STABLE LOW VISCOSITY ANTIBODY FORMULATIONS AND USES THEREOF

Abstract

Provided herein is an aqueous antibody formulation exhibiting improved stability and low viscosity. The formulation comprises an antibody or antigen-binding fragment thereof, a buffer, and a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, or lithium sulfate, and has a pH of about 4 to about 8, and optionally an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg.

Description

[Technical field]

[0001] The present invention relates generally to antibody formulations. In particular, the present invention relates to monoclonal antibodies with improved stability and low viscosity. [Background technology]

[0002] Antibody formulations may lose their efficacy over time, such as by denaturation, oxidation, aggregation, or other decomposition reactions. Decomposition and aggregation of antibodies in antibody formulations may also cause risks such as toxicity or immunogenicity. High solution viscosity may adversely affect the manufacturability and performance of protein therapeutics, especially those formulated with high protein concentrations. Summary of the Invention [Problem to be solved by the invention]

[0003] The low level of stability exhibited by currently available pharmaceutical antibody formulations is disadvantageous, for example, due to the loss of efficacy before administration of antibody formulations and the toxicity and immunogenicity that may occur due to degradation / aggregation.Traditional excipients used to stabilize proteins in solution often can increase the viscosity of the solution.Therefore, there is a need in the art for antibody formulations that can improve the stability of antibodies.Furthermore, there is a need in the art for antibody formulations that can develop stable and low-viscosity antibody solutions. [Means for solving the problem]

[0004] The present invention is based on the discovery that antibodies are stabilized in solution by including a salt selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate. The resulting stabilized antibody solution is also less viscous than a formulation that does not include one of the salts or that contains a conventional excipient used to stabilize proteins, such as a sugar, such as sucrose. The osmolality of a stabilized antibody solution that includes one of the salts is also lower than an antibody solution that includes a sugar and a polyol, such as sucrose, trehalose, sorbitol, mannitol, etc., when formulated at an equipotent concentration.

[0005] In view of this discovery, provided herein is an aqueous antibody formulation comprising about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); about 1 mM to about 100 mM of a buffer (e.g., any of the exemplary buffers described herein or known in the art); and about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8.

[0006] Further provided herein is an aqueous antibody formulation comprising about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); and about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8. In some embodiments of the aqueous antibody formulation, the aqueous antibody formulation is a buffer-free aqueous antibody formulation.

[0007] Some embodiments of any of the aqueous antibody formulations described herein may further include a stabilizer (e.g., any of the exemplary stabilizers described herein or known in the art) and / or a surfactant (e.g., any of the exemplary surfactants described herein or known in the art). Additionally provided are injection devices comprising any of these formulations, and kits comprising one or more vials containing any of these formulations.

[0008] Further provided are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); (ii) a buffer (e.g., any of the exemplary buffers described herein or known in the art); (iii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iv) a stabilizer (e.g., any of the exemplary stabilizers described herein or known in the art); (v) a surfactant (e.g., any of the exemplary surfactants described herein or known in the art); and (vi) sterile water, wherein (i)-(vi) are mixed or combined in sufficient amounts to produce any of the formulations described herein.

[0009] Further provided herein are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); (ii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer (e.g., any of the exemplary stabilizers described herein or known in the art); (iv) a surfactant (e.g., any of the exemplary surfactants described herein or known in the art); and (v) sterile water, wherein (i)-(v) are mixed or combined in sufficient amounts to produce any of the formulations described herein. In some embodiments of these methods, the methods do not include the step of mixing or combining a buffer with (i) and (ii), and the methods result in a buffer-free aqueous antibody formulation.

[0010] Further provided is a method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the formulations described herein.

[0011] Provided herein is an aqueous antibody formulation comprising about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof; about 1 mM to about 100 mM of a buffer solution; and about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8, and optionally an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg.

[0012] Further provided herein is an aqueous antibody formulation comprising about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof; and about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8. In some embodiments of any of the aqueous antibody formulations described herein, the formulation is a buffer-free aqueous antibody formulation.

[0013] In some embodiments of any of the aqueous antibody formulations described herein, the salt is magnesium glutamate, magnesium acetate, magnesium aspartate, or magnesium sulfate, or a combination thereof. In some embodiments of any of the aqueous antibody formulations described herein, the salt is magnesium glutamate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is magnesium acetate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is magnesium aspartate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is magnesium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 10 mM to about 750 mM of salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 20 mM to about 750 mM of salt.

[0014] In some embodiments of any of the aqueous antibody formulations described herein, the salt is sodium acetate, sodium aspartate, sodium glutamate, or sodium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is sodium acetate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is sodium aspartate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is sodium glutamate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is sodium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 10 mM to about 750 mM of salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 20 mM to about 750 mM of salt.

[0015] In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium acetate, lithium aspartate, lithium glutamate, or lithium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium acetate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium aspartate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium glutamate. In some embodiments of any of the aqueous antibody formulations described herein, the salt is lithium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 10 mM to about 750 mM of salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 20 mM to about 750 mM of salt.

[0016] In some embodiments of any of the aqueous antibody formulations described herein, the buffer is selected from the group consisting of acetate, succinate, gluconate, histidine, citrate, and phosphate. In some embodiments of any of the aqueous antibody formulations described herein, the buffer is a histidine buffer. In some embodiments of any of the aqueous antibody formulations described herein, the buffer is an acetate buffer. In some embodiments of any of the aqueous antibody formulations described herein, the buffer is a citrate buffer. In some embodiments of any of the aqueous antibody formulations described herein, the buffer is a phosphate buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 1 mM to about 100 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 1 mM to about 75 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 1 mM to about 50 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 1 mM to about 20 mM of buffer.

[0017] In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a pH of about 5 to about 6. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a pH of about 5.5.

[0018] In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody. In some embodiments of any of the aqueous antibody formulations described herein, the antibody is a monoclonal antibody (mAb). In some embodiments of any of the aqueous antibody formulations described herein, the mAb is a human antibody or a humanized antibody. In some embodiments of any of the aqueous antibody formulations described herein, the mAb comprises an Fc amino acid substitution that reduces conformational stability compared to a similar antibody that does not comprise that Fc amino acid substitution. In some embodiments of any of the aqueous antibody formulations described herein, the mAb is an IgG1 antibody or an IgG4 antibody.

[0019] In some embodiments of any of the aqueous antibody formulations described herein, the mAb is an anti-CXC motif chemokine receptor 3 (CXCR3) mAb. In some embodiments of any of the aqueous antibody formulations described herein, the anti-CXCR3 mAb comprises a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:2.

[0020] In some embodiments of any of the aqueous antibody formulations described herein, the mAb is an Fc-engineered anti-cluster of differentiation 38 (CD38) mAb. In some embodiments of any of the aqueous antibody formulations described herein, the Fc-engineered anti-CD38 mAb comprises a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:4.

[0021] In some embodiments of any of the aqueous antibody formulations described herein, the monoclonal antibody is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody. In some embodiments of any of the aqueous antibody formulations described herein, the anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising SEQ ID NO:8.

[0022] In some embodiments of any of the aqueous antibody formulations described herein, the monoclonal antibody is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody. In some embodiments of any of the aqueous antibody formulations described herein, the Fc-engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10. In some embodiments of any of the aqueous antibody formulations described herein, the Fc-engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:11 and a light chain comprising SEQ ID NO:12. In some embodiments of any of the aqueous antibody formulations described herein, the Fc-engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:13 and a light chain comprising SEQ ID NO:14.

[0023] In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 400 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 250 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 200 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 150 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 100 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises about 0.1 mg / mL to about 50 mg / mL of antibody or antigen-binding antibody fragment. In some embodiments of any of the aqueous antibody formulations described herein, the formulation contains from about 0.1 mg / mL to about 25 mg / mL of antibody or antigen-binding antibody fragment.

[0024] In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a viscosity of about 1 cP to about 50 cP. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a viscosity of about 1 cP to about 40 cP. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a viscosity of about 1 cP to about 30 cP. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has a viscosity of about 1 cP to about 20 cP.

[0025] In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 250 mOsm / kg to about 750 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 250 mOsm / kg to about 500 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 250 mOsm / kg to about 400 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 500 mOsm / kg to about 1500 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 500 mOsm / kg to about 1000 mOsm / kg. In some embodiments of any of the aqueous antibody formulations described herein, the formulation has an osmolality of about 1000 mOsm / kg to about 1500 mOsm / kg.

[0026] In some embodiments of any of the aqueous antibody formulations described herein, the formulation is stable at 25° C. for about 1 week to about 2 years (e.g., % high molecular weight (HMW) by SEC ≦5%). In some embodiments of any of the aqueous antibody formulations described herein, the formulation is stable at 40° C. for about 1 hour to about 8 weeks (e.g., % high molecular weight (HMW) by SEC ≦5%).

[0027] In some embodiments of any of the aqueous antibody formulations described herein, the formulation is suitable for intravenous, intramuscular or subcutaneous administration. In some embodiments of any of the aqueous antibody formulations described herein, the formulation is suitable for intravenous administration. In some embodiments of any of the aqueous antibody formulations described herein, the formulation is suitable for subcutaneous administration.

[0028] Some embodiments of any of the aqueous antibody formulations described herein further comprise one or more of a stabilizer, an antioxidant, a metal chelator, a viscosity modifier, an amino acid, and a surfactant. In some embodiments of any of the aqueous antibody formulations described herein, the stabilizer is fructose, maltose, galactose, glucose, O-mannose, sorbose, lactose, sucrose, trehalose, cellobiose, raffinose, melezitose, maltodextrin, dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sorbitol, amino sugars, sodium chloride, and glycerin.

[0029] In some embodiments of any of the aqueous antibody formulations described herein, the antioxidant is methionine, ascorbic acid or N-acetylcysteine.In some embodiments of any of the aqueous antibody formulations described herein, the metal chelator is sodium ethylenediaminetetraacetate (EDTA), calcium EDTA or diethylenetriaminepentaacetate (DTPA).In some embodiments of any of the aqueous antibody formulations described herein, the viscosity modifier is arginine, histidine, lysine, proline, glycine or sodium chloride.

[0030] In some embodiments of any of the aqueous antibody formulations described herein, the surfactant is sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, glyceryl monocaprylate, glyceryl monomyristate, glyceryl monostearate, decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitol tetra ... The fatty acid is selected from the group consisting of diethylene sorbitol tetraoleate, polyoxyethylene glyceryl monostearate, polyethylene glycol distearate, polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol beeswax, polyoxyethylene lanolin, polyoxyethylene stearamide, sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, polyoxyethylene sodium lauryl sulfate, sodium lauryl sulfosuccinate ester, lecithin, glycerophospholipids, sphingophospholipids, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, Triton-X, polyethylene glycol, and propylene glycol.

[0031] In some embodiments of any of the aqueous antibody formulations described herein, the amino acid is selected from the group of arginine, lysine, histidine, proline, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, and aspartic acid.

[0032] Further provided herein is an injection device comprising any of the aqueous antibody formulations described herein.

[0033] Further provided herein are kits that include one or more vials containing any of the aqueous antibody formulations described herein. In some embodiments of any of the kits described herein, the kits further include an injection device for administering the aqueous antibody formulation to a subject in need thereof.

[0034] Provided herein are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof; (ii) a buffer; (iii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iv) a stabilizer; (v) a surfactant; and (vi) sterile water, wherein (i)-(vi) are mixed or combined in amounts sufficient to produce any of the aqueous antibody formulations described herein.

[0035] Further provided herein is a method of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof; (ii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer; (iv) a surfactant; and (v) sterile water, wherein (i)-(v) are mixed or combined in an amount sufficient to produce any of the aqueous antibody formulations described herein. In some embodiments of any of the aqueous antibody formulations described herein, the method does not include mixing a buffer with (i)-(v), and the method results in the production of a buffer-free aqueous antibody formulation.

[0036] Some embodiments of any of the methods described herein further include mixing or combining one or more (e.g., one, two, or three) of an antioxidant, a metal chelator, and a viscosity modifier with (i)-(vi).

[0037] Further provided herein are methods of treating a subject in need of treatment, the methods comprising administering to the subject a therapeutically effective amount of any of the aqueous antibody formulations described herein.

[0038] The term "stabilizer" refers to an additive (e.g., other than any of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate) that improves or enhances the stability of a protein (e.g., an antibody or an antigen-binding antibody fragment) in a formulation. Non-limiting examples of stabilizers are described herein. Further examples of stabilizers are known in the art. The term "surfactant" generally includes agents that protect a protein (e.g., an antibody or an antigen-binding antibody fragment) from air / solution interface-induced stresses and / or solution / surface-induced stresses. In some embodiments, a surfactant may protect a protein (e.g., an antibody or an antigen-binding antibody fragment) from aggregation. Non-limiting examples of surfactants are described herein. Further examples of surfactants are known in the art.

[0039] The term "subject" refers to any mammal. In some embodiments, the subject or "subject in need of treatment" may be a canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), sheep, cow, pig, goat, primate, such as monkey (e.g., monkey, marmoset, baboon) or ape (e.g., gorilla, chimpanzee, orangutan or gibbon), human, or rodent (e.g., mouse, guinea pig, hamster or rat). In some embodiments, the subject or "subject suitable for treatment" may be a non-human mammal, particularly a mammal that is conventionally used as a model for demonstrating therapeutic efficacy, usually in humans (e.g., mouse, rabbit, pig, dog or primate).

[0040] As used herein, "treating" refers to a reduction in the number, severity, or frequency of one or more symptoms of a medical disease or condition in a subject (e.g., any of the exemplary subjects described herein).

[0041] As used herein, "buffer-free" means free of or trace amounts of buffer (e.g., any of the buffers described herein).

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used.Materials, methods and examples are only illustrative and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated herein in their entirety by reference.In case of conflict, the present specification, including definitions, will control.

[0043] Other features and advantages of the present invention will become apparent from the following detailed description, drawings, and claims. [Brief description of the drawings]

[0044] [Figure 1] 1 is a graph showing the minimum unfolding temperature (Tm1) of Antibody A (1 mg / mL) in histidine buffer (pH 5.5) containing labeled excipients at a concentration of 200 mM. [Diagram 2] 1 is a graph showing the increase in Tm1 (ΔTm1) in histidine buffer (pH 5.5) containing a labeling excipient at a concentration of 200 mM for kagg after storage of 150 mg / mL antibody A at 40° C. A solution without added excipient is the labeling control. [Diagram 3] 1 is a graph showing ΔTm1 of antibody B (1 mg / mL) in histidine buffer (pH 6.2) containing labeled excipient at a concentration of 200 mM. [Figure 4] 1 is a graph showing ΔTm1 in histidine buffer (pH 6.2) containing a labeled excipient at a concentration of 200 mM versus aggregation rate (kagg) after storage at 40° C. for 50 mg / mL of antibody B. A solution without added excipient serves as the labeled control. [Diagram 5] 1 is a graph showing the effect of excipient concentration on Tm1 of antibody A solution (1 mg / mL) in histidine buffer (pH 5.5) containing labeled excipients. [Figure 6] FIG. 1 is a graph showing the percentage of aggregation of 150 mg / mL Antibody A after storage for 4 weeks at 40° C. in histidine buffer (pH 5.5) containing labeled excipients. [Figure 7] 1 is a graph showing the effect of excipient concentration on Tm1 of antibody C (1 mg / mL) in histidine buffer (pH 6.2) containing labeled excipients. [Figure 8] This graph shows the increase in Tm1 of wild-type anti-CEACAM5 antibody and its antibody D mutant, antibody E mutant, and antibody DE mutant (1 mg / mL) in histidine buffer (pH 5.5) containing 200 mM labeling salt, compared to the respective salt-free solutions. [Figure 9] 1 is a graph showing the viscosity of a solution of antibody C at approximately 150 mg / mL in histidine buffer (pH 6.2) containing a concentration of 200 mM labeled excipient at 20° C. A solution with no added excipient is the labeled control. [Figure 10] 1 is a graph showing ΔTm1 in histidine buffer (pH 5.5) containing 200 mM of labeled excipient or between 2% and 30% sucrose (2% sucrose, 5% sucrose, 10% sucrose, 15% sucrose and 30% sucrose) versus viscosity at 20° C. for a solution of approximately 150 mg / mL of antibody A. A solution without added excipient serves as the labeled control. [Figure 11]FIG. 1 is a graph showing ΔTm1 versus osmolality at 20° C. of an approximately 150 mg / mL solution of Antibody A in histidine buffer (pH 5.5) containing a concentration of 200 mM labeled excipient or between 2% and 30% sucrose (2% sucrose, 5% sucrose, 10% sucrose, 15% sucrose and 30% sucrose). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Over the past few decades, therapies involving the use of monoclonal antibodies and other Fc-derived antigen-binding proteins have become a mainstay of modern medicine, with increasing reliance on these complex molecules in various therapeutic areas, including but not limited to oncology, immunology, immuno-oncology, and cardiology, with nearly 100 molecules approved for therapeutic use to date and more than 500 molecules in various stages of development or clinical trials.

[0046] A fundamental aspect in ensuring the transition of these therapeutic entities from the laboratory to manufacturable commercial products of consistent high quality is their stability in dosage forms. Due to their complex chemistry and structure, proteins are susceptible to various forms of physical and chemical degradation that compromise the biological efficacy and safety of the final formulation. Protein aggregation, for example, is a key quality attribute routinely monitored for protein-based products and is important with respect to determining product shelf life. At a fundamental level, protein aggregation is associated with the stability of the native form of the protein, and growth in non-native cells (e.g., non-native mammalian cells) is generally associated with an increased rate and extent of aggregation. It is therefore not surprising that attempts to control and minimize aggregation during product shelf life (kinetic stability) are frequently mediated by the use of excipients or formulation conditions intended to enhance the conformational stability of the protein. Essentially, the intent is to stabilize the protein in its native conformation in order to minimize the population of aggregation-competent "non-native" species. Sugars and polyols, such as sucrose, trehalose, mannitol, sorbitol, etc., are frequently used to stabilize proteins in their native state and reduce the rate of aggregation, however, an undesirable effect of the use of these stabilizers is the concentration-dependent increase in solution viscosity.

[0047] Solution viscosity is a key characteristic of protein products, especially those formulated at high protein concentrations (e.g., ≧100 mg / mL for antibodies or Fc-derived proteins of similar molecular weight), and can critically affect the usefulness and success of the product. Product manufacturability and end use by patients or medical personnel are closely linked to the seamless flowability of the solution. For example, high viscosity can limit product use by requiring the use of specialized dosing equipment or specialized dosing protocols that are not always appropriate for the desired population. In other examples, high solution viscosity can require the application of manufacturing techniques (e.g., high temperature processing) that can adversely affect protein stability. Thus, it is not uncommon to use viscosity-reducing excipients, such as salts and amino acids, in high protein concentration solutions. However, these excipients can adversely affect protein stability, resulting in solutions with increased aggregation rates compared to high viscosity control solutions lacking the viscosity-reducing agent. In essence, commonly used stabilizers and viscosity-reducing excipients can have opposing effects on product performance, complicating their development.

[0048] Another important property of injectable products (most protein-based products) that needs to be considered is their osmolality. Solutions for intravenous injection generally need to be isotonic, whereas solutions for subcutaneous injection are not uncommonly hypertonic. Indeed, there is evidence in the literature for hypertonic formulations resulting in increased bioavailability of proteins following subcutaneous administration (AM Fathallah et al., Biopharm Drug Dispos. March 2015, 36(2):115-25). Therefore, the impact of solution osmolality (and therefore tonicity) on discomfort and / or reactions at the injection site as well as bioavailability in the patient population needs to be carefully monitored and characterized during the clinical development phase.

[0049] Thus, there is a need in the art to formulate antibodies and other Fc-derived products to develop stable, low viscosity solution formulations with well-characterized osmotic properties.

[0050] Provided herein are aqueous antibody formulations comprising about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); about 1 mM to about 100 mM of a buffer (e.g., any of the exemplary buffers described herein or known in the art); and about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8.

[0051] Further provided herein is an aqueous antibody formulation comprising about 0.1 mg / mL to about 500 mg / mL (e.g., any of the subranges of this range described herein) of an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding fragments described herein or known in the art); and about 1 mM to 750 mM (e.g., any of the subranges of this range described herein) of a salt selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate, and having a pH of about 4 to about 8. In some embodiments, the aqueous antibody formulation is a buffer-free antibody formulation.

[0052] Additionally provided are injection devices comprising any of these formulations, and kits comprising one or more vials containing any of these formulations.

[0053] Further provided are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein or known in the art); (ii) a buffer (e.g., any of the exemplary buffers described herein or known in the art); (iii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iv) a stabilizer; (v) a surfactant; and (vi) sterile water, wherein (i)-(vi) are mixed or combined in sufficient amounts to produce any of the formulations described herein.

[0054] Further provided herein are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof; (ii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer; (iv) a surfactant; and (v) sterile water, wherein (i)-(v) are mixed or combined in sufficient amounts to produce any of the aqueous antibody formulations described herein. In some embodiments of the methods described herein, the methods do not include mixing or combining a buffer with (i)-(v), and the methods result in a buffer-free aqueous antibody formulation.

[0055] Further provided is a method of treating a subject in need of treatment comprising administering to the subject a therapeutically effective amount of any of the formulations described herein.

[0056] Non-limiting embodiments of these formulations, injection devices, kits and methods are described below. As one of ordinary skill in the art will recognize, the exemplary embodiments listed below can be used in any combination and can be combined with other embodiments known in the art.

[0057] Antibodies and antigen-binding antibody fragments The aqueous antibody formulations provided herein may have a concentration of, for example, about 0.1 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 480 mg / mL, about 0.1 mg / mL to about 460 mg / mL, about 0.1 mg / mL to about 440 mg / mL, about 0.1 mg / mL to about 420 mg / mL, about 0.1 mg / mL to about 400 mg / mL, about 0.1 mg / mL to about 380 mg / mL, about 0.1 mg / mL to about 360 mg / mL, about 0.1 mg / mL to about 340 mg / mL, about 0.1 mg / mL to about 320 mg / mL, about 0.1 mg / mL to about 300 mg / mL, about 0.1 mg / mL~about 280mg / mL, about 0.1mg / mL~about 260mg / mL, about 0.1mg / mL~about 240mg / mL, about 0.1mg / mL~about 220mg / mL, about 0.1mg / mL~about 200mg / mL, about 0.1mg / mL~about 190mg / mL, about 0.1mg / mL mL~about 180mg / mL, about 0.1mg / mL~about 170mg / mL, about 0.1mg / mL~about 160mg / mL, about 0.1mg / mL~about 140mg / mL, about 0.1mg / mL~about 130mg / mL, about 0.1mg / mL~about 120mg / mL, about 0.1mg / mL~about 110mg / mL, about 0.1mg / mL to about 100mg / mL, about 0.1mg / mL to about 90mg / mL, about 0.1mg / mL to about 80mg / mL, about 0.1mg / mL to about 70mg / mL, about 0.1mg / mL to about 60mg / mL, about 0.1mg / mL to about 50mg / mL , about 0.1 mg / mL to about 45 mg / mL, about 0.1 mg / mL to about 40 mg / mL, about 0.1 mg / mL to about 35 mg / mL, about 0.1 mg / mL to about 30 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL ~15mg / mL, 0.1mg / mL~10mg / mL, 0.1mg / mL~5mg / mL, 0.1mg / mL~2.5mg / mL, 0.1mg / mL~1.0mg / mL, 0.1mg / mL~0.5mg / mL, 0.5mg / mL~500mg / mL, approximately 0.5 mg / mL to approximately 480 mg / mL, approximately 0.5 mg / mL to approximately 460 mg / mL, approximately 0.5 mg / mL to approximately 440 mg / mL, approximately 0.5 mg / mL to approximately 420 mg / mL, approximately 0.1 mg / mL to approximately 400 mg / mL, approximately 0.1 mg / mL to approximately 380 mg / mL,From about 0.5 mg / mL to about 360 mg / mL, from about 0.5 mg / mL to about 340 mg / mL, from about 0.5 mg / mL to about 320 mg / mL, from about 0.5 mg / mL to about 300 mg / mL, from about 0.5 mg / mL to about 280 mg / mL, from about 0.5 mg / mL to about 260 mg / mL, from about 0.5 mg / mL to about 240 mg / mL, from about 0.5 mg / mL to about 220 mg / mL, from about 0.5 mg / mL to about 200 mg / mL, from about 0.5 mg / mL to about 190 mg / mL, from about 0.5 mg / mL to about 180 mg / mL, from about 0.5 mg / mL to about 170 mg / mL, from about 0.5 mg / mL to about 160 mg / mL, from about 0.5 mg / mL to about 140 mg / mL, from about 0.5 mg / mL to about 130 mg / mL, from about 0.5 mg / mL to about 120 mg / mL, from about 0.5 mg / mL to about 110 mg / mL, from about 0.5 mg / mL to about 100 mg / mL, from about 0.5 mg / mL to about 90 mg / mL, from about 0.5 mg / mL to about 80 mg / mL, from about 0.5 mg / mL to about 70 mg / mL, from about 0.5 mg / mL to about 60 mg / mL, from about 0.5 mg / mL to about 50 mg / mL, from about 0.5 mg / mL to about 45 mg / mL, from about 0.5 mg / mL to about 40 mg / mL, from about 0.5 mg / mL to about 35 mg / mL, from about 0.5 mg / mL to about 30 mg / mL, from about 0.5 mg / mL to about 25 mg / mL, from about 0.5 mg / mL to about 20 mg / mL, from about 0.5 mg / mL to about 15 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 2.5 mg / mL, from about 0.5 mg / mL to about 1.0 mg / mL, from about 1.0 mg / mL to about 500 mg / mL, from about 1.0 mg / mL to about 480 mg / mL, from about 1.0 mg / mL to about 460 mg / mL, from about 1.0 mg / mL to about 440 mg / mL, from about 1.0 mg / mL to about 420 mg / mL, from about 1.0 mg / mL to about 400 mg / mL, from about 1.0 mg / mL to about 380 mg / mL, from about 1.0 mg / mL to about 360 mg / mL, from about 1.0 mg / mL to about 340 mg / mL, from about 1.0 mg / mL to about 320 mg / mL, from about 1.0 mg / mL to about 300 mg / mL, from about 1.0 mg / mL to about 280 mg / mL, from about 1.0 mg / mL to about 260 mg / mL, from about 1.0 mg / mL to about 240 mg / mL, from about 1.0 mg / mL to about 220 mg / mL, from about 1.0 mg / mL to about 200 mg / mL,From about 1.0 mg / mL to about 190 mg / mL, from about 1.0 mg / mL to about 180 mg / mL, from about 1.0 mg / mL to about 170 mg / mL, from about 1.0 mg / mL to about 160 mg / mL, from about 1.0 mg / mL to about 140 mg / mL, from about 1.0 mg / mL to about 130 mg / mL, from about 1.0 mg / mL to about 120 mg / mL, from about 1.0 mg / mL to about 110 mg / mL, from about 1.0 mg / mL to about 100 mg / mL, from about 1.0 mg / mL to about 90 mg / mL, from about 1.0 mg / mL to about 80 mg / mL, from about 1.0 mg / mL to about 70 mg / mL, from about 1.0 mg / mL to about 60 mg / mL, from about 1.0 mg / mL to about 50 mg / mL, from about 1.0 mg / mL to about 45 mg / mL, from about 1.0 mg / mL to about 40 mg / mL, from about 1.0 mg / mL to about 35 mg / mL, from about 1.0 mg / mL to about 30 mg / mL, from about 1.0 mg / mL to about 25 mg / mL, from about 1.0 mg / mL to about 20 mg / mL, from about 1.0 mg / mL to about 15 mg / mL, from about 1.0 mg / mL to about 10 mg / mL, from about 1.0 mg / mL to about 5 mg / mL, from about 1.0 mg / mL to about 2.5 mg / mL, from about 2.5 mg / mL to about 500 mg / mL, from about 2.5 mg / mL to about 480 mg / mL, from about 2.5 mg / mL to about 460 mg / mL, from about 2.5 mg / mL to about 440 mg / mL, from about 2.5 mg / mL to about 420 mg / mL, from about 2.5 mg / mL to about 400 mg / mL, from about 2.5 mg / mL to about 380 mg / mL, from about 2.5 mg / mL to about 360 mg / mL, from about 2.5 mg / mL to about 340 mg / mL, from about 2.5 mg / mL to about 320 mg / mL, from about 2.5 mg / mL to about 300 mg / mL, from about 2.5 mg / mL to about 280 mg / mL, from about 2.5 mg / mL to about 260 mg / mL, from about 2.5 mg / mL to about 240 mg / mL, from about 2.5 mg / mL to about 220 mg / mL, from about 2.5 mg / mL to about 200 mg / mL, from about 2.5 mg / mL to about 190 mg / mL, from about 2.5 mg / mL to about 180 mg / mL, from about 2.5 mg / mL to about 170 mg / mL, from about 2.5 mg / mL to about 160 mg / mL, from about 2.5 mg / mL to about 140 mg / mL, from about 2.5 mg / mL to about 130 mg / mL, from about 2.5 mg / mL to about 120 mg / mL, from about 2.5 mg / mL to about 110 mg / mL, from about 2.5 mg / mL to about 100 mg / mL, from about 2.5 mg / mL to about 90 mg / mL,From about 2.5 mg / mL to about 80 mg / mL, from about 2.5 mg / mL to about 70 mg / mL, from about 2.5 mg / mL to about 60 mg / mL, from about 2.5 mg / mL to about 50 mg / mL, from about 2.5 mg / mL to about 45 mg / mL, from about 2.5 mg / mL to about 40 mg / mL, from about 2.5 mg / mL to about 35 mg / mL, from about 2.5 mg / mL to about 30 mg / mL, from about 2.5 mg / mL to about 25 mg / mL, from about 2.5 mg / mL to about 20 mg / mL, from about 2.5 mg / mL to about 15 mg / mL, from about 2.5 mg / mL to about 10 mg / mL, from about 2.5 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 500 mg / mL, from about 5 mg / mL to about 480 mg / mL, from about 5 mg / mL to about 460 mg / mL, from about 5 mg / mL to about 440 mg / mL, from about 5 mg / mL to about 420 mg / mL, from about 5 mg / mL to about 400 mg / mL, from about 5 mg / mL to about 380 mg / mL, from about 5 mg / mL to about 360 mg / mL, from about 5 mg / mL to about 340 mg / mL, from about 5 mg / mL to about 320 mg / mL, from about 5 mg / mL to about 300 mg / mL, from about 5 mg / mL to about 280 mg / mL, from about 5 mg / mL to about 260 mg / mL, from about 5 mg / mL to about 240 mg / mL, from about 5 mg / mL to about 220 mg / mL, from about 5 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 190 mg / mL, from about 5 mg / mL to about 180 mg / mL, from about 5 mg / mL to about 170 mg / mL, from about 5 mg / mL to about 160 mg / mL, from about 5 mg / mL to about 140 mg / mL, from about 5 mg / mL to about 130 mg / mL, from about 5 mg / mL to about 120 mg / mL, from about 5 mg / mL to about 110 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 90 mg / mL, from about 5 mg / mL to about 80 mg / mL, from about 5 mg / mL to about 70 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 45 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 35 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 25 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 500 mg / mL, from about 10 mg / mL to about 480 mg / mL, from about 10 mg / mL to about 460 mg / mL, from about 10 mg / mL to about 440 mg / mL,About 10 mg / mL to about 420 mg / mL, about 10 mg / mL to about 400 mg / mL, about 10 mg / mL to about 380 mg / mL, about 10 mg / mL to about 360 mg / mL, about 10 mg / mL to about 340 mg / mL, about 10 mg / mL to about 320 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 280 mg / mL, about 10 mg / mL to about 260 mg / mL, about 10 mg / mL to about 240 mg / mL, about 10 mg / mL to about 220 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 190 mg / mL, about 10 mg / mL to about 180 mg / mL, about 10 mg / mL to about 170 mg / mL, about 10 mg / mL to about 160 mg / mL, about 10 mg / mL to about 140 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 110 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, About 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 45 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 35 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 25 mg / mL, about 10 mg / mL to about 20 mg / mL, about 10 mg / mL to about 15 mg / mL, about 15 mg / mL to about 500 mg / mL, about 15 mg / mL to about 480 mg / mL, about 15 mg / mL to about 460 mg / mL, about 15 mg / mL to about 440 mg / mL, about 15 mg / mL to about 420 mg / mL, about 15 mg / mL to about 400 mg / mL, about 15 mg / mL to about 380 mg / mL, about 15 mg / mL to about 360 mg / mL, about 15 mg / mL to about 340 mg / mL, about 15 mg / mL to about 320 mg / mL, about 15 mg / mL to about 300 mg / mL, about 15 mg / mL to about 280 mg / mL, about 15 mg / mL to about 260 mg / mL, about 15 mg / mL to about 240 mg / mL, about 15 mg / mL to about 220 mg / mL, about 15 mg / mL to about 200 mg / mL, about 15 mg / mL to about 190 mg / mL, about 15 mg / mL to about 180 mg / mL, about 15 mg / mL to about 170 mg / mL, about 15 mg / mL to about 160 mg / mL, about 15 mg / mL to about 140 mg / mL, about 15 mg / mL to about 130 mg / mL, about 15 mg / mL to about 120 mg / mL, about 15 mg / mL to about 110 mg / mL, about 15 mg / mL to about 100 mg / mL, about 15 mg / mL to about 90 mg / mL, about 15 mg / mL to about 80 mg / mL, about 15 mg / mL to about 70 mg / mL, about 15 mg / mL to about 60 mg / mL, about 15 mg / mL to about 50 mg / mL, about 15 mg / mL to about 45 mg / mL, about 15 mg / mL to about 40 mg / mL, about 15 mg / mL to about 35 mg / mL, about 15 mg / mL to about 30 mg / mL, about 15 mg / mL to about 25 mg / mL, about 15 mg / mL to about 20 mg / mL, about 20 mg / mL to about 500 mg / mL, about 20 mg / mL to about 480 mg / mL, about 20 mg / mL to about 460 mg / mL, about 20 mg / mL to about 440 mg / mL, about 20 mg / mL to about 420 mg / mL, about 20 mg / mL to about 400 mg / mL,From about 20 mg / mL to about 380 mg / mL, from about 20 mg / mL to about 360 mg / mL, from about 20 mg / mL to about 340 mg / mL, from about 20 mg / mL to about 320 mg / mL, from about 20 mg / mL to about 300 mg / mL, from about 20 mg / mL to about 280 mg / mL, from about 20 mg / mL to about 260 mg / mL, from about 20 mg / mL to about 240 mg / mL, from about 20 mg / mL to about 220 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 190 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 170 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 130 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 110 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 70 mg / mL, from about 20 mg / mL to about 60 mg / mL, from about 20 mg / mL to about 50 mg / mL, from about 20 mg / mL to about 45 mg / mL, from about 20 mg / mL to about 40 mg / mL, from about 20 mg / mL to about 35 mg / mL, from about 20 mg / mL to about 30 mg / mL, from about 20 mg / mL to about 25 mg / mL, from about 25 mg / mL to about 500 mg / mL, from about 25 mg / mL to about 480 mg / mL, from about 25 mg / mL to about 460 mg / mL, from about 25 mg / mL to about 440 mg / mL, from about 25 mg / mL to about 420 mg / mL, from about 25 mg / mL to about 400 mg / mL, from about 25 mg / mL to about 380 mg / mL, from about 25 mg / mL to about 360 mg / mL, from about 25 mg / mL to about 340 mg / mL, from about 25 mg / mL to about 320 mg / mL, from about 25 mg / mL to about 300 mg / mL, from about 25 mg / mL to about 280 mg / mL, from about 25 mg / mL to about 260 mg / mL, from about 25 mg / mL to about 240 mg / mL, from about 25 mg / mL to about 220 mg / mL, from about 25 mg / mL to about 200 mg / mL, from about 25 mg / mL to about 190 mg / mL, from about 25 mg / mL to about 180 mg / mL, from about 25 mg / mL to about 170 mg / mL, from about 25 mg / mL to about 160 mg / mL, from about 25 mg / mL to about 140 mg / mL, from about 25 mg / mL to about 130 mg / mL, from about 25 mg / mL to about 120 mg / mL, from about 25 mg / mL to about 110 mg / mL,About 25 mg / mL to about 100 mg / mL, about 25 mg / mL to about 90 mg / mL, about 25 mg / mL to about 80 mg / mL, about 25 mg / mL to about 70 mg / mL, about 25 mg / mL to about 60 mg / mL, about 25 mg / mL to about 50 mg / mL, about 25 mg / mL to about 45 mg / mL, about 25 mg / mL to about 40 mg / mL, about 25 mg / mL to about 35 mg / mL, about 25 mg / mL to about 30 mg / mL, about 30 mg / mL to about 500 mg / mL, about 30 mg / mL to about 480 mg / mL, about 30 mg / mL to about 460 mg / mL, about 30 mg / mL to about 440 mg / mL, about 30 mg / mL to about 420 mg / mL, about 30 mg / mL to about 400 mg / mL, about 30 mg / mL to about 380 mg / mL, about 30 mg / mL to about 360 mg / mL, about 30 mg / mL to about 340 mg / mL, about 30 mg / mL to about 320 mg / mL, about 30 mg / mL to about 300 mg / mL, about 30 mg / mL to about 280 mg / mL, about 30 mg / mL to about 260 mg / mL, about 30 mg / mL to about 240 mg / mL, about 30 mg / mL to about 220 mg / mL, about 30 mg / mL to about 200 mg / mL, about 30 mg / mL to about 190 mg / mL, about 30 mg / mL to about 180 mg / mL, about 30 mg / mL to about 170 mg / mL, about 30 mg / mL to about 160 mg / mL, about 30 mg / mL to about 140 mg / mL, about 30 mg / mL to about 130 mg / mL, about 30 mg / mL to about 120 mg / mL, about 30 mg / mL to about 110 mg / mL, about 30 mg / mL to about 100 mg / mL, about 30 mg / mL to about 90 mg / mL, about 30 mg / mL to about 80 mg / mL, about 30 mg / mL to about 70 mg / mL, about 30 mg / mL to about 60 mg / mL, about 30 mg / mL to about 50 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 500 mg / mL, about 35 mg / mL to about 480 mg / mL, about 35 mg / mL to about 460 mg / mL, about 35 mg / mL to about 440 mg / mL, about 35 mg / mL to about 420 mg / mL, about 35 mg / mL to about 400 mg / mL, about 35 mg / mL to about 380 mg / mL, about 35 mg / mL to about 360 mg / mL, about 35 mg / mL to about 340 mg / mL, about 35 mg / mL to about 320 mg / mL,From about 35 mg / mL to about 300 mg / mL, from about 35 mg / mL to about 280 mg / mL, from about 35 mg / mL to about 260 mg / mL, from about 35 mg / mL to about 240 mg / mL, from about 35 mg / mL to about 220 mg / mL, from about 35 mg / mL to about 200 mg / mL, from about 35 mg / mL to about 190 mg / mL, from about 35 mg / mL to about 180 mg / mL, from about 35 mg / mL to about 170 mg / mL, from about 35 mg / mL to about 160 mg / mL, from about 35 mg / mL to about 140 mg / mL, from about 35 mg / mL to about 130 mg / mL, from about 35 mg / mL to about 120 mg / mL, from about 35 mg / mL to about 110 mg / mL, from about 35 mg / mL to about 100 mg / mL, from about 35 mg / mL to about 90 mg / mL, from about 35 mg / mL to about 80 mg / mL, from about 35 mg / mL to about 70 mg / mL, from about 35 mg / mL to about 60 mg / mL, from about 35 mg / mL to about 50 mg / mL, from about 35 mg / mL to about 45 mg / mL, from about 35 mg / mL to about 40 mg / mL, from about 40 mg / mL to about 500 mg / mL, from about 40 mg / mL to about 480 mg / mL, from about 40 mg / mL to about 460 mg / mL, from about 40 mg / mL to about 440 mg / mL, from about 40 mg / mL to about 420 mg / mL, from about 40 mg / mL to about 400 mg / mL, from about 40 mg / mL to about 380 mg / mL, from about 40 mg / mL to about 360 mg / mL, from about 40 mg / mL to about 340 mg / mL, from about 40 mg / mL to about 320 mg / mL, from about 40 mg / mL to about 300 mg / mL, from about 40 mg / mL to about 280 mg / mL, from about 40 mg / mL to about 260 mg / mL, from about 40 mg / mL to about 240 mg / mL, from about 40 mg / mL to about 220 mg / mL, from about 40 mg / mL to about 200 mg / mL, from about 40 mg / mL to about 190 mg / mL, from about 40 mg / mL to about 180 mg / mL, from about 40 mg / mL to about 170 mg / mL, from about 40 mg / mL to about 160 mg / mL, from about 40 mg / mL to about 140 mg / mL, from about 40 mg / mL to about 130 mg / mL, from about 40 mg / mL to about 120 mg / mL, from about 40 mg / mL to about 110 mg / mL, from about 40 mg / mL to about 100 mg / mL, from about 40 mg / mL to about 90 mg / mL, from about 40 mg / mL to about 80 mg / mL, from about 40 mg / mL to about 70 mg / mL, from about 40 mg / mL to about 60 mg / mL, from about 40 mg / mL to about 50 mg / mL, from about 40 mg / mL to about 45 mg / mL,About 45 mg / mL to about 500 mg / mL, about 45 mg / mL to about 480 mg / mL, about 45 mg / mL to about 460 mg / mL, about 45 mg / mL to about 440 mg / mL, about 45 mg / mL to about 420 mg / mL, about 45 mg / mL to about 400 mg / mL, about 45 mg / mL to about 380 mg / mL, about 45 mg / mL to about 360 mg / mL, about 45 mg / mL to about 340 mg / mL, about 45 mg / mL to about 320 mg / mL, about 45 mg / mL to about 300 mg / mL, about 45 mg / mL to about 280 mg / mL, about 45 mg / mL to about 260 mg / mL, about 45 mg / mL to about 240 mg / mL, about 45 mg / mL to about 220 mg / mL, about 45 mg / mL to about 200 mg / mL, about 45 mg / mL to about 190 mg / mL, about 45 mg / mL to about 180 mg / mL, about 45 mg / mL to about 170 mg / mL, about 45 mg / mL to about 160 mg / mL, about 45 mg / mL to about 140 mg / mL, about 45 mg / mL to about 130 mg / mL, about 45 mg / mL to about 120 mg / mL, about 45 mg / mL to about 110 mg / mL, about 45 mg / mL to about 100 mg / mL, about 45 mg / mL to about 90 mg / mL, About 45 mg / mL to about 80 mg / mL, about 45 mg / mL to about 70 mg / mL, about 45 mg / mL to about 60 mg / mL, about 45 mg / mL to about 50 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 480 mg / mL, about 50 mg / mL to about 460 mg / mL, about 50 mg / mL to about 440 mg / mL, about 50 mg / mL to about 420 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 380 mg / mL, about 50 mg / mL to about 360 mg / mL, about 50 mg / mL to about 340 mg / mL, about 50 mg / mL to about 320 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 280 mg / mL, about 50 mg / mL to about 260 mg / mL, about 50 mg / mL to about 240 mg / mL, about 50 mg / mL to about 220 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 190 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 80 mg / mL, about 50 mg / mL to about 70 mg / mL, about 50 mg / mL to about 60 mg / mL, about 60 mg / mL to about 500 mg / mL, about 60 mg / mL to about 480 mg / mL, about 60 mg / mL to about 460 mg / mL, about 60 mg / mL to about 440 mg / mL, about 60 mg / mL to about 420 mg / mL, about 60 mg / mL to about 400 mg / mL, about 60 mg / mL to about 380 mg / mL, about 60 mg / mL to about 360 mg / mL, about 60 mg / mL to about 340 mg / mL, about 60 mg / mL to about 320 mg / mL, about 60 mg / mL to about 300 mg / mL, about 60 mg / mL to about 280 mg / mL, about 60 mg / mL to about 260 mg / mL, about 60 mg / mL to about 240 mg / mL, about 60 mg / mL to about 220 mg / mL, about 60 mg / mL to about 200 mg / mL, about 60 mg / mL to about 190 mg / mL, about 60 mg / mL to about 180 mg / mL, about 60 mg / mL to about 170 mg / mL, about 60 mg / mL to about 160 mg / mLAbout 60 mg / mL to about 140 mg / mL, about 60 mg / mL to about 130 mg / mL, about 60 mg / mL to about 120 mg / mL, about 60 mg / mL to about 110 mg / mL, about 60 mg / mL to about 100 mg / mL, about 60 mg / mL to about 90 mg / mL, about 60 mg / mL to about 80 mg / mL, about 60 mg / mL to about 70 mg / mL, about 70 mg / mL to about 500 mg / mL, about 70 mg / mL to about 480 mg / mL, about 70 mg / mL to about 460 mg / mL, about 70 mg / mL to about 440 mg / mL, about 70 mg / mL to about 420 mg / mL, about 70 mg / mL to about 400 mg / mL, about 70 mg / mL to about 380 mg / mL, about 70 mg / mL to about 360 mg / mL, about 70 mg / mL to about 340 mg / mL, about 70 mg / mL to about 320 mg / mL, about 70 mg / mL to about 300 mg / mL, about 70 mg / mL to about 280 mg / mL, about 70 mg / mL to about 260 mg / mL, about 70 mg / mL to about 240 mg / mL, about 70 mg / mL to about 220 mg / mL, about 70 mg / mL to about 200 mg / mL, about 70 mg / mL to about 190 mg / mL, about 70 mg / mL to about 180 mg / mL, about 70 mg / mL to about 170 mg / mL, about 70 mg / mL to about 160 mg / mL, about 70 mg / mL to about 140 mg / mL, about 70 mg / mL to about 130 mg / mL, about 70 mg / mL to about 120 mg / mL, about 70 mg / mL to about 110 mg / mL, about 70 mg / mL to about 100 mg / mL, about 70 mg / mL to about 90 mg / mL, about 70 mg / mL to about 80 mg / mL, about 80 mg / mL to about 500 mg / mL, about 80 mg / mL to about 480 mg / mL, about 80 mg / mL to about 460 mg / mL, about 80 mg / mL to about 440 mg / mL, about 80 mg / mL to about 420 mg / mL, about 80 mg / mL to about 400 mg / mL, about 80 mg / mL to about 380 mg / mL, about 80 mg / mL to about 360 mg / mL, about 80 mg / mL to about 340 mg / mL, about 80 mg / mL to about 320 mg / mL, about 80 mg / mL to about 300 mg / mL, about 80 mg / mL to about 280 mg / mL, about 80 mg / mL to about 260 mg / mL, about 80 mg / mL to about 240 mg / mL, about 80 mg / mL to about 220 mg / mL, about 80 mg / mL to about 200 mg / mL, about 80 mg / mL to about 190 mg / mL,About 80 mg / mL to about 180 mg / mL, about 80 mg / mL to about 170 mg / mL, about 80 mg / mL to about 160 mg / mL, about 80 mg / mL to about 140 mg / mL, about 80 mg / mL to about 130 mg / mL, about 80 mg / mL to about 120 mg / mL, about 80 mg / mL to about 110 mg / mL, about 80 mg / mL to about 100 mg / mL, about 80 mg / mL to about 90 mg / mL, about 90 mg / mL to about 500 mg / mL, about 90 mg / mL to about 480 mg / mL, about 90 mg / mL to about 460 mg / mL, about 90 mg / mL to about 440 mg / mL, about 90 mg / mL to about 420 mg / mL, about 90 mg / mL to about 400 mg / mL, about 90 mg / mL to about 380 mg / mL, about 90 mg / mL to about 360 mg / mL, about 90 mg / mL to about 340 mg / mL, about 90 mg / mL to about 320 mg / mL, about 90 mg / mL to about 300 mg / mL, about 90 mg / mL to about 280 mg / mL, about 90 mg / mL to about 260 mg / mL, about 90 mg / mL to about 240 mg / mL, about 90 mg / mL to about 220 mg / mL, about 90 mg / mL to about 200 mg / mL, about 90 mg / mL to about 190 mg / mL, about 90 mg / mL to about 180 mg / mL, about 90 mg / mL to about 170 mg / mL, about 90 mg / mL to about 160 mg / mL, about 90 mg / mL to about 140 mg / mL, about 90 mg / mL to about 130 mg / mL, about 90 mg / mL to about 120 mg / mL, about 90 mg / mL to about 110 mg / mL, about 90 mg / mL to about 100 mg / mL, about 100 mg / mL to about 500 mg / mL, about 100 mg / mL to about 480 mg / mL, about 100 mg / mL to about 460 mg / mL, about 100 mg / mL to about 440 mg / mL, about 100 mg / mL to about 420 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 380 mg / mL, about 100 mg / mL to about 360 mg / mL, about 100 mg / mL to about 340 mg / mL, about 100 mg / mL to about 320 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 280 mg / mL, about 100 mg / mL to about 260 mg / mL, about 100 mg / mL to about 240 mg / mL, about 100 mg / mL to about 220 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 190 mg / mLAbout 100 mg / mL to about 180 mg / mL, about 100 mg / mL to about 170 mg / mL, about 100 mg / mL to about 160 mg / mL, about 100 mg / mL to about 140 mg / mL, about 100 mg / mL to about 130 mg / mL, about 100 mg / mL to about 120 mg / mL, about 100 mg / mL to about 110 mg / mL, about 110 mg / mL to about 500 mg / mL, about 110 mg / mL to about 480 mg / mL, about 110 mg / mL to about 460 mg / mL, about 110 mg / mL to about 440 mg / mL, about 110 mg / mL to about 420 mg / mL, about 110 mg / mL to about 400 mg / mL, about 110 mg / mL to about 380 mg / mL, about 110 mg / mL to about 360 mg / mL, about 110 mg / mL to about 340 mg / mL, about 110 mg / mL to about 320 mg / mL, about 110 mg / mL to about 300 mg / mL, about 110 mg / mL to about 280 mg / mL, about 110 mg / mL to about 260 mg / mL, about 110 mg / mL to about 240 mg / mL, about 110 mg / mL to about 220 mg / mL, about 110 mg / mL to about 200 mg / mL, about 110 mg / mL to about 190 mg / mL, about 110 mg / mL to about 180 mg / mL, about 110 mg / mL to about 170 mg / mL, about 110 mg / mL to about 160 mg / mL, about 110 mg / mL to about 140 mg / mL, about 110 mg / mL to about 130 mg / mL, about 110 mg / mL to about 120 mg / mL, about 120 mg / mL to about 500 mg / mL, about 120 mg / mL to about 480 mg / mL, about 120 mg / mL to about 460 mg / mL, about 120 mg / mL to about 440 mg / mL, about 120 mg / mL to about 420 mg / mL, about 120 mg / mL to about 400 mg / mL, about 120 mg / mL to about 380 mg / mL, about 120 mg / mL to about 360 mg / mL, about 120 mg / mL to about 340 mg / mL, about 120 mg / mL to about 320 mg / mL, about 120 mg / mL to about 300 mg / mL, about 120 mg / mL to about 280 mg / mL, about 120 mg / mL to about 260 mg / mL, about 120 mg / mL to about 240 mg / mL, about 120 mg / mL to about 220 mg / mL, about 120 mg / mL to about 200 mg / mL, about 120 mg / mL to about 190 mg / mL, about 120 mg / mL to about 180 mg / mL, about 120 mg / mL to about 170 mg / mL, about 120 mg / mL to about 160 mg / mLAbout 120 mg / mL to about 140 mg / mL, about 120 mg / mL to about 130 mg / mL, about 130 mg / mL to about 500 mg / mL, about 130 mg / mL to about 480 mg / mL, about 130 mg / mL to about 460 mg / mL, about 130 mg / mL to about 440 mg / mL, about 130 mg / mL to about 420 mg / mL, about 130 mg / mL to about 400 mg / mL, about 130 mg / mL to about 380 mg / mL, about 130 mg / mL to about 360 mg / mL, about 130 mg / mL to about 340 mg / mL, about 130 mg / mL to about 320 mg / mL, about 130 mg / mL to about 300 mg / mL, about 130 mg / mL to about 280 mg / mL, about 130 mg / mL to about 260 mg / mL, about 130 mg / mL to about 240 mg / mL, about 130 mg / mL to about 220 mg / mL, about 130 mg / mL to about 200 mg / mL, about 130 mg / mL to about 190 mg / mL, about 130 mg / mL to about 180 mg / mL, about 130 mg / mL to about 170 mg / mL, about 130 mg / mL to about 160 mg / mL, about 140 mg / mL to about 500 mg / mL, about 140 mg / mL to about 480 mg / mL, about 140 mg / mL to about 460 mg / mL, about 140 mg / mL to about 440 mg / mL, about 140 mg / mL to about 420 mg / mL, about 140 mg / mL to about 400 mg / mL, about 140 mg / mL to about 380 mg / mL, about 140 mg / mL to about 360 mg / mL, about 140 mg / mL to about 340 mg / mL, about 140 mg / mL to about 320 mg / mL, about 140 mg / mL to about 300 mg / mL, about 140 mg / mL to about 280 mg / mL, about 140 mg / mL to about 260 mg / mL, about 140 mg / mL to about 240 mg / mL, about 140 mg / mL to about 220 mg / mL, about 140 mg / mL to about 200 mg / mL, about 140 mg / mL to about 190 mg / mL, about 140 mg / mL to about 180 mg / mL, about 140 mg / mL to about 170 mg / mL, about 140 mg / mL to about 160 mg / mL About 160 mg / mL to about 500 mg / mL, about 160 mg / mL to about 480 mg / mL, about 160 mg / mL to about 460 mg / mL, about 160 mg / mL to about 440 mg / mL, about 160 mg / mL to about 420 mg / mL, about 160 mg / mL to about 400 mg / mL, about 160 mg / mL to about 380 mg / mL, about 160 mg / mL to about 360 mg / mL, about 160 mg / mL to about 340 mg / mL, about 160 mg / mL to about 320 mg / mL, about 160 mg / mL to about 300 mg / mL, about 160 mg / mL to about 280 mg / mL, about 160 mg / mL to about 260 mg / mL, about 160 mg / mL to about 240 mg / mL, about 160 mg / mL to about 220 mg / mL, about 160 mg / mL to about 200 mg / mL, about 160 mg / mL to about 190 mg / mL, about 160 mg / mL to about 180 mg / mL, about 160 mg / mL to about 170 mg / mL, about 170 mg / mL to about 500 mg / mL, about 170 mg / mL to about 480 mg / mL, about 170 mg / mL to about 460 mg / mL, about 170 mg / mL to about 440 mg / mL, about 170 mg / mL to about 420 mg / mL, about 170 mg / mL to about 400 mg / mL, about 170 mg / mL to about 380 mg / mL, about 170 mg / mL to about 360 mg / mL, about 170 mg / mL to about 340 mg / mL, about 170 mg / mL to about 320 mg / mL, about 170 mg / mL to about 300 mg / mL, about 170 mg / mL to about 280 mg / mL, about 170 mg / mL to about 260 mg / mL, about 170 mg / mL to about 240 mg / mL, about 170 mg / mL to about 220 mg / mL, about 170 mg / mL to about 200 mg / mL, about 170 mg / mL to about 190 mg / mL, about 170 mg / mL to about 180 mg / mL, about 180 mg / mL to about 500 mg / mL, about 180 mg / mL to about 480 mg / mL, about 180 mg / mL to about 460 mg / mL, about 180 mg / mL to about 440 mg / mL, about 180 mg / mL to about 420 mg / mL, about 180 mg / mL to about 400 mg / mL, about 180 mg / mL to about 380 mg / mL, about 180 mg / mL to about 360 mg / mL, about 180 mg / mL to about 340 mg / mL, about 180 mg / mL to about 320 mg / mL, about 180 mg / mL to about 300 mg / mL, about 180 mg / mL to about 280 mg / mL, about 180 mg / mL to about 260 mg / mL,About 180 mg / mL to about 240 mg / mL, about 180 mg / mL to about 220 mg / mL, about 180 mg / mL to about 200 mg / mL, about 180 mg / mL to about 190 mg / mL, about 190 mg / mL to about 500 mg / mL, about 190 mg / mL to about 480 mg / mL, about 190 mg / mL to about 460 mg / mL, about 190 mg / mL to about 440 mg / mL, about 190 mg / mL to about 420 mg / mL, about 190 mg / mL to about 400 mg / mL, about 190 mg / mL to about 380 mg / mL, about 190 mg / mL to about 360 mg / mL, about 190 mg / mL to about 340 mg / mL, about 190 mg / mL to about 320 mg / mL, about 190 mg / mL to about 300 mg / mL, about 190 mg / mL to about 280 mg / mL, about 190 mg / mL to about 260 mg / mL, about 190 mg / mL to about 240 mg / mL, about 190 mg / mL to about 220 mg / mL, about 190 mg / mL to about 200 mg / mL, about 200 mg / mL to about 500 mg / mL, about 200 mg / mL to about 480 mg / mL, about 200 mg / mL to about 460 mg / mL, about 200 mg / mL to about 440 mg / mL, about 200 mg / mL to about 420 mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 380 mg / mL, about 200 mg / mL to about 360 mg / mL, about 200 mg / mL to about 340 mg / mL, about 200 mg / mL to about 320 mg / mL, about 200 mg / mL to about 300 mg / mL, about 200 mg / mL to about 280 mg / mL, about 200 mg / mL to about 260 mg / mL, about 200 mg / mL to about 240 mg / mL, about 200 mg / mL to about 220 mg / mL, From about 220 mg / mL to about 500 mg / mL, from about 220 mg / mL to about 480 mg / mL, from about 220 mg / mL to about 460 mg / mL, from about 220 mg / mL to about 440 mg / mL, from about 220 mg / mL to about 420 mg / mL, from about 220 mg / mL to about 400 mg / mL, from about 220 mg / mL to about 380 mg / mL, from about 220 mg / mL to about 360 mg / mL, from about 220 mg / mL to about 340 mg / mL, from about 220 mg / mL to about 320 mg / mL, from about 220 mg / mL to about 300 mg / mL, from about 220 mg / mL to about 280 mg / mL, from about 220 mg / mL to about 260 mg / mL, from about 220 mg / mL to about 240 mg / mL, from about 240 mg / mL to about 500 mg / mL, from about 240 mg / mL to about 480 mg / mL, from about 240 mg / mL to about 460 mg / mL, from about 240 mg / mL to about 440 mg / mL, from about 240 mg / mL to about 420 mg / mL, from about 240 mg / mL to about 400 mg / mL, from about 240 mg / mL to about 380 mg / mL, from about 240 mg / mL to about 360 mg / mL, from about 240 mg / mL to about 340 mg / mL, from about 240 mg / mL to about 320 mg / mL, from about 240 mg / mL to about 300 mg / mL, from about 240 mg / mL to about 280 mg / mL, from about 240 mg / mL to about 260 mg / mL, from about 260 mg / mL to about 500 mg / mL, from about 260 mg / mL to about 480 mg / mL, from about 260 mg / mL to about 460 mg / mL, from about 260 mg / mL to about 440 mg / mL, from about 260 mg / mL to about 420 mg / mL, from about 260 mg / mL to about 400 mg / mL, from about 260 mg / mL to about 380 mg / mL, from about 260 mg / mL to about 360 mg / mL, from about 260 mg / mL to about 340 mg / mL, from about 260 mg / mL to about 320 mg / mL, from about 260 mg / mL to about 300 mg / mL, from about 260 mg / mL to about 280 mg / mL, from about 280 mg / mL to about 500 mg / mL, from about 280 mg / mL to about 480 mg / mL, from about 280 mg / mL to about 460 mg / mL, from about 280 mg / mL to about 440 mg / mL, from about 280 mg / mL to about 420 mg / mL, from about 280 mg / mL to about 400 mg / mL, from about 280 mg / mL to about 380 mg / mL, from about 280 mg / mL to about 360 mg / mL, from about 280 mg / mL to about 340 mg / mL, from about 280 mg / mL to about 320 mg / mL, from about 280 mg / mL to about 300 mg / mLAbout 300 mg / mL to about 500 mg / mL, about 300 mg / mL to about 480 mg / mL, about 300 mg / mL to about 460 mg / mL, about 300 mg / mL to about 440 mg / mL, about 300 mg / mL to about 420 mg / mL, about 300 mg / mL to about 400 mg / mL, about 300 mg / mL to about 380 mg / mL, about 300 mg / mL to about 360 mg / mL, about 300 mg / mL to about 340 mg / mL, about 300 mg / mL to about 320 mg / mL, about 320 mg / mL to about 500 mg / mL, about 320 mg / mL to about 480 mg / mL, about 320 mg / mL to about 460 mg / mL, about 320 mg / mL to about 440 mg / mL, about 320 mg / mL to about 420 mg / mL, about 320 mg / mL to about 400 mg / mL, about 320 mg / mL to about 380 mg / mL, about 320 mg / mL to about 360 mg / mL, about 320 mg / mL to about 340 mg / mL, about 340 mg / mL to about 500 mg / mL, about 340 mg / mL to about 480 mg / mL, about 340 mg / mL to about 460 mg / mL, about 340 mg / mL to about 440 mg / mL, about 340 mg / mL to about 420 mg / mL, about 340 mg / mL to about 400 mg / mL, about 340 mg / mL to about 380 mg / mL, about 340 mg / mL to about 360 mg / mL, about 360 mg / mL to about 500 mg / mL, about 360 mg / mL to about 480 mg / mL, about 360 mg / mL to about 460 mg / mL, about 360 mg / mL to about 440 mg / mL, about 360 mg / mL to about 420 mg / mL, about 360 mg / mL to about 400 mg / mL, about 360 mg / mL to about 380 mg / mL, about 380 mg / mL to about 500 mg / mL, about 380 mg / mL to about 480 mg / mL, about 380 mg / mL to about 460 mg / mL, about 380 mg / mL to about 440 mg / mL, about 380 mg / mL to about 420 mg / mL, about 380 mg / mL to about 400 mg / mL, about 400 mg / mL to about 500 mg / mL, about 400 mg / mL to about 480 mg / mL, about 400 mg / mL to about 460 mg / mL, about 400 mg / mL to about 440 mg / mL, about 400 mg / mL to about 420 mg / mL, about 420 mg / mL to about 500 mg / mL, about 420 mg / mL to about 480 mg / mL, about 420 mg / mL to about 460 mg / mL, about 420 mg / mL to about 440 mg / mL, about 440 mg / mL to about 500 mg / mL,The antibody or antigen-binding antibody fragment (e.g., any of the exemplary antibodies or antigen-binding antibody fragments described herein) may comprise about 440 mg / mL to about 480 mg / mL, about 440 mg / mL to about 460 mg / mL, about 460 mg / mL to about 500 mg / mL, about 460 mg / mL to about 480 mg / mL, or about 480 mg / mL to about 500 mg / mL of the antibody or antigen-binding antibody fragment.

[0058] As used herein, the term "antibody" is used broadly to mean any polypeptide that contains an antigen-binding domain. Non-limiting examples of types of antibodies are described herein. Further examples of antibodies are known in the art.

[0059] The term "antigen-binding antibody fragment" refers to a fragment of a mammalian (e.g., human) IgG1, IgG2, IgG3, IgG4, IgM, IgE or IgA that retains specific binding ability to an antigen. Non-limiting examples of antigen-binding antibody fragments are described herein. Further examples of antigen-binding antibody fragments are known in the art.

[0060] In some embodiments, the antibody can be a VHH domain, a VNAR domain, scFv, BiTe, (scFv)2, nanobody, nanobody-HSA, DART, TandAb, sc diabody, sc diabody-CH3, scFv-CH-CL-scFv, HSA body, sc diabody-HAS, or tandem scFv.

[0061] V H The H domain is a single monomeric variable antibody domain found in camels. NAR The V domain is a single monomeric variable antibody domain found in cartilaginous fish. H H domain and V NARNon-limiting aspects of the domain are described, for example, in Cromie et al., Curr. Top. Med. Chem. 15:2543-2557, 2016; De Genst et al., Dev. Comp. Immunol. 30:187-198, 2006; De Meyer et al., Trends Biotechnol. 32:263-270, 2014; Kijanka et al., Nanomedicine 10:161-174, 2015; Kovaleva et al., Expert. Opin. Biol. Ther. 14:1527-1539, 2014; Krah et al., Immunopharmacol. Immunotoxicol. 38:21-28, 2016; Mujic-Delic et al., Trends Pharmacol. Sci. 35:247-255, 2014; Muyldermans, J. Biotechnol. 74:277-302, 2001; Muyldermans et al., Trends Biochem. Sci. 26:230-235, 2001; Muyldermans, Ann. Rev. Biochem. 82:775-797, 2013; Rahbarizadeh et al., Immunol. Invest. 40:299-338, 2011; Van Audenhove et al., EBioMedicine 8:40-48, 2016; Van Bockstaele et al., Curr. Opin. Investig. Drugs 10:1212-1224, 2009; Vincke et al., Methods Mol. Biol. 911:15-26, 2012; and Wesolowski et al., Med. Microbiol. Immunol. 198:157-174, 2009.

[0062] In some embodiments, the antibody is a VHH-scAb, VHH-Fab, dual scFab, diabody, crossMab, two-in-one, four-in-one, DutaMab, DT-IgG, knobs-in-holes common light chain, knobs-in-hole assembly, charge pair, Fab arm exchange, SEED body, LUZ-Y, Fcab, κλ body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH The antibody may be an IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, sc diabody-Fc, diabody-Fc, tandem scFv-Fc, intrabody, dock-and-lock, ImmTAC, IgG-IgG conjugate, Cov-X-body, and scFv1-PEG-scFv2.

[0063] Non-limiting examples of antigen-binding antibody fragments include Fv fragments, Fab fragments, F(ab')2 fragments, and Fab' fragments. Further examples of antigen-binding antibody fragments include any antigen-binding fragment of IgG (e.g., an antigen-binding fragment of IgG1, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); an antigen-binding fragment of IgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., an antigen-binding fragment of human or humanized IgA, e.g., human or humanized IgA1 or IgA2); an antigen-binding fragment of IgD (e.g., an antigen-binding fragment of human or humanized IgD); an antigen-binding fragment of IgE (an antigen-binding fragment of human or humanized IgE); or an antigen-binding fragment of IgM (e.g., an antigen-binding fragment of human or humanized IM).

[0064] An "Fv" fragment comprises a non-covalent dimer of one heavy- and one light-chain variable domain.

[0065] A "Fab" fragment contains the heavy and light chain variable domains of the Fv fragment as well as the constant domain of the light chain and the first constant domain of the heavy chain (C H1 ).

[0066] An "F(ab')2" fragment contains two Fab fragments joined near the hinge region by disulfide bonds.

[0067] "Dual variable domain immunoglobulins" or "DVD-Ig" refer to multivalent and multispecific binding proteins, as described, for example, in DiGiammarino et al., Methods Mol. Biol. 899:145-156, 2012; Jakob et al., MABs 5:358-363, 2013; and U.S. Pat. Nos. 7,612,181, 8,258,268, 8,586,714, 8,716,450, 8,722,855, 8,735,546, and 8,822,645, each of which is incorporated by reference in its entirety.

[0068] DART is described, for example, in Garber, Nature Reviews Drug Discovery 13:799-801, 2014.

[0069] The antibody or antigen-binding antibody fragment is bound to its epitope or antigen at a concentration of 1x10 -7 Less than M, 1x10 -8 Less than M, 1x10 -9 Less than M, 1x10 -10 Less than M, 1x10 -11 Less than M, 1x10 -12 Less than M or 1x10 -13 The dissociation equilibrium constant (K D In some embodiments, the antibody or antigen-binding antibody fragment can bind to its epitope or antigen at about 1 x 10 -3M ~ approx. 1x10 -5 M, about 1x10 -4 M~1x10 -6 M, about 1x10 -5 M~1x10 -7 M, about 1x10 -6 M ~ approx. 1x10 -8 M, about 1x10 -7 M~1x10 -9 M, about 1x10 -8 M~1x10 -10 M, or about 1x10 -9 M ~ approx. 1x10 -11 K of M D can be combined with

[0070] In some examples, the antibody can be a mAb (eg, a human or humanized monoclonal antibody).

[0071] In some embodiments, the mAb may have an Fc region that contains one or more amino acid substitutions that result in a lower CH2 domain unfolding temperature relative to an antibody having a wild-type Fc region, hi some embodiments, the mAb may have an Fc region that contains one or more amino acid substitutions that reduce the stability of the antibody, for example, relative to the stability of a similar antibody lacking the one or more amino acid substitutions.

[0072] In some embodiments, the mAb may be an IgG1, IgG2, IgG3 or IgG4 antibody (e.g., a human or humanized antibody). In some preferred embodiments, the mAb is an IgG1 or IgG4 antibody.

[0073] In some embodiments, the mAb is an anti-CXC motif chemokine receptor 3 (CXCR3) mAb (e.g., a human or humanized antibody). In some embodiments, the anti-CXCR3 mAb comprises a heavy chain comprising or consisting of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:1, and a light chain comprising or consisting of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:2. In some embodiments, the anti-CXCR3 antibody comprises the three CDRs present in SEQ ID NO:1 and the three CDRs present in SEQ ID NO:2.

[0074] In some embodiments, the mAb is an anti-cluster of differentiation 38 (CD38) mAb (e.g., a human or humanized anti-CD38 antibody). In some embodiments, the anti-CD38 mAb comprises a heavy chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:3, and a light chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:4. In some embodiments, the anti-CD38 mAb comprises the three CDRs present in SEQ ID NO:3 and the three CDRs present in SEQ ID NO:4.

[0075] In some embodiments, the mAb is an Fc-engineered anti-cluster of differentiation 38 (CD38) mAb (e.g., a human or humanized antibody). In some embodiments, the Fc-engineered anti-CD38 mAb comprises a heavy chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:5, and a light chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:6. In some embodiments, the Fc engineered anti-CD38 mAb comprises the three CDRs present in SEQ ID NO:5 and the three CDRs present in SEQ ID NO:6.

[0076] In some embodiments, the mAb is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) mAb (e.g., a human or humanized antibody). In some embodiments, the anti-CEACAM5 mAb comprises a heavy chain comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:7, or a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:7, and a light chain comprising a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:8, or a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:8. In some embodiments, the anti-CEACAM5 antibody comprises the three CDRs present in SEQ ID NO:7 and the three CDRs present in SEQ ID NO:8.

[0077] In some embodiments, the mAb is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) mAb (e.g., a human or humanized antibody). In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises a heavy chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:9, and a light chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical to SEQ ID NO:10. In some embodiments, the Fc engineered anti-CEACAM5 mAb comprises the three CDRs present in SEQ ID NO:9 and the three CDRs present in SEQ ID NO:10.

[0078] In some embodiments, the mAb is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) mAb (e.g., a human or humanized antibody). In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises a heavy chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO:11, and a light chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO:12, or a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO:12. In some embodiments, the Fc engineered anti-CEACAM5 mAb comprises the three CDRs present in SEQ ID NO:11 and the three CDRs present in SEQ ID NO:12.

[0079] In some embodiments, the mAb is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) mAb (e.g., a human or humanized antibody). In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises a heavy chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO: 13, and a light chain that comprises or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO: 14, or a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical to SEQ ID NO: 14. In some embodiments, the Fc engineered anti-CEACAM5 mAb comprises the three CDRs present in SEQ ID NO:13 and the three CDRs present in SEQ ID NO:14.

[0080] In some embodiments, the antibody may be linked to a drug (e.g., a chemotherapeutic drug, a small molecule), a toxin, or a radioisotope. In some embodiments, the antibody may be linked to a drug via a linker. Non-limiting examples of linkers include hydrazone linkers, peptide linkers, disulfide linkers, and thioether linkers. See, for example, Carter et al. (2008) Cancer J. 14(3):154-69; Sanderson et al. (2005) Clin. Cancer Res. 11(2 Part 1):843-852; Chari et al. (2008) Acc Chem Res. 41(1):98-107; Oflazoglu et al. (2008) Clin. Cancer Res. 14(19):6171-6180; and Lu et al. (2016) Int. J. Mol. Sci. 17(4):561.

[0081] An antibody can be produced by introducing a nucleic acid sequence encoding the antibody into a cell to produce a recombinant cell and culturing the recombinant cell under conditions sufficient for expression of the antibody, hi some embodiments, the introducing step comprises introducing an expression vector comprising a sequence encoding the antibody into a cell to produce a recombinant cell.

[0082] The antigens described herein can be produced by any cell, for example, a eukaryotic cell. The term "eukaryotic cell" as used herein refers to a cell that has a separate membrane-bound nucleus. Such cells include, for example, mammalian (e.g., rodent, non-human primate or human) cells, insect cells, fungal cells or plant cells. In some embodiments, the eukaryotic cell is a yeast cell, such as Saccharomyces cerevisiae. In some embodiments, the eukaryotic cell is a higher eukaryotic cell, such as a mammalian cell, an avian cell, a plant cell or an insect cell.

[0083] Methods for culturing cells are well known in the art. Cells can be maintained in vitro under conditions that promote proliferation, differentiation and growth. Briefly, cells can be cultured by contacting cells (e.g., any cell) with cell culture medium that contains growth factors and supplements necessary to support cell viability and growth.

[0084] The method of introducing nucleic acid and expression vector into cell (e.g., eukaryotic cell) is known in the art.Non-limiting examples of the method that can be used to introduce nucleic acid into cell include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell squeezing, sonoporation, optical transfection, impale infection, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral transduction and lentiviral transduction) and nanoparticle transfection.

[0085] Provided herein are methods that further include isolating the antibody from a cell (e.g., a eukaryotic cell) using techniques well known in the art (e.g., ammonium sulfate precipitation, polyethylene glycol precipitation, ion exchange chromatography (anionic or cationic), hydrophobic interaction chromatography, metal affinity chromatography, ligand affinity chromatography, size exclusion chromatography).

[0086] buffer solution The formulations described herein can include a buffer (e.g., one or more buffers) (e.g., any of the non-limiting buffers described herein or known in the art). In some embodiments, the antibody or antigen-binding antibody fragment present in the formulation does not significantly buffer the pH of the formulation.

[0087] Non-limiting examples of buffers (e.g., one or more buffers) that can be present in any of the formulations described herein include acetate, succinate, gluconate, histidine, citrate, phosphate and Tris.In some embodiments of any of the formulations described herein, the formulation can include acetate, histidine or phosphate.Further examples of buffers that can be present in any of the formulations described herein are known in the art.

[0088] The final concentration of the buffer (or the total final concentration of one or more buffers) in any of the formulations described herein may be from about 0.01 mM to about 100 mM, from about 0.01 mM to about 95 mM, from about 0.01 mM to about 90 mM, from about 0.01 mM to about 85 mM, from about 0.01 mM to about 80 mM, from about 0.01 mM to about 75 mM, from about 0.01 mM to about 70 mM, from about 0.01 mM to about 65 mM, from about 0.01 mM to about 60 mM, from about 0.01 mM to about 55 mM, from about 0.01 mM to about 50 mM, from about 0.01 mM to about 45 mM, from about 0.01 mM to about 40 mM, from about 0.01 mM to about 35 mM, mM, about 0.01 mM to about 30 mM, about 0.01 mM to about 25 mM, about 0.01 mM to about 20 mM, about 0.01 mM to about 15 mM, about 0.01 mM to about 10 mM, about 0.01 mM to about 9 mM, about 0.01 mM to about 8.5 mM, about 0.01 mM to about 8 mM, about 0.01 mM to about 7. 5 mM, about 0.01 mM to about 7 mM, about 0.01 mM to about 6.5 mM, about 0.01 mM to about 6 mM, about 0.01 mM to about 5 mM, about 0.01 mM to about 4.5 mM, about 0.01 mM to about 4 mM, about 0.01 mM to about 3.5 mM, about 0.01 mM to about 3 mM, about 0.01 mM to about 2. 5 mM, about 0.01 mM to about 2 mM, about 0.01 mM to about 1.5 mM, about 0.01 mM to about 1 mM, about 0.01 mM to about 0.9 mM, about 0.01 mM to about 0.8 mM, about 0.01 mM to about 0.7 mM, about 0.01 mM to about 0.6 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.4 mM, about 0.01 mM to about 0.3 mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM, about 0.1 mM to about 100 mM, about 0.1 mM to about 95 mM, about 0.1 mM to about 90 mM, about 0.1 mM to about 85 mM, about 0.1 mM to about 80 mM, about 0.1 mM~about 75mM, about 0.1mM~about 70mM, about 0.1mM~about 65mM, about 0.1mM~about 60mM, about 0.1mM~about 55mM, about 0.1mM to about 50mM, about 0.1mM to about 45mM, about 0.1mM to about 40mM, about 0.1mM to about 35mM, about 0.1mM to about 30mM , about 0.1 mM to about 25 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.1 mM to about 10 mM, about 0.1 mM to about 9 mM, about 0.1 mM to about 8 mM, about 0.1 mM to about 7 mM, about 0.1 mM to about 6 mM, about 0.1 mM to about 5 mM, about 0.1 mM to about 4 mM,from about 0.1 mM to about 3 mM, from about 0.1 mM to about 2 mM, from about 0.1 mM to about 1 mM, from about 0.1 mM to about 0.9 mM, from about 0.1 mM to about 0.8 mM, from about 0.1 mM to about 0.7 mM, from about 0.1 mM to about 0.6 mM, from about 0.1 mM to about 0.5 mM, from about 0.1 mM to about 0.4 mM, from about 0.1 mM to about 0.3 mM, from about 0.1 mM to about 0.2 mM, from about 0.2 mM to about 100 mM, from about 0.2 mM to about 95 mM, from about 0.2 mM to about 90 mM, from about 0.2 mM to about 85 mM, from about 0.2 mM to about 80 mM, from about 0.2 mM to about 75 mM, from about 0.2 mM to about 70 mM, from about 0.2 mM to about 65 mM, from about 0.2 mM to about 60 mM, from about 0.2 mM to about 55 mM, from about 0.2 mM to about 50 mM, from about 0.2 mM to about 45 mM, from about 0.2 mM to about 40 mM, from about 0.2 mM to about 35 mM, from about 0.2 mM to about 30 mM, from about 0.2 mM to about 25 mM, from about 0.2 mM to about 20 mM, from about 0.2 mM to about 15 mM, from about 0.2 mM to about 10 mM, from about 0.2 mM to about 9 mM, from about 0.2 mM to about 8 mM, from about 0.2 mM to about 7 mM, from about 0.2 mM to about 6 mM, from about 0.2 mM to about 5 mM, from about 0.2 mM to about 4 mM, from about 0.2 mM to about 3 mM, from about 0.2 mM to about 2 mM, from about 0.2 mM to about 1 mM, from about 0.2 mM to about 0.9 mM, from about 0.2 mM to about 0.8 mM, from about 0.2 mM to about 0.7 mM, from about 0.2 mM to about 0.6 mM, from about 0.2 mM to about 0.5 mM, from about 0.2 mM to about 0.4 mM, from about 0.2 mM to about 0.3 mM, from about 0.5 mM to about 100 mM, from about 0.5 mM to about 95 mM, from about 0.5 mM to about 90 mM, from about 0.5 mM to about 85 mM, from about 0.5 mM to about 80 mM, from about 0.5 mM to about 75 mM, from about 0.5 mM to about 70 mM, from about 0.5 mM to about 65 mM, from about 0.5 mM to about 60 mM, from about 0.5 mM to about 55 mM, from about 0.5 mM to about 50 mM, from about 0.5 mM to about 45 mM, from about 0.5 mM to about 40 mM, from about 0.5 mM to about 35 mM, from about 0.5 mM to about 30 mM, from about 0.5 mM to about 25 mM, from about 0.5 mM to about 20 mM, from about 0.5 mM to about 15 mM, from about 0.5 mM to about 10 mM, from about 0.5 mM to about 0.9 mM, from about 0.5 mM to about 0.8 mM, from about 0.5 mM to about 0.7 mM, from about 0.5 mM to about 0.5 mM to about 0.6 mM, from about 0.5 mM to about 5 mM, from about 0.5 mM to about 4 mM, from about 0.5 mM to about 3 mM, from about 0.5 mM to about 2 mM, from about 0.5 mM to about 1 mM, from about 0.5 mM to about 0.9 mM, from about 0.5 mM to about 0.8 mMFrom about 0.5 mM to about 0.7 mM, from about 0.5 mM to about 0.6 mM, from about 1 mM to about 100 mM, from about 1 mM to about 95 mM, from about 1 mM to about 90 mM, from about 1 mM to about 85 mM, from about 1 mM to about 80 mM, from about 1 mM to about 75 mM, from about 1 mM to about 70 mM, from about 1 mM to about 65 mM, from about 1 mM to about 60 mM, from about 1 mM to about 55 mM, from about 1 mM to about 50 mM, from about 1 mM to about 45 mM, from about 1 mM to about 40 mM, from about 1 mM to about 35 mM, from about 1 mM to about 30 mM, from about 1 mM to about 25 mM, from about 1 mM to about 20 mM, from about 1 mM to about 15 mM, from about 1 mM to about 10 mM, from about 1 mM to about 9 mM, from about 1 mM to about 8 mM, from about 1 mM to about 7 mM, from about 1 mM to about 6 mM, from about 1 mM to about 5 mM, from about 1 mM to about 4 mM, from about 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 1 mM to about 1.8 mM, from about 1 mM to about 1.6 mM, from about 1 mM to about 1.4 mM, from about 1 mM to about 1.2 mM, from about 2 mM to about 100 mM, from about 2 mM to about 95 mM, from about 2 mM to about 90 mM, from about 2 mM to about 85 mM, from about 2 mM to about 80 mM, from about 2 mM to about 75 mM, from about 2 mM to about 70 mM, from about 2 mM to about 65 mM, from about 2 mM to about 60 mM, from about 2 mM to about 55 mM, from about 2 mM to about 50 mM, from about 2 mM to about 45 mM, from about 2 mM to about 40 mM, from about 2 mM to about 35 mM, from about 2 mM to about 30 mM, from about 2 mM to about 25 mM, from about 2 mM to about 20 mM, from about 2 mM to about 15 mM, from about 2 mM to about 10 mM, from about 2 mM to about 9 mM, from about 2 mM to about 8 mM, from about 2 mM to about 7 mM, from about 2 mM to about 6 mM, from about 2 mM to about 5 mM, from about 2 mM to about 4 mM, from about 2 mM to about 3 mM, from about 5 mM to about 100 mM, from about 5 mM to about 95 mM, from about 5 mM to about 90 mM, from about 5 mM to about 85 mM, from about 5 mM to about 80 mM, from about 5 mM to about 75 mM, from about 5 mM to about 70 mM, from about 5 mM to about 65 mM, from about 5 mM to about 60 mM, from about 5 mM to about 55 mM, from about 5 mM to about 50 mM, from about 5 mM to about 45 mM, from about 5 mM to about 40 mM, from about 5 mM to about 35 mM, from about 5 mM to about 30 mM, from about 5 mM to about 25 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 10 mM, from about 5 mM to about 9 mM, from about 5 mM to about 8 mM, from about 5 mM to about 7 mM, from about 5 mM to about 6 mM, from about 10 mM to about 100 mM, from about 10 mM to about 95 mM, from about 10 mM to about 90 mM, from about 10 mM to about 85 mM, from about 10 mM to about 80 mM, from about 10 mM to about 75 mM, from about 10 mM to about 70 mM, from about 10 mM to about 65 mM,From about 10 mM to about 60 mM, from about 10 mM to about 55 mM, from about 10 mM to about 50 mM, from about 10 mM to about 45 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 10 mM to about 25 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, from about 10 mM to about 14 mM, from about 10 mM to about 13 mM, from about 10 mM to about 12 mM, from about 10 mM to about 11 mM, from about 15 mM to about 100 mM, from about 15 mM to about 95 mM, from about 15 mM to about 90 mM, from about 15 mM to about 85 mM, from about 15 mM to about 80 mM, from about 15 mM to about 75 mM, from about 15 mM to about 70 mM, from about 15 mM to about 65 mM, from about 15 mM to about 60 mM, from about 15 mM to about 55 mM, from about 15 mM to about 50 mM, from about 15 mM to about 45 mM, from about 15 mM to about 40 mM, from about 15 mM to about 35 mM, from about 15 mM to about 30 mM, from about 15 mM to about 25 mM, from about 15 mM to about 20 mM, from about 15 mM to about 19 mM, from about 15 mM to about 18 mM, from about 15 mM to about 17 mM, from about 15 mM to about 16 mM, from about 20 mM to about 100 mM, from about 20 mM to about 95 mM, from about 20 mM to about 90 mM, from about 20 mM to about 85 mM, from about 20 mM to about 80 mM, from about 20 mM to about 75 mM, from about 20 mM to about 70 mM, from about 20 mM to about 65 mM, from about 20 mM to about 60 mM, from about 20 mM to about 55 mM, from about 20 mM to about 50 mM, from about 20 mM to about 45 mM, from about 20 mM to about 40 mM, from about 20 mM to about 35 mM, from about 20 mM to about 30 mM, from about 20 mM to about 25 mM, from about 20 mM to about 24 mM, from about 20 mM to about 23 mM, from about 20 mM to about 22 mM, from about 20 mM to about 21 mM, from about 25 mM to about 100 mM, from about 25 mM to about 95 mM, from about 25 mM to about 90 mM, from about 25 mM to about 85 mM, from about 25 mM to about 80 mM, from about 25 mM to about 75 mM, from about 25 mM to about 70 mM, from about 25 mM to about 65 mM, from about 25 mM to about 60 mM, from about 25 mM to about 55 mM, from about 25 mM to about 50 mM, from about 25 mM to about 45 mM, from about 25 mM to about 40 mM, from about 25 mM to about 35 mM, from about 25 mM to about 30 mM, from about 25 mM to about 29 mM, from about 25 mM to about 28 mM, from about 25 mM to about 27 mM, from about 25 mM to about 26 mM from about 30 mM to about 100 mM, from about 30 mM to about 95 mM, from about 30 mM to about 90 mM, from about 30 mM to about 85 mM, from about 30 mM to about 80 mM, from about 30 mM to about 75 mM, from about 30 mM to about 70 mM, from about 30 mM to about 65 mM, from about 30 mM to about 60 mM, from about 30 mM to about 55 mM, from about 30 mM to about 50 mM, from about 30 mM to about 45 mM, from about 30 mM to about 40 mM, from about 30 mM to about 35 mM, from about 30 mM to about 34 mM, from about 30 mM to about 33 mM, from about 30 mM to about 32 mM, from about 30 mM to about 31 mM, from about 35 mM to about 100 mM, from about 35 mM to about 95 mM, from about 35 mM to about 90 mM, from about 35 mM to about 85 mM, from about 35 mM to about 80 mM, from about 35 mM to about 75 mM, from about 35 mM to about 70 mM, from about 35 mM to about 65 mM, from about 35 mM to about 60 mM, from about 35 mM to about 55 mM, from about 35 mM to about 50 mM, from about 35 mM to about 45 mM, from about 35 mM to about 40 mM, from about 35 mM to about 39 mM, from about 35 mM to about 38 mM, from about 35 mM to about 37 mM, from about 35 mM to 36 mM, from about 40 mM to about 100 mM, from about 40 mM to about 95 mM, from about 40 mM to about 90 mM, from about 40 mM to about 85 mM, from about 40 mM to about 80 mM, from about 40 mM to about 75 mM, from about 40 mM to about 70 mM, from about 40 mM to about 65 mM, from about 40 mM to about 60 mM, from about 40 mM to about 55 mM, from about 40 mM to about 50 mM, from about 40 mM to about 45 mM, from about 40 mM to about 44 mM, from about 40 mM to about 43 mM, from about 40 mM to about 42 mM, from about 40 mM to about 41 mM, from about 45 mM to about 100 mM, from about 45 mM to about 95 mM, from about 45 mM to about 90 mM, from about 45 mM to about 85 mM, from about 45 mM to about 80 mM, from about 45 mM to about 75 mM, from about 45 mM to about 70 mM, from about 45 mM to about 65 mM, from about 45 mM to about 60 mM, from about 45 mM to about 55 mM, from about 45 mM to about 50 mM, from about 45 mM to about 49 mM, from about 45 mM to about 48 mM, from about 45 mM to about 47 mM, from about 45 mM to about 46 mM, from about 50 mM to about 100 mM, from about 50 mM to about 95 mM, from about 50 mM to about 90 mM, from about 50 mM to about 85 mM, from about 50 mM to about 80 mM, from about 50 mM to about 75 mM, from about 50 mM to about 70 mM, from about 50 mM to about 65 mM, from about 50 mM to about 60 mM, from about 50 mM to about 55 mM, from about 50 mM to about 54 mM, from about 50 mM to about 53 mM, from about 50 mM to about 52 mM, from about 50 mM to about 51 mM, from about 60 mM to about 100 mM, from about 60 mM to about 95 mM, from about 60 mM to about 90 mMApproximately 60mM to approximately 85mM, approximately 60mM to approximately 80mM, approximately 60mM to approximately 75mM, approximately 60mM to approximately 70mM, approximately 60mM to approximately 65mM, approximately 60mM to approximately 64mM, approximately 60mM ~63mM, 60mM~62mM, 60mM~61mM, 70mM~100mM, 70mM~95mM, 70mM~90mM, 70mM~85m The concentration of the glycerol in the solution may be about 70 mM, about 70 mM to about 80 mM, about 70 mM to about 75 mM, about 70 mM to about 74 mM, about 70 mM to about 73 mM, about 70 mM to about 72 mM, about 70 mM to about 71 mM, about 90 mM to about 100 mM, about 90 mM to about 95 mM, about 90 mM to about 94 mM, about 90 mM to about 93 mM, about 90 mM to about 92 mM, or about 90 mM to about 91 mM.

[0089] salt Aqueous antibody formulations described herein comprise a salt (e.g., one or more salts) selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate. In some embodiments, aqueous antibody formulations described herein comprise a salt (e.g., one or more salts) selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, and magnesium sulfate.

[0090] The final concentration of a salt (or the total final concentration of one or more salts) selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate in any of the formulations described herein can be from about 0.01 mM to about 750 mM (or any of the subranges of this range described herein). In some embodiments, the final concentration of the salt in any of the formulations described herein is from about 0.01 mM to about 750 mM, from about 0.01 mM to about 700 mM, from about 0.01 mM to about 650 mM, from about 0.01 mM to about 600 mM, from about 0.01 mM to about 550 mM, from about 0.01 mM to about 500 mM, from about 0.01 mM to about 450 mM, from about 0.01 mM to about 400 mM, from about 0.01 mM to about 350 mM, or from about 0.01 mM to about 500 mM. M, about 0.01mM to about 300mM, about 0.01mM to about 290mM, about 0.01mM to about 280mM, about 0.01mM to about 270mM, about 0.01mM to about 260mM, about 0.01mM to about 250mM, about 0.01mM to about 240mM, about 0.01mM to about 230mM, about 0.01mM to about 220mM, about 0.01mM to about 210mM, about 0.01mM to about 200mM, about 0.01 mM~about 190mM, about 0.01mM~about 180mM, about 0.01mM~about 170mM, about 0.01mM~about 160mM, about 0.01mM~about 150mM, about 0.01mM~about 140mM, about 0.01mM to about 130mM, about 0.01mM to about 120mM, about 0.01mM to about 110mM, about 0.01mM to about 100mM, about 0.01mM to about 95mM, about 0.01mM to about 90mM , about 0.01mM to about 85mM, about 0.01mM to about 80mM, about 0.01mM to about 75mM, about 0.01mM to about 70mM, about 0.01mM to about 65mM, about 0.01mM to about 60mM, about 0.01mM to about 55mM, about 0.01mM to about 50mM, about 0.01mM to about 45mM, about 0.01mM to about 40mM, about 0.01mM to about 35mM, about 0.01mM to about 30mM, about 0.0.01 mM to about 25 mM, about 0.01 mM to about 20 mM, about 0.01 mM to about 15 mM, about 0.01 mM to about 10 mM, about 0.01 mM to about 9 mM, about 0.01 mM to about 8 mM, about 0.01 mM to about 7 mM, about 0.01 mM to about 6 mM, about 0.01 mM to about 5 mM, about 0.01 mM to about 4 mM, about 0.01 mM to about 3 mM, about 0.01 mM to about 2 mM, about 0.01 mM to about 1 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.1 mM, about 0.1 mM to about 500 mM M, about 0.1mM to about 450mM, about 0.1mM to about 400mM, about 0.1mM to about 350mM, about 0.1mM to about 300mM, about 0.1mM to about 290mM, about 0.1mM to about 280mM, about 0.1mM to about 270mM, about 0.1mM to about 260mM , about 0.1mM to about 250mM, about 0.1mM to about 240mM, about 0.1mM to about 230mM, about 0.1mM to about 220mM, about 0.1mM to about 210mM, about 0.1mM to about 200mM, about 0.1mM to about 190mM, about 0.1mM to about 180mM, about 0.1mM to about 170mM, about 0.1mM to about 160mM, about 0.1mM to about 150mM, about 0.1mM to about 140mM, about 0.1mM to about 130mM, about 0.1mM to about 120mM, about 0.1mM to about 110mM, about 0.1mM to about 100mM, about 0 .1mM to about 95mM, about 0.1mM to about 90mM, about 0.1mM to about 85mM, about 0.1mM to about 80mM, about 0.1mM to about 75mM, about 0.1mM to about 70mM, about 0.1mM to about 65mM, about 0.1mM to about 60mM, about 0.1mM to about 55mM , about 0.1mM to about 50mM, about 0.1mM to about 45mM, about 0.1mM to about 40mM, about 0.1mM to about 35mM, about 0.1mM to about 30mM, about 0.1mM to about 25mM, about 0.1mM to about 20mM, about 0.1mM to about 15mM, about 0.1mM to about 10mM, about 0.1mM to about 9mM, about 0.1mM to about 8mM, about 0.1mM to about 7mM, about 0.1mM to about 6mM, about 0.1mM to about 5mM, about 0.1mM to about 4mM, about 0.1mM to about 3mM, about 0.1mM to about 2mM, about 0.1mM to about 1mM. From about 0.1 mM to about 0.5 mM, from about 0.1 mM to about 0.2 mM, from 0.2 mM to about 750 mM, from about 0.2 mM to about 700 mM, from about 0.2 mM to about 650 mM, from about 0.2 mM to about 600 mM, from about 0.2 mM to about 550 mM, from about 0.2 mM to about 500 mM, from about 0.2 mM to about 450 mM, from about 0.2 mM to about 400 mM, from about 0.2 mM to about 350 mM, from about 0.2 mM to about 300 mM, from about 0.2 mM to about 290 mM, from about 0.2 mM to about 280 mM, from about 0.2 mM to about 270 mM, from about 0.2 mM to about 260 mM, from about 0.2 mM to about 250 mM, from about 0.2 mM to about 240 mM, from about 0.2 mM to about 230 mM, from about 0.2 mM to about 220 mM, from about 0.2 mM to about 210 mM, from about 0.2 mM to about 200 mM, from about 0.2 mM to about 190 mM, from about 0.2 mM to about 180 mM, from about 0.2 mM to about 170 mM, from about 0.2 mM to about 160 mM, from about 0.2 mM to about 150 mM, from about 0.2 mM to about 140 mM, from about 0.2 mM to about 130 mM, from about 0.2 mM to about 120 mM, from about 0.2 mM to about 110 mM, from about 0.2 mM to about 100 mM, from about 0.2 mM to about 95 mM, from about 0.2 mM to about 90 mM, from about 0.2 mM to about 85 mM, from about 0.2 mM to about 80 mM, from about 0.2 mM to about 75 mM, from about 0.2 mM to about 70 mM, from about 0.2 mM to about 65 mM, from about 0.2 mM to about 60 mM, from about 0.2 mM to about 55 mM, from about 0.2 mM to about 50 mM, from about 0.2 mM to about 45 mM, from about 0.2 mM to about 40 mM, from about 0.2 mM to about 35 mM, from about 0.2 mM to about 30 mM, from about 0.2 mM to about 25 mM, from about 0.2 mM to about 20 mM, from about 0.2 mM to about 15 mM, from about 0.2 mM to about 10 mM, from about 0.2 mM to about 9 mM, from about 0.2 mM to about 8 mM, from about 0.2 mM to about 7 mM, from about 0.2 mM to about 6 mM, from about 0.2 mM to about 5 mM, from about 0.2 mM to about 4 mM, from about 0.2 mM to about 3 mM, from about 0.2 mM to about 2 mM, from about 0.2 mM to about 1 mM, from about 0.2 mM to about 0.5 mM, from about 0.5 mM to about 750 mM, from about 0.5 mM to about 700 mM, from about 0.5 mM to about 650 mM, from about 0.5 mM to about 600 mM, from about 0.5 mM to about 550 mM, from about 0.5 mM to about 500 mM, from about 0.5 mM to about 450 mM, from about 0.5 mM to about 400 mM, from about 0.5 mM to about 350 mM, from about 0.5 mM to about 300 mM, from about 0.5 mM to about 290 mM, from about 0.5 mM to about 280 mM, from about 0.5 mM to about 270 mM, from about 0.5 mM to about 260 mMfrom about 0.5 mM to about 250 mM, from about 0.5 mM to about 240 mM, from about 0.5 mM to about 230 mM, from about 0.5 mM to about 220 mM, from about 0.5 mM to about 210 mM, from about 0.5 mM to about 200 mM, from about 0.5 mM to about 190 mM, from about 0.5 mM to about 180 mM, from about 0.5 mM to about 170 mM, from about 0.5 mM to about 160 mM, from about 0.5 mM to about 150 mM, from about 0.5 mM to about 140 mM, from about 0.5 mM to about 130 mM, from about 0.5 mM to about 120 mM, from about 0.5 mM to about 110 mM, from about 0.5 mM to about 100 mM, from about 0.5 mM to about 95 mM, from about 0.5 mM to about 90 mM, from about 0.5 mM to about 85 mM, from about 0.5 mM to about 80 mM, from about 0.5 mM to about 75 mM, from about 0.5 mM to about 70 mM, from about 0.5 mM to about 65 mM, from about 0.5 mM to about 60 mM, from about 0.5 mM to about 55 mM, from about 0.5 mM to about 50 mM, from about 0.5 mM to about 45 mM, from about 0.5 mM to about 40 mM, from about 0.5 mM to about 35 mM, from about 0.5 mM to about 30 mM, from about 0.5 mM to about 25 mM, from about 0.5 mM to about 20 mM, from about 0.5 mM to about 15 mM, from about 0.5 mM to about 10 mM, from about 0.5 mM to about 9 mM, from about 0.5 mM to about 8 mM, from about 0.5 mM to about 7 mM, from about 0.5 mM to about 6 mM, from about 0.5 mM to about 5 mM, from about 0.5 mM to about 4 mM, from about 0.5 mM to about 3 mM, from about 0.5 mM to about 2 mM, from about 0.5 mM to about 1 mM, from about 1 mM to about 750 mM, from about 1 mM to about 700 mM, from about 1 mM to about 650 mM, from about 1 mM to about 600 mM, from about 1 mM to about 550 mM, from about 1 mM to about 500 mM, from about 1 mM to about 450 mM, from about 1 mM to about 400 mM, from about 1 mM to about 350 mM, from about 1 mM to about 300 mM, from about 1 mM to about 290 mM, from about 1 mM to about 280 mM, from about 1 mM to about 270 mM, from about 1 mM to about 260 mM, from about 1 mM to about 250 mM, from about 1 mM to about 240 mM, from about 1 mM to about 230 mM, from about 1 mM to about 220 mM, from about 1 mM to about 210 mM, from about 1 mM to about 200 mM, from about 1 mM to about 190 mM, from about 1 mM to about 180 mM, from about 1 mM to about 170 mM, from about 1 mM to about 160 mM, from about 1 mM to about 150 mM, from about 1 mM to about 140 mM, from about 1 mM to about 130 mM, from about 1 mM to about 120 mM, from about 1 mM to about 110 mM, from about 1 mM to about 100 mM, from about 1 mM to about 95 mM, from about 1 mM to about 90 mM, from about 1 mM to about 85 mM, from about 1 mM to about 80 mM, from about 1 mM to about 75 mM, from about 1 mM to about 70 mMfrom about 1 mM to about 65 mM, from about 1 mM to about 60 mM, from about 1 mM to about 55 mM, from about 1 mM to about 50 mM, from about 1 mM to about 45 mM, from about 1 mM to about 40 mM, from about 1 mM to about 35 mM, from about 1 mM to about 30 mM, from about 1 mM to about 25 mM, from about 1 mM to about 20 mM, from about 1 mM to about 15 mM, from about 1 mM to about 10 mM, from about 1 mM to about 9 mM, from about 1 mM to about 8 mM, from about 1 mM to about 7 mM, from about 1 mM to about 6 mM, from about 1 mM to about 5 mM, from about 1 mM to about 4 mM, from about 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 2 mM to about 750 mM, from about 2 mM to about 700 mM, from about 2 mM to about 650 mM, from about 2 mM to about 600 mM, from about 2 mM to about 550 mM, from about 2 mM to about 500 mM, from about 2 mM to about 450 mM, from about 2 mM to about 400 mM, from about 2 mM to about 350 mM, from about 2 mM to about 300 mM, from about 2 mM to about 290 mM, from about 2 mM to about 280 mM, from about 2 mM to about 270 mM, from about 2 mM to about 260 mM, from about 2 mM to about 250 mM, from about 2 mM to about 240 mM, from about 2 mM to about 230 mM, from about 2 mM to about 220 mM, from about 2 mM to about 210 mM, from about 2 mM to about 200 mM, from about 2 mM to about 190 mM, from about 2 mM to about 180 mM, from about 2 mM to about 170 mM, from about 2 mM to about 160 mM, from about 2 mM to about 150 mM, from about 2 mM to about 140 mM, from about 2 mM to about 130 mM, from about 2 mM to about 120 mM, from about 2 mM to about 110 mM, from about 2 mM to about 100 mM, from about 2 mM to about 95 mM, from about 2 mM to about 90 mM, from about 2 mM to about 85 mM, from about 2 mM to about 80 mM, from about 2 mM to about 75 mM, from about 2 mM to about 70 mM, from about 2 mM to about 65 mM, from about 2 mM to about 60 mM, from about 2 mM to about 55 mM, from about 2 mM to about 50 mM, from about 2 mM to about 45 mM, from about 2 mM to about 40 mM, from about 2 mM to about 35 mM, from about 2 mM to about 30 mM, from about 2 mM to about 25 mM, from about 2 mM to about 20 mM, from about 2 mM to about 15 mM, from about 2 mM to about 10 mM, from about 2 mM to about 9 mM, from about 2 mM to about 8 mM, from about 2 mM to about 7 mM, from about 2 mM to about 6 mM, from about 2 mM to about 5 mM, from about 5 mM to about 750 mM, from about 5 mM to about 700 mM, from about 5 mM to about 650 mM, from about 5 mM to about 600 mM, from about 5 mM to about 550 mM, from about 5 mM to about 500 mM, from about 5 mM to about 450 mM, from about 5 mM to about 400 mM, from about 5 mM to about 350 mM, from about 5 mM to about 300 mM, from about 5 mM to about 290 mM, from about 5 mM to about 280 mM, from about 5 mM to about 270 mM, from about 5 mM to about 260 mM, from about 5 mM to about 250 mM, from about 5 mM to about 240 mM, from about 5 mM to about 230 mM, from about 5 mM to about 220 mM, from about 5 mM to about 210 mM, from about 5 mM to about 200 mM, from about 5 mM to about 190 mM, from about 5 mM to about 180 mM, from about 5 mM to about 170 mM, from about 5 mM to about 160 mM, from about 5 mM to about 150 mM, from about 5 mM to about 140 mM, from about 5 mM to about 130 mM, from about 5 mM to about 120 mM, from about 5 mM to about 110 mM, from about 5 mM to about 100 mM, from about 5 mM to about 95 mM, from about 5 mM to about 90 mM, from about 5 mM to about 85 mM, from about 5 mM to about 80 mM, from about 5 mM to about 75 mM, from about 5 mM to about 70 mM, from about 5 mM to about 65 mM, from about 5 mM to about 60 mM, from about 5 mM to about 55 mM, from about 5 mM to about 50 mM, from about 5 mM to about 45 mM, from about 5 mM to about 40 mM, from about 5 mM to about 35 mM, from about 5 mM to about 30 mM, from about 5 mM to about 25 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 10 mM, from about 10 mM to about 750 mM, from about 10 mM to about 700 mM, from about 10 mM to about 650 mM, from about 10 mM to about 600 mM, from about 10 mM to about 550 mM, from about 10 mM to about 500 mM, from about 10 mM to about 450 mM, from about 10 mM to about 400 mM, from about 10 mM to about 350 mM, from about 10 mM to about 300 mM, from about 10 mM to about 290 mM, from about 10 mM to about 280 mM, from about 10 mM to about 270 mM, from about 10 mM to about 260 mM, from about 10 mM to about 250 mM, from about 10 mM to about 240 mM, from about 10 mM to about 230 mM, from about 10 mM to about 220 mM, from about 10 mM to about 210 mM, from about 10 mM to about 200 mM, from about 10 mM to about 190 mM, from about 10 mM to about 180 mM, from about 10 mM to about 170 mM, from about 10 mM to about 160 mM, from about 10 mM to about 150 mM, from about 10 mM to about 140 mM, from about 10 mM to about 130 mM, from about 10 mM to about 120 mM, from about 10 mM to about 110 mM, from about 10 mM to about 100 mM, from about 10 mM to about 95 mM, from about 10 mM to about 90 mM, from about 10 mM to about 85 mM, from about 10 mM to about 80 mMfrom about 10 mM to about 75 mM, from about 10 mM to about 70 mM, from about 10 mM to about 65 mM, from about 10 mM to about 60 mM, from about 10 mM to about 55 mM, from about 10 mM to about 50 mM, from about 10 mM to about 45 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 10 mM to about 25 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, from about 15 mM to about 750 mM, from about 15 mM to about 700 mM, from about 15 mM to about 650 mM, from about 15 mM to about 600 mM, from about 15 mM to about 550 mM, from about 15 mM to about 500 mM, from about 15 mM to about 450 mM, from about 15 mM to about 400 mM, from about 15 mM to about 350 mM, from about 15 mM to about 300 mM, from about 15 mM to about 290 mM, from about 15 mM to about 280 mM, from about 15 mM to about 270 mM, from about 15 mM to about 260 mM, from about 15 mM to about 250 mM, from about 15 mM to about 240 mM, from about 15 mM to about 230 mM, from about 15 mM to about 220 mM, from about 15 mM to about 210 mM, from about 15 mM to about 200 mM, from about 15 mM to about 190 mM, from about 15 mM to about 180 mM, from about 15 mM to about 170 mM, from about 15 mM to about 160 mM, from about 15 mM to about 150 mM, from about 15 mM to about 140 mM, from about 15 mM to about 130 mM, from about 15 mM to about 120 mM, from about 15 mM to about 110 mM, from about 15 mM to about 100 mM, from about 15 mM to about 95 mM, from about 15 mM to about 90 mM, from about 15 mM to about 85 mM, from about 15 mM to about 80 mM, from about 15 mM to about 75 mM, from about 15 mM to about 70 mM, from about 15 mM to about 65 mM, from about 15 mM to about 60 mM, from about 15 mM to about 55 mM, from about 15 mM to about 50 mM, from about 15 mM to about 45 mM, from about 15 mM to about 40 mM, from about 15 mM to about 35 mM, from about 15 mM to about 30 mM, from about 15 mM to about 25 mM, from about 15 mM to about 20 mM, from about 20 mM to about 750 mM, from about 20 mM to about 700 mM, from about 20 mM to about 650 mM, from about 20 mM to about 600 mM, from about 20 mM to about 550 mM, from about 20 mM to about 500 mM, from about 20 mM to about 450 mM, from about 20 mM to about 400 mM, from about 20 mM to about 350 mM, from about 20 mM to about 300 mM, from about 20 mM to about 290 mM, from about 20 mM to about 280 mM, from about 20 mM to about 270 mM, from about 20 mM to about 260 mM, from about 20 mM to about 250 mM, from about 20 mM to about 240 mM, from about 20 mM to about 230 mM, from about 20 mM to about 220 mM, from about 20 mM to about 210 mM, from about 20 mM to about 200 mM,from about 20 mM to about 190 mM, from about 20 mM to about 180 mM, from about 20 mM to about 170 mM, from about 20 mM to about 160 mM, from about 20 mM to about 150 mM, from about 20 mM to about 140 mM, from about 20 mM to about 130 mM, from about 20 mM to about 120 mM, from about 20 mM to about 110 mM, from about 20 mM to about 100 mM, from about 20 mM to about 95 mM, from about 20 mM to about 90 mM, from about 20 mM to about 85 mM, from about 20 mM to about 80 mM, from about 20 mM to about 75 mM, from about 20 mM to about 70 mM, from about 20 mM to about 65 mM, from about 20 mM to about 60 mM, from about 20 mM to about 55 mM, from about 20 mM to about 50 mM, from about 20 mM to about 45 mM, from about 20 mM to about 40 mM, from about 20 mM to about 35 mM, from about 20 mM to about 30 mM, from about 20 mM to about 25 mM, from about 25 mM to about 750 mM, from about 25 mM to about 700 mM, from about 25 mM to about 650 mM, from about 25 mM to about 600 mM, from about 25 mM to about 550 mM, from about 25 mM to about 500 mM, from about 25 mM to about 450 mM, from about 25 mM to about 400 mM, from about 25 mM to about 350 mM, from about 25 mM to about 300 mM, from about 25 mM to about 290 mM, from about 25 mM to about 280 mM, from about 25 mM to about 270 mM, from about 25 mM to about 260 mM, from about 25 mM to about 250 mM, from about 25 mM to about 240 mM, from about 25 mM to about 230 mM, from about 25 mM to about 220 mM, from about 25 mM to about 210 mM, from about 25 mM to about 200 mM, from about 25 mM to about 190 mM, from about 25 mM to about 180 mM, from about 25 mM to about 170 mM, from about 25 mM to about 160 mM, from about 25 mM to about 150 mM, from about 25 mM to about 140 mM, from about 25 mM to about 130 mM, from about 25 mM to about 120 mM, from about 25 mM to about 110 mM, from about 25 mM to about 100 mM, from about 25 mM to about 95 mM, from about 25 mM to about 90 mM, from about 25 mM to about 85 mM, from about 25 mM to about 80 mM, from about 25 mM to about 75 mM, from about 25 mM to about 70 mM, from about 25 mM to about 65 mM, from about 25 mM to about 60 mM, from about 25 mM to about 50 mM, from about 25 mM to about 45 mM, from about 25 mM to about 40 mM, from about 25 mM to about 35 mM, from about 25 mM to about 30 mM, from about 30 mM to about 750 mM, from about 30 mM to about 700 mM, from about 30 mM to about 650 mM, from about 30 mM to about 600 mM, from about 30 mM to about 550 mM, from about 30 mM to about 500 mM, from about 30 mM to about 450 mM, from about 30 mM to about 400 mM, from about 30 mM to about 350 mM, from about 30 mM to about 300 mM, from about 30 mM to about 290 mMFrom about 30 mM to about 280 mM, from about 30 mM to about 270 mM, from about 30 mM to about 260 mM, from about 30 mM to about 250 mM, from about 30 mM to about 240 mM, from about 30 mM to about 230 mM, from about 30 mM to about 220 mM, from about 30 mM to about 210 mM, from about 30 mM to about 200 mM, from about 30 mM to about 190 mM, from about 30 mM to about 180 mM, from about 30 mM to about 170 mM, from about 30 mM to about 160 mM, from about 30 mM to about 150 mM, from about 30 mM to about 140 mM, from about 30 mM to about 130 mM, from about 30 mM to about 120 mM, from about 30 mM to about 110 mM, from about 30 mM to about 100 mM, from about 30 mM to about 95 mM, from about 30 mM to about 90 mM, from about 30 mM to about 85 mM, from about 30 mM to about 80 mM, from about 30 mM to about 75 mM, from about 30 mM to about 70 mM, from about 30 mM to about 65 mM, from about 30 mM to about 60 mM, from about 30 mM to about 55 mM, from about 30 mM to about 50 mM, from about 30 mM to about 45 mM, from about 30 mM to about 40 mM, from about 30 mM to about 35 mM, from about 35 mM to about 750 mM, from about 35 mM to about 700 mM, from about 35 mM to about 650 mM, from about 35 mM to about 600 mM, from about 35 mM to about 550 mM, from about 35 mM to about 500 mM, from about 35 mM to about 450 mM, from about 35 mM to about 400 mM, from about 35 mM to about 350 mM, from about 35 mM to about 300 mM, from about 35 mM to about 290 mM, from about 35 mM to about 280 mM, from about 35 mM to about 270 mM, from about 35 mM to about 260 mM, from about 35 mM to about 250 mM, from about 35 mM to about 240 mM, from about 35 mM to about 230 mM, from about 35 mM to about 220 mM, from about 35 mM to about 210 mM, from about 35 mM to about 200 mM, from about 35 mM to about 190 mM, from about 35 mM to about 180 mM, from about 35 mM to about 170 mM, from about 35 mM to about 160 mM, from about 35 mM to about 150 mM, from about 35 mM to about 140 mM, from about 35 mM to about 130 mM, from about 35 mM to about 120 mM, from about 35 mM to about 110 mM, from about 35 mM to about 100 mM, from about 35 mM to about 95 mM, from about 35 mM to about 90 mM, from about 35 mM to about 85 mM < from about 35 mM to about 80 mM, from about 35 mM to about 75 mM, from about 35 mM to about 70 mM, from about 35 mM to about 65 mM, from about 35 mM to about 60 mM, from about 35 mM to about 55 mM, from about 35 mM to about 50 mM, from about 35 mM to about 45 mM, from about 35 mM to about 40 mM, from about 40 mM to about 750 mM, from about 40 mM to about 700 mM, from about 40 mM to about 650 mM, from about 40 mM to about 600 mM,About 40 mM to about 550 mM, about 40 mM to about 500 mM, about 40 mM to about 450 mM, about 40 mM to about 400 mM, about 40 mM to about 350 mM, about 40 mM to about 300 mM, about 40 mM to about 290 mM, about 40 mM to about 280 mM, about 40 mM to about 270 mM, about 40 mM to about 260 mM, about 40 mM to about 250 mM, about 40 mM to about 240 mM, about 40 mM to about 230 mM, about 40 mM to about 220 mM, about 40 mM to about 210 mM, about 40 mM to about 200 mM, about 40 mM to about 190 mM, about 40 mM to about 180 mM, about 40 mM to about 170 mM, about 40 mM to about 160 mM, about 40 mM to about 150 mM, about 40 mM to about 140 mM, about 40 mM to about 130 mM, about 40 mM to about 120 mM, about 40 mM to about 110 mM, about 40 mM to about 100 mM, about 40 mM to about 95 mM, about 40 mM to about 90 mM, about 40 mM to about 85 mM, about 40 mM to about 80 mM, about 40 mM to about 75 mM, about 40 mM to about 70 mM, about 40 mM to about 65 mM, about 40 mM to about 60 mM, about 40 mM to about 55 mM, about 40 mM to about 50 mM, about 40 mM to about 45 mM, About 45 mM to about 750 mM, about 45 mM to about 700 mM, about 45 mM to about 650 mM, about 45 mM to about 600 mM, about 45 mM to about 550 mM, about 45 mM to about 500 mM, about 45 mM to about 450 mM, about 45 mM to about 400 mM, about 45 mM to about 350 mM, about 45 mM to about 300 mM, about 45 mM to about 290 mM, about 45 mM to about 280 mM, about 45 mM to about 270 mM, about 45 mM to about 260 mM, about 45 mM to about 250 mM, about 45 mM to about 240 mM, about 45 mM to about 230 mM, about 45 mM to about 220 mM, about 45 mM to about 210 mM, about 45 mM to about 200 mM, about 45 mM to about 190 mM, about 45 mM to about 180 mM, about 45 mM to about 170 mM, about 45 mM to about 160 mM, about 45 mM to about 150 mM, about 45 mM to about 140 mM, about 45 mM to about 130 mM, about 45 mM to about 120 mM, about 45 mM to about 110 mM, about 45 mM to about 100 mM, about 45 mM to about 95 mM, about 45 mM to about 90 mM, about 45 mM to about 85 mM, about 45 mM to about 80 mM, about 45 mM to about 75 mM, about 45 mM to about 70 mM, about 45 mM to about 65 mM, about 45 mM to about 60 mM, about 45 mM to about 55 mM, about 45 mM to about 50 mM,from about 50 mM to about 750 mM, from about 50 mM to about 700 mM, from about 50 mM to about 650 mM, from about 50 mM to about 600 mM, from about 50 mM to about 550 mM, from about 50 mM to about 500 mM, from about 50 mM to about 450 mM, from about 50 mM to about 400 mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM, from about 50 mM to about 290 mM, from about 50 mM to about 280 mM, from about 50 mM to about 270 mM, from about 50 mM to about 260 mM, from about 50 mM to about 250 mM, from about 50 mM to about 240 mM, from about 50 mM to about 230 mM, from about 50 mM to about 220 mM, from about 50 mM to about 210 mM, from about 50 mM to about 200 mM, from about 50 mM to about 190 mM, from about 50 mM to about 180 mM, from about 50 mM to about 170 mM, from about 50 mM to about 160 mM, from about 50 mM to about 150 mM, from about 50 mM to about 140 mM, from about 50 mM to about 130 mM, from about 50 mM to about 120 mM, from about 50 mM to about 110 mM, from about 50 mM to about 100 mM, from about 50 mM to about 95 mM, from about 50 mM to about 90 mM, from about 50 mM to about 85 mM, from about 50 mM to about 80 mM, from about 50 mM to about 75 mM, from about 50 mM to about 70 mM, from about 50 mM to about 65 mM, from about 50 mM to about 60 mM, from about 60 mM to about 750 mM, from about 60 mM to about 700 mM, from about 60 mM to about 650 mM, from about 60 mM to about 600 mM, from about 60 mM to about 550 mM, from about 60 mM to about 500 mM, from about 60 mM to about 450 mM, from about 60 mM to about 400 mM, from about 60 mM to about 350 mM, from about 60 mM to about 300 mM, from about 60 mM to about 290 mM, from about 60 mM to about 280 mM, from about 60 mM to about 270 mM, from about 60 mM to about 260 mM, from about 60 mM to about 250 mM, from about 60 mM to about 240 mM, from about 60 mM to about 230 mM, from about 60 mM to about 220 mM, from about 60 mM to about 210 mM, from about 60 mM to about 200 mM, from about 60 mM to about 190 mM, from about 60 mM to about 180 mM, from about 60 mM to about 170 mM, from about 60 mM to about 160 mM, from about 60 mM to about 150 mM, from about 60 mM to about 140 mM, from about 60 mM to about 130 mM, from about 60 mM to about 120 mM, from about 60 mM to about 110 mM, from about 60 mM to about 100 mM, from about 60 mM to about 95 mM, from about 60 mM to about 90 mM, from about 60 mM to about 85 mM, from about 60 mM to about 80 mM, from about 60 mM to about 75 mM, from about 60 mM to about 70 mM, from about 70 mM to about 750 mM, from about 70 mM to about 700 mM, from about 70 mM to about 650 mM, from about 70 mM to about 600 mMfrom about 70 mM to about 550 mM, from about 70 mM to about 500 mM, from about 70 mM to about 450 mM, from about 70 mM to about 400 mM, from about 70 mM to about 350 mM, from about 70 mM to about 300 mM, from about 70 mM to about 290 mM, from about 70 mM to about 280 mM, from about 70 mM to about 270 mM, from about 70 mM to about 260 mM, from about 70 mM to about 250 mM, from about 70 mM to about 240 mM, from about 70 mM to about 230 mM, from about 70 mM to about 220 mM, from about 70 mM to about 210 mM, from about 70 mM to about 200 mM, from about 70 mM to about 190 mM, from about 70 mM to about 180 mM, from about 70 mM to about 170 mM, from about 70 mM to about 160 mM, from about 70 mM to about 150 mM, from about 70 mM to about 140 mM, from about 70 mM to about 130 mM, from about 70 mM to about 120 mM, from about 70 mM to about 110 mM, from about 70 mM to about 100 mM, from about 70 mM to about 95 mM, from about 70 mM to about 90 mM, from about 70 mM to about 85 mM, from about 70 mM to about 80 mM, from about 80 mM to about 750 mM, from about 80 mM to about 700 mM, from about 80 mM to about 650 mM, from about 80 mM to about 600 mM, from about 80 mM to about 550 mM, from about 80 mM to about 500 mM, from about 80 mM to about 450 mM, from about 80 mM to about 400 mM, from about 80 mM to about 350 mM, from about 80 mM to about 300 mM, from about 80 mM to about 290 mM, from about 80 mM to about 280 mM, from about 80 mM to about 270 mM, from about 80 mM to about 260 mM, from about 80 mM to about 250 mM, from about 80 mM to about 240 mM, from about 80 mM to about 230 mM, from about 80 mM to about 220 mM, from about 80 mM to about 210 mM, from about 80 mM to about 200 mM, from about 80 mM to about 190 mM, from about 80 mM to about 180 mM, from about 80 mM to about 170 mM, from about 80 mM to about 160 mM, from about 80 mM to about 150 mM, from about 80 mM to about 140 mM, from about 80 mM to about 130 mM, from about 80 mM to about 120 mM, from about 80 mM to about 110 mM, from about 80 mM to about 100 mM, from about 80 mM to about 95 mM, from about 80 mM to about 90 mM, from about 90 mM to about 750 mM, from about 90 mM to about 700 mM, from about 90 mM to about 650 mM, from about 90 mM to about 600 mM, from about 90 mM to about 550 mM, from about 90 mM to about 500 mM, from about 90 mM to about 450 mM, from about 90 mM to about 400 mM, from about 90 mM to about 350 mM, from about 90 mM to about 300 mM, from about 90 mM to about 290 mM, from about 90 mM to about 280 mM, from about 90 mM to about 270 mM, from about 90 mM to about 260 mM, from about 90 mM to about 250 mMAbout 90 mM to about 240 mM, about 90 mM to about 230 mM, about 90 mM to about 220 mM, about 90 mM to about 210 mM, about 90 mM to about 200 mM, about 90 mM to about 190 mM, about 90 mM to about 180 mM, about 90 mM to about 170 mM, about 90 mM to about 160 mM, about 90 mM to about 150 mM, about 90 mM to about 140 mM, about 90 mM to about 130 mM, about 90 mM to about 120 mM, about 90 mM to about 110 mM, about 90 mM to about 100 mM, About 100 mM to about 750 mM, about 100 mM to about 700 mM, about 100 mM to about 650 mM, about 100 mM to about 600 mM, about 100 mM to about 550 mM, about 100 mM to about 500 mM, about 100 mM to about 450 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 290 mM, about 100 mM to about 280 mM, about 100 mM to about 270 mM, about 100 mM to about 260 mM, about 100 mM to about 250 mM, about 100 mM to about 240 mM, about 100 mM to about 230 mM, about 100 mM to about 220 mM, about 100 mM to about 210 mM, about 100 mM to about 200 mM, about 100 mM to about 190 mM, about 100 mM to about 180 mM, about 100 mM to about 170 mM, about 100 mM to about 160 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110 mM to about 750 mM, about 110 mM to about 700 mM, about 110 mM to about 650 mM, about 110 mM to about 600 mM, about 110 mM to about 550 mM, about 110 mM to about 500 mM, about 110 mM to about 450 mM, about 110 mM to about 400 mM, about 110 mM to about 350 mM, about 110 mM to about 300 mM, about 110 mM to about 290 mM, about 110 mM to about 280 mM, about 110 mM to about 270 mM, about 110 mM to about 260 mM, about 110 mM to about 250 mM, about 110 mM to about 240 mM, about 110 mM to about 230 mM, about 110 mM to about 220 mM, about 110 mM to about 210 mM, about 110 mM to about 200 mM, about 110 mM to about 190 mM, about 110 mM to about 180 mM, about 110 mM to about 170 mM, about 110 mM to about 160 mM, about 110 mM to about 150 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 750 mM, about 120 mM to about 700 mM, about 120 mM to about 650 mM, about 120 mM to about 600 mM, about 120 mM to about 550 mM, about 120 mM to about 500 mM, about 120 mM to about 450 mM, about 120 mM to about 400 mM, about 120 mM to about 350 mM, about 120 mM to about 300 mM, about 120 mM to about 290 mM, about 120 mM to about 280 mM, about 120 mM to about 270 mM, about 120 mM to about 260 mMFrom about 120 mM to about 250 mM, from about 120 mM to about 240 mM, from about 120 mM to about 230 mM, from about 120 mM to about 220 mM, from about 120 mM to about 210 mM, from about 120 mM to about 200 mM, from about 120 mM to about 190 mM, from about 120 mM to about 180 mM, from about 120 mM to about 170 mM, from about 120 mM to about 160 mM, from about 120 mM to about 150 mM, from about 120 mM to about 140 mM, from about 120 mM to about 130 mM, from about 130 mM to about 750 mM, from about 130 mM to about 700 mM, from about 130 mM to about 650 mM, from about 130 mM to about 600 mM, from about 130 mM to about 550 mM, from about 130 mM to about 500 mM, from about 130 mM to about 450 mM, from about 130 mM to about 400 mM, from about 130 mM to about 350 mM, from about 130 mM to about 300 mM, from about 130 mM to about 290 mM, from about 130 mM to about 280 mM, from about 130 mM to about 270 mM, from about 130 mM to about 260 mM, from about 130 mM to about 250 mM, from about 130 mM to about 240 mM, from about 130 mM to about 230 mM, from about 130 mM to about 220 mM, from about 130 mM to about 210 mM, from about 130 mM to about 200 mM, from about 130 mM to about 190 mM, from about 130 mM to about 180 mM, from about 130 mM to about 170 mM, from about 130 mM to about 160 mM, from about 130 mM to about 150 mM, from about 130 mM to about 140 mM, from about 140 mM to about 750 mM, from about 140 mM to about 700 mM, from about 140 mM to about 650 mM, from about 140 mM to about 600 mM, from about 140 mM to about 550 mM, from about 140 mM to about 500 mM, from about 140 mM to about 450 mM, from about 140 mM to about 400 mM, from about 140 mM to about 350 mM, from about 140 mM to about 300 mM, from about 140 mM to about 290 mM, from about 140 mM to about 280 mM, from about 140 mM to about 270 mM, from about 140 mM to about 260 mM, from about 140 mM to about 250 mM, from about 140 mM to about 240 mM, from about 140 mM to about 230 mM, from about 140 mM to about 220 mM, from about 140 mM to about 210 mM, from about 140 mM to about 200 mM, from about 140 mM to about 190 mM, from about 140 mM to about 180 mM, from about 140 mM to about 170 mM, from about 140 mM to about 160 mM, from about 140 mM to about 150 mM, from about 150 mM to about 750 mM, from about 150 mM to about 700 mM, from about 150 mM to about 650 mM, from about 150 mM to about 600 mM, from about 150 mM to about 550 mM, from about 150 mM to about 500 mM, from about 150 mM to about 450 mM,from about 150 mM to about 400 mM, from about 150 mM to about 350 mM, from about 150 mM to about 300 mM, from about 150 mM to about 290 mM, from about 150 mM to about 280 mM, from about 150 mM to about 270 mM, from about 150 mM to about 260 mM, from about 150 mM to about 250 mM, from about 150 mM to about 240 mM, from about 150 mM to about 230 mM, from about 150 mM to about 220 mM, from about 150 mM to about 210 mM, from about 150 mM to about 200 mM, from about 150 mM to about 190 mM, from about 150 mM to about 180 mM, from about 150 mM to about 170 mM, from about 160 mM to about 750 mM, from about 160 mM to about 700 mM, from about 160 mM to about 650 mM, from about 160 mM to about 600 mM, from about 160 mM to about 550 mM, from about 160 mM to about 500 mM, from about 160 mM to about 450 mM, from about 160 mM to about 400 mM, from about 160 mM to about 350 mM, from about 160 mM to about 300 mM, from about 160 mM to about 290 mM, from about 160 mM to about 280 mM, from about 160 mM to about 270 mM, from about 160 mM to about 260 mM, from about 160 mM to about 250 mM, from about 160 mM to about 240 mM, from about 160 mM to about 230 mM, from about 160 mM to about 220 mM, from about 160 mM to about 210 mM, from about 160 mM to about 200 mM, from about 160 mM to about 190 mM, from about 160 mM to about 180 mM, from about 160 mM to about 170 mM, from about 170 mM to about 750 mM, from about 170 mM to about 700 mM, from about 170 mM to about 650 mM, from about 170 mM to about 600 mM, from about 170 mM to about 550 mM, from about 170 mM to about 500 mM, from about 170 mM to about 450 mM, from about 170 mM to about 400 mM, from about 170 mM to about 350 mM, from about 170 mM to about 300 mM, from about 170 mM to about 290 mM, from about 170 mM to about 280 mM, from about 170 mM to about 270 mM, from about 170 mM to about 260 mM, from about 170 mM to about 250 mM, from about 170 mM to about 240 mM, from about 170 mM to about 230 mM, from about 170 mM to about 220 mM, from about 170 mM to about 210 mM, from about 170 mM to about 200 mM, from about 170 mM to about 190 mM, from about 170 mM to about 180 mM, from about 180 mM to about 750 mM, from about 180 mM to about 700 mM, from about 180 mM to about 650 mM, from about 180 mM to about 600 mM, from about 180 mM to about 550 mM, from about 180 mM to about 500 mM, from about 180 mM to about 450 mM, from about 180 mM to about 400 mM, from about 180 mM to about 350 mMFrom about 180 mM to about 300 mM, from about 180 mM to about 290 mM, from about 180 mM to about 280 mM, from about 180 mM to about 270 mM, from about 180 mM to about 260 mM, from about 180 mM to about 250 mM, from about 180 mM to about 240 mM, from about 180 mM to about 230 mM, from about 180 mM to about 220 mM, from about 180 mM to about 210 mM, from about 180 mM to about 200 mM, from about 180 mM to about 190 mM, from about 190 mM to about 750 mM, from about 190 mM to about 700 mM, from about 190 mM to about 650 mM, from about 190 mM to about 600 mM, from about 190 mM to about 550 mM, from about 190 mM to about 500 mM, from about 190 mM to about 450 mM, from about 190 mM to about 400 mM, from about 190 mM to about 350 mM, from about 190 mM to about 300 mM, from about 190 mM to about 290 mM, from about 190 mM to about 280 mM, from about 190 mM to about 270 mM, from about 190 mM to about 260 mM, from about 190 mM to about 250 mM, from about 190 mM to about 240 mM, from about 190 mM to about 230 mM, from about 190 mM to about 220 mM, from about 190 mM to about 210 mM, from about 190 mM to about 200 mM from about 200 mM to about 750 mM, from about 200 mM to about 700 mM, from about 200 mM to about 650 mM, from about 200 mM to about 600 mM, from about 200 mM to about 550 mM, from about 200 mM to about 500 mM, from about 200 mM to about 450 mM, from about 200 mM to about 400 mM, from about 200 mM to about 350 mM, from about 200 mM to about 300 mM, from about 200 mM to about 290 mM, from about 200 mM to about 280 mM, from about 200 mM to about 270 mM, from about 200 mM to about 260 mM, from about 200 mM to about 250 mM, from about 200 mM to about 240 mM, from about 200 mM to about 230 mM, from about 200 mM to about 220 mM, from about 200 mM to about 210 mM, from about 210 mM to about 750 mM, from about 210 mM to about 700 mM, from about 210 mM to about 650 mM, from about 210 mM to about 600 mM, from about 210 mM to about 550 mM, from about 210 mM to about 500 mM, from about 210 mM to about 450 mM, from about 210 mM to about 400 mM, from about 210 mM to about 350 mM, from about 210 mM to about 300 mM, from about 210 mM to about 290 mM, from about 210 mM to about 280 mM, from about 210 mM to about 270 mM, from about 210 mM to about 260 mM, from about 210 mM to about 250 mM, from about 210 mM to about 240 mM, from about 210 mM to about 230 mM, from about 210 mM to about 220 mM, from about 220 mM to about 750 mM, from about 220 mM to about 700 mM, from about 220 mM to about 650 mM, from about 220 mM to about 600 mM, from about 220 mM to about 550 mM, from about 220 mM to about 500 mM, from about 220 mM to about 450 mM, from about 220 mM to about 400 mM, from about 220 mM to about 350 mM, from about 220 mM to about 300 mM, from about 220 mM to about 290 mM, from about 220 mM to about 280 mM, from about 220 mM to about 270 mM, from about 220 mM to about 260 mM, from about 220 mM to about 250 mM, from about 220 mM to about 240 mM, from about 220 mM to about 230 mM, from about 230 mM to about 750 mM, from about 230 mM to about 700 mM, from about 230 mM to about 650 mM, from about 230 mM to about 600 mM, from about 230 mM to about 550 mM, from about 230 mM to about 500 mM, from about 230 mM to about 450 mM, from about 230 mM to about 400 mM, from about 230 mM to about 350 mM, from about 230 mM to about 300 mM, from about 230 mM to about 290 mM, from about 230 mM to about 280 mM, from about 230 mM to about 270 mM, from about 230 mM to about 260 mM, from about 230 mM to about 250 mM, from about 230 mM to about 240 mM, from about 240 mM to about 750 mMfrom about 240 mM to about 700 mM, from about 240 mM to about 650 mM, from about 240 mM to about 600 mM, from about 240 mM to about 550 mM, from about 240 mM to about 500 mM, from about 240 mM to about 450 mM, from about 240 mM to about 400 mM, from about 240 mM to about 350 mM, from about 240 mM to about 300 mM, from about 240 mM to about 290 mM, from about 240 mM to about 280 mM, from about 240 mM to about 270 mM, from about 240 mM to about 260 mM, from about 240 mM to about 250 mM, from about 250 mM to about 750 mM, from about 250 mM to about 700 mM, from about 250 mM to about 650 mM, from about 250 mM to about 600 mM, from about 250 mM to about 550 mM, from about 250 mM to about 500 mM, from about 250 mM to about 450 mM, from about 250 mM to about 400 mM, from about 250 mM to about 350 mM, from about 250 mM to about 300 mM, from about 250 mM to about 290 mM, from about 250 mM to about 280 mM, from about 250 mM to about 270 mM, from about 250 mM to about 260 mM, from about 260 mM to about 750 mM, from about 260 mM to about 700 mM, from about 260 mM to about 650 mM, from about 260 mM to about 600 mM, from about 260 mM to about 550 mM, from about 260 mM to about 500 mM, from about 260 mM to about 450 mM, from about 260 mM to about 400 mM, from about 260 mM to about 350 mM, from about 260 mM to about 300 mM, from about 260 mM to about 290 mM, from about 260 mM to about 280 mM, from about 260 mM to about 270 mM, from about 270 mM to about 750 mM, from about 270 mM to about 700 mM, from about 270 mM to about 650 mM, from about 270 mM to about 600 mM, from about 270 mM to about 550 mM, from about 270 mM to about 500 mM, from about 270 mM to about 450 mM, from about 270 mM to about 400 mM, from about 270 mM to about 350 mM, from about 270 mM to about 300 mM, from about 270 mM to about 290 mM, from about 270 mM to about 280 mM, from about 280 mM to about 750 mM, from about 280 mM to about 700 mM, from about 280 mM to about 650 mM, from about 280 mM to about 600 mM, from about 280 mM to about 550 mM, from about 280 mM to about 500 mM, from about 280 mM to about 450 mM, from about 280 mM to about 400 mM, from about 280 mM to about 350 mM, from about 280 mM to about 300 mM, from about 280 mM to about 290 mM, from about 290 mM to about 750 mM, from about 290 mM to about 700 mM, from about 290 mM to about 650 mM, from about 290 mM to about 600 mM, from about 290 mM to about 550 mM, from about 290 mM to about 500 mM, from about 290 mM to about 450 mMApproximately 290mM to approximately 400mM, approximately 290mM to approximately 350mM, approximately 290mM to approximately 300mM, approximately 300mM to approximately 750mM, approximately 300mM to approximately 700mM, approximately 300mM to approximately 650mM, approximately 300mM to about 600mM, about 300mM to about 550mM, about 300mM to about 500mM, about 300mM to about 450mM, about 300mM to about 400mM, about 300mM to about 350mM, about 3 50 mM to about 750 mM, about 350 mM to about 700 mM, about 350 mM to about 650 mM, about 350 mM to about 600 mM, about 350 mM to about 550 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 750 mM, about 400 mM to about 700 mM, about 400 mM to about 650 mM, about 400 mM to about 600 mM, about 400 mm~about 550mM, about 400mM~about 500mM, about 400mM~about 450mM, about 450mM~about 750mM, about 450mM~about 700mM, about 450mM~about 650mM, about 450m M ~ about 600mM, about 450mM - about 550mM, about 450mM - about 500mM, about 500mM - about 750mM, about 500mM - about 700mM, about 500mM - about 650mM, about 500mM about 600 mM, about 500 mM to about 550 mM, about 550 mM to about 750 mM, about 550 mM to about 700 mM, about 550 mM to about 650 mM, about 550 mM to about 600 mM, about 600 mM to about 750 mM, about 600 mM to about 700 mM, about 600 mM to about 650 mM, about 650 mM to about 750 mM, about 650 mM to about 700 mM, or about 700 mM to about 750 mM.

[0091] pH Any of the aqueous antibody formulations described herein may have a concentration of about 4 to about 8, about 4 to about 7.8, about 4 to about 7.6, about 4 to about 7.4, about 4 to about 7.2, about 4 to about 7, about 4 to about 6.8, about 4 to about 6.6, about 4 to about 6.4, about 4 to about 6.2, about 4 to about 6, about 4 to about 5.8, about 4 to about 5.6, about 4 to about 5.4, about 4 to about 5.2, about 4 to about 5, about 4 to about 4.8, about 4 to about 4.6, about 4 to about 4.4, about 4 to about 4.2, about 4.2 to about 8, about 4.2 to about 7.8, about 4.2 to about 7.6, about 4.2 to about 7.4, about 4.2 to about 7.2, about 4.2 to about 7, about 4.2 to about 6.8, about 4.2 to about 6.6 , about 4.2 to about 6.4, about 4.2 to about 6.2, about 4.2 to about 6, about 4.2 to about 5.8, about 4.2 to about 5.6, about 4.2 to about 5.4, about 4.2 to about 5.2, about 4.2 to about 5, about 4.2 to about 4.8, about 4.2 to about 4.6, about 4.2 to about 4.4, about 4.4 to about 8, about 4.4 to about 7.8, About 4.4 to about 7.6, about 4.4 to about 7.4, about 4.4 to about 7.2, about 4.4 to about 7, about 4.4 to about 6.8, about 4.4 to about 6.6, about 4.4 to about 6.4, about 4.4 to about 6.2, about 4.4 to about 6, about 4.4 to about 5.8, about 4.4 to about 5.6, about 4.4 to about 5.4, about 4.4 to about 5.2 , about 4.4 to about 5, about 4.4 to about 4.8, about 4.4 to about 4.6, about 4.6 to about 8, about 4.6 to about 7.8, about 4.6 to about 7.6, about 4.6 to about 7.4, about 4.6 to about 7.2, about 4.6 to about 7, about 4.6 to about 6.8, about 4.6 to about 6.6, about 4.6 to about 6.4, about 4.6 to about 6.2, About 4.6 to about 6, about 4.6 to about 5.8, about 4.6 to about 5.6, about 4.6 to about 5.4, about 4.6 to about 5.2, about 4.6 to about 5, about 4.6 to about 4.8, about 4.8 to about 8, about 4.8 to about 7.8, about 4.8 to about 7.6, about 4.8 to about 7.4, about 4.8 to about 7.2, about 4.8 to about 7, about 4. 8 to about 6.8, about 4.8 to about 6.6, about 4.8 to about 6.4, about 4.8 to about 6.2, about 4.8 to about 6, about 4.8 to about 5.8, about 4.8 to about 5.6, about 4.8 to about 5.4, about 4.8 to about 5.2, about 4.8 to about 5, about 5 to about 8, about 5 to about 7.8, about 5 to about 7.6, about 5 to about 7.4, about 5 ~ about 7.4, about 5 to about 7.2, about 5 to about 7, about 5 to about 6.8, about 5 to about 6.6, about 5 to about 6.4, about 5 to about 6.2, about 5 to about 6, about 5 to about 5.8, about 5 to about 5.6, about 5 to about 5.4, about 5 to about 5.2, about 5.2 to about 8, about 5.2 to about 7.8, about 5.2 to about 7.6, about 5.2 to about 7.4, about 5.2 to about 7.2, about 5.2 to about 7, about 5.2 to about 6.8, about 5.2 to about 6.6, about 5.2 to about 6.4, about 5.2 to about 6.2, about 5.2 to about 6, about 5.2 to about 5.8, about 5.2 to about 5.6, about 5.2 to about 5.4, about 5.4 to about 8, about 5.4 to about 7.8, about 5.4 to about 7.6, about 5.4 to about 7.4, about 5.4 to about 7.2, about 5.4 to about 7, about 5.4 to about 6.8, about 5.4 to about 6.6, about 5.4 to about 6.4, about 5.4 to about 6.2, about 5.4 to about 6, about 5.4 to about 5.8, about 5.4 to about 5.6, about 5.6 to about 8, about 5 .6 to about 7.8, about 5.6 to about 7.6, about 5.6 to about 7.4, about 5.6 to about 7.2, about 5.6 to about 7, about 5.6 to about 6.8, about 5.6 to about 6.6, about 5.6 to about 6.4, about 5.6 to about 6.2, about 5.6 to about 6, about 5.6 to about 5.8, about 5.8 to about 8, about 5.8 to about 7.8, about 5.8 to about 7.6, about 5.8 to about 7.4, about 5.8 to about 7.2, about 5.8 to about 7, about 5.8 to about 6.8, about 5.8 to about 6.6, about 5.8 to about 6.4, about 5.8 to about 6.2, about 5.8 to about 6, about 6 to about 8, about 6 to about 7.8, about 6 to about 7.6, about 6 to about about 7.4, about 6 to about 7.2, about 6 to about 7, about 6 to about 6.8, about 6 to about 6.6, about 6 to about 6.4, about 6 to about 6.2, about 6.2 to about 8, about 6.2 to about 7.8, about 6.2 to about 7.6, about 6.2 to about 7.4, about 6.2 to about 7.2, about 6.2 to about 7, about 6.2 to about 6.8, about 6.2 to about 6.6, about 6.2 to about 6.4, about 6.4 to about 8, about 6.4 to about 7.6, about 6.4 to about 7.4, about 6.4 to about 7.2, about 6.4 to about 7, about 6.4 to about 6.8, about 6.4 to about 6.6, about 6.6 to about 8, about 6.6 to about 7.8, about 6.6 to about 7.6, about 6 The pH may be from about 6.6 to about 7.4, from about 6.6 to about 7.2, from about 6.6 to about 7, from about 6.6 to about 6.8, from about 6.8 to about 8, from about 6.8 to about 7.8, from about 6.8 to about 7.6, from about 6.8 to about 7.4, from about 6.8 to about 7.2, from about 6.8 to about 7, from about 7 to about 8, from about 7 to about 7.8, from about 7 to about 7.6, from about 7 to about 7.4, from about 7 to about 7.2, from about 7.2 to about 8, from about 7.2 to about 7.8, from about 7.2 to about 7.6, from about 7.2 to about 7.4, from about 7.4 to about 8, from about 7.4 to about 7.8, from about 7.4 to about 7.6, from about 7.6 to about 8, from about 7.6 to about 7.8, or from about 7.8 to about 8.

[0092] Formulation stability In some embodiments of any of the aqueous antibody formulations described herein, the formulation is a stable formulation. A "stable" formulation is one in which the protein of interest (e.g., an antibody or antigen-binding antibody fragment) therein essentially retains its physical and / or chemical stability and / or biological activity upon storage at about 4°C to about 25°C. Various analytical techniques for measuring protein stability are known in the art. See, for example, Peptide and Protein Drug Delivery, pp. 247-301, edited by Vincent Lee, Marcel Dekker Inc., New York, NY, Published (1991) and A. Jones, Adv. Drug Delivery Rev. 10:29-90 (1993). Further methods for measuring the stability of a protein (e.g., an antibody or antigen-binding antibody fragment) in a formulation are described in the Examples section. In some examples, the stability of a protein (e.g., an antibody or antigen-binding antibody fragment) is determined by the percentage of monomeric protein in solution with a low percentage of degraded (e.g., fragmented) and / or aggregated protein. For example, an aqueous formulation comprising a stable protein may contain at least 95% monomeric protein. Alternatively, the aqueous formulation of the invention may contain 5% or less (e.g., 4.5% or less, 4.0% or less, 3.5% or less, 3.0% or less, 2.5% or less, 2.0% or less, 1.5% or less, 1.0% or less, or 0.5% or less) aggregated and / or degraded protein.

[0093] In some embodiments of any of the aqueous antibody formulations described herein, the formulation has improved stability relative to a control antibody or antigen-binding antibody fragment (e.g., relative to a control antibody formulation containing all the same components except that it does not include any of the following salts: magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate).

[0094] In some embodiments of any of the aqueous antibody formulations described herein, the formulation is stable at 25° C. for about 1 hour to about 2 years (e.g., HMW% by SEC≦5%). In some embodiments of any of the aqueous antibody formulations described herein, the formulation is stable at 25° C. for about 1 hour to about 2 years (e.g., about 1 hour to about 24 months, about 1 hour to about 22 months, about 1 hour to about 20 months, about 1 hour to about 18 months, about 1 hour to about 16 months, about 1 hour to about 14 months, about 1 hour to about 12 months, about 1 hour to about 10 months, about 1 hour to about 8 months, about 1 hour to about 6 months, about 1 hour to about 4 months, about 1 hour to about 2 months, about 1 hour to about 1 month, about 1 hour to about 3 weeks, about 1 hour to about 2 weeks, about 1 hour to about 1 week, about 1 hour to about 6 days, about 1 hour to about 4 days, about 1 hour to about 2 days, about 1 hour to about 1 day, about 1 hour to about 28 days, about 1 hour to about 26 days, about 1 hour to about 24 days, about 1 hour to about 22 days, about 1 hour to about 20 days, about 1 hour to about 18 days, about 1 hour to about 16 days, about 1 hour to about 14 days, about 1 hour to about 12 days, about 1 hour to about 10 days, about 1 hour to about 8 days, about 1 hour to about 7 days, about 1 hour to about 6 days, about 1 hour to about 5 days, about 1 hour to about 4 days, about 1 hour to about 3 days, about 1 hour to about 2 days, about 1 hour to about 1 day , about 1 hour to about 22 hours, about 1 hour to about 20 hours, about 1 hour to about 18 hours, about 1 hour to about 16 hours, about 1 hour to about 14 hours, about 1 hour to about 12 hours, about 1 hour to about 10 hours, about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 2 hours, about 2 hours to about 24 months, about 2 hours to about 22 months, about 2 hours to about 20 months, about 2 hours to about 18 months, about 2 hours to about 16 months, about 2 hours to about 14 months, about 2 hours to about 12 months, about 2 hours to about 10 months, about 2 hours to about 8 months, about 2 hours to about 6 months, about 2 hours to about 4 months, about 2 hours to about 2 months, about 2 hours to about 1 month, about 2 hours to about 3 weeks, about 2 hours to about 2 weeks, about 2 hours to about 1 week, about 2 hours to about 6 days, about 2 hours to about 4 days, about 2 hours to about 2 days, about 2 hours to about 1 day, about 2 hours to about 28 days, about 2 hours to about 26 days, about 2 hours to about 24 days, about 2 hours to about 22 days, about 2 hours to about 20 days, about 2 hours to about 18 days, about 2 hours to about 16 days, about 2 hours to about 14 days, about 2 hours to about 12 days, about 2 hours to about 10 days, about 2 hours to about 8 days, about 2 hours to about 7 days,about 2 hours to about 6 days, about 2 hours to about 5 days, about 2 hours to about 4 days, about 2 hours to about 3 days, about 2 hours to about 2 days, about 2 hours to about 1 day, about 2 hours to about 22 hours, about 2 hours to about 20 hours, about 2 hours to about 18 hours, about 2 hours to about 16 hours, about 2 hours to about 14 hours, about 2 hours to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 4 hours to about 24 months, about 4 hours to about 22 months, about 4 hours to about 20 months, about 4 hours to about 18 months, about 4 hours to about 16 months, about 4 hours to about 14 months, about 4 hours to about 12 months, about 4 hours to About 10 months, About 4 hours to about 8 months, About 4 hours to about 6 months, About 4 hours to about 4 months, About 4 hours to about 2 months, About 4 hours to about 1 month, About 4 hours to about 3 weeks, About 4 hours to about 2 weeks, About 4 hours to about 1 week, About 4 hours to about 6 days, About 4 hours to about 4 days, About 4 hours to about 2 days, About 4 hours to about 1 day, About 4 hours to about 28 days, About 4 hours to about 26 days, About 4 hours to about 24 days, About 4 hours to about 22 days, About 4 hours to about 20 days, About 4 hours to about 18 days, About 4 hours to about 16 days, About 4 hours to about 14 days, About 4 hours to about 12 days, About 4 hours to about 10 days, About 4 hours to about 8 days, About 4 hours ~about 7 days, about 4 hours to about 6 days, about 4 hours to about 5 days, about 4 hours to about 4 days, about 4 hours to about 3 days, about 4 hours to about 2 days, about 4 hours to about 1 day, about 4 hours to about 22 hours, about 4 hours to about 20 hours, about 4 hours to about 18 hours, about 4 hours to about 16 hours, about 4 hours to about 14 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 4 hours to about 6 hours, about 6 hours to about 24 months, about 6 hours to about 22 months, about 6 hours to about 20 months, about 6 hours to about 18 months, about 6 hours to about 16 months, about 6 hours to about 14 months, about 6 hours to about 12 months, about 6 hours to about 10 months , about 6 hours to about 8 months, about 6 hours to about 6 months, about 6 hours to about 4 months, about 6 hours to about 2 months, about 6 hours to about 1 month, about 6 hours to about 3 weeks, about 6 hours to about 2 weeks, about 6 hours to about 1 week, about 6 hours to about 6 days, about 6 hours to about 4 days, about 6 hours to about 2 days, about 6 hours to about 1 day, about 6 hours to about 28 days, about 6 hours to about 26 days, about 6 hours to about 24 days, about 6 hours to about 22 days, about 6 hours to about 20 days, about 6 hours to about 18 days, about 6 hours to about 16 days, about 6 hours to about 14 days, about 6 hours to about 12 days, about 6 hours to about 10 days, about 6 hours to about 8 days, about 6 hours to about 7 days,About 6 hours to about 6 days, About 6 hours to about 5 days, About 6 hours to about 4 days, About 6 hours to about 3 days, About 6 hours to about 2 days, About 6 hours to about 1 day, About 6 hours to about 22 hours, About 6 hours to about 20 hours, About 6 hours to about 18 hours, About 6 hours to about 16 hours, About 6 hours to about 14 hours, About 6 hours to about 12 hours, About 6 hours to about 10 hours, About 6 hours to about 8 hours, About 8 hours to about 24 months, About 8 hours to about 22 months, About 8 hours to about 20 months, About 8 hours to about 18 months, About 8 hours to about 16 months, About 8 hours to about 14 months, About 8 hours to about 12 months, About 8 hours to about 10 months, About 8 hours to about 8 months, About 8 hours 8 hours to about 6 months, about 8 hours to about 4 months, about 8 hours to about 2 months, about 8 hours to about 1 month, about 8 hours to about 3 weeks, about 8 hours to about 2 weeks, about 8 hours to about 1 week, about 8 hours to about 6 days, about 8 hours to about 4 days, about 8 hours to about 2 days, about 8 hours to about 1 day, about 8 hours to about 28 days, about 8 hours to about 26 days, about 8 hours to about 24 days, about 8 hours to about 22 days, about 8 hours to about 20 days, about 8 hours to about 18 days, about 8 hours to about 16 days, about 8 hours to about 14 days, about 8 hours to about 12 days, about 8 hours to about 10 days, about 8 hours to about 8 days, about 8 hours to about 7 days, about 8 hours to about 6 days, about 8 hours to about 5 days, about 8 hours to about 4 days, about 8 hours to about 3 days, about 8 hours to about 2 days, about 8 hours to about 1 day, about 8 hours to about 22 hours, about 8 hours to about 20 hours, about 8 hours to about 18 hours, about 8 hours to about 16 hours, about 8 hours to about 14 hours, about 8 hours to about 12 hours, about 8 hours to about 10 hours, about 10 hours to about 24 months, about 10 hours to about 22 months, about 10 hours to about 20 months, about 10 hours to about 18 months, about 10 hours to about 16 months, about 10 hours to about 14 months, about 10 hours to about 12 months, about 10 hours to about 10 months, about 10 hours to about 8 months, about 10 hours to about 6 months, about 10 hours 10 hours to about 4 months, about 10 hours to about 2 months, about 10 hours to about 1 month, about 10 hours to about 3 weeks, about 10 hours to about 2 weeks, about 10 hours to about 1 week, about 10 hours to about 6 days, about 10 hours to about 4 days, about 10 hours to about 2 days, about 10 hours to about 1 day, about 10 hours to about 28 days, about 10 hours to about 26 days, about 10 hours to about 24 days, about 10 hours to about 22 days, about 10 hours to about 20 days, about 10 hours to about 18 days, about 10 hours to about 16 days, about 10 hours to about 14 days, about 10 hours to about 12 days, about 10 hours to about 10 days, about 10 hours to about 8 days, about 10 hours to about 7 days,about 10 hours to about 6 days, about 10 hours to about 5 days, about 10 hours to about 4 days, about 10 hours to about 3 days, about 10 hours to about 2 days, about 10 hours to about 1 day, about 10 hours to about 22 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, about 10 hours to about 16 hours, about 10 hours to about 14 hours, about 10 hours to about 12 hours, 12 hours to 24 months, 12 hours to 22 months, 12 hours to 20 months, 12 hours to 18 months, 12 hours to 16 months, 12 hours to 14 months, 12 hours to 12 months, 12 hours to 10 months, 12 hours to 8 months, 12 hours to 6 months, 12 hours to 4 months, 12 hours to 2 months, 12 hours to 1 month, 12 hours to 3 weeks, 12 hours to 2 weeks, 12 hours to 1 week, 12 hours to 6 days, 12 hours to 4 days, 12 hours to 2 days, 12 hours to 1 day, 12 hours to 28 days, 12 hours to 2 6 days, about 12 hours to about 24 days, about 12 hours to about 22 days, about 12 hours to about 20 days, about 12 hours to about 18 days, about 12 hours to about 16 days, about 12 hours to about 14 days, about 12 hours to about 12 days, about 12 hours to about 10 days, about 12 hours to about 8 days, about 12 hours to about 7 days, about 12 hours to about 6 days, about 12 hours to about 5 days, about 12 hours to about 4 days, about 12 hours to about 3 days, about 12 hours to about 2 days, about 12 hours to about 1 day, about 12 hours to about 22 hours, about 12 hours to about 20 hours, about 12 hours to about 18 hours, about 12 hours to about 16 hours, about 12 hours to about 14 hours, 14 hours to 24 months, 14 hours to 22 months, 14 hours to 20 months, 14 hours to 18 months, 14 hours to 16 months, 14 hours to 14 months, 14 hours to 12 months, 14 hours to 10 months, 14 hours to 8 months, 14 hours to 6 months, 14 hours to 4 months, 14 hours to 2 months, 14 hours to 1 month, 14 hours to 3 weeks, 14 hours to 2 weeks, 14 hours to 1 week, 14 hours to 6 days, 14 hours to 4 days, 14 hours to 2 days, 14 hours to 1 day, 14 hours to 28 days, 14 hours to 2 6 days, about 14 hours to about 24 days, about 14 hours to about 22 days, about 14 hours to about 20 days, about 14 hours to about 18 days, about 14 hours to about 16 days, about 14 hours to about 14 days, about 14 hours to about 12 days, about 14 hours to about 10 days, about 14 hours to about 8 days, about 14 hours to about 7 days, about 14 hours to about 6 days, about 14 hours to about 5 days, about 14 hours to about 4 days, about 14 hours to about 3 days, about 14 hours to about 2 days, about 14 hours to about 1 day, about 14 hours to about 22 hours, about 14 hours to about 20 hours, about 14 hours to about 18 hours, about 16 hours to about 24 months, about 16 hours to about 22 months,16 hours to 20 months, 16 hours to 18 months, 16 hours to 16 months, 16 hours to 14 months, 16 hours to 12 months, 16 hours to 10 months, 16 hours to 8 months, 16 hours to 6 months, 16 hours to 4 months, 16 hours to 2 months, 16 hours to 1 month, 16 hours to 3 weeks, 16 hours to 2 weeks, 16 hours to 1 week, 16 hours to 6 days, 16 hours to 4 days, 16 hours to 2 days, 16 hours to 1 day, 16 hours to 28 days, 16 hours to 26 days, 16 hours to 24 days, 16 hours to 2 2 days, about 16 hours to about 20 days, about 16 hours to about 18 days, about 16 hours to about 16 days, about 16 hours to about 14 days, about 16 hours to about 12 days, about 16 hours to about 10 days, about 16 hours to about 8 days, about 16 hours to about 7 days, about 16 hours to about 6 days, about 16 hours to about 5 days, about 16 hours to about 4 days, about 16 hours to about 3 days, about 16 hours to about 2 days, about 16 hours to about 1 day, about 16 hours to about 22 hours, about 16 hours to about 20 hours, about 18 hours to about 24 months, about 18 hours to about 22 months, about 18 hours to about 20 months, about 18 hours to about 18 months, about 18 hours to about 16 months, About 18 hours to about 14 months, About 18 hours to about 12 months, About 18 hours to about 10 months, About 18 hours to about 8 months, About 18 hours to about 6 months, About 18 hours to about 4 months, About 18 hours to about 2 months, About 18 hours to about 1 month, About 18 hours to about 3 weeks, About 18 hours to about 2 weeks, About 18 hours to about 1 week, About 18 hours to about 6 days, About 18 hours to about 4 days, About 18 hours to about 2 days, About 18 hours to about 1 day, About 18 hours to about 28 days, About 18 hours to about 26 days, About 18 hours to about 24 days, About 18 hours to about 22 days, About 18 hours to about 20 days, About 18 hours to about 18 days, About 18 hours to about 18 days 6 days, about 18 hours to about 14 days, about 18 hours to about 12 days, about 18 hours to about 10 days, about 18 hours to about 8 days, about 18 hours to about 7 days, about 18 hours to about 6 days, about 18 hours to about 5 days, about 18 hours to about 4 days, about 18 hours to about 3 days, about 18 hours to about 2 days, about 18 hours to about 1 day, about 18 hours to about 22 hours, about 18 hours to about 20 hours, about 20 hours to about 24 months, about 20 hours to about 22 months, about 20 hours to about 20 months, about 20 hours to about 18 months, about 20 hours to about 16 months, about 20 hours to about 14 months, about 20 hours to about 12 months, about 20 hours to about 10 months,About 20 hours to about 8 months, About 20 hours to about 6 months, About 20 hours to about 4 months, About 20 hours to about 2 months, About 20 hours to about 1 month, About 20 hours to about 3 weeks, About 20 hours to about 2 weeks, About 20 hours to about 1 week, About 20 hours to about 6 days, About 20 hours to about 4 days, About 20 hours to about 2 days, About 20 hours to about 1 day, About 20 hours to about 28 days, About 20 hours to about 26 days, About 20 hours to about 24 days, About 20 hours to about 2 2 days, about 20 hours to about 20 days, about 20 hours to about 18 days, about 20 hours to about 16 days, about 20 hours to about 14 days, about 20 hours to about 12 days, about 20 hours to about 10 days, about 20 hours to about 8 days, about 20 hours to about 7 days, about 20 hours to about 6 days, about 20 hours to about 5 days, about 20 hours to about 4 days, about 20 hours to about 3 days, about 20 hours to about 2 days, about 20 hours to about 1 day, about 20 hours to about 22 hours, About 1 day to about 24 months, About 1 day to about 22 months, About 1 day to about 20 months, About 1 day to about 18 months, About 1 day to about 16 months, About 1 day to about 14 months, About 1 day to about 12 months, About 1 day to about 10 months, About 1 day to about 8 months, About 1 day to about 6 months, About 1 day to about 4 months, About 1 day to about 2 months, About 1 day to about 1 month, About 1 day to about 3 weeks, About 1 day to about 2 weeks, About 1 day to about 1 week, About 1 day to about 6 days, About 1 day to about 4 days, About 1 day to about 2 days, About 1 day to about 1 day, About 1 day to about 28 days, About 1 day to about 26 days, About 1 day to about 24 days, About 1 day to about 22 days, about 1 day to about 20 days, about 1 day to about 18 days, about 1 day to about 16 days, about 1 day to about 14 days, about 1 day to about 12 days, about 1 day to about 10 days, about 1 day to about 8 days, about 1 day to about 7 days, about 1 day to about 6 days, about 1 day to about 5 days, about 1 day to about 4 days, about 1 day to about 3 days, about 1 day to about 2 days, about 2 days to about 24 months, about 2 days to about 22 months, about 2 days to about 20 months, about 2 days to about 18 months, about 2 days to about 16 months, about 2 days to about 14 months, about 2 days to about 12 months, about 2 days to about 10 months, about 2 days to about 8 months, about 2 days to about 6 months, about 2 days to about 1 month ... days to about 4 months, about 2 days to about 2 months, about 2 days to about 1 month, about 2 days to about 3 weeks, about 2 days to about 2 weeks, about 2 days to about 1 week, about 2 days to about 6 days, about 2 days to about 4 days, about 2 days to about 2 days, about 2 days to about 2 days, about 2 days to about 28 days, about 2 days to about 26 days, about 2 days to about 24 days, about 2 days to about 22 days, about 2 days to about 20 days, about 2 days to about 18 days, about 2 days to about 16 days, about 2 days to about 14 days, about 2 days to about 12 days, about 2 days to about 10 days, about 2 days to about 8 days, about 2 days to about 7 days, about 2 days to about 6 days, about 2 days to about 5 days, about 2 days to about 4 days, about 2 days to about 3 days, about 4 days to about 24 months, about 4 days to about 22 months, about 4 days to about 20 months, about 4 days to about 18 months, about 4 days to about 16 months, about 4 days to about 14 months, about 4 days to about 12 months, about 4 days to about 10 months, about 4 days to about 8 months, about 4 days to about 6 months, about 4 days to about 4 months, about 4 days to about 2 months, about 4 days to about 1 month, about 4 days to about 3 weeks, about 4 days to about 2 weeks, about 4 days to about 1 week, about 4 days to about 6 days, about 4 days to about 4 days, about 4 days to about 2 days, about 4 days to about 4 days, about 4 days to about 28 days, about 4 days to about 26 days,About 4 days to about 24 days, About 4 days to about 22 days, About 4 days to about 20 days, About 4 days to about 18 days, About 4 days to about 16 days, About 4 days to about 14 days, About 4 days to about 12 days, About 4 days to about 10 days, About 4 days to about 8 days, About 4 days to about 7 days, About 4 days to about 6 days, About 4 days to about 5 days, About 7 days to about 24 months, About 7 days to about 22 months, About 7 days to about 20 months, About 7 days to about 18 months, About 7 days to about 16 months, About 7 days to about 14 months, About 7 days to about 12 months, About 7 days to about 10 months, About 7 days to about 8 months , about 7 days to about 6 months, about 7 days to about 4 months, about 7 days to about 2 months, about 7 days to about 1 month, about 7 days to about 3 weeks, about 7 days to about 2 weeks, about 7 days to about 1 week, about 7 days to about 6 days, about 7 days to about 4 days, about 7 days to about 2 days, about 7 days to about 7 days, about 7 days to about 28 days, about 7 days to about 26 days, about 7 days to about 24 days, about 7 days to about 22 days, about 7 days to about 20 days, about 7 days to about 18 days, about 7 days to about 16 days, about 7 days to about 14 days, about 7 days to about 12 days, about 7 days to about 10 days, about 7 days ~about 8 days, about 1 week to about 24 months, about 1 week to about 22 months, about 1 week to about 20 months, about 1 week to about 18 months, about 1 week to about 16 months, about 1 week to about 14 months, about 1 week to about 12 months, about 1 week to about 10 months, about 1 week to about 8 months, about 1 week to about 6 months, about 1 week to about 4 months, about 1 week to about 2 months, about 1 week to about 1 month, about 1 week to about 3 weeks, about 1 week to about 2 weeks, about 2 weeks to about 24 months, about 2 weeks to about 22 months, about 2 weeks to about 20 months, about 2 weeks to about 18 months, about 2 weeks to about 16 months, about 2 weeks to about 14 months, about 2 weeks to about 12 months, about 2 weeks to about 10 months, about 2 weeks to about 8 months, about 2 weeks to about 6 months, about 2 weeks to about 4 months, about 2 weeks to about 2 months, about 2 weeks to about 1 month, about 2 weeks to about 3 weeks, about 3 weeks to about 24 months, about 3 weeks to about 22 months, about 3 weeks to about 20 months, about 3 weeks to about 18 months, about 3 weeks to about 16 months, about 3 weeks to about 14 months, about 3 weeks to about 12 months, about 3 weeks to about 10 months, about 3 weeks to about 8 months, about 3 weeks to about 6 months, about 3 weeks to about 4 months, about 3 weeks to about 2 months, about 3 weeks to about 1 month, About 1 month to about 24 months, About 1 month to about 22 months, About 1 month to about 20 months, About 1 month to about 18 months, About 1 month to about 16 months, About 1 month to about 14 months, About 1 month to about 12 months, About 1 month to about 10 months, About 1 month to about 8 months, About 1 month to about 6 months, About 1 month to about 4 months, About 1 month to about 2 months, About 2 months to about 24 months, About 2 months to about 22 months, About 2 months to about 20 months, About 2 months to about 18 months, About 2 months to about 16 months, About 2 months to about 14 months, About 2 months to about 12 months, About 2 months to about 10 months, 2 months to 8 months, 2 months to 6 months, 2 months to 4 months, 4 months to 24 months, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 24 months, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 14 months, months to 12 months, 6 months to 10 months, 6 months to 8 months, 10 months to 24 months, 10 months to 22 months, 10 months to 20 months, 10 months to 18 months, 10 months to 16 months, 10 months to 14 months, 10 months to 12 months, 12 months to 24 months, 12 months to 22 months, 12 months to 20 months, 12 months to 18 months, 12 months to 16 months, 12 months to 14 months, 14 months to 24 months, 14 months to 22 months, stable (e.g., HMW% ≦5% by SEC) for 4 months to about 20 months, about 14 months to about 18 months, about 14 months to about 16 months, about 16 months to about 24 months, about 16 months to about 22 months, about 16 months to about 20 months, about 16 months to about 18 months, about 18 months to about 24 months, about 18 months to about 22 months, about 18 months to about 20 months, about 20 months to about 22 months, about 20 months to about 24 months, or about 22 months to about 24 months).

[0095] In some embodiments of any of the aqueous antibody formulations described herein, the formulation is capable of withstanding for about 1 hour to about 8 weeks (e.g., about 1 hour to about 6 weeks, about 1 hour to about 4 weeks, about 1 hour to about 2 weeks, about 1 hour to about 1 week, about 1 hour to about 6 days, about 1 hour to about 4 days, about 1 hour to about 2 days, about 1 hour to about 1 day, about 1 hour to about 22 hours, about 1 hour to about 20 hours, about 1 hour to about 18 hours, about 1 hour to about 16 hours, about 1 hour to about 14 hours, about 1 hour to about 12 hours, about 1 hour to about 10 hours, about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 1 hour, hours to about 2 hours, about 2 hours to about 8 weeks, about 2 hours to about 6 weeks, about 2 hours to about 4 weeks, about 2 hours to about 2 weeks, about 2 hours to about 1 week, about 2 hours to about 6 days, about 2 hours to about 4 days, about 2 hours to about 2 days, about 2 hours to about 1 day, about 2 hours to about 22 hours, about 2 hours to about 20 hours, about 2 hours to about 18 hours, about 2 hours to about 16 hours, about 2 hours to about 14 hours, about 2 hours to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 4 hours to about 8 weeks, about 4 hours to about 6 weeks, about 4 hours to about 4 weeks, about 4 hours to about 2 weeks, about 4 hours ~ about 1 week, about 4 hours to about 6 days, about 4 hours to about 4 days, about 4 hours to about 2 days, about 4 hours to about 1 day, about 4 hours to about 22 hours, about 4 hours to about 20 hours, about 4 hours to about 18 hours, about 4 hours to about 16 hours, about 4 hours to about 14 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 4 hours to about 6 hours, about 6 hours to about 8 weeks, about 6 hours to about 6 weeks, about 6 hours to about 4 weeks, about 6 hours to about 2 weeks, about 6 hours to about 1 week, about 6 hours to about 6 days, about 6 hours to about 4 days, about 6 hours to about 2 days, about 6 hours to about 1 day, about 6 hours to about 22 hours, about 6 hours about 20 hours, about 6 hours to about 18 hours, about 6 hours to about 16 hours, about 6 hours to about 14 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 8 weeks, about 8 hours to about 6 weeks, about 8 hours to about 4 weeks, about 8 hours to about 2 weeks, about 8 hours to about 1 week, about 8 hours to about 6 days, about 8 hours to about 4 days, about 8 hours to about 2 days, about 8 hours to about 1 day, about 8 hours to about 22 hours, about 8 hours to about 20 hours, about 8 hours to about 18 hours, about 8 hours to about 16 hours, about 8 hours to about 14 hours, about 8 hours to about 12 hours, about 8 hours to about 10 hours, about 10 hours to about 8 weeks,about 10 hours to about 6 weeks, about 10 hours to about 4 weeks, about 10 hours to about 2 weeks, about 10 hours to about 1 week, about 10 hours to about 6 days, about 10 hours to about 4 days, about 10 hours to about 2 days, about 10 hours to about 1 day, about 10 hours to about 22 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, about 10 hours to about 16 hours, about 10 hours to about 14 hours, about 10 hours to about 12 hours, about 12 hours to about 8 weeks, about 12 hours to about 6 weeks, about 12 hours to about 4 weeks, about 12 hours to about 2 weeks, about 12 hours to about 1 week, about 12 hours to about 6 days, about 12 hours to about 4 days, about 12 hours to about 2 days, about 12 hours to about 1 day, about 12 hours to about 22 hours, about 12 hours to about 20 hours, about 12 hours to about 18 hours, about 12 hours to about 16 hours, about 12 hours to about 14 hours, about 14 hours to about 8 weeks, about 14 hours to about 6 weeks, about 14 hours to about 4 weeks, about 14 hours to about 2 weeks, about 14 hours to about 1 week, about 14 hours to about 6 days, about 14 hours to about 4 days, about 14 hours to about 2 days, about 14 hours to about 1 day, about 14 hours to about 22 hours, about 14 hours to about 20 hours, about 14 hours to about 18 hours, about 14 hours to about 16 hours, about 16 hours to about 8 weeks, about 16 hours to about 6 weeks, about 16 hours to about 4 weeks 16 hours to about 2 weeks, about 16 hours to about 1 week, about 16 hours to about 6 days, about 16 hours to about 4 days, about 16 hours to about 2 days, about 16 hours to about 1 day, about 16 hours to about 22 hours, about 16 hours to about 20 hours, about 16 hours to about 18 hours, about 18 hours to about 8 weeks, about 18 hours to about 6 weeks, about 18 hours to about 4 weeks, about 18 hours to about 2 weeks, about 18 hours to about 1 week, about 18 hours to about 6 days, about 18 hours to about 4 days, about 18 hours to about 2 days, about 18 hours to about 1 day, about 18 hours to about 22 hours, about 18 hours to about 20 hours, about 20 hours to about 8 weeks, about 20 hours to about 6 weeks, about 20 hours to about 4 weeks, about 20 hours to about 2 weeks, about 20 hours to about 1 week, about 20 hours to about 6 days, about 20 hours to about 4 days, about 20 hours to about 2 days, about 20 hours to about 1 day, about 20 hours to about 22 hours, about 22 hours to about 8 weeks, about 22 hours to about 6 weeks, about 22 hours to about 4 weeks, about 22 hours to about 2 weeks, about 22 hours to about 1 week, about 22 hours to about 6 days, about 22 hours to about 4 days, about 22 hours to about 2 days, about 22 hours to about 24 hours, about 1 day to about 8 weeks, about 1 day to about 6 weeks, about 1 day to about 4 weeks, about 1 day to about 2 weeks, about 1 day to about 1 week, about 1 day to about 6 days,About 1 day to about 4 days, about 1 day to about 2 days, about 2 days to about 8 weeks, about 2 days to about 6 weeks, about 2 days to about 4 weeks, about 2 days to about 2 weeks, about 2 days to about 1 week, about 2 days to about 6 days, about 2 days to about 4 days, about 4 days to about 8 weeks, about 4 days to about 6 weeks, about 4 days to about 4 weeks, about 4 days to about 2 weeks, about 4 days to about 1 week, about 4 days to about 6 days, about 1 week to about 8 weeks, about 1 week to about 6 weeks, about 1 week to about 4 weeks, about 1 week to about 2 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 6 weeks, about 2 weeks to about 4 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 6 weeks, about 6 weeks to about 8 weeks) stable (e.g., HMW% by SEC ≦ 5%) (e.g., measured using high performance size exclusion chromatography).

[0096] In some embodiments, the formulation has a β-amino acid concentration of about 1 cP to about 50 cP, about 1 cP to about 45 cP, about 1 cP to about 40 cP, about 1 cP to about 35 cP, about 1 cP to about 30 cP, about 1 cP to about 25 cP, about 1 cP to about 20 cP, about 1 cP to about 15 cP, about 1 cP to about 10 cP, about 1 cP to about 5 cP, about 5 cP to about 50 cP, about 5 cP to about 5 cP, Approximately 45 cP, approximately 5 cP to approximately 40 cP, approximately 5 cP to approximately 35 cP, approximately 5 cP to approximately 30 cP, approximately 5 cP to approximately 25 cP, approximately 5 cP to approximately 20 cP, approximately 5 cP to approximately 15 cP, approximately 5 cP to approximately 10 cP, approximately 10 cP to approximately 50cP, approximately 10cP to approximately 45cP, approximately 10cP to approximately 40cP, approximately 10cP to approximately 35cP, approximately 10cP to approximately 30cP, approximately 10cP to approximately 25cP, approximately 10cP to approximately 20cP, approximately 10cP to approximately 15cP, approximately 15cP to about 50cP, about 15cP to about 45cP, about 15cP to about 40cP, about 15cP to about 35cP, about 15cP to about 30cP, about 15cP to about 25cP, about 15cP to about 20cP, about 20cP to about 50cP, approximately 20cP to approximately 45cP, approximately 20cP to approximately 40cP, approximately 20cP to approximately 35cP, approximately 20cP to approximately 30cP, approximately 20cP to approximately 25cP, approximately 25cP to approximately 50cP, approximately 25cP to approximately 45cP, approximately It has a viscosity of 25 cP to about 40 cP, about 25 cP to about 35 cP, about 25 cP to about 30 cP, about 30 cP to about 50 cP, about 30 cP to about 45 cP, about 30 cP to about 40 cP, about 30 cP to about 35 cP, about 35 cP to about 50 cP, about 35 cP to about 45 cP, about 35 cP to about 40 cP, about 40 cP to about 50 cP, about 40 cP to about 45 cP, or about 45 cP to about 50 cP (measured, for example, using a viscometer).

[0097] In some embodiments, the formulation may be suitable for subcutaneous, intravenous, intraarterial, intraocular, intraperitoneal, intramuscular, intraarticular, or translaminar administration.

[0098] Stabilizers Some embodiments of any of the formulations described herein may further include a stabilizer (e.g., one or more stabilizers). Non-limiting examples of stabilizers include fructose, maltose, galactose, glucose, O-mannose, sorbose, lactose, sucrose, trehalose, cellobiose, raffinose, melezitose, maltodextrin, dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sorbitol, amino sugars, sodium chloride, and glycerin, and combinations thereof. Further examples of stabilizers are known in the art. The final concentration of the stabilizer (or the total final concentration of one or more stabilizers) in any of the formulations described herein may be from about 0.01 mM to about 1500 mM (or any of the subranges of this range described herein).

[0099] amino acid Some embodiments of any of the formulations described herein may further include an amino acid (e.g., one or more amino acids). Non-limiting examples of amino acids include arginine, lysine, histidine, proline, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, and aspartic acid, and combinations thereof. Additional examples of amino acids are known in the art. The final concentration of an amino acid (or the total final concentration of one or more amino acids) in any of the formulations described herein may be from about 0.01 mM to about 750 mM (or any of the subranges of this range described herein).

[0100] Surfactants Some embodiments of any of the formulations described herein may further include a surfactant (e.g., one or more surfactants). Non-limiting examples of surfactants include sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, glyceryl monocaprylate, glyceryl monomyristate, glyceryl monostearate, decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene glyceryl monostearate, polyethylene glycol dis ... Examples of surfactants include diethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol beeswax, polyoxyethylene lanolin, polyoxyethylene stearamide, sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, polyoxyethylene sodium lauryl sulfate, sodium lauryl sulfosuccinate, lecithin, glycerophospholipids, sphingophospholipids, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, Triton-X, polyethylene glycol, and propylene glycol. Further examples of surfactants are known in the art.

[0101] The final concentration of the surfactant (or the total final concentration of one or more surfactants) in any of the formulations described herein may be from about 0.001% (w / v) to about 2% (w / v), from about 0.001% (w / v) to about 1.8% (w / v), from about 0.001% (w / v) to about 1.6% (w / v), from about 0.001% (w / v) to about 1.4% (w / v), from about 0.001% (w / v) to about 1.2% (w / v), from about 0.001% (w / v) to about 1.0% (w / v), from about 0.001% (w / v) to about 0.9% (w / v), from about 0.001% (w / v) to about 0.8% (w / v), ), approx. 0.001% (w / v) ~ approx. 0.7% (w / v), approx. 0.001% (w / v) ~ approx. 0.6% (w / v), approx. 0.001% (w / v) ) ~ approx. 0.5% (w / v), approx. 0.001% (w / v) ~ approx. 0.45% (w / v), approx. 0.001% (w / v) ~ approx. 0.40% (w / v) , about 0.001% (w / v) to about 0.35% (w / v), about 0.001% (w / v) to about 0.30% (w / v), about 0.001% (w / v) ) ~ approx. 0.25% (w / v), approx. 0.001% (w / v) ~ approx. 0.20% (w / v), approx. 0.001% (w / v) ~ approx. 0.15% (w / v) ), approx. 0.001% (w / v) ~ approx. 0.10% (w / v), approx. 0.001% (w / v) ~ approx. 0.05% (w / v), approx. 0.001% (w / v) ~ approx. 0.01% (w / v), approx. 0.001% (w / v) ~ approx. 0.005% (w / v), approx. 0.005% (w / v) ~ approx. 2.0% (w / v), approximately 0.005% (w / v) ~ approximately 1.8% (w / v), approximately 0.005% (w / v) ~ approximately 1.6% (w / v), approximately 0.005% (w / v) ~ approx. 1.4% (w / v), approx. 0.005% (w / v) ~ approx. 1.2% (w / v), approx. 0.005% (w / v) ~ approx. 1.0% (w / v), Approx. 0.005% (w / v) ~ approx. 0.9% (w / v), approx. 0.005% (w / v) ~ approx. 0.8% (w / v), approx. 0.005% (w / v) ~ approx. 0.7% (w / v), approximately 0.005% (w / v) ~ approximately 0.6% (w / v), approximately 0.005% (w / v) ~ approximately 0.5% (w / v), approximately 0.0 05% (w / v) ~ approx. 0.45% (w / v), approx. 0.005% (w / v) ~ approx. 0.40% (w / v), approx. 0.005% (w / v) ~ approx. 0. 35% (w / v), approximately 0.005% (w / v) ~ approximately 0.30% (w / v), approximately 0.005% (w / v) ~ approximately 0.25% (w / v), approximately 0.005% (w / v) to approximately 0.20% (w / v), approximately 0.005% (w / v) to approximately 0.15% (w / v), approximately 0.005% (w / v) to approximately 0.10% (w / v), approximately 0.005% (w / v) to approximately 0.05% (w / v), approximately 0.005% (w / v) to approximately 0.01% (w / v), approximately 0.01% (w / v) to approximately 2.0% (w / v), approximately 0.01% (w / v) to approximately 1.8% (w / v), approximately 0.01% (w / v) to approximately 1.6% (w / v), approximately 0.01% (w / v) to approximately 1.4% (w / v), approximately 0.01% (w / v) to approximately 1.2% (w / v), approximately 0.01% (w / v) to approximately 1.0% (w / v), approximately 0.01% (w / v) to approximately 0.9% (w / v), approximately 0.01% (w / v) to approximately 0.8% (w / v), approximately 0.01% (w / v) to approximately 0.7% (w / v), approximately 0.01% (w / v) to approximately 0.6% (w / v), approximately 0.01% (w / v) to approximately 0.5% (w / v), approximately 0.01% (w / v) to approximately 0.45% (w / v), approximately 0.01% (w / v) to approximately 0.40% (w / v), approximately 0.01% (w / v) to approximately 0.35% (w / v), approximately 0.01% (w / v) to approximately 0.30% (w / v), approximately 0.01% (w / v) to approximately 0.25% (w / v), approximately 0.01% (w / v) to approximately 0.20% (w / v), approximately 0.01% (w / v) to approximately 0.15% (w / v), approximately 0.01% (w / v) to approximately 0.10% (w / v), approximately 0.01% (w / v) to approximately 0.05% (w / v), approximately 0.05% (w / v) to approximately 2.0% (w / v), approximately 0.05% (w / v) to approximately 1.8% (w / v), approximately 0.05% (w / v) to approximately 1.6% (w / v), approximately 0.05% (w / v) to approximately 1.4% (w / v), approximately 0.05% (w / v) to approximately 1.2% (w / v), approximately 0.05% (w / v) to approximately 1.0% (w / v), approximately 0.05% (w / v) to approximately 0.9% (w / v), approximately 0.05% (w / v) to approximately 0.8% (w / v), approximately 0.05% (w / v) to approximately 0.7% (w / v), approximately 0.05% (w / v) to approximately 0.6% (w / v), approximately 0.05% (w / v) to approximately 0.5% (w / v), approximately 0.05% (w / v) to approximately 0.45% (w / v), approximately 0.05% (w / v) to approximately 0.40% (w / v), approximately 0.05% (w / v) to approximately 0.35% (w / v), approximately 0.05% (w / v) to approximately 0.30% (w / v), approximately 0.05% (w / v) to approximately 0.25% (w / v), approximately 0.05% (w / v) to approximately 0.20% (w / v), approximately 0.05% (w / v) to about 0.15% (w / v), about 0.05% (w / v) to about 0.10% (w / v), about 0.10% (w / v) to about 2.0% (w / v), about 0.10% (w / v) to about 1.8% (w / v), about 0.10% (w / v) to about 1.6% (w / v), about 0.10% (w / v) to about 1.4% (w / v), about 0.10% (w / v) to about 1.2% (w / v), about 0.10% (w / v) to about 1.0% (w / v), about 0.10% (w / v) to about 0.9% (w / v), about 0.10% (w / v) to about 0.8% (w / v), about 0.10% (w / v) to about 0.7% (w / v), about 0.10% (w / v) to about 0.6% (w / v), about 0.10% (w / v) to about 0.5% (w / v), about 0.10% (w / v) to about 0.45% (w / v), about 0.10% (w / v) to about 0.40% (w / v), about 0.10% (w / v) to about 0.35% (w / v), about 0.10% (w / v) to about 0.30% (w / v), about 0.10% (w / v) to about 0.25% (w / v), about 0.10% (w / v) to about 0.20% (w / v), about 0.10% (w / v) to about 0.15% (w / v),... About 0.15% (w / v) to about 2.0% (w / v), about 0.15% (w / v) to about 1.8% (w / v), about 0.15% (w / v) to about 1.6% (w / v), about 0.15% (w / v) to about 1.4% (w / v), about 0.15% (w / v) to about 1.2% (w / v), about 0.15% (w / v) to about 1.0% (w / v), about 0.15% (w / v) to about 0.9% (w / v), about 0.15% (w / v) to about 0.8% (w / v), about 0.15% (w / v) to about 0.7% (w / v), about 0.15% (w / v) to about 0.6% (w / v), about 0.15% (w / v) to about 0.5% (w / v), about 0.15% (w / v) to about 0.45% (w / v), about 0.15% (w / v) to about 0.40% (w / v), about 0.15% (w / v) to about 0.35% (w / v), about 0.15% (w / v) to about 0.30% (w / v), about 0.15% (w / v) to about 0.25% (w / v), about 0.15% (w / v) to about 0.20% (w / v), about 0.20% (w / v) to about 2.0% (w / v), about 0.20% (w / v) to about 1.8% (w / v), about 0.20% (w / v) to about 1.6% (w / v), about 0.20% (w / v) to about 1.4% (w / v), about 0.20% (w / v) to about 1.2% (w / v), about 0.20% (w / v) to about 1.0% (w / v), about 0.20% (w / v) to about 0.9% (w / v), about 0.20% (w / v) to about 0.8% (w / v), about 0.20% (w / v) to about 0.7% (w / v), about 0.20% (w / v) to about 0.6% (w / v), about 0.20% (w / v) to about 0.5% (w / v), about 0.20% (w / v) to about 0.45% (w / v), about 0.20% (w / v) to about 0.40% (w / v), about 0.20% (w / v) to about 0.35% (w / v), about 0.20% (w / v) to about 0.30% (w / v), about 0.20% (w / v) to about 0.25% (w / v), about 0.25% (w / v) to about 2.0% (w / v), about 0.25% (w / v) to about 1.8% (w / v), about 0.25% (w / v) to about 1.6% (w / v), about 0.25% (w / v) to about 1.4% (w / v), about 0.25% (w / v) to about 1.2% (w / v), about 0.25% (w / v) to about 1.0% (w / v), about 0.25% (w / v) to about 0.9% (w / v), about 0.25% (w / v) to about 0.8% (w / v), about 0.25% (w / v) to about 0.7% (w / v), about 0.25% (w / v) to about 0.6% (w / v), about 0.25% (w / v) to about 0.5% (w / v), about 0.25% (w / v) to about 0.45% (w / v), about 0.25% (w / v) to about 0.40% (w / v), about 0.25% (w / v) to about 0.35% (w / v), about 0.25% (w / v) to about 0.30% (w / v), about 0.30% (w / v) to about 2.0% (w / v), about 0.30% (w / v) to about 1.8% (w / v), about 0.30% (w / v) to about 1.6% (w / v), about 0.30% (w / v) to about 1.4% (w / v), about 0.30% (w / v) to about 1.2% (w / v), about 0.30% (w / v) to about 1.0% (w / v), about 0.30% (w / v) to about 0.9% (w / v), about 0.30% (w / v) to about 0.8% (w / v), about 0.30% (w / v) to about 0.7% (w / v), about 0.30% (w / v) to about 0.6% (w / v), about 0.30% (w / v) to about 0.5% (w / v), about 0.30% (w / v) to about 0.45% (w / v), about 0.30% (w / v) to about 0.40% (w / v), about 0.30% (w / v) to about 0.35% (w / v), about 0.35% (w / v) to about 2.0% (w / v), about 0.35% (w / v) to about 1.8% (w / v), about 0.35% (w / v) to about 1.6% (w / v), about 0.35% (w / v) to about 1.4% (w / v), about 0.35% (w / v) to about 1.2% (w / v), about 0.35% (w / v) to about 1.0% (w / v), about 0.35% (w / v) to about 0.9% (w / v), about 0.35% (w / v) to about 0.8% (w / v), about 0.35% (w / v) to about 0.7% (w / v), about 0.35% (w / v) to about 0.6% (w / v), about 0.35% (w / v) to about 0.5% (w / v), about 0.35% (w / v) to about 0.45% (w / v), about 0.35% (w / v) to about 0.40% (w / v), about 0.40% (w / v) to about 2.0% (w / v), about 0.40% (w / v) to about 1.8% (w / v), about 0.40% (w / v) to about 1.6% (w / v), about 0.40% (w / v) to about 1.4% (w / v), about 0.40% (w / v) to about 1.2% (w / v), about 0.40% (w / v) to about 1.0% (w / v), about 0.40% (w / v) to about 0.9% (w / v), about 0.40% (w / v) to about 0.8% (w / v), about 0.40% (w / v) to about 0.7% (w / v), about 0.40% (w / v) to about 0.6% (w / v), about 0.40% (w / v) to about 0.5% (w / v), about 0.40% (w / v) to about 0.45% (w / v), about 0.45% (w / v) to about 2.0% (w / v), about 0.45% (w / v) to about 1.8% (w / v), about 0.45% (w / v) to about 1.6% (w / v), about 0.45% (w / v) to about 1.4% (w / v), about 0.45% (w / v) to about 1.2% (w / v), about 0.45% (w / v) to about 1.0% (w / v), about 0.45% (w / v) to about 0.9% (w / v), about 0.45% (w / v) to about 0.8% (w / v), about 0.45% (w / v) to about 0.7% (w / v), about 0.45% (w / v) to about 0.6% (w / v), about 0.45% (w / v) to about 0.5% (w / v), about 0.5% (w / v) to about 2.0% (w / v), about 0.5% (w / v) to about 1.8% (w / v), about 0.5% (w / v) to about 1.6% (w / v), about 0.5% (w / v) to about 1.4% (w / v), about 0.5% (w / v) to about 1.2% (w / v), about 0.5% (w / v) to about 1.0% (w / v), about 0.5% (w / v) to about 0.9% (w / v), about 0.5% (w / v) to about 0.8% (w / v), about 0.5% (w / v) to about 0.7% (w / v), about 0.5% (w / v) to about 0.6% (w / v),... Approx. 0.6% (w / v) ~ approx. 2.0% (w / v), approx. 0.6% (w / v) ~ approx. 1.8% (w / v), approx. 0.6% (w / v) ~ approx. 1.6% (w / v), about 0.6% (w / v) to about 1.4% (w / v), about 0.6% (w / v) to about 1.2% (w / v), about 0.6% (w / v) to about 1. 0%(w / v), approx. 0.6%(w / v)~approximately 0.9%(w / v), approx. 0.6%(w / v)~approximately 0.8%(w / v), approx. 0.6%(w / v) ~0.7%(w / v), approx. 0.7%(w / v)~2.0%(w / v), approx. 0.7%(w / v)~1.8%(w / v), approx. 0.7%(w / v) ~ approx. 1.6% (w / v), approx. 0.7% (w / v) ~ approx. 1.4% (w / v), approx. 0.7% (w / v) ~ approx. 1.2% (w / v), approx. 0. 7% (w / v) ~ approx. 1.0% (w / v), approx. 0.7% (w / v) ~ approx. 0.9% (w / v), approx. 0.7% (w / v) ~ approx. 0.8% (w / v), Approx. 0.8% (w / v) ~ approx. 2.0% (w / v), approx. 0.8% (w / v) ~ approx. 1.8% (w / v), approx. 0.8% (w / v) ~ approx. 1.6% (w / v), about 0.8% (w / v) to about 1.4% (w / v), about 0.8% (w / v) to about 1.2% (w / v), about 0.8% (w / v) to about 1.0 %(w / v), approximately 0.8%(w / v)~approximately 0.9%(w / v), approximately 0.9%(w / v)~approximately 2.0%(w / v), approximately 0.9%(w / v)~ Approx. 1.8% (w / v), approx. 0.9% (w / v) ~ approx. 1.6% (w / v), approx. 0.9% (w / v) ~ approx. 1.4% (w / v), approx. 0.9% (w / v) ~ approx. 1.2% (w / v), approx. 0.9% (w / v) ~ approx. 1.0% (w / v), approx. 1.0% (w / v) ~ approx. 2.0% (w / v), approx. 1. 0% (w / v) ~ approx. 1.8% (w / v), approx. 1.0% (w / v) ~ approx. 1.6% (w / v), approx. 1.0% (w / v) ~ approx. 1.4% (w / v), It may be about 1.0% (w / v) to about 1.2% (w / v), about 1.2% (w / v) to about 2.0% (w / v), about 1.2% (w / v) to about 1.8% (w / v), about 1.2% (w / v) to about 1.6% (w / v), about 1.2% (w / v) to about 1.4% (w / v), about 1.4% (w / v) to about 2.0% (w / v), about 1.4% (w / v) to about 1.8% (w / v), about 1.4% (w / v) to about 1.6% (w / v), about 1.6% (w / v) to about 2.0% (w / v), about 1.6% (w / v) to about 1.8% (w / v), or about 1.8% (w / v) to about 2.0% (w / v).

[0102] The final concentration of the surfactant (or the total final concentration of one or more surfactants) in any of the formulations described herein may be from about 0.001 mg / mL to about 50 mg / mL, from about 0.001 mg / mL to about 45 mg / mL, from about 0.001 mg / mL to about 40 mg / mL, from about 0.001 mg / mL to about 35 mg / mL, from about 0.001 mg / mL to about 30 mg / mL, from about 0.001 mg / mL to about 28 mg / mL, from about 0.001 mg / mL to about 26 mg / mL, from about 0.001 mg / mL to about 24 mg / mL, from about 0.001 mg / mL to about 22 mg / mL, mL, about 0.001 mg / mL to about 20 mg / mL, about 0.001 mg / mL to about 18 mg / mL, about 0.001 mg / mL to about 16 mg / mL, about 0.001 mg / mL to about 14 mg / mL, about 0.001 mg / mL to about 12 mg / mL, about 0.001 mg / mL to about 10 mg / mL, about 0.001 mg / mL to about 8 mg / mL, about 0.001 mg / mL to about 6 mg / mL, about 0.001 mg / mL to about 5 mg / mL, about 0.001 mg / mL to about 4 mg / mL, about 0.001 mg / mL to about 3 mg / mL, about 0.001 mg / mL to about 2 mg / mL mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.5 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 0.05 mg / mL, about 0.001 mg / mL to about 0.005 mg / mL, about 0.005 mg / mL~about 50mg / mL, about 0.005mg / mL~about 45mg / mL, about 0.005mg / mL~about 40mg / mL, about 0.005mg / mL~about 35mg / mL, about 0.005mg / mL~about 30mg / mL, about 0.005mg / mL~about 28mg / mL, about 0.005 mg / mL~about 26mg / mL, about 0.005mg / mL~about 24mg / mL, about 0.005mg / mL~about 22mg / mL, about 0.005mg / mL~about 20mg / mL, about 0.005mg / mL~about 18mg / mL, about 0.005mg / mL~about 16mg / mL, about 0. 0.005mg / mL to approx. 14mg / mL, approx. 0.005mg / mL to approx. 12mg / mL, approx. 0.005mg / mL to approx. 10mg / mL, approx. 0.005mg / mL to approx. 8mg / mL, approx. 0.005mg / mL to approx. 6mg / mL, approx. 0.005mg / mL to approx. 5mg / mL, approx.005 mg / mL to approximately 4 mg / mL, approximately 0.005 mg / mL to approximately 3 mg / mL, approximately 0.005 mg / mL to approximately 2 mg / mL, approximately 0.005 mg / mL to approximately 1 mg / mL, approximately 0.005 mg / mL to approximately 0.5 mg / mL, approximately 0.005 mg / mL to approximately 0.1 mg / mL, approximately 0.005 mg / mL to approximately 0.05 mg / mL, approximately 0.05 mg / mL to approximately 50 mg / mL, approximately 0.05 mg / mL to approximately 45 mg / mL, approximately 0.05 mg / mL to approximately 40 mg / mL, approximately 0.05 mg / mL to approximately 35 mg / mL, approximately 0.05 mg / mL to approximately 30 mg / mL, approximately 0.05 mg / mL to approximately 28 mg / mL, approximately 0.05 mg / mL to approximately 26 mg / mL, approximately 0.05 mg / mL to approximately 24 mg / mL, approximately 0.05 mg / mL to approximately 22 mg / mL, approximately 0.05 mg / mL to approximately 20 mg / mL, approximately 0.05 mg / mL to approximately 18 mg / mL, approximately 0.05 mg / mL to approximately 16 mg / mL, approximately 0.05 mg / mL to approximately 14 mg / mL, approximately 0.05 mg / mL to approximately 12 mg / mL, approximately 0.05 mg / mL to approximately 10 mg / mL, approximately 0.05 mg / mL to approximately 8 mg / mL, approximately 0.05 mg / mL to approximately 6 mg / mL, approximately 0.05 mg / mL to approximately 5 mg / mL, approximately 0.05 mg / mL to approximately 4 mg / mL, approximately 0.05 mg / mL to approximately 3 mg / mL, approximately 0.05 mg / mL to approximately 2 mg / mL, approximately 0.05 mg / mL to approximately 1 mg / mL, approximately 0.05 mg / mL to approximately 0.5 mg / mL, approximately 0.05 mg / mL to approximately 0.1 mg / mL, approximately 0.1 mg / mL to approximately 50 mg / mL, approximately 0.1 mg / mL to approximately 45 mg / mL, approximately 0.1 mg / mL to approximately 40 mg / mL, approximately 0.1 mg / mL to approximately 35 mg / mL, approximately 0.1 mg / mL to approximately 30 mg / mL, approximately 0.1 mg / mL to approximately 28 mg / mL, approximately 0.1 mg / mL to approximately 26 mg / mL, approximately 0.1 mg / mL to approximately 24 mg / mL, approximately 0.1 mg / mL to approximately 22 mg / mL, approximately 0.1 mg / mL to approximately 20 mg / mL, approximately 0.1 mg / mL to approximately 18 mg / mL, approximately 0.1 mg / mL to approximately 16 mg / mL, approximately 0.1 mg / mL to approximately 14 mg / mL, approximately 0.1 mg / mL to approximately 12 mg / mL, approximately 0.1 mg / mL to approximately 10 mg / mL,. About 0.1 mg / mL to about 8 mg / mL, about 0.1 mg / mL to about 6 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 3 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 0.5 mg / mL, about 0.5 mg / mL to about 50 mg / mL, about 0.5 mg / mL to about 45 mg / mL, about 0.5 mg / mL to about 40 mg / mL, about 0.5 mg / mL to about 35 mg / mL, about 0.5 mg / mL to about 30 mg / mL, about 0.5 mg / mL to about 28 mg / mL, about 0.5 mg / mL to about 26 mg / mL, about 0.5 mg / mL to about 24 mg / mL, about 0.5 mg / mL to about 22 mg / mL, about 0.5 mg / mL to about 20 mg / mL, about 0.5 mg / mL to about 18 mg / mL, about 0.5 mg / mL to about 16 mg / mL, about 0.5 mg / mL to about 14 mg / mL, about 0.5 mg / mL to about 12 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 0.5 mg / mL to about 3 mg / mL, about 0.5 mg / mL to about 2 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 45 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 28 mg / mL, about 1 mg / mL to about 26 mg / mL, about 1 mg / mL to about 24 mg / mL, about 1 mg / mL to about 22 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 18 mg / mL, about 1 mg / mL to about 16 mg / mL, about 1 mg / mL to about 14 mg / mL, about 1 mg / mL to about 12 mg / mL, about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 8 mg / mL, about 1 mg / mL to about 6 mg / mL, about 1 mg / mL to about 5 mg / mL, about 1 mg / mL to about 4 mg / mL, about 1 mg / mL to about 3 mg / mL, about 1 mg / mL to about 2 mg / mL, about 2 mg / mL to about 50 mg / mL, about 2 mg / mL to about 45 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2 mg / mL to about 35 mg / mL, about 2 mg / mL to about 30 mg / mL,From about 2 mg / mL to about 28 mg / mL, from about 2 mg / mL to about 26 mg / mL, from about 2 mg / mL to about 24 mg / mL, from about 2 mg / mL to about 22 mg / mL, from about 2 mg / mL to about 20 mg / mL, from about 2 mg / mL to about 18 mg / mL, from about 2 mg / mL to about 16 mg / mL, from about 2 mg / mL to about 14 mg / mL, from about 2 mg / mL to about 12 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 2 mg / mL to about 6 mg / mL, from about 2 mg / mL to about 5 mg / mL, from about 2 mg / mL to about 4 mg / mL, from about 2 mg / mL to about 3 mg / mL, from about 3 mg / mL to about 50 mg / mL, from about 3 mg / mL to about 45 mg / mL, from about 3 mg / mL to about 40 mg / mL, from about 3 mg / mL to about 35 mg / mL, from about 3 mg / mL to about 30 mg / mL, from about 3 mg / mL to about 28 mg / mL, from about 3 mg / mL to about 26 mg / mL, from about 3 mg / mL to about 24 mg / mL, from about 3 mg / mL to about 22 mg / mL, from about 3 mg / mL to about 20 mg / mL, from about 3 mg / mL to about 18 mg / mL, from about 3 mg / mL to about 16 mg / mL, from about 3 mg / mL to about 14 mg / mL, from about 3 mg / mL to about 12 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 6 mg / mL, from about 3 mg / mL to about 5 mg / mL, from about 3 mg / mL to about 4 mg / mL, from about 4 mg / mL to about 50 mg / mL, from about 4 mg / mL to about 45 mg / mL, from about 4 mg / mL to about 40 mg / mL, from about 4 mg / mL to about 35 mg / mL, from about 4 mg / mL to about 30 mg / mL, from about 4 mg / mL to about 28 mg / mL, from about 4 mg / mL to about 26 mg / mL, from about 4 mg / mL to about 24 mg / mL, from about 4 mg / mL to about 22 mg / mL, from about 4 mg / mL to about 20 mg / mL, from about 4 mg / mL to about 18 mg / mL, from about 4 mg / mL to about 16 mg / mL, from about 4 mg / mL to about 14 mg / mL, from about 4 mg / mL to about 12 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 8 mg / mL, from about 4 mg / mL to about 6 mg / mL, from about 4 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 45 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 35 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 28 mg / mL, from about 5 mg / mL to about 26 mg / mL,From about 5 mg / mL to about 24 mg / mL, from about 5 mg / mL to about 22 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 18 mg / mL, from about 5 mg / mL to about 16 mg / mL, from about 5 mg / mL to about 14 mg / mL, from about 5 mg / mL to about 12 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 6 mg / mL, from about 6 mg / mL to about 50 mg / mL, from about 6 mg / mL to about 45 mg / mL, from about 6 mg / mL to about 40 mg / mL, from about 6 mg / mL to about 35 mg / mL, from about 6 mg / mL to about 30 mg / mL, from about 6 mg / mL to about 28 mg / mL, from about 6 mg / mL to about 26 mg / mL, from about 6 mg / mL to about 24 mg / mL, from about 6 mg / mL to about 22 mg / mL, from about 6 mg / mL to about 20 mg / mL, from about 6 mg / mL to about 18 mg / mL, from about 6 mg / mL to about 16 mg / mL, from about 6 mg / mL to about 14 mg / mL, from about 6 mg / mL to about 12 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 8 mg / mL, from about 8 mg / mL to about 50 mg / mL, from about 8 mg / mL to about 45 mg / mL, from about 8 mg / mL to about 40 mg / mL, from about 8 mg / mL to about 35 mg / mL, from about 8 mg / mL to about 30 mg / mL, from about 8 mg / mL to about 28 mg / mL, from about 8 mg / mL to about 26 mg / mL, from about 8 mg / mL to about 24 mg / mL, from about 8 mg / mL to about 22 mg / mL, from about 8 mg / mL to about 20 mg / mL, from about 8 mg / mL to about 18 mg / mL, from about 8 mg / mL to about 16 mg / mL, from about 8 mg / mL to about 14 mg / mL, from about 8 mg / mL to about 12 mg / mL, from about 8 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 45 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 35 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 28 mg / mL, from about 10 mg / mL to about 26 mg / mL, from about 10 mg / mL to about 24 mg / mL, from about 10 mg / mL to about 22 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 10 mg / mL to about 18 mg / mL, from about 10 mg / mL to about 16 mg / mL, from about 10 mg / mL to about 14 mg / mL, from about 10 mg / mL to about 12 mg / mL, from about 12 mg / mL to about 50 mg / mL, from about 12 mg / mL to about 45 mg / mL, from about 12 mg / mL to about 40 mg / mLAbout 12 mg / mL to about 35 mg / mL, about 12 mg / mL to about 30 mg / mL, about 12 mg / mL to about 28 mg / mL, about 12 mg / mL to about 26 mg / mL, about 12 mg / mL to about 24 mg / mL, about 12 mg / mL to about 22 mg / mL, about 12 mg / mL to about 20 mg / mL, about 12 mg / mL to about 18 mg / mL, about 12 mg / mL to about 16 mg / mL, about 12 mg / mL to about 14 mg / mL, About 14 mg / mL to about 50 mg / mL, about 14 mg / mL to about 45 mg / mL, about 14 mg / mL to about 40 mg / mL, about 14 mg / mL to about 35 mg / mL, about 14 mg / mL to about 30 mg / mL, about 14 mg / mL to about 28 mg / mL, about 14 mg / mL to about 26 mg / mL, about 14 mg / mL to about 24 mg / mL, about 14 mg / mL to about 22 mg / mL, about 14 mg / mL to about 20 mg / mL, about 14 mg / mL to about 18 mg / mL, about 14 mg / mL to about 16 mg / mL, about 16 mg / mL to about 50 mg / mL, about 16 mg / mL to about 45 mg / mL, about 16 mg / mL to about 40 mg / mL, about 16 mg / mL to about 35 mg / mL, about 16 mg / mL to about 30 mg / mL, about 16 mg / mL to about 28 mg / mL, about 16 mg / mL to about 26 mg / mL, about 16 mg / mL to about 24 mg / mL, about 16 mg / mL to about 22 mg / mL, about 16 mg / mL to about 20 mg / mL, about 16 mg / mL to about 18 mg / mL, about 18 mg / mL to about 50 mg / mL, about 18 mg / mL to about 45 mg / mL, about 18 mg / mL to about 40 mg / mL, about 18 mg / mL to about 35 mg / mL, about 18 mg / mL to about 30 mg / mL, about 18 mg / mL to about 28 mg / mL, about 18 mg / mL to about 26 mg / mL, about 18 mg / mL to about 24 mg / mL, about 18 mg / mL to about 22 mg / mL, about 18 mg / mL to about 20 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 28 mg / mL, about 20 mg / mL to about 26 mg / mL, about 20 mg / mL to about 24 mg / mL, about 20 mg / mL to about 22 mg / mL, about 22 mg / mL to about 50 mg / mL, about 22 mg / mL to about 45 mg / mL, about 22 mg / mL to about 40 mg / mL, about 22 mg / mL to about 35 mg / mL, about 22 mg / mL to about 30 mg / mL, about 22 mg / mL to about 28 mg / mL, about 22 mg / mL to about 26 mg / mL, about 22 mg / mL to about 24 mg / mL, about 24 mg / mL to about 50 mg / mL, about 24 mg / mL to about 45 mg / mL, about 24 mg / mL to about 40 mg / mL, about 24 mg / mL to about 35 mg / mL, about 24 mg / mL to about 30 mg / mLApproximately 24 mg / mL to approximately 28 mg / mL, approximately 24 mg / mL to approximately 26 mg / mL, approximately 26 mg / mL to approximately 50 mg / mL, approximately 26 mg / mL to approximately 45 mg / mL, approximately 26 mg / mL to approximately 40 mg / mL, approximately 26 mg / mL to approximately 35 mg / mL mL, about 26 mg / mL to about 30 mg / mL, about 26 mg / mL to about 28 mg / mL, about 28 mg / mL to about 50 mg / mL, about 28 mg / mL to about 45 mg / mL, about 28 mg / mL to about 40 mg / mL, about 28 mg / mL to about 35 m g / mL, about 28 mg / mL to about 30 mg / mL, about 30 mg / mL to about 50 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 35 mg / mL to about 50 mg / mL, about 35 mg / mL to about 45 mg / mL, about 35 mg / mL to about 40 mg / mL, about 40 mg / mL to about 50 mg / mL, about 40 mg / mL to about 45 mg / mL, or about 45 mg / mL to about 50 mg / mL.

[0103] injection device Further provided herein is an injection device that includes any of the aqueous antibody formulations described herein (e.g., one or more doses of any of the aqueous antibody formulations described herein).For example, the injection device can be a pre-filled syringe.Non-limiting examples of such pre-filled syringes are known in the art.

[0104] kit Further provided herein is a kit that includes any of the injection devices provided herein. Further provided herein is a kit that includes one or more vials that contain any of the aqueous antibody formulations described herein. In some embodiments, any of the kits provided herein further includes instructions for administering any of the aqueous antibody formulations to a subject in need thereof.

[0105] Methods for making the formulation Further provided are methods of making any of the aqueous antibody formulations described herein, comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof (e.g., any of the exemplary antibodies or antigen-binding antibody fragments described herein); (ii) a buffer (e.g., any of the buffers described herein or one or more buffers); (iii) a salt (or one or more salts) selected from the group of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iv) a stabilizer; (v) a surfactant; and (vi) water (e.g., sterile water), wherein (i)-(vi) are mixed or combined in amounts sufficient to produce any of the aqueous antibody formulations described herein.

[0106] Some embodiments of these methods may further include filtering the mixed or combined (i)-(vi).Some embodiments of these methods may further include placing or placing the formulation into a sterile vial (e.g., a vacuum-sealed sterile vial) or syringe (e.g., a sterile syringe).

[0107] Some embodiments of any of these methods may further include adding or mixing with (i)-(vi) one or more (e.g., two or three) of a stabilizer (e.g., one or more of any of the exemplary stabilizers described herein or known in the art), an amino acid (e.g., one or more of any of the exemplary amino acids described herein or known in the art), and a surfactant (e.g., one or more of any of the exemplary surfactants described herein or known in the art) in an amount sufficient to provide any of the aqueous antibody formulations described herein.

[0108] Some embodiments of any of these methods may further include the step of adding or mixing with another component one or more additional therapeutic agents.

[0109] As those skilled in the art will appreciate, the order of adding each component of the formulation can be changed.For example, the antibody or antigen-binding antibody fragment can be a lyophilized solid that is dissolved in a buffered aqueous solution that includes salt and buffer.In another example, the solid that includes the antibody or antigen-binding antibody fragment (in the form of a lyophilized powder) and salt can be dissolved in a buffered aqueous solution (including a buffer).In some embodiments, the solid that includes the antibody or antigen-binding fragment (in the form of a lyophilized powder), buffer and salt is dissolved in water (e.g., sterile water).

[0110] Further provided herein are methods of making an aqueous antibody formulation comprising mixing or combining: (i) an antibody or antigen-binding fragment thereof; (ii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, arginine acetate, arginine aspartate, arginine glutamate, arginine sulfate, lysine acetate, lysine aspartate, lysine glutamate, lysine sulfate, sodium acetate, sodium aspartate, sodium glutamate, sodium sulfate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer; (iv) a surfactant; and (v) sterile water, wherein (i)-(v) are mixed or combined in sufficient amounts to produce any of the aqueous antibody formulations described herein. In some embodiments of the methods described herein, the methods do not include mixing or combining a buffer with (i)-(v), and the methods result in a buffer-free aqueous antibody formulation.

[0111] Some embodiments of these methods may further include filtering the mixed or combined (i)-(vi).Some embodiments of these methods may further include placing or placing the formulation into a sterile vial (e.g., a vacuum-sealed sterile vial) or syringe (e.g., a sterile syringe).

[0112] Some embodiments of any of these methods may further include adding or mixing with (i)-(vi) one or more (e.g., two or three) of a stabilizer (e.g., one or more of any of the exemplary stabilizers described herein or known in the art), an amino acid (e.g., any of the exemplary amino acids described herein other than histidine and arginine), and a surfactant (e.g., one or more of any of the exemplary surfactants described herein or known in the art) in an amount sufficient to provide any of the aqueous antibody formulations described herein.

[0113] Some embodiments of any of these methods may further include adding or mixing one or more additional therapeutic agents with another component. The mixing or combining step may be accomplished by pipetting, vortexing, oscillating, or manual stirring. Other means for performing the mixing or combining step are known in the art.

[0114] Methods of Treating Subjects Further provided herein are methods of treating a subject in need of treatment, comprising administering to the subject (e.g., any of the subjects described herein) a therapeutically effective amount of any of the aqueous antibody formulations provided herein. In some embodiments of any of these methods, the aqueous antibody formulation may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, intraarterially, intraocularly, intraarticularly, or translaminarly. In some embodiments of any of these methods, the subject may be administered one or more doses of the aqueous antibody formulation.

[0115] In some embodiments, the subject has been identified or diagnosed (e.g., previously identified or diagnosed as having a disease or condition that would benefit from treatment with an antibody or antigen-binding antibody fragment present in the aqueous antibody formulation).

[0116] In some embodiments of any of the methods described herein, the subject may further be administered one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents may be administered to the subject substantially simultaneously with the aqueous antibody formulation. In some embodiments, the one or more additional therapeutic agents may be administered to the subject before or after the aqueous antibody formulation is administered to the subject. EXAMPLES

[0117] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0118] Exemplary Components of Antibody Formulations Two Fc-engineered mAbs, anti-CXCR3-DE IgG1 ("Antibody A") and anti-CD38-ADE IgG1 ("Antibody B"), and one conventional mAb, anti-CD38 IgG1 ("Antibody C"), were used for conformational and kinetic stability studies and viscosity measurements. Various formulations were prepared with combinations of the following excipients: L-arginine, L-arginine hydrochloride, L-lysine, L-lysine hydrochloride, L-histidine hydrochloride, L-aspartic acid, L-glutamic acid, L-glycine, L-valine, L-methionine, L-serine, hydrochloric acid, sulfuric acid, acetic acid, sodium hydroxide, lithium hydroxide, lithium bromide, magnesium aspartate, magnesium glutamate, magnesium sulfate, magnesium chloride, sodium thiocyanate, sodium acetate, ammonium sulfate, sucrose, trehalose, sorbitol and glycerin, and appropriate pH adjustment.

[0119] Exemplary Sample Preparation Sugar, polyol, amino acid, amino acid salt, and metal salt solutions were all prepared in 10 mM histidine buffer between pH 5.5 and pH 6.2. For thermal (conformational) stability measurements, 1 mg / mL mAb formulations were prepared by adding stock mAb solutions to excipient solutions at approximately 1 / 50 (volume / volume) ratios. For kinetic stability studies and viscosity measurements, stock mAb solutions were concentrated and buffer exchanged into various excipient solutions using Vivaspin-20 30 kilodalton molecular weight cut-off (MWCO) membranes (General Electric). mAb formulations were concentrated to >180 mg / mL and then diluted to 150 mg / mL with the corresponding excipient solutions.

[0120] Exemplary Aqueous Antibody Formulations In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 400 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 0 to about 100 mM buffer (e.g., any of the buffers described herein), about 1 to about 750 mM stabilizing or viscosity salt (e.g., any of the stabilizing or viscosity salts described herein), about 0.001 to about 0.2% surfactant (e.g., any of the surfactants described herein), about 0% to about 10% sugar or polyol, and has a pH of about 4 to about 8. See, e.g., embodiment A of Table 1.

[0121] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 300 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 0 to about 50 mM buffer (e.g., any of the buffers described herein), about 5 to about 500 mM stabilizing or viscosity salt (e.g., any of the stabilizing or viscosity salts described herein), about 0.01 to about 0.1% surfactant (e.g., any of the surfactants described herein), about 1% to about 8% sugar or polyol, and has a pH of about 4.5 to about 7.5. See, e.g., embodiment B of Table 1.

[0122] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 0 to about 25 mM buffer (e.g., any of the buffers described herein), about 25 to about 300 mM stabilizing or viscosity salt (e.g., any of the stabilizing or viscosity salts described herein), about 0.01 to about 0.06% surfactant (e.g., any of the surfactants described herein), about 1.5% to about 8% sugar or polyol, and has a pH of about 5 to about 7. See, e.g., embodiment C of Table 1.

[0123] In some embodiments, the aqueous antibody formulation comprises about 0 to about 10 mM buffer (e.g., any of the buffers described herein), about 300 to about 750 mM stabilizing or viscosity salt (e.g., any of the stabilizing or viscosity salts described herein), and has a pH of about 5 to about 6.5 (see, e.g., embodiment D of Table 1).

[0124] [Table 1]

[0125] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium acetate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium acetate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 1 in Table 2.

[0126] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 2 of Table 2.

[0127] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 3 of Table 2.

[0128] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium sulfate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium sulfate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 4 of Table 2.

[0129] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 5 mM histidine buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 5 of Table 2.

[0130] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 5 mM histidine buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 6 of Table 2.

[0131] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM acetate buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM acetate buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.0. See, e.g., embodiment 7 of Table 2.

[0132] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM acetate buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM acetate buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.0. See, e.g., embodiment 8 of Table 2.

[0133] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 6.0. See, e.g., embodiment 9 of Table 2.

[0134] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 6.0. See, for example, embodiment 10 of Table 2.

[0135] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM lithium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM lithium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 11 of Table 2.

[0136] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM lithium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM lithium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 12 of Table 2.

[0137] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM sodium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM sodium aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 13 of Table 2.

[0138] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM sodium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM sodium glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 14 of Table 2.

[0139] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 200 to about 750 mM arginine aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 300 mM arginine aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 15 of Table 2.

[0140] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 200 to about 750 mM arginine glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 300 mM arginine glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, e.g., embodiment 16 of Table 2.

[0141] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 200 to about 750 mM lysine aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 300 mM lysine aspartate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 17 of Table 2.

[0142] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 200 to about 750 mM lysine glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 300 mM lysine glutamate, about 2% sucrose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 18 of Table 2.

[0143] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% trehalose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium aspartate, about 2% trehalose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 19 of Table 2.

[0144] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% trehalose, about 0.01% to about 0.1% polysorbate 80, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium glutamate, about 2% trehalose, about 0.05% polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 20 of Table 2.

[0145] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 20, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% polysorbate 20, and has a pH of about 5.5. See, e.g., embodiment 21 of Table 2.

[0146] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% polysorbate 20, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% polysorbate 20, and has a pH of about 5.5. See, e.g., embodiment 22 of Table 2.

[0147] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium aspartate, about 1% to about 8% sucrose, about 0.01% to about 0.1% poloxamer 188, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium aspartate, about 2% sucrose, about 0.05% poloxamer 188, and has a pH of about 5.5. See, e.g., embodiment 23 of Table 2.

[0148] In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 1 to about 100 mM histidine buffer, about 100 to about 300 mM magnesium glutamate, about 1% to about 8% sucrose, about 0.01% to about 0.1% poloxamer 188, and has a pH of about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises about 0.1 to about 200 mg / mL of an antibody or antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM histidine buffer, about 200 mM magnesium glutamate, about 2% sucrose, about 0.05% poloxamer 188, and has a pH of about 5.5. See, for example, embodiment 24 of Table 2.

[0149] [Table 2] [Table 3]

[0150] Thermal (conformational) stability by differential scanning calorimetry (DSC) Thermal (conformational) stability was evaluated by measuring the minimum unfolding temperature, T m1 Both the identity and concentration of different excipients were evaluated by measuring T m1 The effect of the solution on the increase in the T value was used to rank its effectiveness in improving conformational stability. Measurements were made by increasing the temperature of the solution from 15° C. to 110° C. at a rate of 1° C. / min. The temperature value at the maximum of the first peak was taken as the T m1 He called it.

[0151] Kinetic stability by size exclusion chromatography (SEC) Kinetic stability was assessed by periodically measuring the amount of aggregates formed in mAb formulations stored at 40°C for 4 weeks. SEC was used to quantify the levels of both aggregated and nonaggregated mAb molecules after 0, 1, 2, and 4 weeks of storage. Samples were measured by eluting 50 μg of total mAb from a TSKgel UP-SW3000 column (Tosoh Co.) with 40 mM phosphate and 150 mM sodium chloride, pH 7.2, at a rate of 0.43 mL / min (detection wavelength: 280 nm). Aggregates that elute more rapidly than nonaggregated mAb monomers are referred to as high molecular weight species (HMWS), and HMWS% was calculated by dividing the amount of aggregates formed by the sum of total aggregated mAb molecules + nonaggregated mAb molecules. Initial aggregation rate, k agg was taken as the slope of the plot of storage time versus HMWS%.

[0152] Viscosity measurements of mAb formulations The viscosity of a 150 mg / mL mAb formulation was measured using an initium rheometer (Rheosense). The mAb formulation was passed through a microchannel at one-sided shear rate and the pressure was measured at 20°C. EXAMPLES

[0153] Stabilization of Fc mutant mAbs Relatively low CH2 domain unfolding temperature (T m1 An Fc-engineered mAb (Antibody A) with a pH of 5.5 was selected. Solutions of the mAb were prepared at 1 mg / mL in 10 mM or 20 mM histidine buffer at pH 5.5. Excipient solutions were prepared at 20 mM and 200 mM. Thermodynamic / conformational stability was assessed by differential scanning calorimetry (DSC). Additionally, solutions of the mAb were prepared at concentrations of 25 or 150 mg / mL in the same buffer-excipient-pH solutions and the aggregation rate (k agg The kinetic or storage stability, as measured by the T m1 Rise (ΔT m1 ) and / or k aggExcipients were evaluated based on their effectiveness in reducing T m1 However, magnesium salts generally produced the greatest effect, increasing T by about 7°C (Figure 1). Arginine salts generally produced the smallest, but still significant, increase for antibody A. Among the anions, aspartate and glutamate were the most effective. m1 were generally most effective at increasing agg (40°C, 150 mg / mL antibody A) ΔT m1 A general decrease was observed with increasing k (Figure 2). Based on the nature of the salt, an approximately 35X decrease in aggregation rate was observed compared to the control formulation. Magnesium salts generally showed a k agg produced the highest reduction in arginine, followed by lysine, lithium and sodium. EXAMPLES

[0154] Stabilization of alternative Fc mutant mAbs Based on the results of Example 1, a subset of excipients was selected and their effectiveness as stabilizers was evaluated at relatively low T m1 Another Fc-engineered mAb (Antibody B) having the following structure was used for evaluation:

[0155] For conformational stability measurements, solutions of antibody B (1 mg / mL) were prepared in 10 mM histidine buffer at pH 5.5 and 6.2. For kinetic stability (40° C.) analysis, solutions of antibody B (50 mg / mL) were prepared in the same buffer-excipient at pH 6.2. Similar to the effect observed for antibody A, a salt-dependent T m1 Magnesium salts generally showed the greatest increase. As for anions, glutamate was associated with a significant increase in T m1 was found to be the most effective in increasing T, followed by aspartate and sulfate. m1 Consistent with the effect on k agg A decrease in k was also observed in the presence of salt (Figure 4). Magnesium salts generally agg was most effective in increasing EXAMPLES

[0156] Stabilization of Fc variant mAb (Antibody A) as a function of excipient concentration Excipients were evaluated at higher concentrations of 500 mM and 750 mM for their stabilizing effect on antibody A in solution. All excipients reduced T in a concentration-dependent manner. m1 It was shown that magnesium salts improve the conformational stability of Antibody A by increasing T m1 The greatest increase in k was observed at 750 mM for magnesium glutamate, approximately 15° C. at 750 mM. Furthermore, the results of the kinetic stability study (FIG. 6) showed that these same excipients at 500 mM reduced aggregation and k agg It was shown that it further reduces EXAMPLES

[0157] Stabilization of wild-type mAb The same excipients used in Example 2 also demonstrated a much higher T than the Fc variants used in our study. m1 The excipients were evaluated for their stabilizing effect on a conventional mAb (Antibody C) having the formula: ##STR00015## With the exception of sulfate, most excipients moderately improved the conformational stability with increasing concentration (200 mM, 500 mM, and 750 mM) (FIG. 7). Aspartate and glutamate were generally better at stabilizing the wild-type antibody. EXAMPLES

[0158] Stabilization of another wild-type mAb and its amino acid single and double mutants Magnesium, lithium and sodium aspartate and glutamate salts were evaluated for their stabilizing effect on wild-type anti-CEACAM5 antibody and its antibody D, E and DE variants at a concentration of 200 mM. All salts improved the conformational stability of the four antibodies tested, with the effect being most pronounced for the antibody DE variant (Figure 8). Of the salts tested, magnesium salts were the most effective at improving the conformational stability of the wild-type anti-CEACAM5 antibody and its antibody D, E and DE variants (Figure 8).m1 was most effective in increasing EXAMPLES

[0159] Effect of excipients on the viscosity and osmolality of mAb solutions. The effect of excipients at 200 mM concentration on the viscosity of antibody solutions was also evaluated. The viscosity of solutions of antibody A and antibody C (approximately 150 mg / mL) was measured in the presence and absence of the excipients and compared to the viscosity in the presence of a traditional stabilizing excipient such as sucrose. The results showed that the selected excipients (i) significantly reduced the viscosity of the solution compared to the control solution (Figure 9) and / or (ii) resulted in a solution with lower viscosity (Figure 10) and lower osmolality (Figure 11) compared to an equipotent concentration of sucrose. For antibody C, the solution viscosity could be reduced by as much as 10X compared to the control, with arginine, lysine and magnesium salts being the most effective, followed by sodium and lithium (Figure 9). In contrast, antibody A solutions were not intractably viscous (control formulation in Figure 10). The addition of sucrose to those solutions to improve conformational stability significantly increased the solution viscosity, especially at concentrations above 10%. No such increase in solution viscosity was observed for any of the salts tested. The effect of the two excipient classes on solution viscosity was >3°C ΔT m1 The results indicate that the viscosity trends associated with the use of sucrose at concentrations not far from those typically used to stabilize protein formulations (approximately 8%) are virtually absent with the excipients listed in this invention. A similar effect was observed in relation to solution osmolality as well (Figure 11). Solutions containing 15% and 30% sucrose exhibited a ΔT m1 The osmolality measured at 1000 s was higher than that of the 200 mM salt solution, without necessarily having a significantly higher stabilizing effect.

[0160] Alternative Embodiments While the present invention has been described with reference to its detailed description, it is to be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0161] Sequence information The amino acid sequences corresponding to the heavy and light chains of the exemplary antibodies described herein are provided.

[0162] Antibody A - Heavy chain of anti-CXCR3-DE (S239D, I332E)-Fc variant (SEQ ID NO: 1) EVQLLESGGGLVQPGGSLRLSCAASGFTFTSYAMSWVRQAPGKGLEWVATISHGGTYTYYPDSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARHPIYSGNYQGYFDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0163] Antibody A - Light chain of anti-CXCR3-DE(S239D, I332E)-Fc mutant (SEQ ID NO:2) DIQLTQSPSFLSASVGDRVTITCRASSGVNYLYWYQQKPGKAPKLWIYFTSTLASGVPSRFSGSGSGNEYTLTISSLQPEDFATYYCQQFTSSPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0164] Antibody C - Anti-CD38 (Isatuximab) - Wild-type IgG1 Fc heavy chain (SEQ ID NO: 3) QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQ GTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0165] Antibody C - Anti-CD38 (Isatuximab) - Light chain of wild type IgG1 Fc (SEQ ID NO: 4) DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0166] Antibody B - Anti-CD38-ADE (G236A, S239D, I332E)-Fc variant heavy chain (SEQ ID NO: 5) QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQ GTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLAGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0167] Antibody B - Anti-CD38-ADE (G236A, S239D, I332E)-Fc variant light chain (SEQ ID NO: 6) DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0168] Anti-CEACAM5-wild type IgG1 Fc heavy chain (SEQ ID NO: 7) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0169] Anti-CEACAM5-wild type IgG1 Fc light chain (SEQ ID NO: 8) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0170] Antibody D - Heavy chain of anti-CEACAM5(S239D)-Fc variant (SEQ ID NO:9) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0171] Antibody D - Light chain of anti-CEACAM5(S239D)-Fc variant (SEQ ID NO: 10) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0172] Antibody E - Anti-CEACAM5(I332E)-Fc variant heavy chain (SEQ ID NO: 11) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0173] Antibody E - Anti-CEACAM5(I332E)-Fc variant light chain (SEQ ID NO: 12) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0174] Antibody DE - Anti-CEACAM5 (S239D, I332E)-Fc variant heavy chain (SEQ ID NO: 13) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0175] Antibody DE - Anti-CEACAM5 (S239D, I332E)-Fc variant light chain (SEQ ID NO: 14) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

1. 1. An aqueous antibody formulation comprising: about 0.1 mg / mL to about 500 mg / mL of an antibody or antigen-binding fragment thereof; about 1 mM to 750 mM of a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, sodium acetate, sodium aspartate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; Including, wherein the formulation has a pH of about 4 to about 8, and the formulation is a buffer-free formulation.

2. 10. The formulation of claim 1 comprising from about 10 mM to about 750 mM of said salt.

3. 3. The formulation of claim 1 or 2, comprising from about 20 mM to about 750 mM of said salt.

4. The formulation of any one of claims 1 to 3, having a pH of about 5 to about 6.

5. 5. The formulation of claim 4 having a pH of about 5.

5.

6. The formulation of any one of claims 1 to 5, comprising an antibody.

7. The formulation of claim 6 , wherein the antibody is a monoclonal antibody.

8. (i) the monoclonal antibody is a human or humanized antibody; and / or (ii) the monoclonal antibody has an Fc amino acid substitution that reduces conformational stability relative to a similar antibody that does not contain that Fc amino acid substitution; and / or (iii) the monoclonal antibody is an IgG1 antibody or an IgG4 antibody; and / or (iv) the monoclonal antibody is an anti-CXC motif chemokine receptor 3 (CXCR3) monoclonal antibody; and / or (v) the monoclonal antibody is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody; and / or (vi) the monoclonal antibody is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody; The formulation of claim 7.

9. said anti-CXCR3 monoclonal antibody comprising a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:2; and / or The anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising SEQ ID NO:

8. The formulation according to claim 8.

10. (1) the Fc engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10; (2) the Fc engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:11 and a light chain comprising SEQ ID NO:12; or (3) The Fc-engineered anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO:

14. The formulation according to claim 8.

11. The formulation of any one of claims 1 to 10, comprising about 0.1 mg / mL to about 400 mg / mL of the antibody or antigen-binding antibody fragment.

12. (i) about 0.1 mg / mL to about 250 mg / mL of the antibody or antigen-binding antibody fragment; (ii) about 0.1 mg / mL to about 200 mg / mL of the antibody or antigen-binding antibody fragment; (iii) about 0.1 mg / mL to about 150 mg / mL of the antibody or antigen-binding antibody fragment; (iv) about 0.1 mg / mL to about 100 mg / mL of the antibody or antigen-binding antibody fragment; (v) about 0.1 mg / mL to about 50 mg / mL of the antibody or antigen-binding antibody fragment; or (vi) about 0.1 mg / mL to about 25 mg / mL of the antibody or antigen-binding antibody fragment; The formulation of claim 11.

13. (i) having a viscosity of about 1 cP to about 50 cP; (ii) has a viscosity of about 1 cP to about 40 cP; (iii) has a viscosity of about 1 cP to about 30 cP; or (iv) having a viscosity of about 1 cP to about 20 cP; The formulation according to any one of claims 1 to 12.

14. (i) having an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg; (ii) having an osmolality of about 250 mOsm / kg to about 750 mOsm / kg; (iii) has an osmolality of about 250 mOsm / kg to about 500 mOsm / kg; or (iv) having an osmolality of about 250 mOsm / kg to about 400 mOsm / kg; The formulation according to any one of claims 1 to 12.

15. (i) is stable at 25° C. for about 1 hour to about 2 years; and / or (ii) is stable at 40° C. for about 1 hour to about 8 weeks; and / or (iii) suitable for intravenous, intramuscular or subcutaneous administration; and / or (iv) further comprising one or more of a stabilizer, an antioxidant, a metal chelator, a viscosity modifier, an amino acid, and a surfactant; 15. The formulation of any one of claims 1 to 14, wherein the stabilizer is selected from the group consisting of fructose, maltose, galactose, glucose, O-mannose, sorbose, lactose, sucrose, trehalose, cellobiose, raffinose, melezitose, maltodextrin, dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sorbitol, amino sugars, sodium chloride and glycerin, and the viscosity modifier is selected from the group consisting of arginine, histidine, lysine, proline, glycine and sodium chloride.

16. (1) the antioxidant is methionine, ascorbic acid or N-acetylcysteine; and / or (2) the metal chelating agent is sodium ethylenediaminetetraacetate (EDTA), calcium EDTA or diethylenetriaminepentaacetate (DTPA); and / or (3) The surfactant is selected from the group consisting of sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, glycerin monocaprylate, glycerin monomyristate, glycerin monostearate, decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene glyceryl monostearate, polyethylene glycol distearate, and polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol beeswax, polyoxyethylene lanolin, polyoxyethylene stearamide, sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, polyoxyethylene sodium lauryl sulfate, sodium lauryl sulfosuccinate, lecithin, glycerophospholipids, sphingophospholipids, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, Triton-X, polyethylene glycol, and propylene glycol; and / or (4) The amino acid is selected from the group consisting of arginine, lysine, histidine, proline, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, and aspartic acid.

16. The formulation of claim 15.

17. An injection device comprising a formulation according to any one of claims 1 to 16.

18. A kit comprising one or more vials containing the formulation according to any one of claims 1 to 16.

19. 20. The kit of claim 18, further comprising an injection device for administering the formulation to a subject in need thereof.

20. 1. A method of making an aqueous antibody formulation, comprising: (i) an antibody or antigen-binding fragment thereof; (ii) a salt selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, magnesium sulfate, sodium acetate, sodium aspartate, lithium acetate, lithium aspartate, lithium glutamate, and lithium sulfate; (iii) a stabilizer; (iv) a surfactant; (v) sterile water; and mixing or combining wherein the stabilizer is selected from the group consisting of fructose, maltose, galactose, glucose, O-mannose, sorbose, lactose, sucrose, trehalose, cellobiose, raffinose, melezitose, maltodextrin, dextran, starch, mannitol, xylitol, maltitol, lactitol, glucitol, sorbitol, amino sugars, sodium chloride and glycerin; A process comprising mixing or combining (i)-(v) in sufficient amounts to produce a formulation according to any one of claims 1-16.

21. (1) does not include a step of mixing or combining a buffer with (i)-(v); and (2) further comprising the step of mixing or combining one or more of an antioxidant, a metal chelating agent, and a viscosity modifier with (i)-(v); The viscosity modifier is selected from the group consisting of arginine, histidine, lysine, proline, glycine and sodium chloride; 21. The method of claim 20.

22. 17. Use of a formulation according to any one of claims 1 to 16 in the manufacture of a medicament for treating a subject in need thereof, said treatment comprising administering to said subject a therapeutically effective amount of said formulation.

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