200 mM, about 140 mM to about 180 mM, about 140 mM to about 160 mM, about 160 mM to about 500 mM, about 160 mM to about 450 mM, about 160 mM to about 400 mM, about 160 mM to about 350 mM, about 160 mM to about 300 mM, about 160 mM to about 250 mM, about 160 mM to about 200 mM, about 160 mM to about 180 mM, about 180 mM to about 500 mM, about 180 mM to about 450 mM, about 180 mM to about 400 mM, about 180 mM to about 350 mM, about 180 mM to about 300 mM, about 180 mM to about 250 mM, about 180 mM to about 200 mM, about 200 mM to about 500 mM, about 200 mM to about 450 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 250 mM to about 500 mM, about 250 mM to about 450 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 300 mM to about 500 mM, about 300 mM to about 450 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, about 350 mM to about 500 mM, about 350 mM to about 450 mM, about 350 mM to about 400 mM, about 400 mM to about 500 mM, about 400 mM to about 450 mM, or about 450 mM to about 500 mM). In another embodiment, the concentration of the amino acid(s) is between about 10 mM and about 350 mM; in related embodiments, the concentration of the amino acid(s) is about 50 mM, 100 mM, 150 mM, 200 mM, 220 mM, 240 mM, 260 mM, 280 mM, 300 mM, 320 mM and 340 mM, for example, 50-100 mM, 100-150 mM, 150-200 mM, 200-300 mM, 200-250 mM, 250-300 mM, and 300-350 mM. 

[0164] Aflibercept Stabilized with Combinations of Sta› bilizers 

[0165] In some embodiments, combinations of stabilizers may act in concert to stabilize aflibercept. In one embodi› ment, an aflibercept formulation comprises a sugar and a polyol. In another example, amino acids, such as praline, serine, or glutamate may be used together with a sugar to achieve a stability profile better than either excipient could provide on its own. In one embodiment, the ratio of a sugar to a polyol ( or amino acid) in the formulation is between 5: 1 and 1:5 (e.g., about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5). In another embodiment, a formulation with a combination of stabilizers has better stability than a formulation with just one of the stabilizers. In another embodiment, a formulation with a combination of stabilizers has better stability than a formulation with just one of the stabilizers where the for› mulation with the combination of stabilizers has a lower total amount of stabilizers than the formulation with the single stabilizer (e.g. a formulation with 100 mM of sucrose and 50 mM arginine has better stability than a formulation with 200 mM sucrose). 

[0166] III. Salts 

[0167] Salts, e.g., NaCl, are often part of protein (e.g., antibody) formulations. For instance, salts such as NaCl, Na$_{2}$SO$_{4}$ , CaCl$_{2}$ , MgCl$_{2}$ , and KC!, together with specific buffer combinations as described above, can confer particu› larly advantageous stability properties. Such salts may be used with as well as without a sugar added ( e.g., sucrose and NaCl) or a polyol added (e.g., mannitol and NaCl). For example, concentrations as low as 20 to 50 mM can provide decreased levels of proteolysis (such as hinge region hydro› lysis), oxidation, deamidation, or other chemical instabili› ties. Furthermore, low levels of salt ( <50 mM) may lead to improved colloidal stability. Likewise, it is known that high 

concentrations of certain salts (up to 400 mM or more) can increase conformational stability. The specific effects of NaCl and other salts on aflibercept is dependent on pH, buffer composition, and stress condition. 

[0168] In specific embodiments, sodium chloride may be replaced with Na$_{2}$SO$_{4}$ , KC!, MgCl 2 , CaCl 2 , MgSO 4 , ZnCl 2 , or other physiologically-acceptable salts. 

[0169] IV. Surfactants 

[0170] Surfactants can confer protection against agitation and freeze/thaw damage, as well as stabilizing a formulation during storage. Surfactants which may be employed with aflibercept formulations of the present invention include Tweenfi-80 (polysorbate 80, PS 80), Tweenfi-20 (polysor› bate 20, PS 20), SDS, polysorbate, polyoxyethylene copo› lymer, Brij 35, Triton X-10, poloxamer 188 (Pluronic F-68), Pluronic F127, and Maltosides, e.g., n-Decyl-~-D-maltopy› ranoside (DM), n-Dodecyl-~-D-maltopyranoside (DDM), and 6-Cyclohexyl-1-hexyl-~-D-maltopyranoside (Cymal- 6). In certain embodiments, surfactants that may be particu› larly advantageous include PS 20, PS 40, PS 60, and PS 80 at different concentrations, as well as DMM and poloxamer 188 (Pluronic F-68). Other zwitterionic or nonionic surfac› tants may be used as well. 

[0171] In the embodiments of the invention where organic co-solvents are excluded, surfactants cannot be present. 

[0172] As above, optimal formulation employing such surfactants may also employ specific buffers at specific pH ranges, and may optionally include other tonicity modifier such as NaCl, polyol, or amino acid(s). 

[0173] V. Polymers 

[0174] Polymers, such as dextrans, starches (e.g., hydroxyl ethyl starch (HETA)), poly(ethylene glycols (PEGs), e.g., PEG-3350 or PEG-4000, may also provide stabilization to aflibercept, presumably by being excluded from the surface of the protein due to steric effects arising from their higher molecular weight. In particular, hydro› philic polymers, such as polyethylene glycols (PEGs), poly› saccharides, and inert proteins, and may be used to stabilize proteins and enhance protein assembly. Examples include dextran, hydroxyl ethyl starch (HETA), PEG-4000, and gelatin. Additionally, non-polar moieties on certain poly› mers such as PEGs and Pluronics can decrease water surface tension rendering them as surfactants that suppress surface adsorption induced aggregation. In one embodiment, the concentration of polymer is between 0.01% and 40% (e.g., about 0.01 % to about 35%, about 0.01 % to about 30%, about 0.01 % to about 25%, about 0.01 % to about 20%, about 0.01% to about 18%, about 0.01% to about 16%, about 0.01% to about 14%, about 0.01% to about 12%, about 0.01 % to about 10%, about 0.01 % to about 8%, about 0.01 % to about 6%, about 0.01 % to about 5%, about 0.01 % to about 4.5%, about 0.01 % to about 4.0%, about 0.01 % to about 3.5%, about 0.01 % to about 3.0%, about 0.01 % to about 2.5%, about 0.01 % to about 2.0%, about 0.01 % to about 1.5%, about 0.01 % to about 1.0%, about 0.01 % to about 0.5%, about 0.01 % to about 0.1 %, about 0.01 % to about 0.05%, about 0.05% to about 40%, about 0.05% to about 35%, about 0.05% to about 30%, about 0.05% to about 25%, about 0.05% to about 20%, about 0.05% to about 18%, about 0.05% to about 16%, about 0.05% to about 14%, about 0.05% to about 12%, about 0.05% to about 10%, about 0.05% to about 8%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4.5%, about 0.05% to about 4.0%, about 0.05% to about 3.5%, about 0.05% to 

