PROTEIN SOLUTION FORMULATION CONTAINING A HIGH CONCENTRATION OF AN ANTI-VEGF ANTIBODY

Abstract

This disclosure provides anti-VEGF antibodies formulated as high-concentration aqueous pharmaceutical compositions suitable for injection, preferably intravitreal injection. Aqueous pharmaceutical compositions are useful for delivering a high concentration of the antibody active ingredient to a patient without high levels of antibody aggregation and without a high level of sub-visible particulate matter. An aqueous composition of the disclosure comprises an antibody having a concentration of at least 50 mg / mL. An aqueous pharmaceutical composition of the disclosure includes a sugar, a buffering agent, and a surfactant.

Description

PROTEIN SOLUTION FORMULATION CONTAINING A HIGH CONCENTRATION OF AN ANTI-VEGF ANTIBODY List of Sequences This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. This ASCII copy, created on December 11, 2019, is named PAT058325_sequence_listing_2019_ST25.txt and has a size of 9 KB. Field of Invention The present invention relates to aqueous pharmaceutical formulations of anti-VEGF antibodies, to a process for preparing the same, and to the uses of the formulations. Background of the Invention Vascular endothelial growth factor (VEGF) is a known regulator of angiogenesis and neovascularization, and has been shown to be a key mediator of neovascularization associated with tumors and intraocular disorders (Ferrara et al. Rev. Endocr. 18:4-25 (1997)). VEGF mRNA is overexpressed in many human tumors, and the concentration of VEGF in ocular fluids is highly correlated with the presence of active blood vessel proliferation in patients with diabetic retinopathy and other ischemia-related conditions (Berkman et al., Rev. Invest Clin. 91:153-159 (1993); Brown et al. Patol. Humana 26:86-91 (1995); Brown et al. Invest. del Cáncer 53:4727-4735 (1993); Mattern et al. Rev. Brit. del Cáncer. 73:931-934 (1996); and Dvorak et al. Rev. Am de Patol. 146:1029-1039 (1995); Aiello et al. Rev. de Med. de N. Engl. 331:1480-1487 (1994)).Furthermore, recent studies have demonstrated the presence of VEGF located in the neovascular ceroid membranes in patients affected by AMD (López et al. Oftalmo. Invest. Cieñe. Vis. 37:855-868 (1996)). Neutralizing anti-VEGF antibodies can be used to suppress the growth of a variety of human tumor cell lines in nude mice and also to inhibit infraocular angiogenesis in models of ischemic retinal disorders (Kim et al. Nature 362:841-844 (1993); Warrcn et al. Rev. Invest Clin. 95:1789-1797 (1995); Borgstrom et al. Cancer Invest. 56:4032-4039 (1996); and Melnyk et al. Cancer Invest. 56:921-924 (1996)) (Adamis et al. Arch. of Ophthalmol. 114:66-71 (1996)). A number of antibodies are approved for therapeutic use in humans and other mammals, including anti-VEGF antibodies. The concentration of therapeutic antibodies in liquid pharmaceutical formulations varies widely depending on factors such as the route of administration. A high-concentration formulation of an antibody is often required when small volumes are desired. For example, high-concentration formulations may be desirable for intravitreal injection or subcutaneous administration. However, high-concentration antibody formulations can have short shelf lives, and formulated antibodies can lose biological activity due to chemical and physical instabilities during storage. Aggregation, deamidation, and oxidation are known to be the most common causes of antibody degradation. In particular, aggregation can potentially lead to an increased immune response in patients, resulting in safety concerns. Therefore, it should be minimized or prevented. Particle formation in biotherapeutic formulations is also a significant quality concern, as particles ranging in size from tens of microns to submillimeters and millimeters are generally visible to the naked eye (see Das, 2012, A APS PharmSciTech, 13:732-746). Particles in therapeutic ophthalmic preparations, even those visible only under a microscope or by dimming light, can cause eye damage. Therefore, regulatory standards exist to ensure that the sub-visible particulate matter content in ophthalmic formulations remains within certain limits.For example, the United States Pharmacopeia Convention (USP) has established requirements for particulate matter in ophthalmic solutions, such as a maximum number of particles > 10 µm in diameter of 50 per mL, a maximum number of particles > 25 µm in diameter of 5 per mL, and a maximum number of particles > 50 µm in diameter of 2 per mL, determined by the microscopic particle counting or light obscuration method (see the General Chapter of the USP). <789> ). Methods for producing high-concentration antibody formulations are known. However, there is no universal approach to overcome the unpredictable impact of an antibody's amino acid sequence on its tendency to aggregate or degrade in the presence of various lamps, pharmaceutical excipients, etc. Furthermore, preparing an ophthalmic formulation with a high concentration of protein (such as an antibody) that contains an acceptable level of sub-visible particles is challenging and unpredictable. Developing formulations for protein drugs requiring high dosages is challenging for proteins with limited solubility and also results in various manufacturing, stability, analytical, and supply challenges. The concentration-dependent degradation aggregation pathway is the greatest challenge in developing protein formulations at these higher concentrations.In addition to the potential for aggregation of non-native proteins and particle formation, reversible self-association can occur, contributing to properties such as viscosity that complicate delivery by injection. Furthermore, aqueous protein formulations can become opaque and cloudy over time when stored, for example, in a refrigerator or freezer. Opacity and cloudiness are generally associated with protein aggregation or crystallization within the formulation. There is a strong preference for avoiding any opacity or cloudiness in a protein formulation to prevent the need for filtration or other clarification methods before injection or other administration to the patient. It is an object of the invention to provide additional and improved formulations with high concentration of anti-VEGF antibodies and low levels of antibody aggregation and sub-visible particles, suitable for administration to a human, in particular to a human eye, and avoiding opacity / turbidity / crystallization. Brief Description of the Invention Accordingly, the present invention relates to an aqueous pharmaceutical composition comprising a high concentration of anti-VEGF antibody suitable for ophthalmic injection. In certain respects, the aqueous pharmaceutical compositions of the invention exhibit low to undetectable levels of antibody aggregation or degradation, with very little to no loss of biological activity during manufacturing, preparation, transport, and long storage periods, the concentration of the anti-VEGF antibody being at least approximately 50 mg / mL, 60 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, or 200 mg / mL. The invention provides aqueous pharmaceutical compositions comprising an anti-VEGF antibody, a stabilizer, a buffer, and a surfactant. In certain aspects, as an aqueous pharmaceutical composition, it comprises: (i) at least 50 mg / mL of an anti-VEGF antibody, (ii) a sugar (such as sucrose) as a stabilizer, (iii) a citrate or histidine buffer, and (iv) polysorbate 80 as a surfactant. In certain aspects, the aqueous pharmaceutical composition comprises at least 50 mg / mL of an anti-VEGF antibody comprising the sequences SEQ ID NO: 1 and SEQ ID NO: 2, approximately 4.5% to 11% (w / v) sucrose, 10-20 mM citrate buffer, and 0.001% to 0.05% polysorbate 80 (w / v), wherein the pH of the composition is approximately 7.0 to approximately 7.6. The specific preferred embodiments of the invention will become evident from the following more detailed description of certain preferred embodiments and of the claims. Brief Description of the Drawings Figure 1: Antibody 1008 in formulations 1 to 6 (F1 to F6) with 5% PEG after 165 days. Detailed Description of the Invention The invention provides aqueous pharmaceutical compositions comprising a high concentration of an anti-VEGF antibody. In certain embodiments, an aqueous pharmaceutical composition of the invention is stable for at least 18 months at 2-8°C and is suitable for administration to the eye, including injection or infusion, e.g., ophthalmic administration, e.g., intravitreal administration. The present invention provides novel pharmaceutical formulations, in particular novel pharmaceutical formulations in which the active ingredient comprises antibodies to human VEGF. In one aspect, the invention relates to an aqueous pharmaceutical composition with a high concentration of anti-VEGF antibodies. The preferred anti-VEGF antibodies in the formulations of the invention are described in WO 2009 / 155724, the full contents of which are incorporated herein by reference. The term “antibody” as used herein includes whole antibodies and any antigen-binding fragment (i.e., “antigen-binding portion,” “antigen-binding polypeptide,” or “immunoagglutinant”) or a single chain thereof. An “antibody” includes a glycoprotein comprising at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain consists of a variable heavy-chain region (abbreviated herein as Vh) and a constant heavy-chain region. The constant heavy-chain region consists of 3 CRcynn / i znz / B / v consists of three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as Vl) and a light chain constant region. The light chain constant region consists of one domain, CL. The Vh and Vl regions can be further subdivided into hypervariability regions, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each Vh and Vl is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.The constant regions of antibodies can mediate the binding of immunoglobulin to host factors or tissues, including various immune system cells (e.g., effector cells) and the first component (Clq) of the classical complement system. The term “antigen-binding portion” of an antibody (or simply “antibody portion”) refers to one or more antibody fragments that retain the ability to bind specifically to an antigen (e.g., VEGF). The antigen-binding function of an antibody has been shown to be carried out by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment composed of the Vl, Vh, CL, and CH1 domains; (ii) an F(ab') fragment, a bivalent fragment consisting of two Fab fragments joined by a disulfide bridge in the hinge region; (iii) an Fd fragment composed of the Vh and CH1 domains; (iv) an Fv fragment composed of the Vl and Vh domains of a single antibody arm; and (v) a dAb fragment or single domain (Ward et al.).(1989) Nature 341:544-546), which consists of a Vh domain; and (vi) an isolated complementarity-determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, Vl and Vh, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be produced as a single protein chain in which the Vl and Vh regions pair to form monovalent molecules (known as single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Acad. Nac. de Cieñe, of the United States 85:5879-5883). These single-chain antibodies are also meant to be understood within the term “antigen-binding portion” of an antibody.These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for their usefulness in the same way as intact antibodies. The antigen-binding portions can be produced using recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins. The antibodies can be of different isotypes, for example, an IgG antibody (e.g., an IgG1, TgG2, IgG3, or lgG4 subtype), IgA1, IgA2, IgD, IgE, or IgM. In a preferred embodiment, an aqueous pharmaceutical composition of the invention comprises a variable heavy chain having the sequence as set forth in SEQ ID NO: 1 and a variable light chain having the sequence as set forth in SEQ ID NO: 2. VH: SEQ ID NO: 1 EVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLDIWGQGTLVTVSS VL: SEQ ID NO: 2 EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGAEFTLTI SSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLG In another preferred embodiment, the anti-VEGF antibody is a single-chain Fv antibody fragment (scFv) comprising the sequence as set out in SEQ ID NO: 3: EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGAEFTLTI SSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLGGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLR LSCTASGFSLTDYYYMTWVRQAPGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCAGGDHNSGWGLDIWGQGTLVTVSS (SEQ ID NO: 3) An anti-VEGF antibody in an aqueous pharmaceutical composition of the invention can be produced, for example, as described in WO 2009 / 155724. A scFv can be produced using an expression vector, as described therein. A methionine derived from the start codon in an expression vector is present in the final protein in cases where it has not been post-translational cleaved. MEIVMTQSPS TLSASVGDRV IITCQASEII HSWLAWYQQK PGKAPKLLIY LASTLASGVP SRFSGSGSGA EFTLTISSLQ PDDFATYYCQ NVYLASTNGA NFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL RLSCTASGFS LTDYYYMTWV RQAPGKGLEW VGFIDPDDDP YYATWAKGRF TISRDNSKNT LYLQMNSLRA EDTAVYYCAG GDHNSGWGLD IWGQGTLVTV SS (SEQ ID NO: 4) In certain embodiments, the anti-VEGF antibody in an aqueous pharmaceutical composition of the invention comprises heavy chain HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 5, 6, and 7, respectively, and light chain LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO: 8, 9, and 10, respectively. CDR SEQ ID Sequence HCDR1 SEQ ID NO: 5 GFSLTDYYYMT HCDR2 SEQ ID NO: 6 FIDPDDDPYYATWAKG HCDR3 SEQ ID NO: 7 GDHNSGWGLDI LCDR1 SEQ ID NO: 8 QASEIIHSWLA LCDR2 SEQ ID NO: 9 LASTLAS LCDR3 SEQ ID NO: 10 QNVYLASTNGAN In one embodiment, the concentration of an anti-VEGF antibody in the aqueous pharmaceutical composition of the invention is at least 50 mg / mL. Preferably, the aqueous pharmaceutical composition of the invention comprises approximately 50 mg / mL, approximately 60 mg / mL, approximately 70 mg / mL, approximately 80 mg / mL, approximately 90 mg / mL, approximately 100 mg / mL, approximately 110 mg / mL, approximately 120 mg / mL, approximately 130 mg / mL, approximately 140 mg / mL, approximately 150 mg / mL, approximately 160 mg / mL, approximately 170 mg / mL, approximately 180 mg / mL, approximately 190 mg / mL, approximately 200 mg / mL, approximately 210 mg / mL, approximately 220 mg / mL, approximately 230 mg / mL, approximately 240 mg / mL, approximately 250 mg / mL or approximately 300 mg / mL of an anti-VEGF antibody. In certain embodiments, the aqueous pharmaceutical composition of the invention comprises between approximately 60 mg / mL and approximately 120 mg / mL of an anti-VEGF antibody, for example, an antibody comprising SEQ ID NO: 1 and SEQ ID NO: 2. In one embodiment, the aqueous pharmaceutical composition of the invention comprises between approximately 60 mg / mL and approximately 120 mg / mL of an anti-VEGF antibody, comprising SEQ ID NO: 3. In one embodiment, the aqueous pharmaceutical composition of the invention comprises approximately 60 mg / mL of an anti-VEGF antibody comprising SEQ ID NO: 3. In one embodiment, the aqueous pharmaceutical composition of the invention comprises approximately 90 mg / mL of an anti-VEGF antibody comprising SEQ ID NO: 3. In another embodiment, the aqueous pharmaceutical composition of the invention comprises approximately 120 mg / mL of an anti-VEGF antibody comprising SEQ ID NO: 3. In one embodiment, the aqueous pharmaceutical composition of the invention comprises between approximately 60 mg / mL and approximately 120 mg / mL of an anti-VEGF antibody, comprising SEQ ID NO: 4. In one embodiment, the aqueous pharmaceutical composition of the invention comprises approximately 60 mg / mL of an anti-VEGF antibody comprising SEQ ID NO: 4. In another embodiment, the aqueous pharmaceutical composition of the invention comprises approximately 120 mg / mL of an anti-VEGF antibody comprising SEQ ID NO: 4. As used herein, the term “approximately” includes and describes the value or parameter itself. For example, approximately x includes and describes x itself. As used herein, the term approximately, when used in association with a measurement, or when used to modify a value, unit, constant, or range of values, refers to variations of ±1–10% in addition to including the value or parameter itself. In some forms, the term approximately, when used in association with a measurement, or when used to modify a value, unit, constant, or range of values, refers to variations of ±1, ±2, ±3, ±4, ±5, ±6, ±7, ±8, ±9, or ±10%. As used herein, the term between includes and describes the value or parameter per se. For example, between x and y includes and describes x and y. As used herein, the term “stable” means that the anti-VEGF antibody as described herein essentially maintains its physical and / or chemical stability and / or biological activity after storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Rev. Advance Drug Delivery 10: 29-90 (1993), for example. Stability can be measured at a selected temperature for a selected time period, for example, using AEX-HPLC (Anion-Exchange High-Performance Liquid Chromatography) as described herein.Preferably, the aqueous formulation is stable at room temperature (approximately 25°C) or at 40°C for at least 1 week and / or stable at approximately 2-8°C for at least 3 months, at least 12 months, at least 18 months, or at least 24 months. The anti-VEGF antibody as described herein maintains its physical stability in a pharmaceutical formulation if it meets the defined release specifications for aggregation, degradation, precipitation and / or denaturation upon visual examination of color and / or clarity, or as measured by UV light scattering, AEX-HPLC, or by size exclusion chromatography (SEC), or other suitable methods known in the art. In particular, it maintains its physical stability if it meets the requirements for ophthalmic solutions stipulated in the General Chapter <789> of the United States Pharmacopeia Convention. In one embodiment, an aqueous pharmaceutical composition of the invention meets the requirements of the USP. <789> relating to the presence of particulate matter. Therefore, in certain embodiments, the maximum number of particles >10 µm in diameter in an aqueous pharmaceutical composition of the invention is 50 per mL, the maximum number of particles >25 µm in diameter in an aqueous pharmaceutical composition of the invention is 5 per mL, and the maximum number of particles >50 µm in diameter in an aqueous pharmaceutical composition of the invention is 2 per mL, said particle numbers being determined by the microscopic particle counting and / or light obscuration method as required by the General Chapter <789> of the United States Pharmacopeia Convention). As used herein, the term protein aggregation means the formation of higher molecular weight protein species, such as oligomers or multimers, instead of the defined species of the desired biopharmaceutical drug (e.g., a monomer). Protein aggregation is therefore a universal term for the formation of all types of undefined multimeric species formed by covalent or non-covalent bonds. Aggregates can be measured by size exclusion chromatography (SE-HPLC or SEC). In one modality, the aggregates of the anti-VEGF antibody in the aqueous pharmaceutical formulation are below the limit of quantification. The anti-VEGF antibody as described herein maintains its stability in an aqueous pharmaceutical formulation if the antibody purity does not decrease, or does not decrease substantially, after storage at room temperature (approximately 25°C) or at 40°C for at least 1 week and / or remains stable at approximately 2–8°C for at least 3 to 18 months. The stability of the anti-VEGF antibody can be assessed by any suitable means, such as size exclusion chromatography (SEC), capillary gel electrophoresis, and / or anion exchange chromatography (AEX). In one modality, the anti-VEGF antibody is considered stable in an aqueous pharmaceutical composition where the % loss in the main peak, as assessed by SEC, is <5%, <4%, <3%, <2%, <1%, <0.5%, <0.4%, <0.3%, <0.2%, or <0.1% evaluated after storage at room temperature (approximately 25°C) or at 40°C for at least 1 week and / or at approximately 2-8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a preferred embodiment, the anti-VEGF antibody has <0.5%, <0.4%, <0.3%, <0.2%, or <0.1% loss in the main peak as evaluated by SEC after storage at approximately 2-8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a particularly preferred modality, the anti-VEGF antibody has <0.1% loss in the major peak as assessed by SEC after storage at approximately 2-8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In one embodiment, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the % loss in the sum of HC and LC evaluated by capillary gel electrophoresis, for example, under reducing conditions, for example, SDS, is <5%, <4%, <3%, <2%, <1%, <0.5%, <0.4%, <0.3%, or <0.2% evaluated after storage at room temperature (approximately 25°C) or at 40°C for at least 1 week and / or at approximately 2-8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a preferred embodiment, the anti-VEGF antibody has <0.5%, <0.4%, <0.3%, or <0.2% loss in the sum of HC and LC as assessed by capillary gel electrophoresis after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a particularly preferred embodiment, the anti-VEGF antibody has <0.2% loss in the sum of HC and LC evaluated by capillary gel electrophoresis after storage at approximately 2-8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In one embodiment, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the % of the sum of acidic peaks, as assessed by anion-exchange chromatography (AEX), is <2%, <1.9%, <1.8%, <1.7%, or <1.6% after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a preferred embodiment, the anti-VEGF antibody has <2% of the sum of acidic peaks, as assessed by anion-exchange chromatography, after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months.In another modality, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the % of the sum of acid peaks evaluated by anion exchange chromatography (AEX) is <6%, <5%, or <4% evaluated after storage at approximately 25°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In one embodiment, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the % of the sum of the basic peaks, as assessed by anion-exchange chromatography (AEX), is <2%, <1.9%, or <1.8% after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. In a preferred embodiment, the anti-VEGF antibody has <2% of the sum of the basic peaks, as assessed by anion-exchange chromatography, after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months.In another modality, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the % of the sum of basic peaks evaluated by means of anion exchange chromatography (AEX) is <6%, <5%, or <4% evaluated after storage at approximately 25°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. The anti-VEGF antibody as described herein maintains its biological activity in an aqueous pharmaceutical formulation if the antibody's biological activity at a given time is within approximately 10% of the biological activity exhibited at the time the pharmaceutical formulation was prepared, as determined in a potency assay, for example, a HUVEC proliferation potency assay. An example of a potency assay is a competitive ELISA. For instance, in a competitive ELISA, the ability of 1008, as described in the Examples section herein, to compete with VEGFR2 / Fc for biotinylated VEGF can be measured. The observed signal is inversely related to the concentration of 1008, since increasing amounts of 1008 effectively block the binding of biotinylated VEGF to its receptor VEGFR2 / Fc.Each sample can be analyzed on a 96-well microtiter plate against a 1008-well reference standard, and the relative potency of the sample can be observed with respect to the reference standard. In one embodiment, the anti-VEGF antibody is stable in an aqueous pharmaceutical composition, wherein the biological activity of the anti-VEGF antibody is between approximately 65% ​​and 135% compared to a reference sample, and wherein the biological activity is evaluated after storage at approximately 2–8°C for at least 3 months, at least 6 months, at least 9 months, at least 12 months, or at least 18 months. As used herein, an aqueous pharmaceutical composition is a composition suitable for pharmaceutical use, wherein the aqueous carrier is distilled water. A composition suitable for pharmaceutical use may be sterile, homogeneous, and / or isotonic.Aqueous pharmaceutical compositions can be prepared either directly in an aqueous form, for example, in a ready-to-use pre-filled syringe or in a syringe prepared from a vial comprising a pharmaceutical composition of the invention (the liquid formulations), or as a lyophilized powder to be reconstituted shortly before use. As used herein, the term aqueous pharmaceutical composition refers to the reconstituted liquid formulation or lyophilized formulation. In certain embodiments, the aqueous pharmaceutical compositions of the invention are suitable for ophthalmic administration to a human subject. In one specific embodiment, the aqueous pharmaceutical compositions of the invention are suitable for intravitreal administration. The aqueous pharmaceutical compositions of the invention comprise, in addition to the anti-VEGF antibody, additional components such as one or more of the following: (i) a stabilizer; (ii) a buffering agent; (iii) a surfactant; and (iv) a free amino acid. The inclusion of each of these additional components can provide compositions with low aggregation of the anti-VEGF antibody. Preferably, the aqueous pharmaceutical compositions of the invention include, in addition to the anti-VEGF antibody: (i) a stabilizer; (ii) a buffering agent; and (iii) a surfactant. A stabilizer suitable for use with the invention may act, for example, as a viscosity-enhancing agent, bulking agent, solubilizing agent, and / or the like. The stabilizer may be ionic or non-ionic (e.g., sugars). Sugars include, but are not limited to, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, sorbitol (glucitol), and the like. For example, the sugar may be sucrose, trehalose, raffinose, maltose, sorbitol, or mannitol. The sugar can be a sugar alcohol or an amino sugar, such as sucrose or trehalose. Sucrose is preferred.As an ionic stabilizer, they may include salts such as NaCl or amino acid components such as arginine-HCl. In a preferred embodiment, a sugar is present in the aqueous pharmaceutical composition of the invention at a concentration of between 3 and 11% (w / v). In certain embodiments, the sugar is sucrose at a concentration of approximately 4.5% to approximately 11%. In other embodiments, the sugar is sucrose at a concentration of approximately 5.5% to approximately 7.0% (w / v). In other embodiments, the sugar is sucrose at a concentration of approximately 5.5% to approximately 6.8% (w / v). In other embodiments, the sugar is trehalose at a concentration of approximately 5% to approximately 10%. In a preferred embodiment, the aqueous pharmaceutical composition comprises a concentration of 5.8% (w / v) sucrose. In another preferred embodiment, the aqueous pharmaceutical composition comprises a concentration of 6.4% (w / v) sucrose. Suitable buffering agents for use with the invention include, but are not limited to, salts of organic acids such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffer. In addition, amino acid components may also be used as buffering agents. Citrate or histidine buffers are particularly useful, including 10–20 mM histidine buffer (e.g., 0.13% to 0.26% (w / v) histidine and 0.03%–0.07% (w / v) histidine hydrochloride monohydrate) or 10–20 mM citrate buffer (e.g., 0.006% to 0.012% citric acid (w / v) and 0.2% to 0.6% sodium citrate (w / v)). The citric acid used in a formulation of the invention can be in any form of hydration, for example anhydrous or monohydrate. In a preferred embodiment, the aqueous pharmaceutical composition comprises a buffering agent at a concentration of between approximately 1 and 60 mM, for example, approximately 10–40 mM, approximately 15–30 mM, approximately 15–25 mM, approximately 10–20 mM, and approximately 10–15 mM. In certain embodiments, the buffering agent is citrate or histidine. In a preferred embodiment, the aqueous pharmaceutical composition comprises approximately 10–15 mM sodium citrate, for example, approximately 0.01 mg / mL citric acid monohydrate and approximately 0.43 mg / mL sodium citrate dihydrate. Aqueous pharmaceutical compositions include such a buffering agent or pH-adjusting agent to provide enhanced pH control. In one embodiment, an aqueous pharmaceutical composition of the invention has a pH between 7.0 and 7.6. In one embodiment, the pH of an aqueous pharmaceutical composition of the invention is approximately 7.0-7.5, or approximately 7.0-7.4, approximately 7.0-7.3, approximately 7.0-7.2, approximately 7.1-7.6, approximately 7.2-7.6, approximately 7.3-7.6, or approximately 7.4-7.6. In one embodiment, an aqueous pharmaceutical composition of the invention has a pH of approximately 7.0, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, or approximately 7.6. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of >7.0. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of approximately 7.2.In another preferred embodiment, the aqueous pharmaceutical composition has a pH of approximately 7.4. In another preferred embodiment, the aqueous pharmaceutical composition has a pH of approximately 7.6. As used herein, the term surfactant refers to organic substances possessing amphipathic structures. Surfactants can be classified, depending on the charge of the active surface residue, as dispersing agents, nonionic, anionic, and cationic surfactants for various pharmaceutical compositions and preparations of biological materials. Suitable surfactants for use with the invention include, but are not limited to, non-ionic surfactants, ionic surfactants, and zwitterionic surfactants. Typical surfactants for use with the invention include, but are not limited to, fatty acid esters of sorbitan (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), sorbitan trioleate, fatty acid esters of glycerol (e.g., glycerol monocaprylate, glycerol monomyristate, glycerol monostearate), fatty acid esters of polyglycerol (e.g., decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate), fatty acid esters of polyoxyethylene sorbitan (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate),polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerin fatty acid esters (e.g., polyoxyethylene glyceryl monostearate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol distearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxypropylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkylphenyl ethers (e.g., polyoxyethylene nonylphenyl ether), hydrogenated polyoxyethylene castor oils (e.g., polyoxyethylene castor oil, hydrogenated castor oil of polyoxyethylene), polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax),Polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin), and polyoxyethylene fatty acid amides (e.g., polyoxyethylene stearic acid amide); Cw-Cis alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate), Cio-Cis alkyl ether sulfate of polyoxyethylene with an average of 2 to 4 moles of added ethylene oxide units (e.g., sodium polyoxyethylene lauryl sulfate), and Ci-Cis alkyl sulfosuccinate ester salts (e.g., sodium lauryl sulfosuccinate ester); and natural surfactants such as lecithin, glycerophospholipids, sphingophospholipids (e.g., sphingomyelin), and sucrose esters of C12-18 fatty acids. A composition may include one or more of these surfactants. The preferred surfactants are fatty acid esters of polyoxyethylene sorbitan, for example, polysorbate 20, 40, 60, or 80. Polysorbate 80 is particularly preferred. In one embodiment,The aqueous pharmaceutical composition comprises 0.001% to 0.05% polysorbate 80 (w / v). In another embodiment, the aqueous pharmaceutical composition comprises 0.001% to 0.01% polysorbate 80 (w / v). In yet another embodiment, the aqueous pharmaceutical composition comprises 0.001% to 0.005% polysorbate 80 (w / v). In a preferred embodiment, the aqueous pharmaceutical composition comprises 0.001%, 0.002%, 0.003%, 0.004%, or 0.005% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.001% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.002% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.003% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.004% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.005% polysorbate 80 (w / v). In another preferred embodiment,The aqueous pharmaceutical composition comprises 0.01% to 0.05% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.01% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.02% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.03% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.04% polysorbate 80 (w / v). In one embodiment, the aqueous pharmaceutical composition comprises 0.05% polysorbate 80 (w / v). Suitable free amino acids for use with the invention include, but are not limited to, arginine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, or aspartic acid. The inclusion of a basic amino acid, i.e., arginine, lysine, and / or histidine, is preferred. If a composition includes histidine, it may act as both a buffering agent and a free amino acid, but when a histidine buffer is used, it is typical to include a non-histidine-free amino acid, e.g., a histidine-lysine buffer. An amino acid may be present in its D- and / or L- form, but the L- form is typical. The amino acid may be present as any suitable salt, e.g., a hydrochloride salt, such as arginine-HCl. In a preferred embodiment, an aqueous pharmaceutical composition of the invention does not comprise any of these free amino acids. Other contemplated excipients that may be used in the aqueous pharmaceutical compositions of the invention include, for example, antimicrobial agents, antioxidants, antistatic agents, lipids such as phospholipids or fatty acids, steroids such as cholesterol, protein excipients such as serum albumin (human serum albumin), recombinant human albumin, gelatin, casein, salt-forming counterions such as sodium, and the like. These and other known excipients and / or pharmaceutical additives suitable for use in the formulations of the invention are known in the art, for example, as listed in The Handbook of Pharmaceutical Excipients, 4th Edition, Rowe et al., Eds., American Pharmaceutical Association (2003); and Remington: The Science and Practice of Pharmacy, 21st Edition, Gennaro, Ed., Lippincott Williams & Wilkins (2005). In one embodiment, the aqueous pharmaceutical composition comprises NaCl.In one embodiment, the aqueous pharmaceutical composition comprises 120 mM NaCl. In one embodiment, the aqueous pharmaceutical composition comprises hyaluronic acid (HA). Hyaluronic acid includes, but is not limited to, HA with a molecular weight of 500-700 kDa. In one embodiment, the aqueous pharmaceutical composition comprises 0.1% HA. In another embodiment, the aqueous pharmaceutical composition comprises 0.2% HA. In certain modalities, the lyophilization of an anti-VEGF antibody is contemplated to provide an aqueous pharmaceutical composition of the invention for the treatment of a patient. The techniques for lyophilizing antibodies are well known in the field; for example, see John F. Carpenter and Michael J. Pikal, 1997 (Inv. Farm. 14, 969-975); Xialin (Charlie) Tang and Michael J. Pikal, 2004 (Inv. Farm. 21, 191-200). Accordingly, in one embodiment, a lyophilized formulation prepared by lyophilizing the aqueous pharmaceutical composition described herein is provided. In another embodiment, a method for preparing a lyophilized formulation is provided, comprising the steps of: (i) preparing an aqueous pharmaceutical composition comprising an anti-VEGF antibody as described herein, and (ii) lyophilizing the aqueous solution. Before a lyophilized product can be administered to a patient, it must be reconstituted with an aqueous reconstituent. This step allows the antibody and other components in the lyophilized product to redissolve, providing a solution suitable for injection into a patient. The volume of aqueous material used for reconstitution determines the antibody concentration in the resulting pharmaceutical composition. Reconstitution with a smaller volume of reconstituent than the pre-lyophilization volume yields a composition that is more concentrated than before lyophilization. The reconstitution factor (volume of the formulation after lyophilization : volume of the formulation before lyophilization) can range from 1:0.5 to 1:6. A reconstitution factor of 1:3 is useful. As mentioned above, the lyophilized products of the invention can be reconstituted to provide aqueous compositions with an anti-VEGF antibody concentration of at least 50 mg / mL (i.e., at least 60, 70, 80, 90, 100, 110, 120, or 130 mg / mL), and the volume of reconstituent will be selected accordingly.If required, the reconstituted formulation 13 may be diluted prior to administration to a patient as appropriate to deliver the intended dose. Typical reconstituents for lyophilized antibodies include buffer or sterile water, which may optionally contain a preservative. If the lyophilized product includes a buffering agent, then the reconstituent may include an additional buffering agent (which may be the same as or different from the buffering agent in the lyophilized product) or it may instead include a non-buffering agent (e.g., water for injection, or physiological saline). The aqueous pharmaceutical composition described herein may be in the form of a liquid. In a preferred embodiment, the aqueous pharmaceutical composition is in the form of a liquid. In one embodiment, the aqueous pharmaceutical composition is contained as a liquid in a vial. The aqueous pharmaceutical compositions of the invention comprising anti-VEGF antibodies can be used to treat a variety of diseases or disorders. Pharmaceutical compositions comprising anti-VEGF antibodies are particularly useful for treating neovascular eye diseases in a subject.A “neovascular eye disease” that can be treated using an aqueous pharmaceutical composition of the invention includes a condition, disease, or disorder associated with ocular neovascularization, including, but not limited to, abnormal angiogenesis, colloid neovascularization (CNV), retinal vascular permeability, retinal edema, diabetic retinopathy (particularly proliferative diabetic retinopathy), diabetic macular edema, neovascular (exudative) age-related macular degeneration (AMD), including CNV associated with nAMD (neovascular AMD), sequelae associated with retinal ischemia, Central Retinal Vein Occlusion (CRVO), and posterior segment neovascularization. The aqueous pharmaceutical compositions of the invention may include additional active ingredients besides the anti-VEGF antibody. The additional pharmacological agents may include, for example, other antibodies useful for the treatment of eye diseases. The terms “treat,” “treating,” and “treatment,” as used herein, refer to the therapeutic measures described herein. The “treatment” methods employ the administration to a subject in need of such treatment of an antibody of the present invention, for example, a subject possessing a VEGF-mediated eye disorder or a subject who may ultimately acquire such a disorder, for the purpose of preventing, curing, delaying, reducing the severity of, or ameliorating one or more symptoms of the disorder or recurrent disorder, or for the purpose of prolonging the survival of a subject beyond that expected in the absence of such treatment. The aqueous pharmaceutical compositions of the invention can be administered to a patient. As used herein, the term “subject” or “patient” refers to human and non-human mammals, including, but not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cattle. Preferably, a subject or patient is a human. Administration will typically be by means of a syringe. Therefore, the invention provides a delivery device (e.g., a syringe) that includes a pharmaceutical composition of the invention (e.g., 14 CRcynn / i znz / B / v pre-filled syringe), and a kit comprising a syringe and a vial containing a pharmaceutical composition of the invention. Patients will receive an effective amount of the anti-VEGF antibody as the main active ingredient (i.e., an amount sufficient to achieve, or at least partially achieve, the desired effect). A therapeutically effective dose is sufficient if it can still produce an incremental change in the symptoms or conditions associated with the disease. The therapeutically effective dose need not completely cure the disease or completely eliminate the symptoms. Preferably, the therapeutically effective dose can at least partially halt the disease and its complications in a patient already suffering from the disease. The effective amounts for this use will depend on the severity of the disorder being treated and the overall condition of the patient's immune system. The dosage amount can be readily determined using dosage-adjustment techniques known to a physician of ordinary skill in treating the disease or condition. The therapeutically effective amount of an anti-VEGF antibody used in an aqueous pharmaceutical composition of the invention is determined by considering the desired dose volumes and mode(s) of administration. Typically, therapeutically effective compositions are administered at a dosage in the range of 0.001 mg / mL to approximately 200 mg / mL per dose. Preferably, a dosage used in a method of the invention is from approximately 60 mg / mL to approximately 120 mg / mL (i.e., approximately 60, 70, 80, 90, 100, 110, or 120 mg / mL). In a preferred embodiment, the dosage of an anti-VEGF antibody used in a method of the invention is either 60 mg / mL or 120 mg / mL. In certain formulations, a single dose is administered directly into one of a patient's eyes. In one formulation, a dose per eye is at least approximately 0.5 mg up to approximately 6 mg. Preferred doses per eye include approximately 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6.0 mg. Doses may be administered in various volumes suitable for ophthalmic administration, such as 50 µL or 100 µL, for example, including 3 mg / 50 µL or 6 mg / 50 µL. Smaller volumes may also be used, including 20 μA or less, for example, approximately 20 μA, approximately 10 μA, or approximately 8.0 μA. In certain modalities, a dose of 2.4 mg / 20 μA, 1.2 mg / 10 μA, or 1 mg / 8.0 μA (for example, 1 mg / 8.3 μA) is delivered to one of a patient's eyes for the treatment or improvement of one or more of the diseases and disorders described above.The delivery can be, for example, by means of intravitreal injection or infusion. The invention also provides formulations (i.e., aqueous pharmaceutical compositions) of the invention for use as medicaments, for example, for use in delivering an antibody to a patient, or for use in the treatment or improvement of one or more of the diseases and disorders described above. The invention further provides a method for delivering an anti-VEGF antibody to a patient, comprising a step of administering an aqueous pharmaceutical composition of the invention to the patient. In certain embodiments, a method for delivering an anti-VEGF antibody to a patient of the invention comprises the steps of: (i) reconstituting a lyophilized powder of the invention to provide an aqueous formulation, and (ii) administering the aqueous formulation to the patient. Step (ii) ideally takes place within 24 hours of step (i) (e.g., within 12 hours, within 6 hours, within 3 hours, or within 1 hour). In one embodiment, the aqueous pharmaceutical composition is contained in a vial. In another embodiment, the aqueous pharmaceutical composition is contained in a delivery device. In one embodiment, said delivery device is a pre-filled syringe. In one embodiment, a method for delivering an anti-VEGF antibody to a patient comprises administering the aqueous pharmaceutical composition by intravitreal injection. Certain specific embodiments of the invention are described as listed below: 1. An aqueous pharmaceutical composition comprising at least 50 mg / mL to approximately 120 mg / mL of an anti-VEGF antibody comprising the sequences SEQ ID NO: 1 and SEQ ID NO: 2, approximately 4.5% to 11% (w / v) sucrose, 5-20 mM sodium citrate, and 0.001% to 0.05% polysorbate 80 (w / v), wherein the pH of the composition is approximately 7.0 to approximately 7.6. 2. The aqueous pharmaceutical composition according to modality 1, wherein the anti-VEGF antibody comprises the sequence SEQ ID NO: 3. 3. The aqueous pharmaceutical composition according to modality 1 or 2, wherein the anti-VEGF antibody comprises the sequence SEQ ID NO: 4. 4. The aqueous pharmaceutical composition of any of the preceding modalities, in composition, is approximately 7.0. 5. The aqueous pharmaceutical composition of any of the preceding modalities, in composition, is approximately 7.1. 6. The aqueous pharmaceutical composition of any of the preceding modalities, in composition, is approximately 7.2. 7. The aqueous pharmaceutical composition of any of the preceding modalities, in composition, is approximately 7.3. 8. The aqueous pharmaceutical composition of any of the preceding forms, wherein the pH of the composition is approximately 7.4. 9. The aqueous pharmaceutical composition of any of the preceding forms, comprising 0.004% polysorbate 80 (w / v). 10. The aqueous pharmaceutical composition of any of the preceding forms, comprising 0.02% polysorbate 80 (w / v). 11. The aqueous pharmaceutical composition of any of the preceding forms, comprising between approximately 60 mg / mL and approximately 120 mg / mL of an anti-VEGF antibody. 12. The aqueous pharmaceutical composition of any of the preceding forms, comprising approximately 60 mg / mL of an anti-VEGF antibody. 13. The aqueous pharmaceutical composition of any of the preceding forms, comprising approximately 120 mg / mL of an anti-VEGF antibody 14. The aqueous pharmaceutical composition of any of the preceding forms, comprising 5.5% to 7.0% (w / v) sucrose. 15. The aqueous pharmaceutical composition of any of the preceding forms, comprising 10-12 mM citrate buffer. 16. The aqueous pharmaceutical composition of any of the preceding forms, comprising 5.9% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, and wherein the pH is approximately 7.2. 17. The aqueous pharmaceutical composition of modality 16, comprising 6 mg of an anti-VEGF antibody. 18. The aqueous pharmaceutical composition of any of the preceding forms, comprising 6.4% (w / v) sucrose, 12 mM sodium citrate, 0.02% (w / v) polysorbate 80, and wherein the pH is approximately 7.2. 19. The aqueous pharmaceutical composition of any of the preceding forms, comprising 5.8% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, and wherein the pH is approximately 7.2. 20. The aqueous pharmaceutical composition of modality 18 or 19, comprising 3 mg of an anti-VEGF antibody. 21. The aqueous pharmaceutical composition of any of the preceding forms, which further comprises NaCl. 22. The aqueous pharmaceutical composition of any of the preceding forms, further comprising 0.1-0.5% hyaluronic acid (HA). 23. The aqueous pharmaceutical composition of any of the preceding forms, wherein said composition is stable for at least 18 months at 2-8°C. 24. The aqueous pharmaceutical composition of any of the preceding modalities, wherein said composition is liquid. 25. A method for delivering an anti-VEGF antibody to a subject, comprising administering to said subject the aqueous pharmaceutical composition of any of modalities 1-24. 26. A method for treating an eye disease or disorder that is mediated by VEGF, comprising administering to a subject the aqueous pharmaceutical composition of any of modalities 1-24. 27. The modality 26 method, wherein said eye disease or disorder is an ocular neovascular disease. 28. The method of any of the modalities 24-27, where said administration is by intravitreal route. 29. An aqueous pharmaceutical composition of any of modality 1-24 for use in the delivery of an anti-VEGF antibody to a subject, comprising a step of administering the aqueous pharmaceutical composition to the subject. 30. An aqueous pharmaceutical composition of any of modality 1-24 for use in the treatment of an eye disease or disorder that is mediated by VEGF, comprising administering the aqueous pharmaceutical composition to a subject. 31. An aqueous pharmaceutical composition for use in accordance with modality 30, wherein said eye disease or disorder is an ocular neovascular disease. 32. An aqueous pharmaceutical composition for use in accordance with any of the modalities 29-31, wherein such administration is by intravitreal route. 33. A dosage form comprising the aqueous pharmaceutical composition of any of the forms 1-24. 34. A delivery device comprising the aqueous pharmaceutical composition of any of modality 1-24. 35. The delivery device for modality 34, which is a pre-filled syringe. The expert person advises that the characteristics, aspects and modalities taught in the text are all combinable with each other and that the particular aspects that combine characteristics and / or modalities from various parts of the text will be considered to be properly disclosed to the expert person. It should be understood that each modality may be combined with one or more other modalities, provided that such combination is consistent with the description of the modalities. It should also be understood that the modalities provided above are intended to include all modalities, including those resulting from combinations of modalities. As used herein, all percentages are percentages by weight, unless otherwise stated. As used herein and unless otherwise indicated, the terms "un" and "una" are taken to mean one, at least one, or one or more. Unless the context otherwise requires, singular terms used herein shall include plurals and plural terms shall include the singular. As used herein, the term “comprising” encompasses “including” as well as “consisting of” and “consisting essentially of”, e.g., a composition comprising X may consist exclusively of X or may include something additional, e.g., X + Y. The term "or" is used herein to mean, and is used interchangeably with the term "and / or", unless the context clearly indicates otherwise. The contents of any of the patents, patent applications, and references cited throughout this descriptive memorandum are hereby incorporated by reference in their entirety. Other embodiments of the present invention will be evident to those skilled in the art from consideration of this specification and from the practice of the present invention disclosed herein. This specification and examples are intended to be considered illustrative only, the true scope and spirit of the invention being indicated by the following claims and their equivalents. EXAMPLES The following examples describe formulation development efforts designed to identify suitable compositions and stabilization approaches to provide stable, highly concentrated solutions comprising antibody 1008, enabling an intravitreal (IVT) formulation with at least a 12-month shelf life under refrigerated storage conditions that meet regulatory requirements for ophthalmic products. Antibody 1008 is a single-chain antibody that binds to and inhibits the biological activity of human vascular endothelial growth factor A (VEGF-A). The amino acid sequence of expressed 1008 is SEQ ID NO: 4. Sub-visible particles were observed at a concentration of 120 mg / mL when 1008 was formulated as an isotonic solution in 15 mM sodium tricitrate / citric acid with 0.05% polysorbate 80 at pH 6.75. The main issue with this initial formulation was particulate matter exceeding the regulatory limits for ophthalmic solutions for injection (USP). <789> ). The following examples summarize the development of the 60 mg / mL and 120 mg / mL formulations of intravitreal (IVT) solutions of 1008, stable at 2-8°C for at least 18 months. The formulation development effort focused on inhibiting the formation of sub-visible particles and meeting USP requirements for content, purity, and potency. ANALYTICAL METHODS The following methods were used throughout the Examples as indicated. Microflow Imaging Method (MFI) The MFI method used for excipient detection analysis, Study 1 and Study 2 for the 60 mg / mL optimization studies was as follows: Total sample volume used: 0.50 mL Purge volume: 0.20 mL Analysis volume: 0.26 mL The lighting optimization step was carried out using purified water free of filtered particles. MFI method used for the analysis of 120 mg / mL of 1008, Study 3 and Study 4: Total sample volume used: 0.80 mL Purge volume: 0.23 mL Analysis volume: 0.48 mL The lighting optimization step was carried out using purified water free of filtered particles. SEC Method Size-exclusion chromatography (SE-HPLC) separates proteins according to their size. Separation is achieved through the exclusion, or differential inclusion, of sample molecules as they pass through the stationary phase of porous particles. A high-performance liquid chromatography system capable of maintaining a flow rate of 0.25 mL / minute and a sample temperature of 4°C was used. It was equipped with a TOSOH SuperSW3000 column (Tosoh Bioscience LLC, King of Prussia, PA) and a detector capable of operating simultaneously at 214 nm and 280 nm. This method was used for purity testing. AEX-HPLC Method AEX-HPLC (High-performance liquid chromatography with anion exchange) separates proteins according to their net charge. This procedure was carried out using high-performance liquid chromatography (HPLC), capable of maintaining a flow rate of 0.8 mL / minute, with a temperature-controlled column compartment (fixed at 25°C) containing a strong anion exchange column, an autosampler (fixed at 4°C), and a variable-wavelength UV detector, capable of operating at 280 nm. CGE Method The capillary gel electrophoresis method was used to determine the identity and purity of proteins with molecular weights between 10 kDa and 225 kDa. The capillary tube was dynamically filled with a proprietary 0.2% Beckman Coulter SDS Gel Buffer, pH 8. Protein separation was performed using molecular sieve electrophoresis. The logarithm of the protein's molecular weight was linearly related to its electrophoretic mobility. Protein identity was determined by comparing its migration to a molecular weight standard. Purity was determined by analyzing the peak area percentage and impurities. A photodiode array detector (PDA) was used to analyze the sample at 220 nm. Example 1 Formulation screening study with 6 formulations A formulation screening study was conducted to identify a suitable formulation to address the issue of crystal formation / opacity / turbidity observed after storage of 1008 at a concentration of 120 mg / mL. Five formulations (F2-F6) with varying amounts of salt (0 and 120 mM NaCl), polysorbate 80 (PS80) (0.05% and 0.004%), and pH values ​​(6.8, 7.0, 7.3, and 7.6) were evaluated and compared with the control (F1). Table 1 provides details of the composition in formulations F1 through F6. Table 1. Formulation sieving Antibody Formulation 1008 pH Sucrose Citrate Buffer Polysorbate 80 NaCl Formulation 1 (F1) 120 mg / mL 6.8 5.9% 10 mM 0.05% 0 Formulation 2 (F2) 120 mg / mL 6.8 5.9% 10 mM 0.004% 120 mM Formulation 3 (F3) 120 mg / mL 7.0 5.9% 10 mM 0.004% 0 Formulation 4 (F4) 120 mg / mL 7.3 5.9% 10 mM 0.004% 0 Formulation 5 (F5) 120 mg / mL 7.3 5.9% 10 mM 0.05% 0 Formulation 6 (F6) 120 mg / mL 7.6 5.9% 10 mM 0.004% 0 Turbidity and pH In formulation 2, an increase in turbidity was observed with a concentration of 120 mM NaCl at pH 6.8 after 4 weeks at 40°C (Figure 1). In Figure 1, the results were correlated with pH to show the effect of pH. Formulations 4 and 5 were formulated at pH 7.3 with low and high concentrations of polysorbate 80. The turbidity values ​​for these two formulations (F4 and F5) were within one digit of each other under all conditions and time points (Table 2), and these values ​​were not considered significantly different. A pH effect was observed in the data, where higher pH values ​​corresponded to lower turbidity. Slightly higher turbidity was also observed at 5°C and 25°C with F2 containing NaCl compared to the formulations without NaCl. For all six formulations, the target pH was stable after storage at 5°C and 25°C for up to 12 months.All pH values ​​were found to be within the acceptable range of the target pH. Sub-visible particle through light obscuration Particle counts for all formulations up to 52 weeks at 5°C and 25°C were found to be within USP limits <789> The measurements were performed using a non-USP small-volume light-obscuring method. No difference was observed between the formulations. Purity / main peak using SEC Purity, as assessed by size exclusion chromatography (SEC), was stable for 12 months at 5°C, with no significant decrease observed for any of the formulations. A significant decrease in the purity of the main peak was observed by SEC at 25°C with increasing pH and increasing polysorbate 80 concentration. Overall, the model showed that polysorbate 80 had a more significant effect than pH on the main peak as measured by SEC. The formulations that maximized the purity of the main peak by SEC at 25°C were those containing low concentrations of polysorbate 80 and pH values ​​of 6.8 and 7.0. The decrease in the main peak was primarily due to aggregate formation as measured by SEC. Purity / main peak using AEX Purity, as assessed by anion-exchange chromatography (AEX), decreased during 12 months of stability at 5°C (approximately a 1% decrease in AEX purity over 12 months at 5°C). Under accelerated and stressed stability conditions, a significant decrease in AEX purity was observed (approximately a 12% decrease in AEX purity over 6 months at 25°C). Changes in the main AEX peak appeared to be primarily driven by temperature and time. No significant differences were observed between pH set points. The effect of NaCl was observed at 5°C and 25°C by AEX for formulation F2 (pH 6.8, 0.004% PS80, 120 mM NaCl), suggesting that NaCl had a stabilizing effect and minimized the decrease in AEX purity due to temperature stress. Purity by AEX decreased approximately 27% up to 6 weeks at 40°C. The highest concentration of polysorbate 80 (0.0.05%) resulted in a significant decrease in the purity of the main peak when compared to formulations with a lower concentration of polysorbate 80 (0.004%). Combined purity data (SEC and AEX) for all six formulations at 40°C (4 weeks) showed a decrease in purity with increasing pH and increasing polysorbate 80 concentration. Purity / Main Peak using CE-SDS The purity of antibody 1008, as assessed by sodium dodecyl sulfate capillary electrophoresis (CESDS) under reducing conditions, decreased by approximately 0.7% over 12 months at 5°C. Under accelerated conditions at 25°C for up to 6 months, the purity of antibody 1008, as assessed by CE-SDS under reducing conditions, decreased by approximately 5%, confirming that the fragmentation level increased with increasing pH but showing no impact with respect to the polysorbate 80 concentration. Overall, the stability results for pH, ionic strength, and polysorbate 80 concentration confirmed that pH and polysorbate 80 concentration were the most significant factors at all temperatures. Formulations with higher pH and higher polysorbate 80 concentrations resulted in lower purity as measured by SEC and AEX. Salt addition had a minimal impact on stability, with no relevant impact on sub-visible particles. All analytical results up to 12 months (52 weeks) from the formulation stability study are summarized in Table 2. Table 2. Analytical results of the sieving stability of the formulation. Point- Formulation Turbidity PS 80 pH Darkening EC-SDS of light (# / mL) (reducing agent) time NTU % >10 >25 >50 Total counts Purity 5 (w / w) pm pm pm pm (sum of LCyHC particles [%]) T=0 F1 6.6 0.067 6.83 27 0 0 761 99.5 F2 8.06 0.003 6.83 10 0 0 238 99.5 F3 5.99 0.003 6.97 10 2 0 262 99.5 10 F4 5.34 0.004 7.27 9 0 0 203 99.6 F5 5.48 0.069 7.3 18 0 0 296 99.6 F6 5.7 0.005 7.57 0 0 0 115 99.5 T=2S F1 7.32 nt 6.8 40 1 0 475 98.2 (40°C) F2 10.8 nt 6.78 51 7 0 1534 98.2 15 F3 6.69 nt 6.96 30 0 0 509 97.9 F4 6.14 nt 7.29 14 7 0 338 97.4 F5 6.28 nt 7.26 39 6 0 241 97.5 F6 5.9 nt 7.53 7 0 0 323 96.9 T=4S F1 10.7 nt 6.83 5 2 0 510 97.1 20 (40°C) F2 23.3 nt 6.8 20 0 0 812 97.2 F3 9.95 nt 6.98 1 0 0 480 96.8 F4 8.45 nt 7.27 9 0 0 737 96 F5 8.93 nt 7.29 0 0 0 160 96.1 F6 10.2 nt 7.59 8 1 0 308 95.2 25 T=6S F1 6.32 nt 6.75 10 1 0 477 99.6 (5°C) F2 8.41 nt 6.74 21 1 0 789 99.7 F3 6.18 nt 6.93 15 1 0 341 99.5 F4 5.13 n.t 7.23 4 1 0 130 99.6 F5 6.23 n.t 7.23 9 0 0 273 99.6 30 F6 5.71 n.t 7.47 20 1 0 319 99.6 T=6S F1 6.85 n.t 6.76 1 0 0 306 98.8 (25°C) F2 8.15 n.t 6.75 15 1 0 650 98.8 F3 6.26 n.t 6.93 24 1 0 607 98.7 F4 5.65 n.t 7.24 19 3 0 414 98.4 F5 5.72 n.t 7.29 12 1 0 476 98.5 35. pRCjnnn ζηζ / Β / γΐ Time point Formulation Turbidity PS80 pH Light darkening (# / mL) CE-SDS (reducing agent) NTU % >10 >25 >50 Counts Purity (w / w) pm pm pm totals of (sum of 5 60 LCyt particles 1 9 5 [%.]) F 396 98 T=3M F1 6.22 nt 6.8 22 3 0 449 nt (5°C) F2 7.89 nt 6.82 7 0 0 181 nt F3 6.19 nt 6.98 9 0 0 204 n F6 7.3 nt 5.6 5.10 224 nt F5 5.15 nt 7.29 10 0 0 490 nt F6 5.39 nt 7.54 16 0 0 288 nt T=3M F1 6.39 nt 6.8 10 0 0 541 nt 12 6.1°C) 1076 nt 15 F3 5.92 nt 6.96 7 0 0 508 nt F4 5.43 nt 7.28 6 0 0 393 nt F5 5.92 nt 7.3 11 0 0 310 nt F6 8 2 93 5.59 nt T=6M F1 6.09 0.069 6.8 0 0 0 327 99.1 20 (5°C) F2 8.29 0.004 6.75 1 0 0 461 99.1 F3 6.15 0.084 4 0.90 6.80 0.006 7.25 0 0 0 28 98.8 F5 5.84 0.069 7.28 1 1 0 74 98.8 F6 5.25 0.005 7.55 2 2 0 250 98.5 80. 80 .64 F1 6 352 96.3 25 (25°C) F2 8.03 0.002 6.78 0 0 0 203 95.9 F3 5.98 0.005 6.98 1 1 0 164 95.4 F4 29 5.37 7 0.34 5.33 0.071 7.28 3 0 0 229 93.7 F6 5.12 0.004 7.56 0 0 0 280 92.6 30 T=9M F1 7.75 n.t 6.77 0 0 0 248 n.t (5°C) F2 8.67 n.t 6.74 6 0 0 268 n.t F3 6.58 n.t 6.93 0 0 0 1395 n.t F4 6.51 n.t 7.24 4 0 0 86 n.t F5 6.49 n.t 7.24 0 0 0 117 n.t 35. PRCjnnil 7Λ7.ΙΒΜ Light Point Formulation Turbidity PS80 pH Darkening EC-SDS (reducing) time NTU % >10 >25 >50 • Total Counts Purity (w / w) pm pm pm pm (sum of 5 particles LC and HC [%]) F6 6.28 nt 7.5 0 0 0 9 nt T=12M F1 6.67 0.062 6.79 1 0 0 178 99 (5°C) F2 7.94 0.003 6.74 1 0 0 60 98.9 F3 6.31 0.004 6.94 4 0 0 67 98.9 10 F4 5.65 0.004 7.28 1 0 0 51 98.7 F5 5.54 0.063 7.29 1 0 0 51 98.7 F6 5.63 0.004 7.54 3 0 0 39 98.4 Table 2 cont Point- Formulation Turbidity PS pH AEX SEC of lation 80 [%] time NTU % AEX AEX AEX Area Area SEC (w / w) sum of main peaks sum of main peaks 20 peaks 1.5 1.53 % basic acidic T=0 F1 6.6 0.067 6.83 0.7 97.95 1.34 0 0 100 F2 8.06 0.003 6.83 0.7 97.88 1.42 0 0 100 F3 5.99 0.003 6.97 0.68 97.99 1.33 0 0 100 25 F4 5.34 0.004 7.27 0.65 97.96 1.39 0 0 100 F5 5.48 0.069 7.3 0.6 98.11 1.29 0 0 100 F6 5.7 0.005 7.57 0.62 98.04 1.34 0 0 100 T=2S F1 7.32 nt 6.8 5.67 83.19 11.14 1.05 6.74 90.3 (40cC) F2 10.8 nt 6.78 5.09 87.14 7.77 0.49 1.25 94.5 30 F3 6.69 n.t 6.96 5.45 86.44 8.11 0.56 1.19 94 F4 6.14 n.t 7.29 4.08 86.77 9.16 0.46 1.33 93.1 F5 6.28 n.t 7.26 3.81 83.08 13.1 0.65 3.12 88.4 F6 5.9 n.t 7.53 3.53 86.23 10.24 0.6 1.6 92.1. PRCjnnil 7Λ7.ΙΒΜ Point- Form- Turbidity PS pH AEX SEC of lation 80 [%] NTU time % AEX AEX AEX Area SEC area (w / w) peak sum relative sum peak 5 of main aRRT main peaks peaks 1.5 1.53 % basic T 6.83 6.94 66.27 26.8 2.39 7.56 74.4 (40cC) F2 23.3 nt 6.8 6.3 74.41 19.29 1.57 4.11 84.2 10 F3.66 8.95 19.51 0 15.71 83.2 F4 8.45 nt 7.27 5.18 73.36 21.46 0 17.61 81 F5 8.93 nt 7.29 4.55 n 64.74 30.27.1 F 46 0 2 7.59 4.32 71.75 23.93 0 19.93 78.7 T=6S F1 6.32 nt 6.75 1.14 97.36 1.5 0 0 100 15 (5°C) F2 8.41 79 nt 4.6 100 F3 6.18 nt 6.93 1.09 97.39 1.52 0 0 100 F4 5.13 nt 7.23 1.06 97.43 1.52 0 0 100 F5 6.23 nt 7.5 8 1.29 0 0 99.9 20 F6 5.71 nt 7.47 1.06 97.43 1.51 0 0.01 100 T=6S F1 6.85 nt 6.76 3.52 94.29 2.19 0.07 0.02 F (2 8.29 9.19) 2.94 94.96 2.19 0.04 0.01 99.8 F3 6.26 nt 6.93 3.14 94.8 2.06 0.05 0.01 99.8 F4 5.65 nt 7.24 2.7.70 9.4 99.7 25 F5 5.72 nt 7.29 2.7 94.91 2.39 0.11 0.03 99.5 F6 5.08 n.t 7.56 2.74 94.65 2.61 0.11 0.03 99.6 T=3M F1 6.22 n.t 6.8 1.1 97.33 1.57 0 0 99.9 (5°C) F2 7.89 n.t 6.82 1.05 97.37 1.58 0 0 99.9 30 F3 6.19 n.t 6.98 1.07 97.34 1.58 0 0 99.8 F4 5.6 n.t 7.34 1.02 97.37 1.61 0 0 99.9 F5 5.15 n.t 7.29 0.99 97.37 1.64 0 0.02 99.9 F6 5.39 n.t 7.54 1.03 97.27 1.69 0 0.01 99.9 T=3M F1 6.39 n.t 6.8 5.29 91.4 3.31 0.17 0.12 99.1 35 (25CC). pRpjnmi ζηζ / Β / γΐ Point- Form- Turbidity PS pH AEX SEC of lation 80 [%] time NTU % AEX AEX AEX Area SEC area (w / w) peak sum relative sum peak 5 of main of aRRT aRRT main peaks peaks 1.5 1.53 .18 % basic F 4.31 92.55 3.13 0.1 0.09 99.4 F3 5.92 nt 6.96 4.71 92.19 3.09 0.12 0.09 99.4 F4 5.43 nt 7.99 3.4.4.15 9 10 F5 5.92 nt 7.3 3.81 92.31 3.88 0.3 0.13 98.8 F6 5.59 nt 7.57 3.69 92.37 3.94 0.28 0.1 99 T=6.6M 9.09 F1.8.6 96.62 1.78 0 0 99.9 (5°C) F2 8.29 0.004 6.75 1.38 96.83 1.79 0 0 99.9 F3 6.15 0.004 6.94 1.40 1.45 17.7 5.88 0.006 7.25 1.37 96.77 1.85 0 0 99.9 F5 5.84 0.069 7.28 1.29 96.89 1.81 0 0 99.9 F6 5.25 5.6 74 0.50 0 0 99.9 T=6M F1 6.71 0.067 6.81 8.62 83.68 7.7 0.1 0.15 95.9 20 (25CC) F2 8.03 0.002 6.78 7.72 3.5 8.3 86.2 5.98 0.005 6.98 7.82 85.49 6.69 0.08 0.14 97.5 F4 5.37 0.004 7.3 6.34 86.09 7.56 0.14 0.23 7 97.33 F 5 84.8 9.2 0.21 0.24 94.8 F6 5.12 0.004 7.56 6.02 85 8.98 0.15 0.26 95.8 25 T=9M F1 7.75 nt 6.77 1.75 96.3 1.62 0 0.01 99.9 (5°C) F2 8.67 nt 6.74 1.48 96.6 1.63 0 0.01 99.9 F3 6.58 nt 6.93 1.6 96.5 1.6 0 0.01 99.9 F4 6.51 nt 7.24 1.41 96.5 1.71 0 0.01 99.9 30 F5 6.49 nt 7.24 1.38 96.5 1.72 0.01 0.02 99.8 F6 6.28 nt 7.5 1.54 96.3 1.86 0.01 0.02 99.8 T=12M F1 6.67 0.062 6.79 1.78 96.2 1.58 0.02 0 99.8 (5°C) F2 7.94 0.003 6.74 1.57 96.5 1.59 0.01 0 99.9 35 F3 6.31 0.004 6.94 1.68 96.43 1.57 0.01 0 99.9. PRCjnnil 7Λ7.ΙΒΜ Time point Formulation Turbidity PS 80 pH AEX [%] SEC NTU % (w / w) AEX sum of basic peaks AEX sum of principal peaks AEX sum of acidic peaks Relative area aRRT 1.5 Relative area aRRT 1.53 SEC main peak % F4 5.65 0.004 7.28 1.53 96.41 1.71 0.02 0.01 99.9 F5 5.54 0.063 7.29 1.37 96.39 1.7 0.04 0.02 99.8 F6 5.63 0.004 7.54 1.59 96.06 1.87 0.02 0.02 99.8 Ensayo de Modelo de PEG A PEG model was developed to enable the rapid selection of suitable formulations for antibody 1008 at 120 mg / mL. First, a suitable PEG concentration was defined at which antibody 1008 in the original formulation at pH 6.8 would form visible crystals after approximately 7 days of storage at 2–8°C. PEG concentrations of 1, 2, 4, 5, 6, and 8% were prepared. Table 3. PEG assay - concentration selection Sample ID No. Antibody 1008 pH Sucrose Citrate Polysorbate 80 PEG 20kDa 1 120 mg / mL 6.75 5.9% 10 mM 0.004% 1% 2 120 mg / mL 6.75 5.9% 10 mM 0.004% 2% 3 120 mg / mL 6.75 5.9% 10 mM 0.004% 4% 5 120 mg / mL 6.75 5.9% 10 mM 0.004% 5% 6 120 mg / mL 6.75 5.9% 10 mM 0.004% 6% 4 120 mg / mL 6.75 5.9% 10 mM 0.004% 8% PEG granules were added directly to antibody 1008 and dissolved for approximately 10 minutes using magnetic stirring. Five 1 mL vials were prepared for each PEG concentration and stored under two temperature-temperature conditions (2–8°C, with cycles to a stable 40°C). Daily visual observations were made in each vial for one week. All vials containing the 8% PEG formulation developed a solid crystalline formation after 48 hours, which was subsequently observed to separate into two phases. For the 6% PEG vials, crystallization began on day three in three vials, and all five vials formed solid white crystals after six days. For the 5% PEG samples, all vials began crystallizing on day six. For the PEG 4% vials, crystallization began on day eight in 4 of the 5 vials and the 5th vial crystallized after 30 days.All vials of 1% and 2% PEG remained clear after 30 days. Based on these results, the 5% PEG concentration was selected for further screening studies. Five vials, each containing 1 mL, were prepared for formulations 1 through 6 as described in Table 1. Daily visual inspection was performed on each vial. The study design and assay conditions are described in Table 4, and the results after 165 days (5.5 months) are shown in Figure 1. All vials of F1 (control, pH 6.8) precipitated after 7 days. Precipitation began after 19 days for the F2 vials (120 mM NaCl, pH 6.8) and after 22 days for the F3 vials (pH 7.0). All vials of the remaining formulations (F4, F5, and F6) were clear after 165 days. Based on this study, crystallization was mitigated for three times longer at pH 7.0 compared to the control (up to 22 days) and even longer at a higher pH (7.3 to 7.6), with all vials of F4, F5, and F6 remaining clear after 165 days (5.5 months). Higher pH levels (>7.0) correlated with the avoidance of crystallization.The presence of NaCl was also correlated with the avoidance of crystallization, but for a shorter period of time. Table 4. Formulation screening study with 5 percent PEG Formulation Antibody 1008 PH Sucrose Citrate [mM] Polysorbate 80 NaCl [mM] PEG (20 kDa) Precipitation Onset F1 120 mg / mL 6.8 5.9% 10 0.05% 0 5% Day 7 F2 120 mg / mL 6.8 5.9% 10 0.004% 120 5% Day 19 F3 120 mg / mL 7.0 5.9% 10 0.004% 0 5% Day 22 F4 120 mg / mL 7.3 5.9% 10 0.004% 0 5% none F5 120 mg / mL 7.3 5.9% 10 0.05% 0 5% none F6 120 mg / mL 7.6 5.9% 10 0.004% 0 5% none Robustness study A robustness study of antibody 1008 at 120 mg / mL was designed to confirm the selected polysorbate 80 concentration and pH. A target pH of 7.2, with a minimum pH of 7.0, was selected to minimize degradation, chemical aggregation, and the risk of crystal formation. A minimum pH range of ±0.2 was allowed during manufacturing and long-term storage. A target polysorbate 80 concentration of 0.02% was selected to minimize aggregation, and sufficient polysorbate 80 was allowed to minimize adsorption and maintain homogeneity. Ten formulations were selected, with formulation 1 (Fl) serving as a control, at varying amounts of polysorbate 80 (0.01%, 0.03%, and target 0.02%) and pH values ​​(7.0–7.4, target 7.2). In addition, all samples were shaken at 250 rpm for 3 days at room temperature before being placed in stability to simulate realistic manufacturing handling and transport conditions.The concentration of the components used in the formulation sieving is summarized in Table 5. In addition, all formulations also included 5.9% sucrose and 10 mM sodium citrate buffer. Table 5. Formulations used in the robustness study. Sample ID Antibody 1008 pH Polysorbate 80 F1 (control) 120 mg / mL 6.8 0.05% F2 120 mg / mL 7.0 0.01% F3 120 mg / mL 7.0 0.02% F4 120 mg / mL 7.0 0.03% F5 120 mg / mL 7.2 0.01% F6 (target) 120 mg / mL 7.2 0.02% F7 120 mg / mL 7.2 0.03% F8 120 mg / mL 7.4 0.01% F9 120 mg / mL 7.4 0.02% FIO 120 mg / mL 7.4 0.03% There was no decrease in purity as assessed by SEC and AEX for all levels of polysorbate 80 and pH at 25°C (T=0) after 3 days of agitation stress. An increase in particulate matter counts larger than 10 microns was observed after 3 days of agitation for F1 (control), as well as for F5 with lower polysorbate 80 (0.01%) and F9 with higher pH (7.4). This increase was not observed for F6. The analytical results for the robustness study after 3 days of agitation are summarized in Tables 6A and 6B below. Table 6A. Analytical results of the robustness study for 10 different formulations (T0 and T3 days after shaking) Time Point Formulation UV Vis Turbidity PS80 pH Light Obscuration (# / mL) EC-SDS (reducing) SEC [%] mg / mL (NTU) % >10 >25 >50 Counts Purity SEC (w / w) pm pm pm of (sum of 5 main LCyHC particles total [%]) T=0 F1 120.1 7.83 0.06 6.85 3 0 0 98 99.4 100 F2 116.1 7.04 0.01 7.01 0 0 0 69 99.4 100 F3 116.1 9.03 0.02 7.04 0 0 0 96 99.4 100 F4 117.2 18 0.03 7.05 12 1 0 119 99.4 100 10 F5 118.3 8.66 0.01 7.24 1 0 0 67 99.3 100 F6 116 9.58 0.02 7.25 3 0 0 55 99.4 100 F7 115.8 11.9 0.03 7.25 3 0 0 71 99.3 100 F8 117.3 11.9 0.01 7.45 0 0 0 64 99.3 99.9 F9 117.6 11.6 0.02 7.45 0 0 0 42 99.3 99.9 FIO 118.6 7.26 0.04 nt 3 0 0 76 99.2 99.9 15 T=3 d of F1 120.4 9.59 0.06 6.81 7 0 0 157 99.5 100 agitation F2 116.8 10.1 0.01 7.01 3 0 0 124 99.4 100 (25°C) F3 117.8 11.5 0.02 7.02 0 0 0 150 99.4 100 F4 117.3 12.4 0.03 7.03 6 0 0 225 99.2 100 20 F5 119.3 10.6 0.01 7.21 4 3 0 146 99.3 99.9 F6 115.9 12.5 0.02 7.22 1 0 0 146 99.2 99.9 F7 113.9 9.34 0.03 7.24 0 0 0 106 99.3 99.9 F8 117.4 11 0.01 7.43 1 0 0 81 99.3 99.9 F9 117.5 7.79 0.02 7.44 11 1 0 1333 99.2 99.9 FIO 119.3 8.17 0.04 7.42 1 0 0 278 99.3 99.9. 25______________________________________________________________________________________________________ Table 6B. Analytical results of the robustness study for 10 different formulations (TO and T3 days after shaking) Formulation Point UV Vis Turbidity PS80 pH AEX [%] time mg / mL (NTU) % AEX AEX AEX Area Area (w / w) sum of peaks sum of peaks relative to 5 main peaks aRRT aRRT basic acidic 1.5 1.53 T=0 F1 120.1 7.83 0.06 6.85 0.96 97.46 1.58 0 0 F2 116.1 7.04 0.01 7.01 0.93 97.5 1.58 0 0 F3 116.1 9.03 0.02 7.04 0.97 97.41 1.62 0 0 F4 117.2 18 0.03 7.05 0.91 97.5 1.59 0 0 10 F5 118.3 8.66 0.01 7.24 0.88 97.53 1.59 0 0 F6 116 9.58 0.02 7.25 0.92 97.46 1.62 0 0 F7 115.8 11.9 0.03 7.25 0.91 97.5 1.59 0 0 F8 117.3 11.9 0.01 7.45 0.89 97.49 1.63 0 0 F9 117.6 11.6 0.02 7.45 0.91 97.44 1.64 0 0 FIO 118.6 7.26 0.04 nt 0.9 97.48 1.63 0 0 15 T=3 d of F1 120.4 9.59 0.06 6.81 1.18 97.22 1.6 0 0 agitation F2 116.8 10.1 0.01 7.01 1.06 97.34 1.6 0 0 (25°C) F3 117.8 11.5 0.02 7.02 1.07 97.32 1.61 0 0 F4 117.3 12.4 0.03 7.03 1.06 97.33 1.61 0 0 20 F5 119.3 10.6 0.01 7.21 1.03 97.33 1.64 0 0 F6 115.9 12.5 0.02 7.22 1.06 97.3 1.64 0 0 F7 113.9 9.34 0.03 7.24 1.06 97.31 1.63 0 0 F8 117.4 11 0.01 7.43 1.01 97.33 1.66 0 0 F9 117.5 7.79 0.02 7.44 1.03 97.3 1.67 0 0 FIO 119.3 8.17 0.04 7.42 1.04 97.29 1.67 0 0 25 Up to stability time points of 52 weeks at 5°C and 25°C, particle counts in the range of. Sizes >10 pm and >25 pm remained well below the USP limit <789> of 50 particles / mL and 5 particles / mL, respectively, for all formulations. Turbidity levels for all formulations at 120 mg / mL stored at 2–8°C ranged from 5 to 12 NTU above the mean, with one isolated portion at 18 NTU (F4) at the initial time point. (There was no decrease in purity as assessed by SEC and AEX for all polysorbate 80 levels and pH at 25°C (T=0) after 3 days of agitation stress. An increase in particulate matter counts larger than 10 microns was observed after 3 days of agitation for F1 (control), as well as for F5 with lower polysorbate 80 (0.01%) and F9 with higher pH (7.4). This was not observed for F6. The analytical results for the robustness study after 3 days of agitation are summarized in the Tables 6A and 6B below. Table 6). The turbidity level in the solution decreased slightly from 10.8 to 6.3 NTU after 3 months of stability storage. Beyond this point, there was no significant change for any of the formulations until 52 weeks. No relevant change in color or pH value was observed for any of the formulations. All formulations showed minimal changes, with an approximate 1.1–1.2% decrease over 52 weeks in terms of main peak purity as assessed by AEX and SEC. No observable differences were found, indicating that the formulations are robust during 12 months of storage at 2–8°C. Purity by SEC: No relevant change in aggregate levels was observed, with the maximum change being 0.1%. The monomer peak was >99% and showed virtually no change during 12 months of storage at 2-8°C. Aggregates by SEC: All formulations were stable at 2-8°C for 12 months as the levels of aggregates evaluated by SEC were found to be below the limit of quantification. Purity by EC-SDS: A slight decrease was observed over 12 months at 5°C (approximately 1%), which was more pronounced for formulations with a higher pH. The concentration of polysorbate 80 is independent of fragmentation. Purity data (25°C, 6 months) confirm that the fragmentation level increases with increasing pH. No impact of polysorbate 80 concentration on purity by EC-SDS was observed. The analytical results for the robustness studies are summarized in Table 7 below. Table 7. Analytical results of the robustness study for 10 formulations (T2S, T4S, T5S, T3M, T6M, T9M and T12M) Time point Formulation UV Turbidity Vis PS80 AEX [%] (NTU) mg / mL % (w / w) AEX sum of basic peaks AEX main peak AEX sum of acidic peaks Relative area aRRT 1.5 nRelative area aRRT.1.3 F8 83.26 11.36 1.16 2.39 (40°C) F2 7.18 nt 4.65 85.31 10.05 0.95 1.69 F3 7.3 nt 4.54 84.31 11.184 F 180 nt 4.54 84.31 83.85 11.73 1.08 2.44 F5 7.77 nt nt 3.97 85.07 10.97 0.96 1.86 F6 9.67 nt 3.87 83.86 12.27 1.3.6 nt 2.4 nt 83.52 12.68 1.05 2.67 F8 8.35 nt nt 3.43 84.53 12.04 0.97 2.17 F9 10 nt 3.32 83.46 13.23 1.03 nt 9.62 F 14.02 1.04 3.01 F1 11.6 nt 6.8 65.78 27.42 2.84 7.86 F2 9.63 nt 5.97 69.8 24.22 2.32 5.94 33 Time point Formulation UV Turbidity Vis PS80 AEX [%] 5 (NTU) mg / mL % (w / w) AEX sum of basic peaks AEX main peak AEX sum of acidic peaks Relative area aRRT 1.5 Relative area aRRT T=4S F3 9.69 n.t n.t 5.66 67.24 27.1 2.37 7.26 (40°C) F4 10.1 n.t n.t 5.6 66.33 28.07 2.4 7.91 F5 8.79 n.t n.t 5.01 69.27 25.72 2.1 6.53 F6 9.63 n.t n.t 4.85 65.82 29.34 2.17 8.26 F7 9.23 n.t n.t 4.7 64.81 30.49 2.17 8.92 10 F8 8.65 n.t n.t 4.32 67.32 28.37 1.99 7.38 F9 9.75 n.t n.t 4.14 64.74 31.12 1.99 8.88 FIO 9.13 n.t n.t 4.12 62.97 32.91 2.01 9.71 T=5S Fl 9.79 n.t 0.06 1.19 97.14 1.67 0 0.07 (5°C) F2 7.41 n.t 0.01 1.14 97.18 1.69 0 0.05 F3 8.17 n.t 0.02 1.15 97.2 1.65 0 0.04 F4 8.62 n.t 0.03 1.12 97.25 1.62 0 0.02 15 F5 8.53 n.t 0.01 1.07 97.29 1.63 0 0.02 F6 7.67 n.t 0.02 1.09 97.23 1.68 0 0.02 F7 8 n.t 0.04 1.08 97.29 1.63 0 0.02 F8 7.88 n.t 0.01 1.06 97.26 1.69 0 0.03 F9 8.03 n.t 0.02 1.06 97.29 1.65 0 0.03 FIO 8.9 n.t 0.04 1.06 97.28 1.66 0 0.02 2U T=5S Fl 10.7 n.t 0.05 3.22 94.23 2.53 0.08 0.04 (25°C) F2 9.2 n.t 0.01 3.01 94.36 2.61 0.07 0.03 )F3 7.93 n.t 0.02 2.84 94.45 2.71 0.08 0.04 F4 8.19 n.t 0.03 2.83 94.49 2.68 0.08 0.04 F5 7.02 n.t 0.01 2.57 94.53 2.86 0.08 0.05 F6 8.25 nt 0.02 2.63 94.61 2.75 0.1 0.03 25 F7 9.6 nt 0.03 2.63 94.58 2.79 0.11 0.05 F8 12.4 nt 0.01 3940 2.54 F9 10.1 nt 0.02 2.41 94.56 3.04 0.13 0.05 FIO 14.7 nt 0.03 2.44 94.54 3.03 0.12 0.06 T=3M Fl 7.15 NA 0.19 NA 7.47 118.2 0.0125 AND AND AND 30 F3 5.99 120.4 0.0265 AND AND AND F4 5.81 120.6 0.0405 AND AND AND F5 6.32 118.7 1 0.01 AND F5 0.0279 NA NA NA NA F7 5.85 118.4 0.0396 NA NA NA NA F8 5.71 118.5 0.0129 NA NA NA NA F9 6.12 117.2 0.0279 NA NA NA NA NA Time point Formulation UV Turbidity Vis PS80 AEX [%] 5 (NTU) mg / mL % (w / w) AEX sum of basic peaks AEX main peak AEX sum of acidic peaks Relative area aRRT 1.5 Relative area aRRT FIO 6.49 120.8 0.0418 N.A N.A N.A N.A N.A T=3M F1 6.57 121.5 0.0675 6.07 89.19 4.76 0.13 0.11 (25°C) F2 6.01 121.1 0.0122 4.89 91.04 4.07 0.15 0.16 F3 5.94 120.3 0.0268 5.26 89.85 4.88 0.21 0.08 10 F4 6.35 119.1 0.0406 5.28 89.75 4.97 0.23 0.1 F5 6.06 119.7 0.0123 4.38 91.04 4.58 0.2 0.17 F6 5.7 118.3 0.0268 4.8 90.1 5.1 0.26 0.08 F7 6.31 120.4 0.0404 4.76 89.67 5.57 0.3 0.09 F8 5.41 120.5 0.0122 4.47 89.81 5.71 0.3 0.09 F9 5.37 121.5 0.026 4.27 90.04 5.69 0.35 0.1 15 FIO 5.5 122.4 0.0406 4.34 90.16 5.5 0.37 0.1 T=6M F1 5.86 n.t 0.0679 1.61 96.41 1.65 0.013 0.018 (5°C) F2 6.01 n.t 0.0125 1.35 96.56 1.66 0.008 0.02 F3 6.04 n.t 0.0258 1.35 96.58 1.68 0.017 0.012 F4 6.23 n.t 0.0383 1.31 96.55 1.69 0.019 0.016 20 F5 5.88 n.t 0.0127 1.25 96.6 1.72 0.019 0.015 F6 5.9 n.t 0.0291 1.33 96.54 1.75 0.017 0.022 F7 5.85 n.t 0.0413 1.35 96.52 1.74 0.015 0.019 F8 5.49 n.t 0.0124 1.28 96.64 1.76 0.014 0.024 F9 5.42 n.t 0.0253 1.28 96.63 1.77 0.012 0.03 FIO 5.84 n.t 0.0414 1.33 96.48 1.82 0.014 0.018 T=6M F1 6.53 n.t 0.0679 8.36 82.65 8.5 0.301 0.542 25 (25°C) F2 6.24 n.t 0.0125 7.17 84.19 8.17 0.324 0.399 F3 6.25 n.t 0.0258 6.92 84.09 8.38 0.34 0.472 F4 6.27 n.t 0.0383 6.82 83.83 8.89 0.345 0.501 F5 5.88 n.t 0.0127 6.16 84.86 8.42 0.361 0.372 F6 6 n.t 0.0291 5.95 84.22 9.19 0.405 0.499 F7 5.81 n.t 0.0413 5.88 84.09 9.39 0.393 0.539 F8 5.82 n.t 0.0124 5.31 84.7 9.3 0.411 0.455 30 F9 5.78 n.t 0.0253 5.49 83.65 10.39 0.423 0.55 FIO 5.71 n.t 0.0414 5.48 83.3 10.52 0.425 0.609 T=9M F1 6.61 n.t 0.0675 1.91 96.19 1.62 0.01 0 (5°C) F2 6.14 n.t 0.0119 1.72 96.39 1.65 0.01 0.01 F3 6.42 n.t 0.0258 1.73 96.33 1.66 0.01 0.01 F4 6.01 n.t 0.0396 1.71 96.35 1.65 0.02 0.01 35 F5 6.17 n.t 0.0116 1.6 96.37 1.73 0.02 0.02. Time point Formulation UV Turbidity Vis PS80 AEX [%] (NTU) mg / mL % (w / w) AEX sum of AEX peak AEX sum of Relative area Relative area 5 main peaks aRRT peaks aRRT basic acids 1.61 96.34 1.75 0.02 0.02 F7 5.92 nt 0.0392 1.59 96.36 1.73 0.02 0.02 F8 5.4 nt 0.0119 nt 1.49 96.5.27 1.02 0.026 1.47 96.24 1.85 0.03 0.02 FIO 5.74 nt 0.0404 1.47 96.29 1.83 0.03 0.02 10 F1 7.27 nt 0.0702 9 06 2 7.09 nt 0.0117 1.77 96.26 1.63 0.01 0.01 F3 7.39 nt 0.0264 1.77 96.23 1.64 0.02 0.01 F4 6.72 nt 1.673 6 6 0.04 0.02 0.01 F5 6.37 nt 0.0118 1.72 96.3 1.71 0.02 0.01 F6 6.71 nt 0.0267 1.59 96.3 1.7 0.03 0.02 9.739 nt F7 6.7 1.69 0.03 0.01 15 F8 6.2 nt 0.0115 1.64 96.2 1.8 0.03 0.02 F9 6.42 nt 0.0261 1.63 96.19 1.79 79 0.124 FIO 0. 1.57 96.19 1.79 0.04 0.02 Table 7 continued Point Form- UV Turbidity Vis PS 80 PH Darkening EC-SDS Light lation SEC (# / mL) (reducer) [%] time (NTU) mg / mL % >10 >25 >50 Counts Purity (w / w) µ neither total FTIs nor pm µs] THC µ2 of (sum 8.12 nt nt 6.66 4 0 0 193 nt (40°C) F2 7.18 nt 7.05 0 0 0 108 nt F3 7.3 nt 7.05 nt F3 0 0 127 nt F4 15 7.85 nt 7.77 nt nt 7.26 0 0 0 169 nt F6 9.67 nt nt 7.29 1 0 0 182 nt F7 7.65 nt 7.3 1 0 0 150 nt F8 8.35 nt 0 1 5 7.4 Time point Formulation UV Turbidity Vis PS80 pH Light darkening (# / mL) CE-SDS (reducing) SEC [%] (NTU) mg / mL % >10 >25 >50 Counts Purity (w / w) pm pm pm of (10 LC total nt)t particles nHC 7.48 10 1 0 259 nt FIO 9.65 nt nt 7.5 4 0 0 227 nt T=4S F1 11.6 nt nt 6.86 10 0 0 1271 96.3 (40°Ο F2 4 9.63. nt 95.4 F3 9.69 nt nt 7.03 17 0 0 666 95.5 F4 10.1 nt 7.03 9 0 0 1061 95.5 F5 8.79 nt 7.2 nt 9 0 7.63 725 F 94 0 586 94.6 F7 9.23 nt nt 7.2 17 0 0 619 94.5 F8 8.65 nt 7.41 9 0 0 321 93.7 F9 9.75 nt 7.19 30 F IO 4 0 0 6 7.38 9 0 0 571 93.6 T=5S F1 9.79 nt 0.06 6.81 3 0 0 156 nt (5°C) F2 7.41 nt 0.01 7.01 3 0 0 143 nt 7.1 nt F3 0.01 8.0. 135 nt F4 8.62 nt 0.03 7.04 1 0 0 320 nt F5 8.53 nt 0.01 7.22 0 0 0 185 nt F6 7.67 nt 0.02 7.24 0 0 0 73 nt F 0.28 0 180 0 0 152 nt F8 7.88 nt 0.01 7.43 0 0 0 143 nt F9 8.03 nt 0.02 7.43 0 0 0 216 nt FIO 8.9 nt 0.04 7.43 3 0 0 536 n.t T=5S F1 10.7 n.t 0.05 6.84 0 0 0 427 n.t (25°C) F2 9.2 n.t 0.01 7.04 0 0 0 164 n.t ) F3 7.93 n.t 0.02 7.05 0 0 0 288 n.t F4 8.19 n.t 0.03 7.05 0 0 0 329 n.t F5 7.02 n.t 0.01 7.24 0 0 0 231 n.t F6 8.25 n.t 0.02 7.25 0 0 0 187 n.t F7 9.6 n.t 0.03 7.24 1 0 0 176 n.t F8 12.4 n.t 0.01 7.44 0 0 0 120 n.t F9 10.1 n.t 0.02 7.46 0 0 0 275 n.t FIO 14.7 n.t 0.03 7.45 0 0 0 211 n.t T=3M F1 7.15 119.1 0.0725 6.81 1 0 0 183 n.t (5°C) F2 7.47 118.2 0.0125 7.01 0 0 0 327 n.t F3 5.99 120.4 0.0265 7.03 0 0 0 202 n.t F4 5.81 120.6 0.0405 7.03 2 1 0 219 n.t. PRCjnnil 7f\7!W Time point Formulation UV Turbidity Vis PS80 pH Light darkening (# / mL) CE-SDS (reducing) SEC [%] (NTU) mg / mL % (w / w) >10 >25 >50 pm pm pm Particle counts [sum of total % [6]) yHC (FLC 118.9 0.0125 7.23 1 0 0 160 nt F6 5.97 118.2 0.0279 7.24 1 0 0 179 nt F7 5.85 118.4 0.0396 7.51 81 F 61 3 40 0.0129 7.44 1 0 0 231 nt F9 6.12 117.2 0.0279 7.44 1 0 0 236 nt FIO 6.49 120.8 0.0418 7.44 0 275 0 T 6.3M 238 n 0.0675 6.8 1 0 0 331 nt (25°C) F2 6.01 121.1 0.0122 7.05 3 0 0 175 nt F3 5.94 120.3 0.0268 nt 7.35 F 216 0 40 0.0406 7.06 0 0 0 352 nt F5 6.06 119.7 0.0123 7.23 0 0 0 451 nt F6 5.7 118.3 0.0268 7.25 3 0 0 0 20.1 204.t 7.26 1 0 0 299 nt F8 5.41 120.5 0.0122 7.46 0 0 0 216 nt F9 5.37 121.5 0.026 7.46 6 0 0 702 nt FIO 1.206 4.4 5.5 0 255 nt T=6M F1 5.86 nt 0.0679 6.74 4 0 0 564 99.5 (5°C) F2 6.01 nt 0.0125 6.97 1 0 0 379 99.4 F3 06 0.02 n 321 99.4 F4 6.23 nt 0.0383 6.97 3 0 0 460 99.4 F5 5.88 n.t 0.0127 7.17 6 0 0 326 99.4 F6 5.9 n.t 0.0291 7.17 0 0 0 379 99.4 F7 5.85 n.t 0.0413 7.16 1 1 0 557 99.4 F8 5.49 n.t 0.0124 7.37 0 0 0 413 99.2 F9 5.42 n.t 0.0253 7.37 3 0 0 775 99.2 FIO 5.84 n.t 0.0414 7.39 0 0 0 382 99.2 T=6M F1 6.53 n.t 0.0679 6.8 3 0 0 329 97 (25°C) F2 6.24 n.t 0.0125 6.99 4 0 0 377 95.9 F3 6.25 n.t 0.0258 7.02 1 0 0 275 96.1 F4 6.27 n.t 0.0383 7.01 1 1 0 293 96 F5 5.88 n.t 0.0127 7.18 0 0 0 282 95 F6 6 n.t 0.0291 7.18 0 0 0 353 95.1 F7 5.81 n.t 0.0413 7.19 1 0 0 476 95.1 F8 5.82 n.t 0.0124 7.38 3 0 0 261 94.1 F9 5.78 n.t 0.0253 7.38 1 0 0 331 94.2. PRCjnnil 7Λ7.ΙΒΓΥ Point Form- UV Turbidity Vis PS80 pH Darkening EC-SDS Light lation SEC (# / mL) (reducer) [%] time (NTU) mg / mL % >10 >25 >50 Counts Purity (w / w) pm pm pm of (LC] total particle ys) nt 0.0414 7.39 3 0 0 417 94 T=9M F1 6.61 nt 0.0675 6.81 1 0 0 491 nt (5°C) F2 6.14 nt 0.0119 nt 7.01 83 6 0.40 7.01 6 0 0 341 nt F4 6.01 nt 0.0396 7.01 3 0 0 591 nt F5 6.17 nt 0.0116 7.2 6 0 0 606 nt F6 6.46 nt 71 0.02 5.92 nt 0.0392 7.2 1 0 0 437 nt F8 5.4 nt 0.0119 7.4 0 0 0 520 nt F9 5.98 nt 0.026 7.4 3 0 0 472 0.704 nt FIO 5.4 nt 799 nt F1 7.27 nt 0.0701 6.76 1 0 0 485 99 F2 7.09 nt 0.0117 7.03 1 0 0 664 98.8 F3 7.39 nt 0.0264 85 4 7.00 6.72 nt 0.0403 7 8 1 0 424 98.9 F5 6.37 nt 0.0118 7.2 1 0 0 360 98.8 F6 6.71 nt 0.0267 7.22 73 F 79 90.67 7.2 8 0 0 510 98.6 F8 6.2 nt 0.0115 7.4 1 0 0 711 98.5 F9 6.42 nt 0.0261 7.4 1 0 0 488 98.4 FIO 7.19 nt4 0 0 0 393 98.4. The present invention and its embodiments have been described in detail. However, the scope of the present invention is not intended to be limited to the particular embodiments of any process, preparation, material composition, compounds, means, methods, and / or steps described in the specification. Various modifications, substitutions, and variations may be made to the disclosed material without departing from the spirit and / or essential characteristics of the present invention. Consequently, a person skilled in the art will readily appreciate from the disclosure that further modifications, substitutions, and / or variations may be used that substantially accomplish the same function or achieve substantially the same result as the embodiments described herein, in accordance with said embodiments of the present invention.Therefore, the following claims are intended to include within their scope modifications, substitutions, and variations to the processes, formulations, compositions of matter, compounds, means, methods, and / or steps disclosed herein. The claims should not be construed as being limited to the order or elements described unless otherwise indicated. It should be understood that various changes in form and detail may be made without departing from the scope of the appended claims.

Claims

1. An aqueous pharmaceutical composition comprising at least 50 mg / mL to approximately 120 mg / mL of an anti-VEGF antibody comprising the sequences SEQ ID NO: 1 and SEQ ID NO: 2, approximately 4.5% to 11% (w / v) sucrose, 5-20 mM sodium citrate, and 0.001% to 0.05% polysorbate 80 (w / v), wherein the pH of the composition is approximately 7.0 to approximately 7.

6.

2. The aqueous pharmaceutical composition according to claim 1, wherein the anti-VEGF antibody comprises the sequence SEQ ID NO: 3 or 4.

3. The aqueous pharmaceutical composition according to claim 1 or 2, wherein the anti-VEGF antibody comprises the sequence SEQ ID NO: 3 and 4.

4. The aqueous pharmaceutical composition of any of the preceding claims, wherein the pH of the composition is approximately 6.

8.

5. The aqueous pharmaceutical composition of any of the preceding claims, wherein the pH of the composition is approximately 7.

2.

6. The aqueous pharmaceutical composition of any of the preceding claims, comprising 0.004% polysorbate 80 (w / v).

7. The aqueous pharmaceutical composition of any of the preceding claims, comprising 0.02% polysorbate 80 (w / v).

8. The aqueous pharmaceutical composition of any of the preceding claims, comprising from approximately 60 mg / mL to approximately 120 mg / mL of an anti-VEGF antibody.

9. The aqueous pharmaceutical composition of any of claims 1 to 7, comprising approximately 20 mg / mL of an anti-VEGF antibody.

10. The aqueous pharmaceutical composition of any of the preceding claims, comprising 5.5% to 7.0% (w / v) sucrose.

11. The aqueous pharmaceutical composition of claim 1, comprising 6.5% (w / v) sucrose, 12 mM sodium citrate, 0.02% (w / v) polysorbate 80, and wherein the pH is approximately 7.

2.

12. The aqueous pharmaceutical composition of claim 11, comprising 3 mg of an anti-VEGF antibody.

13. The aqueous pharmaceutical composition of any of claim 1, comprising 5.8% (w / v) sucrose, 10 mM sodium citrate, 0.02% (w / v) polysorbate 80, and wherein the pH is approximately 7.

2.

14. The aqueous pharmaceutical composition of claim 13, comprising 6 mg of an anti-VEGF antibody.

15. The aqueous pharmaceutical composition of any of the preceding claims, wherein said composition is stable for at least 18 months at 2-8°C.

16. The aqueous pharmaceutical composition of any of the preceding claims, wherein said composition is liquid.

17. A method for delivering an anti-VEGF antibody to a subject, comprising administering to said subject the aqueous pharmaceutical composition of any of the preceding claims.

18. A method for treating an eye disease or disorder that is mediated by VEGF, comprising administering to a subject the aqueous pharmaceutical composition of any of the preceding claims.

19. The method of claim 18, wherein said eye disease or disorder is an ocular neovascular disease.

20. The method of any of claims 17-19, wherein said administration is intravitreal.

21. An aqueous pharmaceutical composition of any of the preceding claims for use in delivering an anti-VEGF antibody to a subject, comprising a step of administering the aqueous pharmaceutical composition to the subject.

22. An aqueous pharmaceutical composition of any of the preceding claims for use in the treatment of an eye disease or disorder that is mediated by VEGF, comprising administering the aqueous pharmaceutical composition to a subject.

23. An aqueous pharmaceutical composition for use according to claim 22, wherein said eye disease or disorder is an ocular neovascular disease.

24. An aqueous pharmaceutical composition for use according to any of claims 21-23, wherein said administration is intravitreal.

25. A dosage form comprising the aqueous pharmaceutical composition of any of claims 1-16 or 21-24.

26. A delivery device comprising the aqueous pharmaceutical composition of claims 1-16 or 21-24.

27. The delivery device of claim 26, which is a pre-filled syringe.