the three categories: conjunctiva (injection, edema), aqueous humor flare, and iris. Group means and standard deviations or medians were calculated for AH leukocyte density, AH protein concentration, cumulative ocular clinical score, and body weight.

[0350] Transient cloudiness was observed in Group 7 (CER-S Cort). Cloudiness score range of 1 to 3 is defined as follows: 1. The test article is clear but may result in a refractive shift when viewing the underlying fundus structures. 2. The test article is translucent, allowing only a hazy view of the underlying fundus structures. 3. The test article is opaque and obscures the view of the underlying fundus structures.

[0351] Turbidity results for Group 7 at 0, 6, and 24 hours post-induction are shown in Figure 4. Data are expressed as mean ± SEM. * :p<0.05; ** :p<0.01; **** One-way ANOVA test with p<0.0001.

[0352] The tolerability for the various treatment groups is shown in Figures 2A-2C, while the aqueous humor cellular infiltration and protein content are shown in Figures 3A-3B, respectively. CER-001 (containing a high dose of 8 mg / ml) in a single intravitreal administration with or without dexamethasone palmitate induced significant tolerability (Figures 2A-2C). Positive effects on cellular infiltration and protein in the aqueous humor were observed as well (Figures 3A-3B). This example further supports the use of CER-001 and similar lipid-binding protein-based conjugates to treat ocular diseases such as uveitis, as well as the use of CER-001 and similar lipid-binding protein-based conjugates to deliver ophthalmic drugs to the eye to treat ocular diseases such as uveitis.

[0353] 7.7. Example 7: Efficacy of a Single IVT Administration of CER-001 in a Rabbit Model of DL-α-Aminoadipic Acid-Induced Retinal Neovascularization The efficacy of CER-001 against retinal DL-α-aminoadipic acid (DL-AAA)-induced neovascularization and permeability was evaluated after a single IVT administration in pigmented rabbits. DL-α-aminoadipic acid (AAA) is a retinal glial cytotoxin known to cause glial dysfunction and death, leading to blood-retinal barrier breakdown and persistent retinal neovascularization for 10-12 weeks.

[0354] Briefly, pigmented rabbits were randomly assigned to one of three groups: 8 mg / mL CER-001 (n=6), 15 mg / ml CER-001 (n=4), or vehicle (n=5). Twelve weeks prior to the initiation of CER-001 treatment, neovascularization was induced in the right eyes of all rabbits by IVT administration of 50 μL of DL-AAA.

[0355] Baseline Heidelberg Retinal Angiography (HRA) assessments were performed prior to administration of CER-001 or vehicle by IVT to the right eye of each rabbit. HRA assessments were performed weekly following administration of CER-001 or vehicle on day 0. Laser flare meter (LFM) and intraocular pressure (IOP) assessments were performed on day 25 for the CER-001-treated group and on day 18 for the vehicle-treated group. IOP was used to assess treatment-related changes in intraocular fluid pressure, and LFM was used to assess intraocular inflammation. Rabbits were euthanized and tissues were sampled on day 40 for the CER-001-treated group and on day 33 for the vehicle-treated group.

[0356] Fluorescence angiography HRA results were used to assess vascular leakage. Both CER-001 treatments were associated with reduced vascular leakage, corresponding to reduced neovascularization and permeability (Table 3). During all HRA assessments, floaters were observed in the vitreous humor of CER-001-treated rabbits in both groups, whereas they were absent in vehicle-treated rabbits.

[0357] [Table 7]

[0358] Intraocular pressure (IOP) values ​​were comparable between the left (control) and right (treated) eyes of rabbits in the CER-001 (8 mg / mL) and vehicle groups. A slight (<20%) decrease in IOP in the right eye was observed in 50% of rabbits in the CER-001 (15 mg / mL) group (data not shown). Similarly, as shown in Table 4, the laser flare meter (LFM) values ​​of CER-001 (15 mg / mL)-treated rabbits were elevated compared to those observed in the low-dose CER-001 and vehicle groups.

[0359] [Table 8]

[0360] The results of this example demonstrate that CER-001 can reduce retinal neovascularization and permeability.

[0361] 7.8. Example 8: Efficacy and Ocular Tolerability of CER-001 in a Rabbit Model of Retinal Vascular Hyperpermeability The efficacy and ocular tolerability of various doses of CER-001 on retinal vascular hyperpermeability were evaluated after a single IVT administration. Briefly, 50 μL of CER-001 (1, 2, 4, or 6 mg / mL), aflibercept (40 mg / mL), or vehicle was administered to pigmented rabbit eyes by IVT 2 days prior to administration of VEGF by IVT. Group 1, n=5, received 6 mg / mL of CER-001 in the right eye and 4 mg / mL of CER-001 in the left eye. Group 2, n=5, received 2 mg / mL of CER-001 in the right eye and 1 mg / mL of CER-001 in the left eye. Group 3, n=5, received vehicle in the right eye and aflibercept in the left eye. Vascular leakage was assessed by fluorometry 2 days after VEGF administration and compared to baseline values ​​determined prior to day -2. Tolerability was assessed by the McDonald-Shadduck scoring system on days -2 (CER-001, aflibercept, or vehicle administration), 0 (VEGF administration), and 2 (vascular leakage assessment). Vascular leakage assessment results are presented in Table 5 as the ratio of area under the curve (AUC) for the vitreoretinal segment at day 2 relative to baseline.

[0362] [Table 9]

[0363] Fluorescence results showed that administration of the positive control aflibercept resulted in the lowest vitreous-retinal fluorescence ratio. Furthermore, the vitreous-retinal fluorescence ratio was lower in all CER-001-treated groups compared to the vehicle group. CER-001 administration was associated with floaters in the vitreous humor. McDonald-Shadduck assessment did not reveal any significant clinical signs following administration of any CER-001 dose. Taken together, these results indicate that CER-001 can reduce VEGF-induced retinal vascular permeability.

[0364] In a second assessment, the efficacy of CER-001 in a rabbit model of retinal vascular hyperpermeability was evaluated after multiple IVT administrations. This time, 50 μL of CER-001 (8.1 mg / mL) or vehicle was administered by IVT to the right eye of pigmented rabbits 3 days before and 1 day after administration of VEGF by IVT. Vascular leakage was assessed by fluorometry 2 days after VEGF administration.

[0365] The vitreoretinal fluorescence ratio of treated / untreated eyes was lower in the CER-001-treated group compared to the vehicle group on day 2. Specifically, the mean ratio for the CER-001-treated group was 14±9 and the mean ratio for the vehicle group was 31±18. These results indicate that CER-001 administered by IVT can reduce VEGF-induced retinal vascular permeability.

[0366] 7.9. Example 9: Efficacy of CER-001 Treatment Against Mycobacterium tuberculosis-Induced Chronic Panuveitis in Rabbits The efficacy of multiple IV doses of CER-001 against Mycobacterium tuberculosis-induced uveitis was evaluated in albino rabbits. Briefly, on day 1, each rabbit was injected subcutaneously (SC) with H37Ra to sensitize the rabbits to M. tuberculosis antigens. Uveitis induction was accompanied by IVT injections of H37Ra on days 15 and 30. Rabbits were randomly assigned to treatment groups with either CER-001 (8.1 mg / mL) (n=4) or vehicle (n=4). IV treatment with CER-001 (2 mL / kg, 16.2 mg / kg) or vehicle was administered on days 1, 5, 9, 13, 17, 21, 25, and 29. Slit-lamp ocular examination was performed to evaluate ocular inflammation in the anterior and posterior segments.

[0367] IVT injection of H37Ra antigen resulted in panuveitis in both the anterior and posterior segments of the vehicle-treated rabbits' eyes. For example, inflammation in the anterior and posterior segments peaked 72 hours after each IVT injection. Rabbits in the CER-001-treated group exhibited less pronounced levels of inflammation in both the anterior and posterior segments after the first IVT injection. After the second IVT injection, the inflammation scores in the posterior segments did not differ between the two treatment groups. The slit lamp evaluation results are summarized in Table 6 below.

[0368] [Table 10]

[0369] 8. Specific embodiments Various aspects of the disclosure are described in the embodiments set forth in Group 1 below in the numbered paragraphs.

[0370] Group 1: 1. A method of treating a subject having an ocular disease, comprising administering to the subject an amount of a lipid-binding protein-based complex, optionally in combination with one or more ocular drugs, effective to reduce the severity of the ocular disease, and optionally (a) the subject has cataracts or acute anterior uveitis; and / or (b) The method, wherein the lipid-binding protein-based complex is administered by suprachoroidal injection, episcleral injection, implant, iontophoresis, or electroporation. 2. The method of embodiment 1, wherein the eye disease is a disease associated with lipid accumulation. 3. The method of embodiment 2, wherein the eye disease is fish eye disease. 4. The method of embodiment 2, wherein the eye disease is lipokeratopathy. 5. The method of embodiment 4, wherein the lipokeratopathy is secondary lipokeratopathy. 6. The method of embodiment 2, wherein the eye disease is a corneal dystrophy, such as a hereditary corneal dystrophy, anterior or superficial corneal dystrophy, corneal stromal dystrophy, or posterior corneal dystrophy. 7. The method of any one of embodiments 1 to 6, wherein the subject has corneal opacity and the amount of lipid-binding protein-based complex is an amount effective to reduce corneal opacity in the subject. 8. The method of embodiment 7, wherein opacity is measured by anterior optical coherence tomography (OCT). 9. The method of any one of embodiments 1 to 8, wherein the amount of the lipid-binding protein-based complex is an amount effective to improve the contrast sensitivity of the subject. 10. The method of any one of embodiments 1 to 9, wherein the amount of the lipid binding protein-based complex is an amount effective to reduce stray light levels in a subject. 11. The method of any one of embodiments 1 to 10, wherein the subject is homozygous for the LCAT mutation. 12. The method of any one of embodiments 1 to 10, wherein the subject is heterozygous for an LCAT mutation. 13. The method of any one of embodiments 1 to 2 and 4 to 10, except as subject to embodiment 3, wherein the subject does not have an LCAT deficiency. 14. The method of embodiment 1 or embodiment 2, wherein the subject has cataracts. 15. The method of embodiment 1 or embodiment 2, wherein the eye disease is dry eye. 16. The method of embodiment 15, wherein the dry eye is associated with meibomian gland dysfunction (MGD). 17. The method of embodiment 16, wherein the MGD is obstructive MGD. 18. The method of embodiment 15, wherein the dry eye is associated with lacrimal gland dysfunction. 19. The method of embodiment 1 or embodiment 2, wherein the eye disease is blepharitis. 20. The method of embodiment 1 or embodiment 2, wherein the eye disease is an inflammatory eye disease. 21. The method of embodiment 1 or embodiment 2, wherein the eye disease is uveitis. 22. The method of embodiment 21, wherein the uveitis is anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. 23. The method of embodiment 22, wherein the uveitis is anterior uveitis. 24. The method of embodiment 23, wherein the uveitis is acute anterior uveitis. 25. The method of embodiment 22, wherein the uveitis is intermediate uveitis. 26. The method of embodiment 22, wherein the uveitis is posterior uveitis. 27. The method of embodiment 22, wherein the uveitis is panuveitis. 28. The method of any one of embodiments 21 to 27, wherein the uveitis is caused by a bacterial infection. 29. The method of embodiment 1 or embodiment 2, wherein the eye disease is macular edema, macular degeneration, retinal detachment, eye tumor, fungal infection, viral infection, bacterial infection (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, or glaucoma. 30. The method of embodiment 1 or embodiment 2, wherein the eye disease is dry macular degeneration. 31. The method of embodiment 1 or embodiment 2, wherein the eye disease is wet macular degeneration. 32. The method of embodiment 1 or embodiment 2, wherein the eye disease is diabetic retinopathy, and optionally the subject has diabetic macular edema. 33. The method of embodiment 1 or embodiment 2, wherein the eye disease is Stargardt's disease. 34. The method of any one of embodiments 1 to 33, wherein the subject has impaired vision due to an eye disease, and the amount of lipid-binding protein-based complex is an amount that improves the subject's vision. 35. The method of any one of embodiments 1 to 34, wherein the subject has ocular lipid deposits. 36. The method of embodiment 35, wherein the ocular lipid deposits include corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof. 37. The method of embodiment 36, wherein the ocular lipid deposits include corneal lipid deposits. 38. The method of embodiment 36 or embodiment 37, wherein the ocular lipid deposits include retinal lipid deposits. 39. The method of any one of embodiments 36 to 38, wherein the ocular lipid deposits include eyelid lipid deposits. 40. The method of any one of embodiments 35 to 39, wherein the ocular lipid deposits are not calcified. 41. The method of any one of embodiments 35 to 40, wherein the lipid deposits include lipid deposits within drusen deposits. 42. The method of any one of embodiments 35 to 40, wherein the lipid deposits comprise lipofuscin granules. 43. The method of any one of embodiments 35 to 40, wherein the lipid deposits include cholesterol retention. 44. A method according to any one of embodiments 35 to 43, comprising administering to a subject an amount of a lipid-binding protein-based complex effective to reduce the size and / or number of ocular lipid deposits. 45. The lipid-binding protein-based complex comprises apolipoprotein AI (ApoA-I), and optionally the ApoA-I is ミラノ 45. The method of any one of the preceding embodiments, wherein the 46. ​​The method of any one of embodiments 1 to 45, wherein the lipid-binding protein-based complex does not comprise an apolipoprotein mimetic. 47. The method of any one of embodiments 1 to 46, wherein the lipid-binding protein-based complex is a reconstituted HDL or HDL mimic. 48. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises CER-001. 49. The method of embodiment 48, wherein CER-001 is a lipoprotein complex comprising ApoA-I and phospholipids in a 1:2.7±20% ApoA-I weight:total phospholipid weight ratio, and the phospholipids sphingomyelin and DPPG in a 97:3±20% sphingomyelin:DPPG weight:weight ratio. 50. The method of embodiment 48, wherein CER-001 is a lipoprotein complex comprising ApoA-I and phospholipids in a 1:2.7±10% ApoA-I weight:total phospholipid weight ratio, and the phospholipids sphingomyelin and DPPG in a 97:3±10% sphingomyelin:DPPG weight:weight ratio. 51. The method of embodiment 48, wherein CER-001 is a lipoprotein complex comprising ApoA-I and phospholipids in an ApoA-I weight:total phospholipid weight ratio of 1:2.7, and the phospholipids sphingomyelin and DPPG in a sphingomyelin:DPPG weight:weight ratio of 97:3. 52. The method of any one of embodiments 49 to 51, wherein ApoA-I has the amino acid sequence of amino acids 25 to 267 of SEQ ID NO: 1 of WO 2012 / 109162. 53. The method of any one of embodiments 49 to 52, wherein ApoA-I is recombinantly expressed. 54. The method of any one of embodiments 49 to 53, wherein CER-001 comprises natural sphingomyelin. 55. The method of embodiment 54, wherein the native sphingomyelin is chicken egg sphingomyelin. 56. The method of any one of embodiments 49 to 53, wherein CER-001 comprises synthetic sphingomyelin. 57. The method of embodiment 56, wherein the synthetic sphingomyelin is palmitoyl sphingomyelin. 58. The method of any one of embodiments 48 to 57, wherein CER-001 is administered in the form of a formulation in which CER-001 is at least 95% homogeneous. 59. The method of embodiment 58, wherein CER-001 is administered in the form of a formulation in which CER-001 is at least 97% homogeneous. 60. The method of embodiment 58, wherein CER-001 is administered in the form of a formulation in which CER-001 is at least 98% homogeneous. 61. The method of embodiment 58, wherein CER-001 is administered in the form of a formulation in which CER-001 is at least 99% homogeneous. 62. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises CSL-111. 63. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises CSL-112. 64. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises ETC-216. 65. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises CER-522. 66. The method of embodiment 47, wherein the lipid-binding protein-based complex comprises delipidated HDL. 67. The method of any one of embodiments 1 to 45, wherein the lipid-binding protein-based complex is a Cargomer. 68. The method of any one of embodiments 1 to 67, wherein the lipid-binding protein-based complex is a carrier for one or more ophthalmic drugs, and optionally one or more of the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble. 69. The method of any one of embodiments 1 to 68, wherein the lipid-binding protein-based conjugate comprises a lipid-binding protein-based conjugate having one or more ophthalmic drugs conjugated thereto, and optionally, one or more of the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble. 70. The method of embodiment 68 or embodiment 69, wherein the one or more ophthalmic drugs include a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, a prostaglandin analog, or a combination thereof. 71. The one or more ophthalmic drugs are azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-2-propanol, phenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib Nib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide 71. The method of any one of embodiments 68 to 70, comprising administering to the patient an effective amount of any of the following: methazolamide, acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, or a combination thereof. 72. The one or more ophthalmic drugs are azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-2-propanol, phenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib Nib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir The method of any one of embodiments 68 to 70, comprising administering to the patient an effective amount of any of the following: chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, dexamethasone palmitate, or a combination thereof. 73. The method of any one of embodiments 68 to 72, wherein the one or more ophthalmic drugs comprises azithromycin. 74. The method of any one of embodiments 68 to 73, wherein the one or more ophthalmic drugs comprises spironolactone. 75. The method of any one of embodiments 68 to 74, wherein the one or more ophthalmic drugs comprises dexamethasone palmitate. 76. The method of any one of embodiments 68 to 75, wherein the one or more ophthalmic drugs comprises cyclosporine. 77. The method of any one of embodiments 68 to 76, wherein the one or more ophthalmic drugs comprise latanoprost, travoprost, bimatoprost, tafluprost, or a combination thereof. 78. The method of embodiment 77, wherein the one or more ophthalmic drugs include latanoprost. 79. The method of any one of embodiments 68 to 78, wherein the one or more ophthalmic drugs comprises dexamethasone. 80. The method of any one of embodiments 68 to 79, wherein the one or more ophthalmic drugs comprises loteprednol etabonate. 81. The method of any one of embodiments 68 to 80, wherein the one or more ophthalmic drugs comprises triamcinolone. 82. The method of any one of embodiments 68 to 81, wherein the one or more ophthalmic drugs comprises acyclovir. 83. The method of any one of embodiments 68 to 82, wherein the one or more ophthalmic drugs comprises travoprost. 84. The method of any one of embodiments 68 to 83, wherein the one or more ophthalmic drugs comprises bimatoprost. 85. The method of any one of embodiments 68 to 84, wherein the one or more ophthalmic drugs comprises tafluprost. 86. The method of any one of embodiments 68 to 85, wherein the one or more ophthalmic drugs comprises pazopanib. 87. The method of any one of embodiments 68 to 86, wherein the one or more ophthalmic drugs comprises sirolimus. 88. The method of any one of embodiments 68 to 86, wherein the one or more ophthalmic drugs comprises tacrolimus. 89. The method of any one of embodiments 68 to 86, wherein the one or more ophthalmic drugs comprises nepafenac. 90. The method of any one of embodiments 1 to 46, wherein the lipid-binding protein-based complex is an apomer. 91. A method according to any one of embodiments 1 to 90, wherein the lipid-binding protein-based complex is administered peripherally, optionally by injection. 92. Lipid-binding protein-based complexes are (a) an induction regimen; and / or (b) an intensive regimen; and / or (c) Maintenance regimen 92. The method of embodiment 91, wherein the lipid binding protein-based complex comprises CER-001, and optionally the lipid binding protein-based complex comprises CER-001. 93. The method of embodiment 92, comprising administering one or more doses of the lipid-binding protein-based complex according to an induction regimen. 94. The method of embodiment 93, wherein the induction regimen comprises administering to the subject multiple doses of the lipid-binding protein-based complex. 95. The method of embodiment 94, wherein the induction regimen comprises administering to the subject at least three doses of the lipid-binding protein-based complex. 96. The method of embodiment 94 or embodiment 95, wherein the multiple doses in the induction regimen are separated by one or more days. 97. The method of any one of embodiments 93 to 96, wherein doses after the first dose of the induction regimen are separated by no more than 3 days. 98. The method of embodiment 97, wherein doses after the first dose of the induction regimen are separated by 1 to 3 days. 99. The method of embodiment 97, wherein doses after the first dose of the induction regimen are separated by 2 to 3 days. 100. The method of embodiment 97, wherein doses after the first dose of the induction regimen are separated by 1 to 2 days. 101. The method of any one of embodiments 93 to 100, wherein the induction regimen is of at least one week duration. 102. The method of embodiment 101, wherein the induction regimen is of two weeks duration. 103. The method of embodiment 101, wherein the induction regimen is of three weeks duration. 104. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject three doses of the lipid-binding protein-based complex per week. 105. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject four or more doses of the lipid-binding protein-based complex. 106. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject five or more doses of the lipid-binding protein-based complex. 107. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject six or more doses of the lipid-binding protein-based complex. 108. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject seven or more doses of the lipid-binding protein-based complex. 109. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject eight or more doses of the lipid-binding protein-based complex. 110. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject 9 or more doses of the lipid-binding protein-based complex. 111. The method of embodiment 110, wherein the induction regimen includes administering to the subject an initial dose of the lipid-binding protein-based complex on day 1, and administering to the subject subsequent doses of the induction regimen on days 2, 4, 7, 9, 11, 14, 16, and 18. 112. The method of any one of embodiments 93 to 103, wherein the induction regimen comprises administering to the subject 10 or more doses of the lipid-binding protein-based complex. 113. The method of embodiment 92, which does not include an induction regimen. 114. The method of any one of embodiments 92 to 113, comprising administering to the subject one or more doses of the lipid-binding protein-based complex according to an intensification regimen. 115. The method of embodiment 114, wherein the intensification regimen comprises administering to the subject multiple doses of the lipid-binding protein-based complex. 116. The method of embodiment 115, wherein the multiple doses in the intensive regimen are separated by 2 or more days. 117. The method of any one of embodiments 114 to 116, wherein the intensive regimen comprises administering to the subject at least two doses of the lipid-binding protein-based complex within one week. 118. The method of any one of embodiments 114 to 117, wherein the doses of the intensive regimen are separated by at most 4 days. 119. The method of any one of embodiments 114 to 118, wherein the doses of the intensive regimen are separated from each other by 3 or 4 days. 120. The method of any one of embodiments 114 to 119, wherein the intensive regimen is of at least 3 weeks duration. 121. The method of any one of embodiments 114 to 120, wherein the intensification regimen comprises administering to the subject three or more doses of the lipid-binding protein-based complex. 122. The method of any one of embodiments 114 to 120, wherein the consolidation regimen comprises administering to the subject four or more doses of the lipid-binding protein-based complex. 123. The method of any one of embodiments 114 to 120, wherein the consolidation regimen comprises administering to the subject five or more doses of the lipid-binding protein-based complex. 124. The method of any one of embodiments 114 to 120, wherein the intensification regimen comprises administering to the subject six or more doses of the lipid-binding protein-based complex. 125. The method of embodiment 124, wherein the intensification regimen comprises administering to the subject six doses of the lipid-binding protein-based complex. 126. The method of embodiment 125, wherein the consolidation regimen comprises administering to the subject six doses of the lipid-binding protein-based complex on days 21, 24, 28, 31, 35, and 38 following an induction regimen beginning on day 1. 127. The method of any one of embodiments 114 to 120, wherein the intensification regimen comprises administering to the subject seven or more doses of the lipid-binding protein-based complex. 128. The method of any one of embodiments 114 to 120, wherein the intensification regimen comprises administering to the subject eight or more doses of the lipid-binding protein-based complex. 129. The method of any one of embodiments 114 to 120, wherein the consolidation regimen comprises administering to the subject 9 or more doses of the lipid-binding protein-based complex. 130. The method of any one of embodiments 114 to 120, wherein the intensification regimen comprises administering to the subject 10 or more doses of the lipid-binding protein-based complex. 131. The method of any one of embodiments 92 to 113, which does not include a consolidation regimen. 132. The method of any one of embodiments 92 to 131, comprising administering to the subject multiple doses of the lipid-binding protein-based complex according to a maintenance regimen. 133. The method of embodiment 132, wherein the maintenance regimen comprises administering a dose of the lipid-binding protein-based complex to the subject once every 3 or more days. 134. The method of embodiment 132, wherein the maintenance regimen comprises administering a dose of the lipid-binding protein-based complex to the subject once every 5 days or more. 135. The method of embodiment 132, wherein the maintenance regimen comprises administering to the subject a dose of the lipid-binding protein-based complex every week. 136. The method of embodiment 135, wherein the maintenance regimen doses are administered ±2 days before or after a strict weekly date. 137. The method of embodiment 132, wherein the maintenance regimen comprises administering a dose of the lipid-binding protein-based complex to the subject twice a week. 138. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least one month. 139. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least two months. 140. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least 3 months. 141. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least 6 months. 142. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least 9 months. 143. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least one year. 144. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least 18 months. 145. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least two years. 146. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject indefinitely. 147. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for 16 weeks or more. 148. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for 20 weeks or more. 149. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for 30 weeks or more. 150. The method of any one of embodiments 132 to 137, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for 40 weeks or more. 151. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 4 to 30 mg / kg (on a protein weight basis). 152. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 5 to 15 mg / kg (on a protein weight basis). 153. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 10 to 20 mg / kg (on a protein weight basis). 154. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 15 to 25 mg / kg (on a protein weight basis). 155. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 8 mg / kg (on a protein weight basis). 156. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 10 mg / kg (on a protein weight basis). 157. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 300 mg to 3000 mg. 158. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 300 mg to 1500 mg. 159. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 400 mg to 1500 mg. 160. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 500 mg to 1200 mg. 161. The method of any one of embodiments 92 to 150, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen is 500 mg to 1000 mg. 162. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 4 to 30 mg / kg (on a protein weight basis). 163. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 5 to 15 mg / kg (on a protein weight basis). 164. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 10 to 20 mg / kg (on a protein weight basis). 165. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 15 to 25 mg / kg (on a protein weight basis). 166. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 8 mg / kg (on a protein weight basis). 167. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 10 mg / kg (on a protein weight basis). 168. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 300 mg to 3000 mg. 169. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 300 mg to 1500 mg. 170. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 400 mg to 1500 mg. 171. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 500 mg to 1200 mg. 172. The method of any one of embodiments 92 to 161, wherein the dose of the lipid-binding protein-based complex administered in the intensive regimen is 500 mg to 1000 mg. 173. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 4 to 30 mg / kg (on a protein weight basis). 174. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 5 to 15 mg / kg (on a protein weight basis). 175. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 10 to 20 mg / kg (on a protein weight basis). 176. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 15 to 25 mg / kg (on a protein weight basis). 177. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 8 mg / kg (on a protein weight basis). 178. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 10 mg / kg (on a protein weight basis). 179. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 20 mg / kg (on a protein weight basis). 180. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 300 mg to 3000 mg. 181. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 300 mg to 1500 mg. 182. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 400 mg to 1500 mg. 183. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 500 mg to 1200 mg. 184. The method of any one of embodiments 92 to 172, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 500 mg to 1000 mg. 185. The method of any one of embodiments 92 to 184, comprising both an induction regimen and a maintenance regimen. 186. The method of embodiment 185, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen and the dose of the lipid-binding protein-based complex administered in the maintenance regimen are the same. 187. The method of embodiment 185, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen and the dose of the lipid-binding protein-based complex administered in the maintenance regimen are different. 188. The method of embodiment 187, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is greater than the dose of the lipid-binding protein-based complex administered in the induction regimen. 189. The method of embodiment 188, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is 1.5 to 3 times the dose of the lipid-binding protein-based complex administered in the induction regimen. 190. The method of embodiment 188, wherein the dose of the lipid-binding protein-based complex administered in the maintenance regimen is twice the dose administered in the induction regimen. 191. A method according to any one of embodiments 1 to 90, wherein the lipid-binding protein-based complex is administered locally. 192. The method of embodiment 191, wherein the lipid-binding protein-based complex is administered intraocularly. 193. The method of embodiment 192, wherein the lipid-binding protein-based complex is administered by intraocular injection. 194. The method of embodiment 193, wherein the intraocular injection is a suprachoroidal injection. 195. The method of embodiment 193, wherein the intraocular injection is an episcleral injection. 196. The method of embodiment 193, wherein the intraocular injection is an intravitreal injection. 197. The method of embodiment 193, wherein the intraocular injection is a subconjunctival injection. 198. The method of embodiment 193, wherein the intraocular injection is a paraocular injection. 199. The method of embodiment 193, wherein the intraocular injection is a periocular injection. 200. The method of embodiment 193, wherein the intraocular injection is a retrobulbar injection. 201. The method of embodiment 191 or embodiment 192, wherein the lipid-binding protein-based complex is administered as an implant. 202. The method of embodiment 201, wherein the implant is a disk. 203. The method of embodiment 201, wherein the embedment is a sheet. 204. The method of embodiment 201, wherein the implant is a filling. 205. The method of embodiment 201, wherein the implant is a rod. 206. The method of embodiment 201, wherein the implant is a small pellet. 207. The method of any one of embodiments 201 to 206, wherein the implant is biodegradable. 208. The method of any one of embodiments 201 to 206, wherein the implant is not biodegradable. 209. The method of embodiment 191, wherein the lipid-binding protein-based complex is administered by iontophoresis. 210. The method of embodiment 209, wherein the lipid-binding protein-based complex is administered by transcorneal iontophoresis. 211. The method of embodiment 209, wherein the lipid-binding protein-based complex is administered by transcleral iontophoresis. 212. The method of embodiment 191, wherein the lipid-binding protein-based complex is administered by electroporation. 213. The method of embodiment 191, wherein the lipid-binding protein-based complex is administered locally. 214. The method of embodiment 213, wherein the lipid-binding protein-based complex is formulated as an eye drop. 215. Lipid-binding protein-based complexes are (a) an induction regimen; and / or (b) an intensive regimen; and / or (c) Maintenance regimen and optionally the lipid binding protein-based complex is CER-001. 216. The method of embodiment 215, comprising an induction regimen. 217. The method of embodiment 215 or embodiment 216, comprising a consolidation regimen. 218. The method of any one of embodiments 215 to 217, comprising a maintenance regimen. 219. The method of any one of embodiments 1 to 218, wherein an antihistamine is administered prior to administration of one or more lipid-binding protein-based complex doses. 220. The method of any one of embodiments 1 to 219, wherein the subject is also treated with a lipid-regulating medication. 221. The method of embodiment 220, wherein the lipid-regulating medication comprises a statin. 222. The method of embodiment 221, wherein the statin is atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, or pravastatin. 223. The method of any one of embodiments 220 to 222, wherein the lipid-regulating medication comprises a cholesterol absorption inhibitor. 224. The method of embodiment 223, wherein the cholesterol absorption inhibitor is ezetimibe. 225. The method of any one of embodiments 220 to 224, wherein the lipid-regulating medication comprises niacin. 226. The method of any one of embodiments 220 to 225, wherein the lipid-regulating medication comprises aspirin. 227. The method of any one of embodiments 220 to 226, wherein the lipid-regulating medication comprises a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor. 228. The method of embodiment 227, wherein the PCSK9 inhibitor is an antibody. 229. The method of embodiment 228, wherein the antibody is alirocumab, bococizumab, evolocumab, 1D05-IgG2, or LY3015014. 230. The method of embodiment 227, wherein the PCSK9 inhibitor is an RNAi therapeutic. 231. The method of embodiment 230, wherein the RNAi therapeutic is an ALN-PCSSC. 232. The method of any one of embodiments 220 to 231, further comprising administering to the subject a therapeutically effective amount of a lipid-regulating medication. 233. The method of any one of embodiments 1 to 232, wherein the subject is also treated with standard of care therapy for the ocular disease. 234. The method of embodiment 233, further comprising administering standard of care therapy to the subject. 235. The method of any one of embodiments 1 to 234, wherein the subject is also treated with an antihypertensive medication, optionally comprising one, two, or all three of amlodipine, urapidil, and furosemide. 236. The method of any one of embodiments 1 to 235, wherein the lipid-binding protein-based complex does not contain or is not administered together with a cell-penetrating peptide. 237. The method of any one of embodiments 1 to 236, wherein the lipid-binding protein-based complex does not include or is not administered together with a chemical permeation enhancer. 238. The method of any one of embodiments 1 to 237, wherein the lipid-binding protein-based complex does not contain or is not administered together with a cell affinity peptide. 239. A composition comprising a lipid-binding protein-based conjugate and one or more ophthalmic drugs, wherein the composition is produced by a process comprising a step of thermal cycling a mixture comprising the lipid-binding protein-based conjugate and the one or more ophthalmic drugs, and optionally, one or more of the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly or insoluble in water. 240. Thermal circulation is (a) heating the mixture from a temperature in a first temperature range to a temperature in a second temperature range; (b) cooling the mixture of (a) from a temperature in the second temperature range to a temperature in the first temperature range; and (c) optionally repeating steps (a) and (b) at least one time. 240. The composition of embodiment 239, comprising: 241. The composition of embodiment 240, wherein the thermal cycling comprises repeating steps (a) and (b) once. 242. The composition of embodiment 240, wherein the thermal cycling comprises repeating steps (a) and (b) twice. 243. The composition of embodiment 240, wherein the thermal cycling comprises repeating steps (a) and (b) three times. 244. The composition of embodiment 240, wherein the thermal cycling comprises repeating steps (a) and (b) four times. 245. The composition of embodiment 240, wherein the thermal cycling comprises repeating steps (a) and (b) five times. 246. The composition of any one of embodiments 240 to 245, wherein the first temperature range is 30°C to 45°C. 247. The composition described in embodiment 246, wherein the temperature in the first temperature range is 37°C. 248. The composition of any one of embodiments 240 to 247, wherein the second temperature range is 50°C to 65°C. 249. The composition of embodiment 248, wherein the temperature in the second temperature range is 55°C. 250. The composition of any one of embodiments 239 to 249, wherein thermocycling comprises thermocycling the mixture between 37°C and 55°C. 251. A composition comprising a lipid-binding protein-based conjugate and one or more ophthalmic drugs conjugated thereto, optionally wherein one or more of the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly or insoluble in water. 252. The composition of any one of embodiments 239 to 251, wherein the lipid-binding protein-based complex comprises a lipid-binding protein molecule described in Section 6.1.4. 253. The lipid-binding protein-based complex includes apolipoprotein AI (ApoA-I), and optionally the ApoA-I is ミラノ The composition of any one of embodiments 239 to 251, which is not 254. The composition of any one of embodiments 239 to 253, wherein the lipid-binding protein-based complex does not comprise an apolipoprotein mimetic. 255. A composition described in any one of embodiments 239 to 254, wherein the lipid-binding protein-based complex comprises one or more amphiphilic molecules described in Section 6.1.5. 256. A composition described in any one of embodiments 239 to 255, wherein the lipid-binding protein-based complex comprises one or more neutral lipids. 257. The composition described in embodiment 256, wherein the one or more neutral lipids comprise sphingomyelin. 258. A composition described in any one of embodiments 239 to 257, wherein the lipid-binding protein-based complex comprises one or more negatively charged lipids. 259. The composition of embodiment 258, wherein the one or more negatively charged lipids comprise 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol) (DPPG) or a salt thereof. 260. The composition of any one of embodiments 239 to 259, wherein the lipid-binding protein-based complex is a reconstituted HDL or HDL mimetic. 261. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is CER-001. 262. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is CSL-111. 263. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is CSL-112. 264. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is ETC-216. 265. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is CER-522. 266. The composition described in embodiment 260, wherein the lipid-binding protein-based complex is delipidated HDL. 267. A composition described in any one of embodiments 239 to 259, wherein the lipid-binding protein-based complex is an Apomer. 268. A composition described in any one of embodiments 239 to 259, wherein the lipid-binding protein-based complex is a Cargomer. 269. The composition of any one of embodiments 239 to 268, wherein the one or more ophthalmic drugs include a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, or a combination thereof. 270. The one or more ophthalmic drugs are azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)- 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl) (7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), pazopanib, regorafenib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dol The composition of any one of embodiments 239 to 269 comprising zolamide, ethoxyzolamide, methazolamide, acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, or a combination thereof. 271. The one or more ophthalmic drugs may be azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4 -fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), Pazopanib, regorafenib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyquin The composition of any one of embodiments 239 to 269, comprising ramidol, methazolamide, acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, dexamethasone palmitate, or a combination thereof. 272. The composition of embodiment 270 or embodiment 271, wherein the one or more ophthalmic drugs comprise azithromycin, and optionally, the concentration of azithromycin in the composition is 10 mg / ml. 273. The composition of any one of embodiments 270 to 272, wherein the one or more ophthalmic drugs comprise spironolactone, and optionally, the concentration of spironolactone in the composition is 1.5 mg / ml. 274. The composition of any one of embodiments 270 to 273, wherein the one or more ophthalmic drugs comprise dexamethasone palmitate, and optionally the concentration of dexamethasone palmitate in the composition is 1 mg / ml. 275. The composition of any one of embodiments 270 to 274, wherein the one or more ophthalmic drugs comprise cyclosporine, and optionally the concentration of cyclosporine in the composition is 1 mg / ml. 276. The composition of any one of embodiments 239 to 275, wherein the one or more ophthalmic drugs comprises latanoprost, travoprost, bimatoprost, tafluprost, or a combination thereof. 277. The composition of embodiment 276, wherein the one or more ophthalmic drugs comprises latanoprost. 278. The composition of any one of embodiments 239 to 277, wherein the one or more ophthalmic drugs comprises dexamethasone. 279. The composition of any one of embodiments 239 to 278, wherein the one or more ophthalmic drugs comprises loteprednol etabonate. 280. The composition of any one of embodiments 239 to 279, wherein the one or more ophthalmic drugs comprises triamcinolone. 281. The composition of any one of embodiments 239 to 280, wherein the one or more ophthalmic drugs comprises acyclovir. 282. The composition of any one of embodiments 239 to 281, wherein the one or more ophthalmic drugs comprises travoprost. 283. The composition of any one of embodiments 239 to 282, wherein the one or more ophthalmic drugs comprises bimatoprost. 284. The composition of any one of embodiments 239 to 283, wherein the one or more ophthalmic drugs comprises tafluprost. 285. The composition of any one of embodiments 239 to 284, wherein the one or more ophthalmic drugs comprises pazopanib. 286. The composition of any one of embodiments 239 to 285, wherein the one or more ophthalmic drugs comprises sirolimus. 287. The composition of any one of embodiments 239 to 286, wherein the one or more ophthalmic drugs comprises tacrolimus. 288. The composition of any one of embodiments 239 to 287, wherein the one or more ophthalmic drugs comprises nepafenac. 289. A composition described in any one of embodiments 239 to 288, which does not contain a cell-penetrating peptide. 290. The composition of any one of embodiments 239 to 289, which does not contain a chemical permeation enhancer. 291. A composition described in any one of embodiments 239 to 290, which does not contain a cell affinity peptide. 292. The composition of any one of embodiments 239 to 291, which is a pharmaceutical composition further comprising one or more buffers, preservatives, excipients, diluents, or combinations thereof. 293. A composition described in any one of embodiments 239 to 292, for use in a method described in any one of embodiments 1 to 238. 294. A process for producing a composition comprising a lipid-binding protein-based complex and one or more ophthalmic drugs, optionally wherein the composition is a composition described in any one of embodiments 251 to 293, the process comprising a step of thermocycling a mixture comprising the lipid-binding protein-based complex and one or more ophthalmic drugs. 295. Thermal circulation is (a) heating the mixture from a temperature in a first temperature range to a temperature in a second temperature range; (b) cooling the mixture of (a) from a temperature in the second temperature range to a temperature in the first temperature range; and (c) optionally repeating steps (a) and (b) at least one time. 295. The process of embodiment 294, comprising: 296. The process of embodiment 295, wherein steps (a) and (b) are repeated once. 297. The process of embodiment 295, wherein steps (a) and (b) are repeated twice. 298. The process of embodiment 295, wherein steps (a) and (b) are repeated three times. 299. The process of embodiment 295, wherein steps (a) and (b) are repeated four times. 300. The process of embodiment 295, wherein steps (a) and (b) are repeated five times. 301. The process of any one of embodiments 295 to 300, wherein the first temperature range is 30°C to 45°C. 302. The process of embodiment 301, wherein the temperature in the first temperature zone is 37° C. 303. The process of any one of embodiments 295 to 302, wherein the second temperature range is 50°C to 65°C. 304. The process of embodiment 303, wherein the temperature in the second temperature zone is 55° C. 305. The process of any one of embodiments 294 to 303, comprising thermocycling the mixture between 37°C and 55°C. 306. A composition produced by a method comprising the process of any one of embodiments 294 to 305, optionally wherein the method further comprises combining a product of the process with one or more buffers, preservatives, excipients, diluents, or combinations thereof. 307. A lipid-binding protein-based conjugate for use in treating an ocular disease in a subject, optionally in combination with one or more ophthalmic drugs, wherein an administered amount of the lipid-binding protein-based conjugate is effective to reduce the severity of the ocular disease. 308. The lipid-binding protein-based complex for use according to embodiment 307, wherein the eye disease is a disease associated with lipid accumulation; preferably, the eye disease is selected from eye diseases associated with LCAT deficiency, such as fish eye disease; dry eye disease, such as dry eye disease associated with meibomian gland dysfunction (MGD) or lacrimal gland dysfunction; blepharitis; inflammatory eye diseases, such as uveitis; diseases of the cornea, such as lipokeratopathy; macular edema; macular degeneration; retinal detachment; eye tumors; fungal infections; viral infections; bacterial infections; multifocal choroiditis; diabetic retinopathy; proliferative vitreoretinopathy (PVR); sympathetic ophthalmia; Vogt-Koyanagi-Harada (VKH) syndrome; histoplasmosis; uveal diffusion; vascular occlusion; and endophthalmitis. 309. The lipid-binding protein-based complex for use according to any one of embodiments 307 or 308, wherein the eye disease is fish eye disease and the subject is homozygous or heterozygous for an LCAT mutation. 310. The lipid-binding protein-based complex for use according to any one of embodiments 307 to 309, wherein the lipid-binding protein-based complex is a reconstituted HDL, an HDL mimic, a cargomer, or an apomer; preferably, the lipid-binding protein-based complex is selected from CER-001, CSL-111, CSL-112, CER-522, or ETC-216; more preferably, the lipid-binding protein-based complex is CER-001. 311. The lipid-binding protein-based conjugate for use according to any one of embodiments 307 to 310, wherein the lipid-binding protein-based conjugate comprises one or more ophthalmic drugs conjugated to the lipid-binding protein-based conjugate, and the one or more ophthalmic drugs comprise a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, or a combination thereof. 312. The one or more ophthalmic drugs are azithromycin, spironolactone, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)- 4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, sorafenib, thrombin Facitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir, chloramphenicol, chlortetracycline, ciprofloxa The lipid-binding protein-based complex for use according to any one of embodiments 307 to 311, comprising cyclosporine, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, tafluprost, dexamethasone palmitate, cyclosporine, or a combination thereof. 313. Lipid-binding protein-based complexes are (a) an induction regimen; and / or (b) an intensive regimen; and / or (c) Maintenance regimen 313. The lipid binding protein-based complex for use according to any one of embodiments 307 to 312, administered according to a dosing regimen comprising: 314. A lipid-binding protein-based complex for use according to embodiment 313, wherein the dosing regimen comprises an induction regimen comprising administering to the subject multiple doses of the lipid-binding protein-based complex, the multiple doses being separated by one or more days. 315. A lipid-binding protein-based complex for use according to embodiment 314, wherein doses after the first dose of the induction regimen are separated by at most 3 days, preferably, doses after the first dose of the induction regimen are separated by 1 to 3 days. 316. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 315, wherein the induction regimen is of at least 1 week duration, preferably, the induction regimen is of 2 weeks duration, more preferably, of 3 weeks duration. 317. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 316, wherein the induction regimen comprises administering to the subject three doses of the lipid-binding protein-based complex per week. 318. The lipid-binding protein-based complex for use according to any one of embodiments 313 to 317, wherein the induction regimen comprises administering to the subject at least three doses of the lipid-binding protein-based complex; preferably four or more doses, five or more doses, six or more doses, seven or more doses, eight or more doses, or nine or more doses; more preferably, the induction regimen comprises administering to the subject nine or more doses of the lipid-binding protein-based complex. 319. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 318, wherein the induction regimen comprises administering to the subject a first dose of the lipid-binding protein-based complex on day 1, and administering to the subject subsequent doses of the induction regimen on days 2, 4, 7, 9, 11, 14, 16, and 18. 320. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 319, wherein the dosing regimen comprises an intensive regimen comprising administering to the subject multiple doses of the lipid-binding protein-based complex, the multiple doses being separated by 2 or more days. 321. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 320, wherein the doses of the intensification regimen are separated from each other by at most 4 days, preferably, the doses of the intensification regimen are separated from each other by 3 or 4 days. 322. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 321, wherein the intensification regimen is of at least 3 weeks duration. 323. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 322, wherein the intensive regimen comprises administering to the subject at least two doses of the lipid-binding protein-based complex per week. 324. The lipid-binding protein-based complex for use according to any one of embodiments 313 to 323, wherein the intensification regimen comprises administering to the subject at least two doses of the lipid-binding protein-based complex; preferably three or more doses, four or more doses, five or more doses, or six or more doses; more preferably, the intensification regimen comprises administering to the subject six or more doses of the lipid-binding protein-based complex. 325. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 324, wherein the consolidation regimen comprises administering to the subject six doses of the lipid-binding protein-based complex on days 21, 24, 28, 31, 35, and 38 following an induction regimen beginning on day 1. 326. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 325, wherein the dosing regimen comprises a maintenance regimen comprising administering to the subject a dose of the lipid-binding protein-based complex once every 3 or more days, preferably once every 5 or more days, more preferably once a week. 327. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 326, wherein the maintenance regimen comprises administering the lipid-binding protein-based complex to the subject for at least one month. 328. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 327, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen, in the consolidation regimen and / or in the maintenance regimen is 4 to 30 mg / kg (based on protein weight); preferably 5 to 15 mg / kg (based on protein weight), 10 to 20 mg / kg (based on protein weight), or 15 to 25 mg / kg (based on protein weight). 329. A lipid-binding protein-based complex for use according to any one of embodiments 313 to 328, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen, in the consolidation regimen and / or in the maintenance regimen is 8 mg / kg (protein weight basis) or 10 mg / kg (protein weight basis). 330. The lipid-binding protein-based complex for use according to any one of embodiments 313 to 329, wherein the dose of the lipid-binding protein-based complex administered in the induction regimen, in the consolidation regimen and / or in the maintenance regimen is 300 mg to 3000 mg; preferably 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg. 331. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 330, wherein the lipid-binding protein-based complex is administered peripherally, optionally by injection. 332. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 330, wherein the lipid-binding protein-based complex is administered locally, e.g. intraocularly, e.g. by intraocular injection (e.g. suprachoroidal or suprascleral injection), or locally, e.g. by eye drops or by implants (e.g. biodegradable or non-biodegradable disks, sheets, fillers, rods or pellets). 333. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 332, wherein an antihistamine is administered prior to administration of one or more lipid-binding protein-based complex doses. 334. The subject is also treated with a lipid-regulating medicament; preferably, the lipid-regulating medicament comprises a statin such as atorvastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin, or pravastatin; a cholesterol absorption inhibitor such as ezetimibe; niacin; aspirin; a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor such as an antibody selected from alirocumab, bococizumab, evolocumab, 1D05-IgG2, and LY3015014; or an RNAi therapeutic agent such as ALN-PCSSC; or a lipid-binding protein-based complex for use according to any one of embodiments 307 to 333. 335. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 334, wherein the subject is also treated with a standard of care therapy for the eye disease. 336. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 335, wherein the lipid-binding protein-based complex does not comprise or is not administered together with a cell-penetrating peptide. 337. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 336, wherein the lipid-binding protein-based complex does not contain or is not administered together with a chemical permeation enhancer. 338. A lipid-binding protein-based complex for use according to any one of embodiments 307 to 337, wherein the lipid-binding protein-based complex does not comprise or is not administered together with a cell affinity peptide. 339. The lipoprotein complex comprises an ApoA-I apolipoprotein fraction and a lipid fraction comprising one or more phospholipids; The subject has ocular lipid deposits. A lipoprotein complex for use in treating an ocular disease in a subject in need thereof. 340. A lipoprotein complex for use according to embodiment 339, wherein the lipoprotein complex comprises an ApoA-I apolipoprotein fraction and a lipid fraction comprising at least one neutral phospholipid and optionally one or more negatively charged phospholipids. 341. A lipoprotein complex for use according to embodiment 339 or embodiment 340, wherein the lipoprotein complex is selected from CER-001, CSL-111, and ETC-216. 342. A lipoprotein complex for use according to any one of embodiments 339 to 341, wherein the lipoprotein complex comprises an ApoA-I apolipoprotein fraction and a lipoprotein fraction comprising sphingomyelin and one or more negatively charged phospholipids. 343. A lipoprotein complex for use according to any one of embodiments 339 to 342, wherein the lipoprotein complex comprises an ApoA-I apolipoprotein fraction and a lipid fraction, the lipid fraction consisting essentially of sphingomyelin and about 0.2 to 6 wt% negatively charged phospholipids, and the molar ratio of the lipid fraction to the ApoA-I apolipoprotein fraction ranges from about 2:1 to 200:1. 344. A lipoprotein complex for use according to any one of embodiments 340 to 343, wherein the negatively charged phospholipid comprises 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol) (DPPG) or a salt thereof. 345. A lipoprotein complex for use according to any one of embodiments 339 to 344, wherein the lipoprotein complex is CER-001. 346. A lipoprotein complex for use according to any one of embodiments 339 to 345, wherein the ocular lipid deposits are corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof. 347. Eye diseases include dry eye associated with lipid accumulation, including dry eye associated with meibomian gland dysfunction (MGD) and dry eye associated with lacrimal gland dysfunction, blepharitis, inflammatory eye diseases, uveitis including anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis, diseases of the cornea including lipokeratopathy, eye diseases associated with LCAT deficiency including fish eye disease, dry macular degeneration (dry AMD), Stargardt's disease, and Leber's idiopathic stellate retinal glaucoma. The lipoprotein complex for use according to any one of embodiments 339 to 346, selected from neuroretinitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal infections, viral infections, bacterial infections including bacterial conjunctivitis and trachoma, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, and glaucoma. 348. A lipoprotein complex for use according to any one of embodiments 339 to 347, wherein the administered amount of the lipoprotein complex is effective to reduce ocular lipid deposits in a subject. 349. A lipoprotein complex for use according to any one of embodiments 339 to 348, wherein the lipoprotein complex further comprises one or more ophthalmic drugs. 350. The ophthalmic drug is a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial, an antiviral, an antihistamine, an anti-inflammatory, a prostaglandin analog, or a combination thereof; preferably, the ophthalmic drug is azithromycin, dexamethasone, dexamethasone palmitate, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prostaglandin analog, or a combination thereof. Rednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino] -6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazola 350. The lipoprotein complex for use according to embodiment 349, wherein the lipoprotein complex is selected from the group consisting of benzodiazepine, benzoyl pertazolamide ... 351. A lipoprotein complex for use according to any one of embodiments 339 to 350, wherein the lipoprotein complex is administered peripherally, optionally by injection. 352. A lipoprotein complex for use according to any one of embodiments 339 to 350, wherein the lipoprotein complex is administered intraocularly, preferably by intraocular injection, more preferably by intravitreal, suprachoroidal, or suprascleral injection. 353. A lipoprotein complex for use according to any one of embodiments 339 to 350, wherein the lipoprotein complex is administered by a local route, preferably using eye drops. 354. A lipoprotein complex for use according to any one of embodiments 339 to 353, wherein the lipoprotein complex does not contain and is not administered together with a cell-penetrating peptide. 355. A lipoprotein complex for use according to any one of embodiments 339 to 354, wherein the lipoprotein complex does not contain or is not administered together with a chemical permeation enhancer. 356. A lipoprotein complex for use according to any one of embodiments 339 to 355, wherein the lipoprotein complex does not contain and is not administered together with a cell affinity peptide. 357. A method of treating an eye disease in a subject, comprising: (a) administering to a subject a formulation of Apolipoprotein AI ("ApoA-I") that includes ApoA-I and one or more lipids. wherein the ApoA-I and lipids are in the form of a lipoprotein complex; (i) the subject has cataract, uveitis, eye disease associated with lipid accumulation, lipokeratopathy, corneal dystrophy, corneal opacity, dry eye disease, blepharitis, inflammatory eye disease, macular edema, macular degeneration, retinal detachment, ocular tumor, fungal infection, viral infection, bacterial infection (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, glaucoma, Stargardt's disease, ocular lipid deposition; and / or (ii) The method, wherein the formulation is administered by suprachoroidal injection, suprascleral injection, implant, iontophoresis, or electroporation. 358. The method of embodiment 357, wherein ApoA-I has the amino acid sequence of amino acids 25 to 267 of SEQ ID NO:2. 359. The method of embodiment 357 or embodiment 358, wherein ApoA-I is recombinantly expressed. 360. The method of any one of embodiments 357 to 359, wherein the one or more lipids comprise a neutral lipid. 361. The method of embodiment 360, wherein the neutral lipid comprises sphingomyelin. 362. The method of embodiment 361, wherein the neutral lipid consists of sphingomyelin. 363. The method of embodiment 361 or embodiment 362, wherein the sphingomyelin comprises natural sphingomyelin. 364. The method of embodiment 363, wherein the native sphingomyelin is chicken egg sphingomyelin. 365. The method of embodiment 361 or embodiment 362, wherein the sphingomyelin comprises synthetic sphingomyelin. 366. The method of embodiment 365, wherein the synthetic sphingomyelin is palmitoyl sphingomyelin. 367. The method of any one of embodiments 357 to 362, wherein the one or more lipids further comprise a negatively charged lipid. 368. The method of embodiment 367, wherein the negatively charged lipid comprises 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 369. The method of embodiment 368, wherein the negatively charged lipid consists of 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 370. The method of any one of embodiments 363 to 369, wherein the molar ratio of negatively charged lipids to neutral lipids to ApoA-I components in the formulation is 2-6:90-120:1. 371. The method of any one of embodiments 360 to 370, wherein the lipids consist of 95 to 99% by weight of neutral phospholipids and 1 to 5% by weight of negatively charged phospholipids. 372. The method of embodiment 371, wherein the lipids consist of 96-98% by weight of neutral phospholipids and 2-4% by weight of negatively charged phospholipids. 373. The method of embodiment 372, wherein the lipids consist of 97% by weight neutral phospholipids and 3% by weight negatively charged phospholipids. 374. The method of any one of embodiments 357 to 373, having an ApoA-I to lipid ratio ranging from 1:2 to 1:3 by weight. 375. The method of embodiment 374, having an ApoA-I to lipid ratio of about 1:2.7 by weight. 376. The method of any one of embodiments 357 to 375, wherein the lipoprotein complex is at least 95% homogeneous, as reflected by a single peak in gel permeation chromatography. 377. The method of any one of embodiments 357 to 376, wherein the formulation is a carrier for or is complexed with one or more ophthalmic drugs, optionally one or more of the one or more ophthalmic drugs being (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble. 378. The method of embodiment 377, wherein the one or more ophthalmic drugs comprise a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, a prostaglandin analog, or a combination thereof. 379. The one or more ophthalmic drugs may be azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-2-propanol, phenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib Nib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir The method of embodiment 377 or embodiment 378, comprising rifabutin, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, dexamethasone palmitate, or a combination thereof. 380. The method of any one of embodiments 357 to 379, wherein the eye disease is fish eye disease. 381. The method of any one of embodiments 357 to 379, wherein the eye disease is secondary lipokeratopathy, hereditary corneal dystrophy, anterior or superficial corneal dystrophy, corneal stromal dystrophy, or posterior corneal dystrophy. 382. The method of any one of embodiments 357 to 379, wherein the subject has corneal opacity, and the method comprises administering a lipid-binding protein-based complex in an amount effective to reduce corneal opacity in the subject. 383. The method of any one of embodiments 357 to 379, wherein the ocular disease is (a) associated with meibomian gland dysfunction (MGD), optionally wherein the MGD is obstructive MGD, or (b) dry eye disease associated with lacrimal gland dysfunction. 384. The method of any one of embodiments 357 to 379, wherein the ocular disease is blepharitis, inflammatory eye disease, anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. 385. The method of embodiment 384, wherein the ocular disease is acute anterior uveitis. 386. The method of any one of embodiments 357 to 379, wherein the eye disease is dry macular degeneration. 387. The method of any one of embodiments 357 to 379, wherein the eye disease is wet macular degeneration. 388. The method of any one of embodiments 357 to 379, wherein the eye disease is diabetic macular edema. 389. The method of any one of embodiments 357 to 388, wherein the subject has impaired vision due to an eye disease, and the method comprises administering to the subject an amount of a lipid-binding protein-based complex that improves the subject's vision. 390. The method of any one of embodiments 357 to 389, wherein the subject has ocular lipid deposits, and optionally the ocular lipid deposits include corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof. 391. An Apolipoprotein AI ("ApoA-I") formulation for treating an ocular disease in a subject, comprising ApoA-I and one or more lipids, wherein the ApoA-I and the lipids are in the form of a lipoprotein complex; (i) the subject has cataract, uveitis, eye disease associated with lipid accumulation, lipokeratopathy, corneal dystrophy, corneal opacity, dry eye disease, blepharitis, inflammatory eye disease, macular edema (e.g., diabetic macular edema), macular degeneration, retinal detachment, ocular tumor, fungal infection, viral infection, bacterial infection (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, glaucoma, Stargardt's disease, ocular lipid deposition; and / or (ii) the formulation is administered by suprachoroidal injection, episcleral injection, implant, iontophoresis, or electroporation; ApoA-I preparation. 392. The formulation for use according to embodiment 391, wherein the ApoA-I has the amino acid sequence of amino acids 25 to 267 of SEQ ID NO:2. 393. The formulation for use according to embodiment 391 or embodiment 392, wherein ApoA-I is recombinantly expressed. 394. A formulation described in any one of embodiments 391 to 393, wherein the one or more lipids comprise a neutral lipid. 395. The formulation of embodiment 394, wherein the neutral lipid comprises sphingomyelin. 396. The formulation of embodiment 395, wherein the neutral lipid consists of sphingomyelin. 397. The formulation for use according to embodiment 395 or embodiment 396, wherein the sphingomyelin comprises natural sphingomyelin. 398. The formulation for use according to embodiment 397, wherein the natural sphingomyelin is chicken egg sphingomyelin. 399. The formulation for use according to embodiment 395 or embodiment 396, wherein the sphingomyelin comprises synthetic sphingomyelin. 400. The formulation for use according to embodiment 399, wherein the synthetic sphingomyelin is palmitoyl sphingomyelin. 401. A formulation for use according to any one of embodiments 391 to 396, wherein the one or more lipids further comprise a negatively charged lipid. 402. The formulation for use of embodiment 401, wherein the negatively charged lipid comprises 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 403. The formulation for use according to embodiment 402, wherein the negatively charged lipid consists of 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 404. A formulation for use according to any one of embodiments 397 to 403, wherein the molar ratio of negatively charged lipids to neutral lipids to ApoA-I components in the formulation is 2-6:90-120:1. 405. A formulation for use according to any one of embodiments 394 to 404, wherein the lipids consist of 95 to 99% by weight of neutral phospholipids and 1 to 5% by weight of negatively charged phospholipids. 406. The method of embodiment 405, wherein the lipids consist of 96-98% by weight of neutral phospholipids and 2-4% by weight of negatively charged phospholipids. 407. A formulation for use according to embodiment 406, wherein the lipids consist of 97% by weight of neutral phospholipids and 3% by weight of negatively charged phospholipids. 408. A formulation for use according to any one of embodiments 391 to 407, having an ApoA-I to lipid ratio ranging from 1:2 to 1:3 by weight. 409. A formulation for use according to embodiment 408, having an ApoA-I to lipid ratio of about 1:2.7 by weight. 410. A formulation for use according to any one of embodiments 391 to 409, wherein the lipoprotein complex is at least 95% homogeneous, as reflected by a single peak in gel permeation chromatography. 411. A formulation for use according to any one of embodiments 391 to 410, wherein the formulation is a carrier for or is complexed with one or more ophthalmic drugs, optionally one or more of the one or more ophthalmic drugs being (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble. 412. The formulation for use of embodiment 411, wherein the one or more ophthalmic drugs include a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial, an antiviral, an antihistamine, an anti-inflammatory, a prostaglandin analog, or a combination thereof. 413. The one or more ophthalmic drugs are azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-2-propanol, 2-methyl ... N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, Sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir, chloramphenicol, bromodiamine ... The formulation for use according to embodiment 411 or embodiment 412, comprising muphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, dexamethasone palmitate, or combinations thereof. 414. The formulation for use according to any one of embodiments 391 to 413, wherein the eye disease is fish eye disease. 415. The formulation for use according to any one of embodiments 391 to 413, wherein the eye disease is secondary lipokeratopathy, hereditary corneal dystrophy, anterior or superficial corneal dystrophy, corneal stromal dystrophy, or posterior corneal dystrophy. 416. A formulation for use according to any one of embodiments 391 to 413, wherein the subject has corneal opacity and the method comprises administering a lipid-binding protein-based complex in an amount effective to reduce corneal opacity in the subject. 417. A formulation for use according to any one of embodiments 391 to 413, wherein the ocular disease is (a) associated with meibomian gland dysfunction (MGD), optionally wherein the MGD is obstructive MGD, or (b) dry eye disease associated with lacrimal gland dysfunction. 418. The formulation for use according to any one of embodiments 391 to 413, wherein the ocular disease is blepharitis, inflammatory eye disease, anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. 419. The formulation for use according to embodiment 418, wherein the ocular disease is acute anterior uveitis. 420. A formulation for use according to any one of embodiments 391 to 413, wherein the ocular disease is dry macular degeneration. 421. A formulation for use according to any one of embodiments 391 to 413, wherein the ocular disease is wet macular degeneration. 422. A formulation for use according to any one of embodiments 391 to 413, wherein the ocular disease is diabetic macular edema. 423. A formulation for use according to any one of embodiments 391 to 422, wherein the subject has impaired vision due to an eye disease, and the method comprises administering to the subject an amount of a lipid-binding protein-based complex that improves the subject's vision. 424. A formulation for use according to any one of embodiments 391 to 423, wherein the subject has ocular lipid deposits, and optionally the ocular lipid deposits include corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof. 425. An Apolipoprotein AI ("ApoA-I") formulation comprising one or more lipids for the manufacture of a medicament for treating an ocular disease in a subject, wherein the ApoA-I and the lipid are in the form of a lipoprotein complex; (i) the subject has cataract, uveitis, eye disease associated with lipid accumulation, lipokeratopathy, corneal dystrophy, corneal opacity, dry eye disease, blepharitis, inflammatory eye disease, macular edema (e.g., diabetic macular edema), macular degeneration, retinal detachment, ocular tumor, fungal infection, viral infection, bacterial infection (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, glaucoma, Stargardt's disease, ocular lipid deposition; and / or (ii) the formulation is administered by suprachoroidal injection, episcleral injection, implant, iontophoresis, or electroporation; ApoA-I preparation. 426. The formulation for use according to embodiment 425, wherein ApoA-I has the amino acid sequence of amino acids 25 to 267 of SEQ ID NO:2. 427. The formulation for use according to embodiment 425 or embodiment 426, wherein ApoA-I is recombinantly expressed. 428. A formulation described in any one of embodiments 425 to 427, wherein the one or more lipids comprise a neutral lipid. 429. The formulation of embodiment 428, wherein the neutral lipid comprises sphingomyelin. 430. The formulation of embodiment 429, wherein the neutral lipid consists of sphingomyelin. 431. The formulation for use according to embodiment 429 or embodiment 430, wherein the sphingomyelin comprises natural sphingomyelin. 432. The formulation for use according to embodiment 431, wherein the natural sphingomyelin is chicken egg sphingomyelin. 433. The formulation for use according to embodiment 429 or embodiment 430, wherein the sphingomyelin comprises synthetic sphingomyelin. 434. The formulation for use according to embodiment 433, wherein the synthetic sphingomyelin is palmitoyl sphingomyelin. 435. A formulation for use according to any one of embodiments 425 to 430, wherein the one or more lipids further comprise a negatively charged lipid. 436. The formulation for use according to embodiment 435, wherein the negatively charged lipid comprises 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 437. The formulation for use according to embodiment 436, wherein the negatively charged lipid consists of 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] ("DPPG") or a salt thereof. 438. A formulation for use according to any one of embodiments 431 to 437, wherein the molar ratio of negatively charged lipids to neutral lipids to ApoA-I components in the formulation is 2-6:90-120:1. 439. A formulation for use according to any one of embodiments 428 to 438, wherein the lipids consist of 95 to 99% by weight of neutral phospholipids and 1 to 5% by weight of negatively charged phospholipids. 440. The method of embodiment 439, wherein the lipids consist of 96 to 98% by weight of neutral phospholipids and 2 to 4% by weight of negatively charged phospholipids. 441. A formulation for use according to embodiment 440, wherein the lipids consist of 97% by weight of neutral phospholipids and 3% by weight of negatively charged phospholipids. 442. A formulation for use according to any one of embodiments 425 to 441, having an ApoA-I to lipid ratio ranging from 1:2 to 1:3 by weight. 443. A formulation for use according to embodiment 442, having an ApoA-I to lipid ratio of about 1:2.7 by weight. 444. A formulation for use according to any one of embodiments 425 to 443, wherein the lipoprotein complex is at least 95% homogeneous, as reflected by a single peak in gel permeation chromatography. 445. A formulation for use according to any one of embodiments 425 to 444, wherein the formulation is a carrier for or is complexed with one or more ophthalmic drugs, optionally one or more of the one or more ophthalmic drugs being (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble. 446. The formulation for use of embodiment 445, wherein the one or more ophthalmic drugs include a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial, an antiviral, an antihistamine, an anti-inflammatory, a prostaglandin analog, or a combination thereof. 447. The one or more ophthalmic drugs may be azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-2-propanol, 2-methyl ... N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, Sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir, chloramphenicol, bromodiamine ... The formulation for use according to embodiment 445 or embodiment 446, comprising muphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, dexamethasone palmitate, or combinations thereof. 448. A formulation for use according to any one of embodiments 425 to 447, wherein the eye disease is fish eye disease. 449. A formulation for use according to any one of embodiments 425 to 447, wherein the eye disease is secondary lipokeratopathy, hereditary corneal dystrophy, anterior or superficial corneal dystrophy, corneal stromal dystrophy, or posterior corneal dystrophy. 450. A formulation for use according to any one of embodiments 425 to 447, wherein the subject has corneal opacity and the method comprises administering a lipid-binding protein-based complex in an amount effective to reduce corneal opacity in the subject. 451. The formulation for use according to any one of embodiments 425 to 447, wherein the ocular disease is (a) associated with meibomian gland dysfunction (MGD), optionally wherein the MGD is obstructive MGD, or (b) dry eye disease associated with lacrimal gland dysfunction. 452. The formulation for use according to any one of embodiments 425 to 447, wherein the ocular disease is blepharitis, inflammatory eye disease, anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. 453. The formulation for use according to embodiment 452, wherein the ocular disease is acute anterior uveitis. 454. A formulation for use according to any one of embodiments 425 to 447, wherein the ocular disease is dry macular degeneration. 455. A formulation for use according to any one of embodiments 425 to 447, wherein the ocular disease is wet macular degeneration. 456. A formulation for use according to any one of embodiments 425 to 447, wherein the ocular disease is diabetic macular edema. 457. A formulation for use according to any one of embodiments 425 to 456, wherein the subject has impaired vision due to an eye disease, and the method comprises administering to the subject an amount of a lipid-binding protein-based complex that improves the subject's vision. 458. The formulation for use according to any one of embodiments 425 to 457, wherein the subject has ocular lipid deposits, and optionally the ocular lipid deposits include corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof.

[0371] Various aspects of the disclosure are described in the embodiments set forth in the following numbered paragraphs of Group 2.

[0372] Group 2: 1. A lipid-binding protein-based conjugate for use in a method of treating an ocular disease in a subject, the lipid-binding protein-based conjugate being (a) CER-001, and / or (b) a carrier for one or more ophthalmic drugs, and optionally: (a) the subject has cataracts or acute anterior uveitis; and / or (b) The lipid-binding protein-based complex is administered by suprachoroidal injection, episcleral injection, implant, iontophoresis, or electroporation. 2. The lipid-binding protein-based complex for use according to embodiment 1, wherein the eye disease is a disease associated with lipid accumulation. 3. The lipid-binding protein-based complex for use according to embodiment 2, wherein the eye disease is fish eye disease. 4. A lipid-binding protein-based conjugate for use according to embodiment 2, wherein the eye disease is lipokeratopathy, and optionally the lipokeratopathy is secondary lipokeratopathy. 5. The lipid-binding protein-based complex for use according to embodiment 2, wherein the eye disease is a corneal dystrophy, such as a hereditary corneal dystrophy, anterior or superficial corneal dystrophy, stromal corneal dystrophy, or posterior corneal dystrophy. 6. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 5, wherein the subject has corneal opacity and the method comprises administering an amount of a lipid-binding protein-based complex effective to reduce corneal opacity in the subject. 7. The lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the subject has cataracts. 8. The lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the ocular disease is dry eye disease, and optionally, (a) the dry eye disease is associated with meibomian gland dysfunction (MGD), and optionally, the MGD is obstructive MGD, or (b) the dry eye disease is associated with lacrimal gland dysfunction. 9. A lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is blepharitis. 10. A lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is an inflammatory eye disease. 11. The lipid-binding protein-based conjugate for use according to embodiment 1 or embodiment 2, wherein the ocular disease is uveitis, and optionally the uveitis is anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. 12. The lipid-binding protein-based conjugate for use according to embodiment 11, wherein the eye disease is acute anterior uveitis. 13. The lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is macular edema, macular degeneration, retinal detachment, eye tumor, fungal infection, viral infection, bacterial infection (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, vascular occlusion, endophthalmitis, or glaucoma. 14. A lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is dry macular degeneration. 15. A lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is wet macular degeneration. 16. The lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is Stargardt's disease. 17. A lipid-binding protein-based complex for use according to embodiment 1 or embodiment 2, wherein the eye disease is diabetic retinopathy and optionally the subject has diabetic macular edema. 18. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 17, wherein the subject has impaired vision due to an eye disease, and the method comprises administering to the subject an amount of the lipid-binding protein-based complex that improves the subject's vision. 19. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 18, wherein the subject has ocular lipid deposits, and optionally the ocular lipid deposits include corneal lipid deposits, retinal lipid deposits, eyelid lipid deposits, or a combination thereof. 20. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 19, wherein the lipid-binding protein-based complex is CER-001. 21. The lipid-binding protein-based complex for use according to any one of embodiments 1 to 20, wherein the lipid-binding protein-based complex is a carrier for one or more ophthalmic drugs, and optionally (I) the lipid-binding protein-based complex is CER-001, CSL-111, CSL-112, ETC-216, CER-522, delipidated HDL, Apomer, or Cargomer, and / or (II) the one or more ophthalmic drugs are (i) hydrophobic, and / or (ii) poorly water-soluble or water-insoluble. 22. The lipid-binding protein-based conjugate for use according to embodiment 21, wherein the one or more ophthalmic drugs comprise a steroid, a kinase inhibitor, an angiotensin II receptor antagonist, an aldose reductase inhibitor, an immunosuppressant, a carbonic anhydrase inhibitor, an antimicrobial agent, an antiviral agent, an antihistamine, an anti-inflammatory agent, a prostaglandin analogue, or a combination thereof. 23. The one or more ophthalmic drugs are dexamethasone palmitate, azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)- 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, orantinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)urea), pazopanib, Regorafenib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, methazolamide, acyclovir 23. The lipid-binding protein-based complex for use according to embodiment 21 or embodiment 22, comprising: chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, or a combination thereof. 24. A lipid-binding protein-based complex for use according to any one of embodiments 21 to 23, wherein the one or more ophthalmic drugs comprise dexamethasone palmitate. 25. A lipid-binding protein-based complex for use according to any one of embodiments 21 to 23, wherein the one or more ophthalmic drugs comprise dexamethasone. 26. A lipid-binding protein-based conjugate for use according to any one of embodiments 21 to 23, wherein the one or more ophthalmic drugs comprises tacrolimus. 27. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 26, wherein the method comprises administering the lipid-binding protein-based complex peripherally, optionally by injection. 28. The method is (a) an induction regimen; and / or (b) an intensive regimen; and / or (c) Maintenance regimen 28. The lipid-binding protein-based complex for use according to embodiment 27, comprising administering the lipid-binding protein-based complex according to a dosing regimen comprising: 29. A lipid-binding protein-based complex for use according to any one of embodiments 1 to 26, wherein the method comprises administering the lipid-binding protein-based complex locally. 30. A lipid-binding protein-based complex for use according to embodiment 29, wherein the method comprises administering the lipid-binding protein-based complex intraocularly. 31. The lipid-binding protein-based complex for use according to embodiment 30, wherein the method comprises administering the lipid-binding protein-based complex by intraocular injection, and optionally the intraocular injection is a suprachoroidal injection, an episcleral injection, an intravitreal injection, a subconjunctival injection, a parabulbar injection, a peribulbar injection, or a retrobulbar injection. 32. A lipid-binding protein-based complex for use according to embodiment 29, wherein the method comprises administering the lipid-binding protein-based complex via an implant, optionally the implant being a biodegradable or non-biodegradable disk, sheet, wadding, rod, or pellet. 33. A lipid-binding protein-based complex for use according to embodiment 29, wherein the method comprises administering the lipid-binding protein-based complex locally. 34. The lipid-binding protein-based complex for use according to embodiment 33, wherein the lipid-binding protein-based complex is formulated as an eye drop. 35. A process for making a composition comprising a lipid-binding protein-based complex and one or more ophthalmic drugs, the process comprising a step of thermocycling a mixture comprising the lipid-binding protein-based complex and the one or more ophthalmic drugs, optionally wherein (I) the lipid-binding protein-based complex is CER-001, CSL-111, CSL-112, ETC-216, CER-522, delipidated HDL, Apomer, or Cargomer, and / or (II) one or more of the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly or insoluble in water. 36. The thermal cycle is (a) heating the mixture from a temperature in a first temperature range to a temperature in a second temperature range; (b) cooling the mixture of (a) from a temperature in the second temperature range to a temperature in the first temperature range; and (c) optionally repeating steps (a) and (b) at least one time. 36. The process of claim 35, comprising: 37. The process of...

Claims

1. A lipid-binding protein-based complex used in a method for treating an eye disease in a subject, wherein the lipid-binding protein-based complex is (a) CER-001 and / or (b) a carrier for one or more ophthalmic drugs, (a) The subject has cataracts or acute anterior uveitis; and / or (b) The lipid-binding protein-based complex is administered by choroidal injection, scleral injection, implantation, iontophoresis, or electroporation.

2. The lipid-binding protein-based complex according to claim 1, wherein the eye disease is a disease associated with lipid accumulation.

3. The lipid-binding protein-based complex according to claim 2, wherein the aforementioned eye disease is fish-eye disease.

4. The lipid-binding protein-based complex according to claim 2, wherein the eye disease is fatty keratopathy, and the fatty keratopathy may be secondary fatty keratopathy.

5. The lipid-binding protein-based complex according to claim 2, wherein the eye disease is a corneal dystrophy, such as hereditary corneal dystrophy, anterior corneal or superficial corneal dystrophy, corneal stromal dystrophy, or posterior corneal dystrophy.

6. The lipid-binding protein-based complex according to claim 1, wherein the subject has corneal opacity, and the method comprises the step of administering an amount of the lipid-binding protein-based complex effective in reducing the corneal opacity of the subject.

7. The aforementioned subject has cataracts, and the lipid-binding protein-based complex is as described in claim 1 or claim 2.

8. The aforementioned eye disease is, (i) (a) a dry eye disorder, wherein the dry eye disorder is associated with meibomian gland dysfunction (MGD), and the MGD may be obstructive MGD, or (b) the dry eye disorder is associated with lacrimal gland dysfunction; (ii) blepharitis; (iii) inflammatory eye diseases; (iv) Uveitis, which may be anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis; (v) Macular edema, macular degeneration, retinal detachment, eye tumors, fungal infections, viral infections, bacterial infections (e.g., bacterial conjunctivitis or trachoma), multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmitis, Vogt-Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveitis, vascular occlusion, endophthalmitis, or glaucoma; (vi) Macular degeneration in dry skin; (vii) Exudative macular degeneration; (viiii) Stargard disease; or, (ix) Diabetic retinopathy, and the subject may have diabetic macular edema. A lipid-binding protein-based complex according to claim 1 or claim 2.

9. The lipid-binding protein-based complex according to claim 8, wherein the eye disease is acute anterior uveitis.

10. The lipid-binding protein-based complex according to claim 1, wherein the subject has ocular lipid deposition, and the ocular lipid deposition includes corneal lipid deposition, retinal lipid deposition, eyelid lipid deposition, or a combination thereof.

11. The lipid-binding protein-based complex is a carrier for one or more ophthalmic drugs, and (i) the lipid-binding protein-based complex is CER-001, CSL-111, CSL-112, ETC-216, CER-522, defatted HDL, Apomer, or Cargomer, and / or (II) the one or more ophthalmic drugs are (i) hydrophobic and / or (ii) poorly soluble or insoluble, according to claim 1.

12. The lipid-binding protein-based complex according to claim 11, wherein the one or more ophthalmic drugs include steroids, kinase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, immunosuppressants, carbonic anhydrase inhibitors, antimicrobial agents, antiviral agents, antihistamines, anti-inflammatory agents, prostaglandin analogs, or combinations thereof.

13. The aforementioned one or more ophthalmic drugs include dexamethasone palmitate, azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etavonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, and BMS-794833 (N-(4-((2-amino-3-chloropyridine-4-yl)oxy)-3-fluorophosphate). Nyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, olanthinib, PD173074 (N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine-7-yl]-N'-(1,1-dimethylethyl)urea), Zopanib, regorafenib, sorafenib, tofacitinib, ZM323881 (5-((7-benzyloxyquinazoline-4-yl)amino)-4-fluoro-2-methylphenol), candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, 2-methylsorbino, sirolimus, cyclosporine, tacrolimus, acetazolamide, brinzolamide, dorzolamide, ethoxyzolamide, metazolamide A lipid-binding protein-based complex according to claim 11 or claim 12, comprising acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, latanoprost, travoprost, bimatoprost, or a combination thereof.

14. The lipid-binding protein-based complex according to claim 1, comprising the step of locally administering the lipid-binding protein-based complex.

15. The method described above is: (a) Intraocular; (b) an implant, which may be a biodegradable or non-biodegradable disc, sheet, filler, rod, or sphere; or (c) Local; The lipid-binding protein-based complex according to claim 14, comprising the step of administering the lipid-binding protein-based complex to a person, wherein the lipid-binding protein-based complex is formulated as an eye drop.

16. A composition that is an implant, the implant may be a biodegradable or non-biodegradable disc, sheet, filler, rod, or sphere containing a lipid-binding protein-based complex and one or more ophthalmic drugs, (i) the lipid-binding protein-based complex may be CER-001, CSL-111, CSL-112, ETC-216, CER-522, defatted HDL, Apomer, or Cargomer, and / or (II) one or more of the one or more ophthalmic drugs may be (i) hydrophobic and / or (ii) poorly water-soluble or water-insoluble.

17. The composition according to claim 16, wherein the lipid-binding protein-based complex is CER-001.

18. The aforementioned one or more ophthalmic drugs are (a) Steroids, kinase inhibitors, angiotensin II receptor antagonists, aldose reductase inhibitors, immunosuppressants, carbonic anhydrase inhibitors, antimicrobial agents, antiviral agents, antihistamines, anti-inflammatory agents, or combinations thereof; (b) Dexamethasone palmitate, azithromycin, dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, roteprednol etavonate, prednisolone, triamcinolone, rimexolone, spironolactone, axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridine-4-yl)oxy)-3-fluoro (Phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide), cabozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, oranthinib, PD173074(N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine-7-yl]-N'-(1, 1-Dimethylethyl Urea), Pazopanib, Regorafenib, Sorafenib, Tofacitinib, ZM323881 (5-((7-Benzyloxyquinazoline-4-yl)amino)-4-Fluoro-2-methylphenol), Candesartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, 2-Methylsorbino, Sirolimus, Cyclosporine, Tacrolimus, Acetazolamide The composition according to claim 16, comprising brinzolamide, dorzolamide, ethoxyzolamide, metazolamide, acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline, zidovudine, levocabastine, bromfenac, diclofenac, indomethacin, nepafenac, or a combination thereof.

19. The composition according to claim 18, wherein the one or more ophthalmic drugs include (a) dexamethasone palmitate, the concentration of dexamethasone palmitate in the composition may be 1 mg / ml, (b) dexamethasone, and (c) tacrolimus.

20. The composition according to claim 16, further comprising one or more buffers, preservatives, excipients, diluents, or combinations thereof, wherein the pharmaceutical composition may be formulated as eye drops.

21. A composition comprising an implant containing a lipid-binding protein-based complex, wherein the lipid-binding protein-based complex may be CER-001, and the implant may be a biodegradable or non-biodegradable disc, sheet, filler, rod, or sphere.

22. The composition according to claim 16, used in a method for treating an eye disease in a subject.

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