Stable, low-viscosity antibody formulations and uses thereof

Abstract

To provide an aqueous antibody formulation that exhibits improved stability and low viscosity, an injection device and a kit comprising the formulation, and a method for preparing the formulation.SOLUTION: An aqueous antibody formulation comprises: about 0.1 mg / mL to about 500 mg / mL of an antibody or an antigen-binding fragment thereof; about 1 mM to about 100 mM of a buffer selected from the group consisting of succinate, gluconate, histidine, citrate, and phosphate; and about 1 mM to about 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. Therein the formulation has a pH of about 4 to about 8.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Antibody formulations can lose their efficacy over time due to the effects of denaturation, oxidation, aggregation, or other degradation reactions. Degradation and aggregation of antibodies in antibody formulations can also cause risks such as toxicity or immunogenicity. High solution viscosity can have an adverse effect on the manufacturability and performance of protein therapeutics, particularly those formulated at high protein concentrations.

Summary of the Invention

Problems 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 loss of efficacy prior to administration of the antibody formulation and toxicity and immunogenicity resulting from degradation / aggregation. Conventional excipients used to stabilize proteins in solution can frequently increase the viscosity of the solution. Accordingly, there is a need in the art for antibody formulations that enable improvement in the stability of antibodies. Further, there is a need in the art for antibody formulations that enable the development of stable and low-viscosity antibody solutions.

Means for Solving the Problems

[0004] The present invention is based on the discovery that antibodies are stabilized in solution by including salts 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. The resulting stabilized antibody solutions are also less viscous compared to formulations containing conventional excipients, such as sugars like sucrose, used to stabilize formulations or proteins that do not contain one of these salts. The osmolality of the stabilized antibody solutions containing one of these salts is also lower than that of antibody solutions containing sugars and polyols such as sucrose, trehalose, sorbitol, mannitol, etc. when formulated at equipotent concentrations.

[0005] In view of this discovery, provided herein is an aqueous antibody formulation comprising from 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); from 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 from 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 from about 4 to about 8.

[0006] Furthermore, an aqueous antibody formulation is provided herein that contains 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) at about 0.1 mg / mL to about 500 mg / mL; 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, and lithium sulfate at about 1 mM to 750 mM, 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). Further provided is an injection device containing any of those formulations, and a kit comprising one or more vials containing any of those formulations.

[0008] Furthermore, a method for preparing an aqueous antibody formulation is provided, which comprises the step of mixing or combining (i) an antibody or an 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) to (vi) are mixed or combined in an amount sufficient to produce any of the formulations described herein.

[0009] Furthermore, a method for preparing an aqueous antibody formulation is provided herein, which comprises the step of mixing or combining (i) an antibody or an 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 an amount sufficient to produce any of the formulations described herein. In some embodiments of these methods, the method does not comprise the step of mixing or combining a buffer with (i) and (ii) and results in a buffer-free aqueous antibody formulation.

[0010] Furthermore, a method for treating a subject in need of treatment is provided herein, which comprises the step of administering to the subject a therapeutically effective amount of any of the formulations described herein.

[0011] An aqueous antibody formulation is provided herein, comprising an antibody or antigen-binding fragment thereof at about 0.1 mg / mL to about 500 mg / mL; a buffer at about 1 mM to about 100 mM; 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, and lithium sulfate at about 1 mM to 750 mM, having a pH of about 4 to about 8, and optionally having an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg.

[0012] Further provided herein is an aqueous antibody formulation comprising an antibody or antigen-binding fragment thereof at about 0.1 mg / mL to about 500 mg / mL; 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, and lithium sulfate at about 1 mM to 750 mM, 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 from about 10 mM to about 750 mM of the salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from about 20 mM to about 750 mM of the 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 from about 10 mM to about 750 mM of the salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from about 20 mM to about 750 mM of the 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 anti body formulations described herein, the salt is lithium sulfate. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from about 10 mM to about 750 mM of salt. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from 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 from about 1 mM to about 100 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from about 1 mM to about 75 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from about 1 mM to about 50 mM of buffer. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises from 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 contains 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 contains an Fc amino acid substitution that reduces conformational stability compared to a similar antibody that does not contain 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-C-X-C motif chemokine receptor 3 (CXCR3) mAb. In some embodiments of any of the aqueous antibody formulations described herein, the anti-CXCR3 mAb contains 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 contains 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) mono clonal 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 an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 400 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 250 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 200 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 150 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 100 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 50 mg / mL. In some embodiments of any of the aqueous antibody formulations described herein, the formulation comprises an antibody or antigen-binding antibody fragment at about 0.1 mg / mL to about 25 mg / mL.

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

[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 sugar, 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 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 monolinoate, 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, 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 stearic acid amide, sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, sodium polyoxyethylene lauryl sulfate, sodium lauryl sulfosuccinate ester, lecithin, glycerophospholipid, sphingophospholipid, 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 consisting of arginine, lysine, histidine, proline, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, and aspartic acid.

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

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

[0034] (i) an antibody or an 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 an amount sufficient to produce any of the aqueous antibody formulations described herein, and a method for preparing an aqueous antibody formulation is provided herein.

[0035] Furthermore, provided herein is a method for preparing an aqueous antibody formulation, comprising the step of mixing or combining (i) an antibody or an 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 the step of mixing a buffer with (i)-(v) and results in the production of a buffer-free aqueous antibody formulation.

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

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

[0038] The term "stabilizer" relates to additives (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 improve or enhance 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 interfacial stress and / or solution / surface interfacial stress. In some embodiments, a surfactant can 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" relates to any mammal. In some embodiments, the subject or "subject in need of treatment" can be a canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), sheep, cow, pig, goat, primate, e.g., ape (e.g., monkey, marmoset, baboon) or hominid (e.g., gorilla, chimpanzee, orangutan or gibbon), human, or rodent (e.g., mouse, guinea pig, hamster or rat). In some embodiments, the subject or "suitable subject for treatment" can be a non-human mammal, particularly a mammal (e.g., mouse, rabbit, pig, dog or primate) that has conventionally been used as a model for demonstrating therapeutic efficacy in humans, typically.

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

[0041] As used herein, "buffer-free" means without or with trace amounts of a buffer (e.g., any of the buffers described herein).

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill 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 may also be used. The materials, methods and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

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

Brief Description of the Drawings

[0044]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Modes for Carrying Out the Invention

[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. In various therapeutic fields, including but not limited to oncology, immunology, immuno-oncology, and cardiology, confidence in these complex molecules continues to grow with nearly 100 molecules that have been approved to date for therapeutic use and over 500 molecules at various stages of development or clinical trials.

[0046] An essential aspect in ensuring the transition of those therapeutic entities from the laboratory into a consistently high-quality manufacturable product is their stability in the dosage form. Due to their complex chemistry and structure, proteins are prone to various forms of physical and chemical degradation, compromising the biological efficacy and safety of the final formulation. For example, protein aggregation is a major quality attribute routinely monitored for protein-based products and is important in determining the product shelf-life. At a basic level, protein aggregation is associated with the native stability of the protein, and growth in non-native cells (e.g., non-native mammalian cells) is generally associated with an increase in the rate and extent of aggregation. Thus, it is not surprising that attempts to control and minimize aggregation during the 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. In essence, the intent is to stabilize the protein in its native conformation to minimize the population of aggregatable “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 aggregation rate. However, an undesirable effect of using these stabilizers is an increase in solution viscosity that is concentration-dependent.

[0047] Solution viscosity is a major property 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 utility and success of the product. The manufacturability of the product and its end use by patients or healthcare providers are closely related to the seamless fluidity of the solution. For example, high viscosity can limit the use of the product by requiring the use of special dosing devices or special dosing protocols that may not always be appropriate for the desired population. In other cases, high solution viscosity may require the application of manufacturing techniques (e.g., heat treatment) that can adversely affect the stability of the protein. Thus, it is not uncommon to use viscosity-reducing excipients, such as salts and amino acids, in high protein concentration solutions. However, those excipients can result in solutions with increased aggregation rates compared to high viscosity control solutions. In essence, the commonly used stabilizers and the viscosity-reducing excipients can have opposing effects on product performance, complicating their development.

[0048] Another important property to consider for injectable products (most protein-based products) is their osmolality. While intravenous solutions generally need to be isotonic, subcutaneous solutions are often hypertonic. In fact, there is evidence in the literature for hypertonic formulations that result in increased bioavailability of proteins following subcutaneous administration (A.M. Fathallah et al., Biopharm Drug Dispos. March 2015, 36(2):115-25). Thus, the influence of solution osmolality (and thus tonicity) on injection site discomfort and / or reactions and on bioavailability in the patient population needs to be carefully monitored and characterized during clinical development.

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

[0050] An aqueous antibody formulation is provided herein that comprises 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) at about 0.1 mg / mL to about 500 mg / mL; a buffer (e.g., any of the exemplary buffers described herein or known in the art) at about 1 mM to about 100 mM; 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, and lithium sulfate at about 1 mM to 750 mM, and has a pH of about 4 to about 8.

[0051] Further provided herein is an aqueous antibody formulation that comprises 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) at about 0.1 mg / mL to about 500 mg / mL (e.g., any of the subranges within this range described herein); 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, and lithium sulfate at about 1 mM to 750 mM (e.g., any of the subranges within this range described herein), and has a pH of about 4 to about 8. In some embodiments, the aqueous antibody formulation is a buffer-free antibody formulation.

[0052] Furthermore, there is provided an injection device comprising any of those formulations, and a kit comprising one or more vials containing any of those formulations.

[0053] Furthermore, (i) an antibody or an 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 are mixed or combined, wherein (i)-(vi) are mixed or combined in an amount sufficient to produce any of the formulations described herein, to provide a method for preparing an aqueous antibody formulation. Furthermore, there is provided a method for preparing an aqueous antibody formulation comprising the step of mixing or combining (i) an antibody or an 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 an amount sufficient to produce any of the formulations described herein.

[0054] Furthermore, a method for preparing an aqueous antibody formulation is provided herein, which comprises the step of mixing or combining (i) an antibody or an 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 the methods described herein, the method does not include the step of mixing or combining a buffer with (i)-(v) and the method results in a buffer-free aqueous antibody formulation.

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

[0056] Non-limiting aspects of these formulations, injection devices, kits and methods are described below. As will be appreciated by those skilled in the art, the exemplary aspects listed below can be used in any combination and can be combined with other aspects known in the art.

[0057] Antibodies and antigen-binding antibody fragments The aqueous antibody formulations provided in this specification are, for example, from about 0.1 mg / mL to about 500 mg / mL, from about 0.1 mg / mL to about 480 mg / mL, from about 0.1 mg / mL to about 460 mg / mL, from about 0.1 mg / mL to about 440 mg / mL, from about 0.1 mg / mL to about 420 mg / mL, from about 0.1 mg / mL to about 400 mg / mL, from about 0.1 mg / mL to about 380 mg / mL, from about 0.1 mg / mL to about 360 mg / mL, from about 0.1 mg / mL to about 340 mg / mL, from about 0.1 mg / mL to about 320 mg / mL, from about 0.1 mg / mL to about 300 mg / mL, from about 0.1 mg / mL to about 280 mg / mL, from about 0.1 mg / mL to about 260 mg / mL, from about 0.1 mg / mL to about 240 mg / mL, from about 0.1 mg / mL to about 220 mg / mL, from about 0.1 mg / mL to about 200 mg / mL, from about 0.1 mg / mL to about 190 mg / mL, from about 0.1 mg / mL to about 180 mg / mL, from about 0.1 mg / mL to about 170 mg / mL, from about 0.1 mg / mL to about 160 mg / mL, from about 0.1 mg / mL to about 140 mg / mL, from about 0.1 mg / mL to about 130 mg / mL, from about 0.1 mg / mL to about 120 mg / mL, from about 0.1 mg / mL to about 110 mg / mL, from about 0.1 mg / mL to about 100 mg / mL, from about 0.1 mg / mL to about 90 mg / mL, from about 0.1 mg / mL to about 80 mg / mL, from about 0.1 mg / mL to about 70 mg / mL, from about 0.1 mg / mL to about 60 mg / mL, from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 45 mg / mL, from about 0.1 mg / mL to about 40 mg / mL, from about 0.1 mg / mL to about 35 mg / mL, from about 0.1 mg / mL to about 30 mg / mL, from about 0.1 mg / mL to about 25 mg / mL, from about 0.1 mg / mL to about 20 mg / mL, from about 0.1 mg / mL to about 15 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 2.5 mg / mL, from about 0.1 mg / mL to about 1.0 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, about 0.5 mg / mL to about 500 mg / mL, about 0.5 mg / mL to about 480 mg / mL, about 0.5 mg / mL to about 460 mg / mL, about 0.5 mg / mL to about 440 mg / mL, about 0.5 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 0.5 mg / mL to about 360 mg / mL, about 0.5 mg / mL to about 340 mg / mL, about 0.5 mg / mL to about 320 mg / mL, about 0.5 mg / mL to about 300 mg / mL, about 0.5 mg / mL to about 280 mg / mL, about 0.5 mg / mL to about 260 mg / mL, about 0.5 mg / mL to about 240 mg / mL, about 0.5 mg / mL to about 220 mg / mL, about 0.5 mg / mL to about 200 mg / mL, about 0.5 mg / mL to about 190 mg / mL, about 0.5 mg / mL to about 180 mg / mL, about 0.5 mg / mL to about 170 mg / mL, about 0.5 mg / mL to about 160 mg / mL, about 0.5 mg / mL to about 140 mg / mL, about 0.5 mg / mL to about 130 mg / mL, about 0.5 mg / mL to about 120 mg / mL, about 0.5 mg / mL to about 110 mg / mL, about 0.5 mg / mL to about 100 mg / mL, about 0.5 mg / mL to about 90 mg / mL, about 0.5 mg / mL to about 80 mg / mL, about 0.5 mg / mL to about 70 mg / mL, about 0.5 mg / mL to about 60 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 25 mg / mL, about 0.5 mg / mL to about 20 mg / mL, about 0.5 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 2.5 mg / mL, about 0.5 mg / mL to about 1.0 mg / mL, about 1.0 mg / mL to about 500 mg / mL, about 1.0 mg / mL to about 480 mg / mL, about 1.0 mg / mL to about 460 mg / mL, about 1.0 mg / mL to about 440 mg / mL, about 1.0 mg / mL to about 420 mg / mL, about 1.0 mg / mL to about 400 mg / mL, about 1.0 mg / mL to about 380 mg / mL, about 1.0 mg / mL to about 360 mg / mL, about 1.0 mg / mL to about 340 mg / mL, about 1.0 mg / mL to approximately 320 mg / mL, approximately 1.0 mg / mL to approximately 300 mg / mL, approximately 1.0 mg / mL to approximately 280 mg / mL, approximately 1.0 mg / mL to approximately 260 mg / mL, approximately 1.0 mg / mL to approximately 240 mg / mL, approximately 1.0 mg / mL to approximately 220 mg / mL, approximately 1.0 mg / mL to approximately 200 mg / mL, approximately 1.0 mg / mL to approximately 190 mg / mL, approximately 1.0 mg / mL to approximately 180 mg / mL, approximately 1.0 mg / mL to approximately 170 mg / mL, approximately 1.0 mg / mL to approximately 160 mg / mL, approximately 1.0 mg / mL to approximately 140 mg / mL, approximately 1.0 mg / mL to approximately 130 mg / mL, approximately 1.0 mg / mL to approximately 120 mg / mL, approximately 1.0 mg / mL to approximately 110 mg / mL, approximately 1.0 mg / mL to approximately 100 mg / mL, approximately 1.0 mg / mL to approximately 90 mg / mL, approximately 1.0 mg / mL to approximately 80 mg / mL, approximately 1.0 mg / mL to approximately 70 mg / mL, approximately 1.0 mg / mL to approximately 60 mg / mL, approximately 1.0 mg / mL to approximately 50 mg / mL, approximately 1.0 mg / mL to approximately 45 mg / mL, approximately 1.0 mg / mL to approximately 40 mg / mL, approximately 1.0 mg / mL to approximately 35 mg / mL, approximately 1.0 mg / mL to approximately 30 mg / mL, approximately 1.0 mg / mL to approximately 25 mg / mL, approximately 1.0 mg / mL to approximately 20 mg / mL, approximately 1.0 mg / mL to approximately 15 mg / mL, approximately 1.0 mg / mL to approximately 10 mg / mL, approximately 1.0 mg / mL to approximately 5 mg / mL, approximately 1.0 mg / mL to approximately 2.5 mg / mL, approximately 2.5 mg / mL to approximately 500 mg / mL, approximately 2.5 mg / mL to approximately 480 mg / mL, approximately 2.5 mg / mL to approximately 460 mg / mL, approximately 2.5 mg / mL to approximately 440 mg / mL, approximately 2.5 mg / mL to approximately 420 mg / mL, approximately 2.5 mg / mL to approximately 400 mg / mL, approximately 2.5 mg / mL to approximately 380 mg / mL, approximately 2.5 mg / mL to approximately 360 mg / mL, approximately 2.5 mg / mL to approximately 340 mg / mL, approximately 2.5 mg / mL to approximately 320 mg / mL, approximately 2.5 mg / mL to approximately 300 mg / mL, approximately 2.5 mg / mL to approximately 280 mg / mL, approximately 2.5 mg / mL to approximately 260 mg / mL, approximately 2.5 mg / mL to approximately 240 mg / mL, approximately 2.5 mg / mL to approximately 220 mg / mL, approximately 2.5 mg / mL to approximately 200 mg / mL, approximately 2.5 mg / mL to approximately 190 mg / mL, approximately 2.5 mg / mL to approximately 180 mg / mL, approximately 2.5 mg / mL to approximately 170 mg / mL, approximately 2.5 mg / mL to approximately 160 mg / mL, approximately... 2.5 mg / mL to approximately 140 mg / mL, 2.5 mg / mL to approximately 130 mg / mL, 2.5 mg / mL to approximately 120 mg / mL, 2.5 mg / mL to approximately 110 mg / mL, 2.5 mg / mL to approximately 100 mg / mL, 2.5 mg / mL to approximately 90 mg / mL, 2.5 mg / mL to approximately 80 mg / mL, 2.5 mg / mL to approximately 70 mg / mL, 2.5 mg / mL to approximately 60 mg / mL, 2.5 mg / mL to approximately 50 mg / mL, 2.5 mg / mL to approximately 45 mg / mL, 2.5 mg / mL to approximately 40 mg / mL, 2.5 mg / mL to approximately 35 mg / mL, 2.5 mg / mL to approximately 30 mg / mL, 2.5 mg / mL to approximately 25 mg / mL, 2.5 mg / mL to approximately 20 mg / mL, 2.5 mg / mL to approximately 15 mg / mL, 2.5 mg / mL to approximately 10 mg / mL, 2.5 mg / mL to approximately 5 mg / mL, 5 mg / mL to approximately 500 mg / mL, 5 mg / mL to approximately 480 mg / mL, 5 mg / mL to approximately 460 mg / mL, 5 mg / mL to approximately 440 mg / mL, 5 mg / mL to approximately 420 mg / mL, 5 mg / mL to approximately 400 mg / mL, 5 mg / mL to approximately 380 mg / mL, 5 mg / mL to approximately 360 mg / mL, 5 mg / mL to approximately 340 mg / mL, 5 mg / mL to approximately 320 mg / mL, 5 mg / mL to approximately 300 mg / mL, 5 mg / mL to approximately 280 mg / mL, 5 mg / mL to approximately 260 mg / mL, 5 mg / mL to approximately 240 mg / mL, 5 mg / mL to approximately 220 mg / mL, 5 mg / mL to approximately 200 mg / mL, 5 mg / mL to approximately 190 mg / mL, 5 mg / mL to approximately 180 mg / mL, 5 mg / mL to approximately 170 mg / mL, 5 mg / mL to approximately 160 mg / mL, 5 mg / mL to approximately 140 mg / mL, 5 mg / mL to approximately 130 mg / mL, 5 mg / mL to approximately 120 mg / mL, 5 mg / mL to approximately 110 mg / mL, 5 mg / mL to approximately 100 mg / mL, 5 mg / mL to approximately 90 mg / mL, 5 mg / mL to approximately 80 mg / mL, 5 mg / mL to approximately 70 mg / mL, 5 mg / mL to approximately 60 mg / mL, 5 mg / mL to approximately 50 mg / mL, 5 mg / mL to approximately 45 mg / mL, 5 mg / mL to approximately 40 mg / mL, 5 mg / mL to approximately 35 mg / mL, 5 mg / mL to approximately 30 mg / mL, 5 mg / mL to approximately 25 mg / mL, 5 mg / mL to approximately 20 mg / mLAbout 5 mg / mL to about 15 mg / mL, about 5 mg / mL to about 10 mg / mL, about 10 mg / mL to about 500 mg / mL, about 10 mg / mL to about 480 mg / mL, about 10 mg / mL to about 460 mg / mL, 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 m g / 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, about 20 mg / mL to about 380 mg / mL, about 20 mg / mL to about 360 mg / mL, about 20 mg / mL to about 340 mg / mL, about 20 mg / mL to about 320 mg / mL, about 20 mg / mL to about 300 mg / mL, about 20 mg / mL to about 280 mg / mL, about 20 mg / mL to about 260 mg / mL, about 20 mg / mL to about 240 mg / mL, about 20 mg / mL to about 220 mg / mL, about 20 mg / mL to about 200 mg / mL, about 20 mg / mL to about 190 mg / mL, about 20 mg / mL to about 180 mg / mL, about 20 mg / mL to about 170 mg / mL, about 20 mg / mL to about 160 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 130 mg / mL, about 20 mg / mL to about 120 mg / mL, about 20 mg / mL to about 110 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 80 mg / mL, about 20 mg / mL to about 70 mg / mL, about 20 mg / mL to about 60 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 25 mg / mL, about 25 mg / mL to about 500 mg / mL, about 25 mg / mL to about 480 mg / mL, about 25 mg / mL to about 460 mg / mL, about 25 mg / mL to about 440 mg / mL, about 25 mg / mL to about 420 mg / mL, about 25 mg / mL to about 400 mg / mL, about 25 mg / mL to about 380 mg / mL, about 25 mg / mL to about 360 mg / mL, about 25 mg / mL to about 340 mg / mL, about 25 mg / mL to about 320 mg / mL, about 25 mg / mL to about 300 mg / mL, about 25 mg / mL to about 280 mg / mL, about 25 mg / mL to about 260 mg / mL, about 25 mg / mL to about 240 mg / mL, about 25 mg / mL to about 220 mg / mL, about 25 mg / mL to about 200 mg / mL, about 25 mg / mL to about 190 mg / mL, about 25 mg / mL to about 180 mg / mL, about 25 mg / mL to about 170 mg / mL, about 25 mg / mL to about 160 mg / mL, about 25 mg / mL to about 140 mg / mL, about 25 mg / mL to about 130 mg / mL, about 25 mg / mL to about 120 mg / mL, 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 2, 20 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, about 35 mg / mL to about 300 mg / mL, about 35 mg / mL to about 280 mg / mL, about 35 mg / mL to about 260 mg / mL, about 35 mg / mL to about 240 mg / mL, about 35 mg / mL to about 220 mg / mL, about 35 mg / mL to about 200 mg / mL, about 35 mg / mL to about 190 mg / mL, about 35 mg / mL to about 180 mg / mL, about 35 mg / mL to about 170 mg / mL, about 35 mg / mL to about 160 mg / mL, about 35 mg / mL to about 140 mg / mL, about 35 mg / mL to about 130 mg / mL, about 35 mg / mL to about 120 mg / mL, about 35 mg / mL to about 110 mg / mL, about 35 mg / mL to about 100 mg / mL, about 35 mg / mL to about 90 mg / mL, about 35 mg / mL to about 80 mg / mL, about 35 mg / mL to about 70 mg / mL, about 35 mg / mL to about 60 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 500 mg / mL, about 40 mg / mL to about 480 mg / mL, 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, from about 45 mg / mL to about 500 mg / mL, from about 45 mg / mL to about 480 mg / mL, from about 45 mg / mL to about 460 mg / mL, from about 45 mg / mL to about 440 mg / mL, from about 45 mg / mL to about 420 mg / mL, from about 45 mg / mL to about 400 mg / mL, from about 45 mg / mL to about 380 mg / mL, from about 45 mg / mL to about 360 mg / mL, from about 45 mg / mL to about 340 mg / mL, from about 45 mg / mL to about 320 mg / mL, from about 45 mg / mL to about 300 mg / mL, from about 45 mg / mL to about 280 mg / mL, from about 45 mg / mL to about 260 mg / mL, from about 45 mg / mL to about 240 mg / mL, from about 45 mg / mL to about 220 mg / mL, from about 45 mg / mL to about 200 mg / mL, from about 45 mg / mL to about 190 mg / mL, from about 45 mg / mL to about 180 mg / mL, from about 45 mg / mL to about 170 mg / mL, from about 45 mg / mL to about 160 mg / mL, from about 45 mg / mL to about 140 mg / mL, from about 45 mg / mL to about 130 mg / mL, from about 45 mg / mL to about 120 mg / mL, from about 45 mg / mL to about 110 mg / mL, from 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, 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,From about 100 mg / mL to about 190 mg / mL, from about 100 mg / mL to about 180 mg / mL, from about 100 mg / mL to about 170 mg / mL, from about 100 mg / mL to about 160 mg / mL, from about 100 mg / mL to about 140 mg / mL, from about 100 mg / mL to about 130 mg / mL, from about 100 mg / mL to about 120 mg / mL, from about 100 mg / mL to about 110 mg / mL, from about 110 mg / mL to about 500 mg / mL, from about 110 mg / mL to about 480 mg / mL, from about 110 mg / mL to about 460 mg / mL, from about 110 mg / mL to about 440 mg / mL, from about 110 mg / mL to about 420 mg / mL, from about 110 mg / mL to about 400 mg / mL, from about 110 mg / mL to about 380 mg / mL, from about 110 mg / mL to about 360 mg / mL, from about 110 mg / mL to about 340 mg / mL, from about 110 mg / mL to about 320 mg / mL, from about 110 mg / mL to about 300 mg / mL, from about 110 mg / mL to about 280 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 110 mg / mL to about 240 mg / mL, from about 110 mg / mL to about 220 mg / mL, from about 110 mg / mL to about 200 mg / mL, from about 110 mg / mL to about 190 mg / mL, from about 110 mg / mL to about 180 mg / mL, from about 110 mg / mL to about 170 mg / mL, from about 110 mg / mL to about 160 mg / mL, from about 110 mg / mL to about 140 mg / mL, from about 110 mg / mL to about 130 mg / mL, from about 110 mg / mL to about 120 mg / mL, from about 120 mg / mL to about 500 mg / mL, from about 120 mg / mL to about 480 mg / mL, from about 120 mg / mL to about 460 mg / mL, from about 120 mg / mL to about 440 mg / mL, from about 120 mg / mL to about 420 mg / mL, from about 120 mg / mL to about 400 mg / mL, from about 120 mg / mL to about 380 mg / mL, from about 120 mg / mL to about 360 mg / mL, from about 120 mg / mL to about 340 mg / mL, from about 120 mg / mL to about 320 mg / mL, from about 120 mg / mL to about 300 mg / mL, from about 120 mg / mL to about 280 mg / mL, from about 120 mg / mL to about 260 mg / mL, from about 120 mg / mL to about 240 mg / mL, from about 120 mg / mL to about 220 mg / mL, from about 120 mg / mL to about 200 mg / mL, from about 120 mg / mL to about 190 mg / mL, from about 120 mg / mL to about 180 mg / mL, from about 120 mg / mL to about 170 mg / mLAbout 120 mg / mL to about 16, 0 mg / mL, about 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 130 mg / mL to about 140 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, About 220 mg / mL to about 500 mg / mL, about 220 mg / mL to about 480 mg / mL, about 220 mg / mL to about 460 mg / mL, about 220 mg / mL to about 440 mg / mL, about 220 mg / mL to about 420 mg / mL, about 220 mg / mL to about 400 mg / mL, about 220 mg / mL to about 380 mg / mL, about 220 mg / mL to about 360 mg / mL, about 220 mg / mL to about 340 mg / mL, about 220 mg / mL to about 320 mg / mL, about 220 mg / mL to about 300 mg / mL, about 220 mg / mL to about 280 mg / mL, about 220 mg / mL to about 260 mg / mL, about 220 mg / mL to about 240 mg / mL, about 240 mg / mL to about 500 mg / mL, about 240 mg / mL to about 480 mg / mL, about 240 mg / mL to about 460 mg / mL, about 240 mg / mL to about 440 mg / mL, about 240 mg / mL to about 420 mg / mL, about 240 mg / mL to about 400 mg / mL, about 240 mg / mL to about 380 mg / mL, about 240 mg / mL to about 360 mg / mL, about 240 mg / mL to about 340 mg / mL, about 240 mg / mL to about 320 mg / mL, about 240 mg / mL to about 300 mg / mL, about 240 mg / mL to about 280 mg / mL, about 240 mg / mL to about 260 mg / mL, about 260 mg / mL to about 500 mg / mL, about 260 mg / mL to about 480 mg / mL, about 260 mg / mL to about 460 mg / mL, about 260 mg / mL to about 440 mg / mL, about 260 mg / mL to about 420 mg / mL, about 260 mg / mL to about 400 mg / mL, about 260 mg / mL to about 380 mg / mL, about 260 mg / mL to about 360 mg / mL, about 260 mg / mL to about 340 mg / mL, about 260 mg / mL to about 320 mg / mL, about 260 mg / mL to about 300 mg / mL, about 260 mg / mL to about 280 mg / mL, about 280 mg / mL to about 500 mg / mL, about 280 mg / mL to about 480 mg / mL, about 280 mg / mL to about 460 mg / mL, about 280 mg / mL to about 440 mg / mL, about 280 mg / mL to about 420 mg / mL, about 280 mg / mL to about 400 mg / mL, about 280 mg / mL to about 380 mg / mL, about 280 mg / mL to about 360 mg / mL, about 280 mg / mL to about 340 mg / mL, about 280 mg / mL to about 320 mg / mL, 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, An antibody or antigen-binding antibody fragment (e.g., any of the exemplary antibodies or antigen-binding antibody fragments described herein) may comprise from about 340 mg / mL to about 480 mg / mL, from about 340 mg / mL to about 460 mg / mL, from about 340 mg / mL to about 440 mg / mL, from about 340 mg / mL to about 420 mg / mL, from about 340 mg / mL to about 400 mg / mL, from about 340 mg / mL to about 380 mg / mL, from about 340 mg / mL to about 360 mg / mL, from about 360 mg / mL to about 500 mg / mL, from about 360 mg / mL to about 480 mg / mL, from about 360 mg / mL to about 460 mg / mL, from about 360 mg / mL to about 440 mg / mL, from about 360 mg / mL to about 420 mg / mL, from about 360 mg / mL to about 400 mg / mL, from about 360 mg / mL to about 380 mg / mL, from about 380 mg / mL to about 500 mg / mL, from about 380 mg / mL to about 480 mg / mL, from about 380 mg / mL to about 460 mg / mL, from about 380 mg / mL to about 440 mg / mL, from about 380 mg / mL to about 420 mg / mL, from about 380 mg / mL to about 400 mg / mL, from about 400 mg / mL to about 500 mg / mL, from about 400 mg / mL to about 480 mg / mL, from about 400 mg / mL to about 460 mg / mL, from about 400 mg / mL to about 440 mg / mL, from about 400 mg / mL to about 420 mg / mL, from about 420 mg / mL to about 500 mg / mL, from about 420 mg / mL to about 480 mg / mL, from about 420 mg / mL to about 460 mg / mL, from about 420 mg / mL to about 440 mg / mL, from about 440 mg / mL to about 500 mg / mL, from about 440 mg / mL to about 480 mg / mL, from about 440 mg / mL to about 460 mg / mL, from about 460 mg / mL to about 500 mg / mL, from about 460 mg / mL to about 480 mg / mL, or from about 480 mg / mL to about 500 mg / mL.

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

[0059] The term "antigen-binding antibody fragment" relates to fragments of mammalian (e.g., human) IgG1, IgG2, IgG3, IgG4, IgM, IgE or IgA that retain 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, 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. V NAR The domain is a single monomeric variable antibody domain found in cartilaginous fish. V H Non-limiting aspects of the H domain and V NAR domain are, for example, 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 are described.

[0062] In some embodiments, the antibody can be a VHH-scAb, VHH-Fab, dual scFab, diabody, crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, knobs-in-holes common light chain, knobs-in-holes 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 IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, diabody-CH3, triple body, mini-antibody, 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’) 2It includes fragments and Fab’ fragments. Further examples of antigen-binding antibody fragments include any antigen-binding fragment of IgG (e.g., antigen-binding fragments of IgG1, IgG2, IgG3, or IgG4) (e.g., antigen-binding fragments of human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); antigen-binding fragments of IgA (e.g., antigen-binding fragments of IgA1 or IgA2) (e.g., human or humanized IgA, e.g., antigen-binding fragments of human or humanized IgA1 or IgA2); antigen-binding fragments of IgD (e.g., antigen-binding fragments of human or humanized IgD); antigen-binding fragments of IgE (antigen-binding fragments of human or humanized IgE); or antigen-binding fragments of IgM (e.g., antigen-binding fragments of human or humanized IgM).

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

[0065] The "Fab" fragment contains, in addition to the heavy-chain variable domain and the light-chain variable domain of the Fv fragment, the constant domain of the light chain and the first constant domain (C H1 ) of the heavy chain.

[0066] The "F(ab’) 2 " fragment contains two Fab fragments linked near the hinge region by a disulfide bond.

[0067] "Dual variable domain immunoglobulin" or "DVD-Ig" relates 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. Patent 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] An antibody or antigen-binding antibody fragment can bind to its epitope or antigen with a dissociation equilibrium constant (K -7 d) of less than 1x10 -8 M, less than 1x10 -9 M, less than 1x10 -10 M, less than 1x10 -11 M, less than 1x10 -12 M, less than 1x10 -13 M, or less than 1x10 D M. In some embodiments, the antibody or antigen-binding antibody fragment can bind to its epitope or antigen with a K -3 d of about 1x10 -5 M to about 1x10 -4 M, about 1x10 -6 M to 1x10 -5 M, about 1x10 -7 M to 1x10 -6 M, about 1x10 -8 M to about 1x10 -7 M, about 1x10 -9 M to 1x10 -8 M, about 1x10 -10 M to 1x10 -9 M, or about 1x10 -11 M to about 1x10 D M.

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

[0071] In some embodiments, the mAb can have an Fc region that includes one or more amino acid substitutions that result in a lower CH2 domain unfolding temperature compared to an antibody having a wild-type Fc region. In some embodiments, the mAb can have an Fc region that includes one or more amino acid substitutions that decrease the stability of the antibody compared to the stability of a similar antibody lacking the one or more amino acid substitutions.

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

[0073] In some embodiments, the mAb is an anti-C-X-C motif chemokine receptor 3 (CXCR3) mAb (e.g., a human or humanized antibody). In some embodiments, the anti-CXCR3 mAb comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 1, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 1, and a light chain that comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 2, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 2. In some embodiments, the anti-CXCR3 antibody comprises three CDRs present in SEQ ID NO: 1 and 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 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, or consists of a heavy chain 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 a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 99% identical, or 100% identical to SEQ ID NO: 4, or consists of a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 99% identical, or 100% identical to SEQ ID NO: 4. In some embodiments, the anti-CD38 mA b comprises three CDRs present in SEQ ID NO: 3 and 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 sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 5, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 5, and a light chain that comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 6, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 6. In some embodiments, the Fc-engineered anti-CD38 mAb comprises three CDRs present in SEQ ID NO: 5 and 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 sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 7, or consists of a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 7 and a light chain that comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 8, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 8. In some embodiments, the anti-CEACAM5 antibody comprises three CDRs present in SEQ ID NO: 7 and 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 sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 9, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 9, and a light chain that comprises a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 10, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 10. In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises three CDRs present in SEQ ID NO: 9 and 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 sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 11, or consists of a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 11, and a light chain that comprises a sequence that is at least 8 A heavy chain consisting of a sequence that is 0%, at least 85%, at least 90%, at least 95%, at least 99% identical, or 100% identical, and a light chain that contains 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: 12, 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: 12. In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises three CDRs present in SEQ ID NO: 11 and 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 contains 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: 13, or consists of a heavy chain with 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: 13, and contains 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: 14, or consists of a light chain with 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: 14. In some embodiments, the Fc-engineered anti-CEACAM5 mAb comprises three CDRs present in SEQ ID NO: 13 and three CDRs present in SEQ ID NO: 14.

[0080] In some embodiments, the antibody may be conjugated to a drug (e.g., a chemotherapeutic agent, a small molecule), a toxin, or a radioisotope. In some embodiments, the antibody may be conjugated 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 Pt 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] The antibody can be produced by introducing a nucleic acid sequence encoding the antibody into a cell and culturing the recombinant cell under conditions sufficient for expression of the antibody. In some embodiments, the introducing step comprises introducing into the cell an expression vector comprising the sequence encoding the antibody to produce a recombinant cell.

[0082] The antigens described herein can be produced by any cell, e.g., a eukaryotic cell. As used herein, the term “eukaryotic cell” refers to a cell having a distinct 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 of culturing cells are well known in the art. Cells can be cultured It can be maintained under conditions that promote proliferation, differentiation, and growth. Briefly, cells can be cultured by contacting the cells (e.g., any cells) with a cell culture medium containing growth factors and supplements necessary to support cell viability and growth.

[0084] Methods for introducing nucleic acids and expression vectors into cells (e.g., eukaryotic cells) are known in the art. Non-limiting examples of methods that can be used to introduce nucleic acids into cells include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell squeezing, sonoporation, optical transfection, impalefection, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral transduction and lentiviral transduction), and nanoparticle transfection.

[0085] Also provided herein are methods that further include the isolation of antibodies from cells (e.g., eukaryotic cells) using techniques well known in the art (e.g., ammonium sulfate precipitation, polyethylene glycol precipitation, ion exchange chromatography (anion or cation), hydrophobic interaction chromatography, metal affinity chromatography, ligand affinity chromatography, size exclusion chromatography).

[0086] buffer The formulations described herein may 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 may be present in any of the formulations described herein include acetates, succinates, gluconates, histidines, citrates, phosphates, and tris. In some embodiments of any of the formulations described herein, the formulation may include an acetate, histidine, or phosphate. Further examples of buffers that may 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 is 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, from about 0.01 mM to about 30 mM, from about 0.01 mM to about 25 mM, from about 0.01 mM to about 20 mM, from about 0.01 mM to about 15 mM, from about 0.01 mM to about 10 mM, from about 0.01 mM to about 9 mM, from about 0.01 mM to about 8.5 mM, from about 0.01 mM to about 8 mM, from about 0.01 mM to about 7.5 mM, from about 0.01 mM to about 7 mM, from about 0.01 mM to about 6.5 mM, from about 0.01 mM to about 6 mM, from about 0.01 mM to about 5 mM, from about 0.01 mM to about 4.5 mM, from about 0.01 mM to about 4 mM, from about 0.01 mM to about 3.5 mM, from about 0.01 mM to about 3 mM, from about 0.01 mM to about 2.5 mM, from about 0.01 mM to about 2 mM, from about 0.01 mM to about 1.5 mM, from about 0.01 mM to about 1 mM, from about 0.01 mM to about 0.9 mM, from about 0.01 mM to about 0.8 mM, from about 0.01 mM to about 0.7 mM, from about 0.01 mM to about 0.6 mM, from about 0.01 mM to about 0.5 mM, from about 0.01 mM to about 0.4 mM, from about 0.01 mM ~ about 0.3 mM, about 0.01 mM ~ about 0.2 mM, about 0.01 mM ~ about 0.1 mM, about 0.1 mM ~ about 100 mM, about 0.1 mM ~ about 95 mM, about 0.1 mM ~ about 90 mM, about 0.1 mM ~ about 85 mM, about 0.1 mM ~ about 80 mM, about 0.1 mM ~ about 75 mM, about 0.1 mM ~ about 70 mM, about 0.1 mM ~ about 65 mM, about 0.1 mM ~ about 60 mM, about 0.1 mM ~ about 55 mM, about 0.1 mM ~ about 50 mM, about 0.1 mM ~ about 45 mM, about 0.1 mM ~ about 40 mM, about 0.1 mM ~ about 35 mM, about 0.1 mM ~ about 30 mM, about 0.1 mM ~ about 25 mM, about 0.1 mM ~ about 20 mM, about 0.1 mM ~ about 15 mM, about 0.1 mM ~ about 10 mM, about 0.1 mM ~ about 9 mM, about 0.1 mM ~ about 8 mM, about 0.1 mM ~ about 7 mM, about 0.1 mM ~ about 6 mM, about 0.1 mM ~ about 5 mM, about 0.1 mM ~ about 4 mM, about 0.1 mM ~ about 3 mM, about 0.1 mM ~ about 2 mM, about 0.1 mM ~ about 1 mM, about 0.1 mM ~ about 0.9 mM, about 0.1 mM ~ about 0.8 mM, about 0.1 mM ~ about 0.7 mM, about 0.1 mM ~ about 0.6 mM, about 0.1 mM ~ about 0.5 mM, about 0.1 mM ~ about 0.4 mM, about 0.1 mM ~ about 0.3 mM, about 0.1 mM ~ about 0.2 mM, about 0.2 mM ~ about 100 mM, about 0.2 mM ~ about 95 mM, about 0.2 mM ~ about 90 mM, about 0.2 mM ~ about 85 mM, about 0.2 mM ~ about 80 mM, about 0.2 mM ~ about 75 mM, about 0.2 mM ~ about 70 mM, about 0.2 mM ~ about 65 mM, about 0.2 mM ~ about 60 mM, about 0.2 mM ~ about 55 mM, about 0.2 mM ~ about 50 mM, about 0.2 mM ~ about 45 mM, about 0.2 mM ~ about 40 mM, about 0.2 mM ~ about 35 mM, about 0.2 mM ~ about 30 mM, about 0.2 mM ~ about 25 mM, about 0.2 mM ~ about 20 mM, about 0.2 mM ~ about 15 mM, about 0.2 mM ~ about 10 mM, about 0.2 mM ~ about 9 mM, about 0.2 mM ~ about 8 mM, about 0.2 mM ~ about 7 mM, about 0.2 mM ~ about 6 mM, about 0.2 mM ~ about 5 mM, about 0.2 mM ~ about 4 mM, about 0.2 mM ~ about 3 mM, about 0.2 mM ~ about 2 mM, about 0.2 mM ~ about 1 mM, about 0.2 mM ~ about 0.9 mM, about 0.2 mM ~ about 0.8 mM, about 0.2 mM ~ about 0.7 mM, about 0.2 mM ~ about 0.6 mM, about 0.2 mM ~ about 0.5 mM, about 0.2 mM ~ about 0.4 mM, about 0.2 mM ~ about 0.3 mM, about 0.5 mM ~ about 100 mM, about 0.5 mM ~ about 95 mM, about 0.5 mM to approximately 90 mM, approximately 0.5 mM to approximately 85 mM, approximately 0.5 mM to approximately 80 mM, approximately 0.5 mM to approximately 75 mM, approximately 0.5 mM to approximately 70 mM, approximately 0.5 mM to approximately 65 mM, approximately 0.5 mM to approximately 60 mM, approximately 0.5 mM to approximately 55 mM, approximately 0.5 mM to approximately 50 mM, approximately 0.5 mM to approximately 45 mM, approximately 0.5 mM to approximately 40 mM, approximately 0.5 mM to approximately 35 mM, approximately 0.5 mM to approximately 30 mM, approximately 0.5 mM to approximately 25 mM, approximately 0.5 mM to approximately 20 mM, approximately 0.5 mM to approximately 15 mM, approximately 0.5 mM to approximately 10 mM, approximately 0.5 mM to approximately 0.9 mM, approximately 0.5 mM to approximately 0.8 mM, approximately 0.5 mM to approximately 0.7 mM, approximately 0.5 mM to approximately 0.6 mM, approximately 0.5 mM to approximately 5 mM, approximately 0.5 mM to approximately 4 mM, approximately 0.5 mM to approximately 3 mM, approximately 0.5 mM to approximately 2 mM, approximately 0.5 mM to approximately 1 mM, approximately 0.5 mM to approximately 0.9 mM, approximately 0.5 mM to approximately 0.8 mM, approximately 0.5 mM to approximately 0.7 mM, approximately 0.5 mM to approximately 0.6 mM, approximately 1 mM to approximately 100 mM, approximately 1 mM to approximately 95 mM, approximately 1 mM to approximately 90 mM, approximately 1 mM to approximately 85 mM, approximately 1 mM to approximately 80 mM, approximately 1 mM to approximately 75 mM, approximately 1 mM to approximately 70 mM, approximately 1 mM to approximately 65 mM, approximately 1 mM to approximately 60 mM, approximately 1 mM to approximately 55 mM, approximately 1 mM to approximately 50 mM, approximately 1 mM to approximately 45 mM, approximately 1 mM to approximately 40 mM, approximately 1 mM to approximately 35 mM, approximately 1 mM to approximately 30 mM, approximately 1 mM to approximately 25 mM, approximately 1 mM to approximately 20 mM, approximately 1 mM to approximately 15 mM, approximately 1 mM to approximately 10 mM, approximately 1 mM to approximately 9 mM, approximately 1 mM to approximately 8 mM, approximately 1 mM to approximately 7 mM, approximately 1 mM to approximately 6 mM, approximately 1 mM to approximately 5 mM, approximately 1 mM to approximately 4 mM, approximately 1 mM to approximately 3 mM, approximately 1 mM to approximately 2 mM, approximately 1 mM to approximately 1.8 mM, approximately 1 mM to approximately 1.6 mM, approximately 1 mM to approximately 1.4 mM, approximately 1 mM to approximately 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, about 2 m. M is about 3 mM, about 5 mM to about 100 mM, about 5 mM to about 95 mM, about 5 mM to about 90 mM, about 5 mM to about 85 mM, about 5 mM to about 80 mM, about 5 mM to about 75 mM, about 5 mM to about 70 mM, about 5 mM to about 65 mM, about 5 mM to about 60 mM, about 5 mM to about 55 mM, about 5 mM to about 50 mM, about 5 mM to about 45 mM, about 5 mM to about 40 mM, about 5 mM to about 35 mM, about 5 mM to about 30 mM, about 5 mM to about 25 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 10 mM, about 5 mM to about 9 mM, about 5 mM to about 8 mM, about 5 mM to about 7 mM, about 5 mM to about 6 mM, about 10 mM to about 100 mM, about 10 mM to about 95 mM, about 10 mM to about 90 mM, about 10 mM to about 85 mM, about 10 mM to about 80 mM, about 10 mM to about 75 mM, about 10 mM to about 70 mM, about 10 mM to about 65 mM, about 10 mM to about 60 mM, about 10 mM to about 55 mM, about 10 mM to about 50 mM, about 10 mM to about 45 mM, about 10 mM to about 40 mM, about 10 mM to about 35 mM, about 10 mM to about 30 mM, about 10 mM to about 25 mM, about 10 mM to about 20 mM, about 10 mM to about 15 mM, about 10 mM to about 14 mM, about 10 mM to about 13 mM, about 10 mM to about 12 mM, about 10 mM to about 11 mM, about 15 mM to about 100 mM, about 15 mM to about 95 mM, about 15 mM to about 90 mM, about 15 mM to about 85 mM, about 15 mM to about 80 mM, about 15 mM to about 75 mM, about 15 mM to about 70 mM, about 15 mM to about 65 mM, about 15 mM to about 60 mM, about 15 mM to about 55 mM, about 15 mM to about 50 mM, about 15 mM to about 45 mM, about 15 mM to about 40 mM, about 15 mM to about 35 mM, about 15 mM to about 30 mM, about 15 mM to about 25 mM, about 15 mM to about 20 mM, about 15 mM to about 19 mM, about 15 mM to about 18 mM, about 15 mM to about 17 mM, about 15 mM to about 16 mM, about 20 mM to about 100 mM, about 20 mM to about 95 mM, about 20 mM to about 90 mM, about 20 mM to about 85 mM, about 20 mM to about 80 mM, about 20 mM to about 75 mM, about 20 mM to about 70 mM, about 20 mM to about 65 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, about 20 mM to about 24 mM, about 20 mM to about 23 mMAbout 20 mM to about 22 mM, about 20 mM to about 21 mM, about 25 mM to about 100 mM, about 25 mM to about 95 mM, about 25 mM to about 90 mM, about 25 mM to about 85 mM, about 25 mM to about 80 mM, about 25 mM to about 75 mM, about 25 mM to about 70 mM, about 25 mM to about 65 mM, about 25 mM to about 60 mM, about 25 mM to about 55 mM, about 25 mM to about 50 mM, about 25 mM to about 45 mM, about 25 mM to about 40 mM, about 25 mM to about 35 mM, about 25 mM to about 30 mM, about 25 mM to about 29 mM, about 25 mM to about 28 mM, about 25 mM to about 27 mM, about 25 mM to about 26 mM About 30 mM to about 100 mM, about 30 mM to about 95 mM, about 30 mM to about 90 mM, about 30 mM to about 85 mM, about 30 mM to about 80 mM, about 30 mM to about 75 mM, about 30 mM to about 70 mM, about 30 mM to about 65 mM, about 30 mM to about 60 mM, about 30 mM to about 55 mM, about 30 mM to about 50 mM, about 30 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 35 mM, about 30 mM to about 34 mM, about 30 mM to about 33 mM, about 30 mM to about 32 mM, about 30 mM to about 31 mM, about 35 mM to about 100 mM, about 35 mM to about 95 mM, about 35 mM to about 90 mM, about 35 mM to about 85 mM, about 35 mM to about 80 mM, about 35 mM to about 75 mM, about 35 mM to about 70 mM, about 35 mM to about 65 mM, about 35 mM to about 60 mM, about 35 mM to about 55 mM, about 35 mM to about 50 mM, about 35 mM to about 45 mM, about 35 mM to about 40 mM, about 35 mM to about 39 mM, about 35 mM to about 38 mM, about 35 mM to about 37 mM, about 35 mM to 36 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 40 mM to about 44 mM, about 40 mM to about 43 mM, about 40 mM to about 42 mM, about 40 mM to about 41 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, 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 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 60 mM to about 65 mM, from about 60 mM to about 64 mM, from about 60 mM to about 63 mM, from about 60 mM to about 62 mM, from about 60 mM to about 61 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 70 mM to about 75 mM, from about 70 mM to about 74 mM, from about 70 mM to about 73 mM, from about 70 mM to about 72 mM, from about 70 mM to about 71 mM, from about 90 mM to about 100 mM, from about 90 mM to about 95 mM, from about 90 mM to about 94 mM, from about 90 mM to about 93 mM, from about 90 mM to about 92 mM, or from about 90 mM to about 91 mM.

[0089] salt The aqueous antibody formulations described herein include a salt (e.g., one or more salts) 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. In some embodiments, the aqueous antibody formulations described herein include a salt (e.g., one or more salts) selected from the group consisting of magnesium glutamate, magnesium acetate, magnesium aspartate, and magnesium sulfate.

[0090] The final concentration 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 (or the total final concentration of one or more salts) in any of the formulations described herein can be from about 0.01 mM to about 750 mM (or any sub-range within 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, from about 0.01 mM to about 300 mM, from about 0.01 mM to about 290 mM, from about 0.01 mM to about 280 mM, from about 0.01 mM to about 270 mM, from about 0.01 mM to about 260 mM, from about 0.01 mM to about 250 mM, from about 0.01 mM to about 240 mM, from about 0.01 mM to about 230 mM, from about 0.01 mM to about 220 mM, from about 0.01 mM to about 210 mM, from about 0.01 mM to about 200 mM, from about 0.01 mM to about 190 mM, from about 0.01 mM to about 180 mM, from about 0.01 mM to about 170 mM, from about 0.01 mM to about 160 mM, from about 0.01 mM to about 150 mM, from about 0.01 mM to about 140 mM, from about 0.01 mM to about 130 mM, from about 0.01 mM to about 120 mM, from about 0.01 mM to about 110 mM, 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 5 5 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, from about 0.01 mM to about 30 mM, from about 0.01 mM to about 25 mM, from about 0.01 mM to about 20 mM, from about 0.01 mM to about 15 mM, from about 0.01 mM to about 10 mM, from about 0.01 mM to about 9 mM, from about 0.01 mM to about 8 mM, from about 0.01 mM to about 7 mM, from about 0.01 mM to about 6 mM, from about 0.01 mM to about 5 mM, from about 0.01 mM to about 4 mM, from about 0.01 mM to about 3 mM, from about 0.01 mM to about 2 mM, from about 0.01 mM to about 1 mM, from about 0.01 mM to about 0.5 mM, from about 0.01 mM to about 0.2 mM, from about 0.01 mM to about 0.1 mM, from about 0.1 mM to about 500 mM, from about 0.1 mM to about 450 mM, from about 0.1 mM to about 400 mM, from about 0.1 mM to about 350 mM, from about 0.1 mM to about 300 mM, from about 0.1 mM to about 290 mM, from about 0.1 mM to about 280 mM, from about 0.1 mM to about 270 mM, from about 0.1 mM to about 260 mM, from about 0.1 mM to about 250 mM, from about 0.1 mM to about 240 mM, from about 0.1 mM to about 230 mM, from about 0.1 mM to about 220 mM, from about 0.1 mM to about 210 mM, from about 0.1 mM to about 200 mM, from about 0.1 mM to about 190 mM, from about 0.1 mM to about 180 mM, from about 0.1 mM to about 170 mM, from about 0.1 mM to about 160 mM, from about 0.1 mM to about 150 mM, from about 0.1 mM to about 140 mM, from about 0.1 mM to about 130 mM, from about 0.1 mM to about 120 mM, from about 0.1 mM to about 110 mM, from about 0.1 mM to about 100 mM, from about 0.1 mM to about 95 mM, from about 0.1 mM to about 90 mM, from about 0.1 mM to about 85 mM, from about 0.1 mM to about 80 mM, from about 0.1 mM to about 75 mM, from about 0.1 mM to about 70 mM, from about 0.1 mM to about 65 mM, from about 0.1 mM to about 60 mM, from about 0.1 mM to about 55 mM, from about 0.1 mM to about 50 mM, from about 0.1 mM to about 45 mM, from about 0.1 mM to about 40 mM, from about 0.1 mM to about 35 mM, from about 0.1 mM to about 30 mM, from about 0.1 mM to about 25 mM, from about 0.1 mM to about 20 mM, from about 0.1 mM to about 15 mM, from about 0.1 mM to about 10 mM, from about 0.1 mM to about 9 mM, from about 0.1 mM to about 8 mM, from about 0.1 mM to about 7 mM, from about 0.1 mM to about 6 mM, from about 0.1 mM to about 5 mM, from 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 0.5 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 mM, about...0.5 mM to about 250 mM, about 0.5 mM to about 240 mM, about 0.5 mM to about 230 mM, about 0.5 mM to about 220 mM, about 0.5 mM to about 210 mM, about 0.5 mM to about 200 mM, about 0.5 mM to about 190 mM, about 0.5 mM to about 180 mM, about 0.5 mM to about 170 mM, about 0.5 mM to about 160 mM, about 0.5 mM to about 150 mM, about 0.5 mM to about 140 mM, about 0.5 mM to about 130 mM, about 0.5 mM to about 120 mM, about 0.5 mM to about 110 mM, about 0.5 mM to about 100 mM, about 0.5 mM to about 95 mM, about 0.5 mM to about 90 mM, about 0.5 mM to about 85 mM, about 0.5 mM to about 80 mM, about 0.5 mM to about 75 mM, about 0.5 mM to about 70 mM, about 0.5 mM to about 65 mM, about 0.5 mM to about 60 mM, about 0.5 mM to about 55 mM, about 0.5 mM to about 50 mM, about 0.5 mM to about 45 mM, about 0.5 mM to about 40 mM, about 0.5 mM to about 35 mM, about 0.5 mM to about 30 mM, about 0.5 mM to about 25 mM, about 0.5 mM to about 20 mM, about 0.5 mM to about 15 mM, about 0.5 mM to about 10 mM, about 0.5 mM to about 9 mM, about 0.5 mM to about 8 mM, about 0.5 mM to about 7 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1 mM, about 1 mM to about 750 mM, about 1 mM to about 700 mM, about 1 mM to about 650 mM, about 1 mM to about 600 mM, about 1 mM to about 550 mM, about 1 mM to about 500 mM, about 1 mM to about 450 mM, about 1 mM to about 400 mM, about 1 mM to about 350 mM, about 1 mM to about 300 mM, about 1 mM to about 290 mM, about 1 mM to about 280 mM, about 1 mM to about 270 mM, about 1 mM to about 260 mM, about 1 mM to about 250 mM, about 1 mM to about 240 mM, about 1 mM to about 230 mM, about 1 mM to about 220 mM, about 1 mM to about 210 mM, about 1 mM to about 200 mM, about 1 mM to about 190 mM, about 1 mM to about 180 mM, about 1 mM to about 170 mM, about 1 mM to about 160 mM, about 1 mM to about 150 mM, about 1 mM to about 140 mM, about 1 mM to about 130 mM, about 1 mM to about 120 mM, about 1 mM to about 110 mM, about 1 mM to about 100 mM, about 1 mM to about 95 mM, about 1 mM to about 90 mM, about 1 mM to about 85 mM, about 1 mM to about 80 mM, about 1 mM to about 75 mM, 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~about 260 mM, about 5 mM~about 250 mM, about 5 mM~about 240 mM, about 5 mM~about 230 mM, about 5 mM~about 220 mM, about 5 mM~about 210 mM, about 5 mM~about 200 mM, about 5 mM~about 190 mM, about 5 mM~about 180 mM, about 5 mM~about 170 mM, about 5 mM~about 160 mM, about 5 mM~about 150 mM, about 5 mM~about 140 mM, about 5 mM~about 130 mM, about 5 mM~about 120 mM, about 5 mM~about 110 mM, about 5 mM~about 100 mM, about 5 mM~about 95 mM, about 5 mM~about 90 mM, about 5 mM~about 85 mM, about 5 mM~about 80 mM, about 5 mM~about 75 mM, about 5 mM~about 70 mM, about 5 mM~about 65 mM, about 5 mM~about 60 mM, about 5 mM~about 55 mM, about 5 mM~about 50 mM, about 5 mM~about 45 mM, about 5 mM~about 40 mM, about 5 mM~about 35 mM, about 5 mM~about 30 mM, about 5 mM~about 25 mM, about 5 mM~about 20 mM, about 5 mM~about 15 mM, about 10 mM~about 750 mM, about 10 mM~about 700 mM, about 10 mM~about 650 mM, about 10 mM~about 600 mM, about 10 mM~about 550 mM, about 10 mM~about 500 mM, about 10 mM~about 450 mM, about 10 mM~about 400 mM, about 10 mM~about 350 mM, about 10 mM~about 300 mM, about 10 mM~about 290 mM, about 10 mM~about 280 mM, about 10 mM~about 270 mM, about 10 mM~about 260 mM, about 10 mM~about 250 mM, about 10 mM~about 240 mM, about 10 mM~about 230 mM, about 10 mM~about 220 mM, about 10 mM~about 210 mM, about 10 mM~about 200 mM, about 10 mM~about 190 mM, about 10 mM~about 180 mM, about 10 mM~about 170 mM, about 10 mM~about 160 mM, about 10 mM~about 150 mM, about 10 mM~about 140 mM, about 10 mM~about 130 mM, about 10 mM~about 120 mM, about 10 mM~about 110 mM, about 10 mM~about 100 mM, about 10 mM~about 95 mM, about 10 mM~about 90 mM, about 10 mM~about 85 mM, about 10 mM~about 80 mM, about 10 mM~about 75 mM, about 10 mM~about 70 mM, about 10 mM~about 65 mM, about 10 mM~about 60 mM, about 10 mM~about 55 mM, about 10 mM~about 50 mM, about 10 mM~about 45 mM, about 10 mM~about 40 mM, about 10 mM~about 35 mM, about 10 mM~about 30 mM, about 10 mM~about 25 mM, about 10 mM~about 20 mM, about 10 mM~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 mMFrom 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 mM, from 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 mMfrom 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, from about 40 mM to about 550 mM, from about 40 mM to about 500 mM, from about 40 mM to about 450 mM, from about 40 mM to about 400 mM, from about 40 mM to about 350 mM, from about 40 mM to about 300 mM, from about 40 mM to about 290 mM, from about 40 mM to about 280 mM, from about 40 mM to about 270 mM, from about 40 mM to about 260 mM, from about 40 mM to about 250 mM, from about 40 mM to about 240 mM,About 40 mM to about 230 mM, about 40 mM to about 22, 0 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, about 70 m M ~ about 230 mM, about 70 mM to about 220 mM, about 70 mM to about 210 mM, about 70 mM to about 200 mM, about 70 mM to about 190 mM, about 70 mM to about 180 mM, about 70 mM to about 170 mM, about 70 mM to about 160 mM, about 70 mM to about 150 mM, about 70 mM to about 140 mM, about 70 mM to about 130 mM, about 70 mM to about 120 mM, about 70 mM to about 110 mM, about 70 mM to about 100 mM, about 70 mM to about 95 mM, about 70 mM to about 90 mM, about 70 mM to about 85 mM, about 70 mM to about 80 mM, about 80 mM to about 750 mM, about 80 mM to about 700 mM, about 80 mM to about 650 mM, about 80 mM to about 600 mM, about 80 mM to about 550 mM, about 80 mM to about 500 mM, about 80 mM to about 450 mM, about 80 mM to about 400 mM, about 80 mM to about 350 mM, about 80 mM to about 300 mM, about 80 mM to about 290 mM, about 80 mM to about 280 mM, about 80 mM to about 270 mM, about 80 mM to about 260 mM, about 80 mM to about 250 mM, about 80 mM to about 240 mM, about 80 mM to about 230 mM, about 80 mM to about 220 mM, about 80 mM to about 210 mM, about 80 mM to about 200 mM, about 80 mM to about 190 mM, about 80 mM to about 180 mM, about 80 mM to about 170 mM, about 80 mM to about 160 mM, about 80 mM to about 150 mM, about 80 mM to about 140 mM, about 80 mM to about 130 mM, about 80 mM to about 120 mM, about 80 mM to about 110 mM, about 80 mM to about 100 mM, about 80 mM to about 95 mM, about 80 mM to about 90 mM, about 90 mM to about 750 mM, about 90 mM to about 700 mM, about 90 mM to about 650 mM, about 90 mM to about 600 mM, about 90 mM to about 550 mM, about 90 mM to about 500 mM, about 90 mM to about 450 mM, about 90 mM to about 400 mM, about 90 mM to about 350 mM, about 90 mM to about 300 mM, about 90 mM to about 290 mM, about 90 mM to about 280 mM, about 90 mM to about 270 mM, about 90 mM to about 260 mM, about 90 mM to about 250 mM, about 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 mMabout 90 mM to about 120 mM, about 90 mM to about 110 mM, about 90 mM to about 100 mM, From about 100 mM to about 750 mM, from about 100 mM to about 700 mM, from about 100 mM to about 650 mM, from about 100 mM to about 600 mM, from about 100 mM to about 550 mM, from about 100 mM to about 500 mM, from about 100 mM to about 450 mM, from about 100 mM to about 400 mM, from about 100 mM to about 350 mM, from about 100 mM to about 300 mM, from about 100 mM to about 290 mM, from about 100 mM to about 280 mM, from about 100 mM to about 270 mM, from about 100 mM to about 260 mM, from about 100 mM to about 250 mM, from about 100 mM to about 240 mM, from about 100 mM to about 230 mM, from about 100 mM to about 220 mM, from about 100 mM to about 210 mM, from about 100 mM to about 200 mM, from about 100 mM to about 190 mM, from about 100 mM to about 180 mM, from about 100 mM to about 170 mM, from about 100 mM to about 160 mM, from about 100 mM to about 150 mM, from about 100 mM to about 140 mM, from about 100 mM to about 130 mM, from about 100 mM to about 120 mM, from about 110 mM to about 750 mM, from about 110 mM to about 700 mM, from about 110 mM to about 650 mM, from about 110 mM to about 600 mM, from about 110 mM to about 550 mM, from about 110 mM to about 500 mM, from about 110 mM to about 450 mM, from about 110 mM to about 400 mM, from about 110 mM to about 350 mM, from about 110 mM to about 300 mM, from about 110 mM to about 290 mM, from about 110 mM to about 280 mM, from about 110 mM to about 270 mM, from about 110 mM to about 260 mM, from about 110 mM to about 250 mM, from about 110 mM to about 240 mM, from about 110 mM to about 230 mM, from about 110 mM to about 220 mM, from about 110 mM to about 210 mM, from about 110 mM to about 200 mM, from about 110 mM to about 190 mM, from about 110 mM to about 180 mM, from about 110 mM to about 170 mM, from about 110 mM to about 160 mM, from about 110 mM to about 150 mM, from about 110 mM to about 140 mM, from about 110 mM to about 130 mM, from about 110 mM to about 120 mM, from about 120 mM to about 750 mM, from about 120 mM to about 700 mM, from about 120 mM to about 650 mM, from about 120 mM to about 600 mM, from about 120 mM to about 550 mM, from about 120 mM to about 500 mM, from about 120 mM to about 450 mM, from about 120 mM to about 400 mM, from about 120 mM to about 350 mM, from about 120 mM to about 300 mM, from about 120 mM to about 290 mM, from about 120 mM to about 280 mM, from about 120 mM to about 270 mM, from about 120 mM to about 260 mM, from 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 ~about 400 mM, about 180 mM to about 350 mM, about 180 mM to about 300 mM, about 180 mM to about 290 mM, about 180 mM to about 280 mM, about 180 mM to about 270 mM, about 180 mM to about 260 mM, about 180 mM to about 250 mM, about 180 mM to about 240 mM, about 180 mM to about 230 mM, about 180 mM to about 220 mM, about 180 mM to about 210 mM, about 180 mM to about 200 mM, about 180 mM to about 190 mM, about 190 mM to about 750 mM, about 190 mM to about 700 mM, about 190 mM to about 650 mM, about 190 mM to about 600 mM, about 190 mM to about 550 mM, about 190 mM to about 500 mM, about 190 mM to about 450 mM, about 190 mM to about 400 mM, about 190 mM to about 350 mM, about 190 mM to about 300 mM, about 190 mM to about 290 mM, about 190 mM to about 280 mM, about 190 mM to about 270 mM, about 190 mM to about 260 mM, about 190 mM to about 250 mM, about 190 mM to about 240 mM, about 190 mM to about 230 mM, about 190 mM to about 220 mM, about 190 mM to about 210 mM, 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 mMAbout 240 mM to about 700 mM, about 240 mM to about 650 mM, about 240 mM to about 600 mM, about 240 mM to about 550 mM, about 240 mM to about 500 mM, about 240 mM to about 450 mM, about 240 mM to about 400 mM, about 240 mM to about 350 mM, about 240 mM to about 300 mM, about 240 mM to about 290 mM, about 240 mM to about 280 mM, about 240 mM to about 270 mM, about 240 mM to about 260 mM, about 240 mM to about 250 mM, about 250 mM to about 750 mM, about 250 mM to about 700 mM, about 250 mM to about 650 mM, about 250 mM to about 600 mM, about 250 mM to about 550 mM, about 250 mM to about 500 mM, about 250 mM to about 450 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 250 mM to about 290 mM, about 250 mM to about 280 mM, about 250 mM to about 270 mM, about 250 mM to about 260 mM, about 260 mM to about 750 mM, about 260 mM to about 700 mM, about 260 mM to about 650 mM, about 260 mM to about 600 mM, about 260 mM to about 550 mM, about 260 mM to about 500 mM, about 260 mM to about 450 mM, about 260 mM to about 400 mM, about 260 mM to about 350 mM, about 260 mM to about, 300 mM, about 260 mM to about 290 mM, about 260 mM to about 280 mM, about 260 mM to about 270 mM, about 270 mM to about 750 mM, about 270 mM to about 700 mM, about 270 mM to about 650 mM, about 270 mM to about 600 mM, about 270 mM to about 550 mM, about 270 mM to about 500 mM, about 270 mM to about 450 mM, about 270 mM to about 400 mM, about 270 mM to about 350 mM, about 270 mM to about 300 mM, about 270 mM to about 290 mM, about 270 mM to about 280 mM, about 280 mM to about 750 mM, about 280 mM to about 700 mM, about 280 mM to about 650 mM, about 280 mM to about 600 mM, about 280 mM to about 550 mM, about 280 mM to about 500 mM, about 280 mM to about 450 mM, about 280 mM to about 400 mM, about 280 mM to about 350 mM, about 280 mM to about 300 mM, about 280 mM to about 290 mM, about 290 mM to about 750 mM, about 290 mM to about 700 mM, about 290 mM to about 650 mM, about 290 mM to about 600 mM, about 290 mM to about 550 mM, about 290 mM to about 500 mM, about 290 mM to about 450 mM, about 290 mM to about 400 mM, about 290 mM to about 350 mM, about 290 mM to about 300 mM, about 300 mM to about 750 mM, about 300 mM to about 700 mM, about 300 mM to about 650 mM, about 300 mM to about 600 mM, about 300 mM to about 550 mM, about 300 mM to about 500 mM, about 300 mM to about 450 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, about 350 mM to about 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 to about 550 mM, about 400 mM to about 500 mM, about 400 mM to about 450 mM, about 450 mM to about 750 mM, about 450 mM to about 700 mM, about 450 mM to about 650 mM, about 450 mM to about 600 mM, about 450 mM to about 550 mM, about 450 mM to about 500 mM, about 500 mM to about 750 mM, about 500 mM to about 700 mM, about 500 mM to about 650 mM, about 500 mM to about 600 mM, about 500 mM to about 550 mM,It can be from about 550 mM to about 750 mM, from about 550 mM to about 700 mM, from about 550 mM to about 650 mM, from about 550 mM to about 600 mM, from about 600 mM to about 750 mM, from about 600 mM to about 700 mM, from about 600 mM to about 650 mM, from about 650 mM to about 750 mM, from about 650 mM to about 700 mM, or from about 700 mM to about 750 mM.

[0091] pH Any of the aqueous antibody formulations described herein has a pH of from about 4 to about 8, from about 4 to about 7.8, from about 4 to about 7.6, from about 4 to about 7.4, from about 4 to about 7.2, from about 4 to about 7, from about 4 to about 6.8, from about 4 to about 6.6, from about 4 to about 6.4, from about 4 to about 6.2, from about 4 to about 6, from about 4 to about 5.8, from about 4 to about 5.6, from about 4 to about 5.4, from about 4 to about 5.2, from about 4 to about 5, from about 4 to about 4.8, from about 4 to about 4.6, from about 4 to about 4.4, from about 4 to about 4.2, from about 4.2 to about 8, from about 4.2 to about 7.8, from about 4.2 to about 7.6, from about 4.2 to about 7.4, from about 4.2 to about 7.2, from about 4.2 to about 7, from about 4.2 to about 6.8, from about 4.2 to about 6.6, from about 4.2 to about 6.4, from about 4.2 to about 6.2, from about 4.2 to about 6, from about 4.2 to about 5.8, from about 4.2 to about 5.6, from about 4.2 to about 5.4, from about 4.2 to about 5.2, from about 4.2 to about 5, from about 4.2 to about 4.8, from about 4.2 to about 4.6, from about 4.2 to about 4.4, from about 4.4 to about 8, from about 4.4 to about 7.8, from about 4.4 to about 7.6, from about 4.4 to about 7.4, from about 4.4 to about 7.2, from about 4.4 to about 7, from about 4.4 to about 6.8, from about 4.4 to about 6.6, from about 4.4 to about 6.4, from about 4.4 to about 6.2, from about 4.4 to about 6, from about 4.4 to about 5.8, from about 4.4 to about 5.6, from about 4.4 to about 5.4, from about 4.4 to about 5.2, from about 4.4 to about 5, from about 4.4 to about 4.8, from about 4.4 to about 4.6, from about 4.6 to about 8, from about 4.6 to about 7.8, from about 4.6 to about 7.6, from about 4.6 to about 7.4, from about 4.6 to about 7.2, from about 4.6 to about 7, from about 4.6 to about 6.8, from about 4.6 to about 6.6, from about 4.6 to about 6.4, from about 4.6 to about 6.2, from about 4.6 to about 6, from about 4.6 to about 5.8, from about 4.6 to about 5.6, from about 4.6 to about 5.4, from about 4.6 to about 5.2, from about 4.6 to about 5, from about 4.6 to about 4.8, from about 4.8 to about 8, from about 4.8 to about 7.8, from about 4.8 to about 7.6, from about 4.8 to about 7.4, from about 4.8 to about 7.2, from about 4.8 to about 7, from about 4.8 to about 6.8, from about 4 .8 to approximately 6.6, approximately 4.8 to approximately 6.4, approximately 4.8 to approximately 6.2, approximately 4.8 to approximately 6, approximately 4.8 to approximately 5.8, approximately 4.8 to approximately 5.6, approximately 4.8 to approximately 5.4, approximately 4.8 to approximately 5.2, approximately 4.8 to approximately 5, approximately 5 to approximately 8, approximately 5 to approximately 7.8, approximately 5 to approximately 7.6, approximately 5 to approximately 7.4, approximately 5 to approximately 7.4, approximately 5 to approximately 7.2, approximately 5 to approximately 7, approximately 5 to approximately 6.8, approximately 5 to approximately 6.6, approximately 5 to approximately 6.4, approximately 5 to approximately 6.2, approximately 5 to approximately 6, approximately 5 to approximately 5.8, approximately 5 to approximately 5.6, approximately 5 to approximately 5.4, approximately 5 to approximately 5.2, approximately 5.2 to approximately 8, approximately 5.2 to approximately 7.8, approximately 5.2 to approximately 7.6, approximately 5.2 to approximately 7.4, approximately 5.2 to approximately 7.2, approximately 5.2 to approximately 7, approximately 5.2 to approximately 6.8, approximately 5.2 to approximately 6.6, approximately 5.2 to approximately 6.4, approximately 5.2 to approximately 6.2, approximately 5.2 to approximately 6, approximately 5.2 to approximately 5.8, approximately 5.2 to approximately 5.6, approximately 5.2 to approximately 5.4, approximately 5.4 to approximately 8, approximately 5.4 to approximately 7.8, approximately 5.4 to approximately 7.6, approximately 5.4 to approximately 7.4, approximately 5.4 to approximately 7.2, approximately 5.4 to approximately 7, approximately 5.4 to approximately 6.8, approximately 5.4 to approximately 6.6, approximately 5.4 to approximately 6.4, approximately 5.4 to approximately 6.2, approximately 5.4 to approximately 6, approximately 5.4 to approximately 5.8, approximately 5.4 to approximately 5.6, approximately 5.6 to approximately 8, approximately 5.6 to approximately 7.8, approximately 5.6 to approximately 7.6, approximately 5.6 to approximately 7.4, approximately 5.6 to approximately 7.2, approximately 5.6 to approximately 7, approximately 5.6 to approximately 6.8, approximately 5.6 to approximately 6.6, approximately 5.6 to approximately 6.4, approximately 5.6 to approximately 6.2, approximately 5.6 to approximately 6, approximately 5.6 to approximately 5.8, approximately 5.8 to approximately 8, approximately 5.8 to approximately 7.8, approximately 5.8 to approximately 7.6, approximately 5.8 to approximately 7.4, approximately 5.8 to approximately 7.2, approximately 5.8 to approximately 7, approximately 5.8 to approximately 6.8, approximately 5.8 to approximately 6.6, approximately 5.8 to approximately 6.4, approximately 5.8 to approximately 6.2, approximately 5.8 to approximately 6, approximately 6 to approximately 8, approximately 6 to approximately 7.8, approximately 6 to approximately 7.6, approximately 6 to approximately 7.4, approximately 6 to approximately 7.2, approximately 6 to approximately 7, approximately 6 to approximately 6.8, approximately 6 to approximately 6.6, approximately 6 to approximately 6.4, approximately 6 to approximately 6.2, approximately 6.2 to approximately 8, approximately 6.2 to approximately 7.8, approximately 6.2 to approximately 7.6, approximately 6.2 to approximately 7.4, approximately 6.2 to approximately 7.2, approximately 6.2 to approximately 7, approximately 6.2 to approximately 6.8, approximately 6.2 to approximately 6.6, approximately 6.2 to approximately 6.4, approximately 6.4 to approximately 8, approximately 6.4 to approximately 7.6, approximately 6.4 to approximately 7.4, approximately 6.4 to approximately 7.2, approximately 6.4 to approximately 7, approximately 6.4 to approximately 6.8, approximately 6.4 to approximately 6.6, approximately 6.6 to approximately 8, approximately 6.6 to approximately 7.8, approximately 6.6 to approximately 7.6, approximately 6.6 to approximately 7.4, approximately 6.6 to approximately 7.2, approximately 6.6 to approximately 7, approximately 6.6 to approximately 6.8, approximately 6.8 to approximately 8, approximately 6.8 to approximately 7.8, approximately 6.It may have a pH of from about 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 therein (e.g., an antibody or antigen-binding antibody fragment) essentially retains its physical stability and / or chemical stability and / or biological activity upon storage at from 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, pages 247 - 301, edited by Vincent Lee, Marcel Dekker, New York, N.Y., 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 where the percentage of degraded (e.g., fragmented) and / or aggregated protein is low. For example, an aqueous formulation containing a stable protein may contain at least 95% monomeric protein. Alternatively, the aqueous formulations 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 compared to a control antibody formulation containing all the same components except for not containing 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 (e.g., compared to a control antibody formulation).

[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,From about 2 hours to about 6 days, from about 2 hours to about 5 days, from about 2 hours to about 4 days, from about 2 hours to about 3 days, from about 2 hours to about 2 days, from about 2 hours to about 1 day, from about 2 hours to about 22 hours, from about 2 hours to about 20 hours, from about 2 hours to about 18 hours, from about 2 hours to about 16 hours, from about 2 hours to about 14 hours, from about 2 hours to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 2 hours to about 6 hours, from about 2 hours to about 4 hours, from about 4 hours to about 24 months, from about 4 hours to about 22 months, from about 4 hours to about 20 months, from about 4 hours to about 18 months, from about 4 hours to about 16 months, from about 4 hours to about 14 months, from about 4 hours to about 12 months, from about 4 hours to about 10 months, from about 4 hours to about 8 months, from about 4 hours to about 6 months, from about 4 hours to about 4 months, from about 4 hours to about 2 months, from about 4 hours to about 1 month, from about 4 hours to about 3 weeks, from about 4 hours to about 2 weeks, from about 4 hours to about 1 week, from about 4 hours to about 6 days, from about 4 hours to about 4 days, from about 4 hours to about 2 days, from about 4 hours to about 1 day, from about 4 hours to about 28 days, from about 4 hours to about 26 days, from about 4 hours to about 24 days, from about 4 hours to about 22 days, from about 4 hours to about 20 days, from about 4 hours to about 18 days, from about 4 hours to about 16 days, from about 4 hours to about 14 days, from about 4 hours to about 12 days, from about 4 hours to about 10 days, from about 4 hours to about 8 days, from about 4 hours to about 7 days, from about 4 hours to about 6 days, from about 4 hours to about 5 days, from about 4 hours to about 4 days, from about 4 hours to about 3 days, from about 4 hours to about 2 days, from about 4 hours to about 1 day, from about 4 hours to about 22 hours, from about 4 hours to about 20 hours, from about 4 hours to about 18 hours, from about 4 hours to about 16 hours, from about 4 hours to about 14 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, 4 hours Between approximately 8 hours, approximately 4 to 6 hours, approximately 6 hours to 24 months, approximately 6 hours to 22 months, approximately 6 hours to 20 months, approximately 6 hours to 18 months, approximately 6 hours to 16 months, approximately 6 hours to 14 months, approximately 6 hours to 12 months, approximately 6 hours to 10 months, approximately 6 hours to 8 months, approximately 6 hours to 6 months, approximately 6 hours to 4 months, approximately 6 hours to 2 months, approximately 6 hours to 1 month, approximately 6 hours to 3 weeks, approximately 6 hours to 2 weeks, approximately 6 hours to 1 week, approximately 6 hours to 6 days, approximately 6 hours to 4 days, approximately 6 hours to 2 days, approximately 6 hours to 1 day, approximately 6 hours to 28 days, approximately 6 hours to 26 days, approximately 6 hours to 24 days, approximately 6 hours to 22 days, approximately 6 hours to 20 days, approximately 6 hours to 18 days, approximately 6 hours to 16 days, approximately 6 hours to 14 days, approximately 6 hours to 12 days, approximately 6 hours to 10 days, approximately 6 hours to 8 days, approximately 6 hours to 7 days, approximately 6 hours to 6 days, approximately 6 hours to 5 days, approximately 6 hours to 4 days, approximately 6 hours to 3 days, approximately 6 hours to 2 days, approximately 6 hours to 1 day, approximately 6 hours to 22 hours, approximately 6 hours to 20 hours, approximately 6 hours to 18 hours, approximately 6 hours to 16 hours, approximately 6 hours to 14 hours, approximately 6 hours to 12 hours, approximately 6 hours to 10 hours, approximately 6 hours to 8 hours, approximately 8 hours to 24 months, approximately 8 hours to 22 months, approximately 8 hours to 20 months, approximately 8 hours to 18 months, approximately 8 hours to 16 months, approximately 8 hours to 14 months, approximately 8 hours to 12 months, approximately 8 hours to 10 months, approximately 8 hours to 8 months, approximately 8 hours to 6 months, approximately 8 hours to 4 months, approximately 8 hours to 2 months, approximately 8 hours to 1 month, approximately 8 hours to 3 weeks, approximately 8 hours to 2 weeks, approximately 8 hours to 1 week, approximately 8 hours to 6 days, approximately 8 hours to 4 days, approximately 8 hours to 2 days, approximately 8 hours to 1 day, approximately 8 hours to 28 days, approximately 8 hours to 26 days, approximately 8 hours to 24 days, approximately 8 hours to 22 days, approximately 8 hours to 20 days, approximately 8 hours to 18 days, approximately 8 hours to 16 days, approximately 8 hours to 14 days, approximately 8 hours to 12 days, approximately 8 hours to 10 days, approximately 8 hours to 8 days, approximately 8 hours to 7 days, approximately 8 hours to 6 days, approximately 8 hours to 5 days, approximately 8 hours to 4 days, approximately 8 hours to 3 days, approximately 8 hours to 2 days, approximately 8 hours to 1 day, approximately 8 hours to 22 hours, approximately 8 hours to 20 hours, approximately 8 hours to 18 hours, approximately 8 hours to 16 hours, approximately 8 hours to 14 hours, approximately 8 hours to 12 hours, approximately 8 hours to 10 hours, approximately 10 hours to 24 months, approximately 10 hours to 22 months,From about 10 hours to about 20 months, from about 10 hours to about 18 months, from about 10 hours to about 16 months, from about 10 hours to about 14 months, from about 10 hours to about 12 months, from about 10 hours to about 10 months, from about 10 hours to about 8 months, from about 10 hours to about 6 months, from about 10 hours to about 4 months, from about 10 hours to about 2 months, from about 10 hours to about 1 month, from about 10 hours to about 3 weeks, from about 10 hours to about 2 weeks, from about 10 hours to about 1 week, from about 10 hours to about 6 days, from about 10 hours to about 4 days, from about 10 hours to about 2 days, from about 10 hours to about 1 day, from about 10 hours to about 28 days, from about 10 hours to about 26 days, from about 10 hours to about 24 days, from about 10 hours to about 22 days, from about 10 hours to about 20 days, from about 10 hours to about 18 days, from about 10 hours to about 16 days, from about 10 hours to about 14 days, from about 10 hours to about 12 days, from about 10 hours to about 10 days, from about 10 hours to about 8 days, from about 10 hours to about 7 days, from about 10 hours to about 6 days, from about 10 hours to about 5 days, from about 10 hours to about 4 days, from about 10 hours to about 3 days, from about 10 hours to about 2 days, from about 10 hours to about 1 day, from about 10 hours to about 22 hours, from about 10 hours to about 20 hours, from about 10 hours to about 18 hours, from about 10 hours to about 16 hours, from about 10 hours to about 14 hours, from about 10 hours to about 12 hours From about 12 hours to about 24 months, from about 12 hours to about 22 months, from about 12 hours to about 20 months, from about 12 hours to about 18 months, from about 12 hours to about 16 months, from about 12 hours to about 14 months, from about 12 hours to about 12 months, from about 12 hours to about 10 months, from about 12 hours to about 8 months, from about 12 hours to about 6 months, from about 12 hours to about 4 months, from about 12 hours to about 2 months, from about 12 hours to about 1 month, from about 12 hours to about 3 weeks, from about 12 hours to about 2 weeks, from about 12 hours to about 1 week, from about 12 hours to about 6 days, from about 12 hours to about 4 days, from about 12 hours to about 2 days, from about 12 hours to about 1 day, from about 12 hours to about 28 days, from about 12 hours to about 26 days, from about 12 hours to about 24 days, from about 12 hours to about 22 days, from about 12 hours to about 20 days, from about 12 hours to about 18 days, from about 12 hours to about 16 days, from about 12 hours to about 14 days, from about 12 hours to about 12 days, from about 12 hours to about 10 days, from about 12 hours to about 8 days, from about 12 hours to about 7 days, from about 12 hours to about 6 days, from about 12 hours to about 5 days, from about 12 hours to about 4 days, from about 12 hours to about 3 days, from about 12 hours to about 2 days, from about 12 hours to about 1 day, from about 12 hours to about 22 hours, from about 12 hours to about 20 hours, from about 12 hours to about 18 hours, from about 12 hours to about 1 6 hours, about 12 to about 14 hours, about 14 to about 24 months, about 14 to about 22 months, about 14 to about 20 months, about 14 to about 18 months, about 14 to about 16 months, about 14 to about 14 months, about 14 to about 12 months, about 14 to about 10 months, about 14 to about 8 months, about 14 to about 6 months, about 14 to about 4 months, about 14 to about 2 months, about 14 to about 1 month, about 14 to about 3 weeks, about 14 to about 2 weeks, about 14 to about 1 week, about 14 to about 6 days, about 14 to about 4 days, about 14 to about 2 days, about 14 to about 1 day, about 14 to about 28 days, about 14 to about 26 days, about 14 to about 24 days, about 14 to about 22 days, about 14 to about 20 days, about 14 to about 18 days, about 14 to about 16 days, about 14 to about 14 days, about 14 to about 12 days, about 14 to about 10 days, about 14 to about 8 days, about 14 to about 7 days, about 14 to about 6 days, about 14 to about 5 days, about 14 to about 4 days, about 14 to about 3 days, about 14 to about 2 days, about 14 to about 1 day, about 14 to about 22 hours, about 14 to about 20 hours, about 14 to about 18 hours, about 16 to about 24 months, about 16 to about 22 months, about 16 to about 20 months, about 16 to about 18 months, about 16 to about 16 months, about 16 to about 14 months, about 16 to about 12 months, about 16 to about 10 months, about 16 to about 8 months, about 16 to about 6 months, about 16 to about 4 months, about 16 to about 2 months, about 16 to about 1 month, about 16 to about 3 weeks, about 16 to about 2 weeks, about 16 to about 1 week, about 16 to about 6 days, about 16 to about 4 days, about 16 to about 2 days, about 16 to about 1 day, about 16 to about 28 days, about 16 to about 26 days, about 16 to about 24 days, about 16 to about 22 days, about 16 to about 20 days, about 16 to about 18 days, about 16 to about 16 days, about 16 to about 14 days, about 16 to about 12 days, about 16 to about 10 days, about 16 to about 8 days, about 16 to about 7 days, about 16 to about 6 days, about 16 to about 5 days, about 16 to about 4 days, about 16 to about 3 days, about 16 to about 2 days, about 16 to about 1 day, about 16 to about 22 hours, about 16 to about 20 hours, about 18 to about 24 months, about 18 to about 22 months, about 18 to about 20 months, about 18 to about 18 months,From about 18 hours to about 16 months, from about 18 hours to about 14 months, from about 18 hours to about 12 months, from about 18 hours to about 10 months, from about 18 hours to about 8 months, from about 18 hours to about 6 months, from about 18 hours to about 4 months, from about 18 hours to about 2 months, from about 18 hours to about 1 month, from about 18 hours to about 3 weeks, from about 18 hours to about 2 weeks, from about 18 hours to about 1 week, from about 18 hours to about 6 days, from about 18 hours to about 4 days, from about 18 hours to about 2 days, from about 18 hours to about 1 day, from about 18 hours to about 28 days, from about 18 hours to about 26 days, from about 18 hours to about 24 days, from about 18 hours to about 22 days, from about 18 hours to about 20 days, from about 18 hours to about 18 days, from about 18 hours to about 16 days, from about 18 hours to about 14 days, from about 18 hours to about 12 days, from about 18 hours to about 10 days, from about 18 hours to about 8 days, from about 18 hours to about 7 days, from about 18 hours to about 6 days, from about 18 hours to about 5 days, from about 18 hours to about 4 days, from about 18 hours to about 3 days, from about 18 hours to about 2 days, from about 18 hours to about 1 day, from about 18 hours to about 22 hours, from about 18 hours to about 20 hours, from about 20 hours to about 24 months, from about 20 hours to about 22 months, from about 20 hours to about 20 months, from about 20 hours to about 18 months, from about 20 hours to about 16 months, from about 20 hours to about 14 months, from about 20 hours to about 12 months, from about 20 hours to about 10 months, from about 20 hours to about 8 months, from about 20 hours to about 6 months, from about 20 hours to about 4 months, from about 20 hours to about 2 months, from about 20 hours to about 1 month, from about 20 hours to about 3 weeks, from about 20 hours to about 2 weeks, from about 20 hours to about 1 week, from about 20 hours to about 6 days, from about 20 hours to about 4 days, from about 20 hours to about 2 days, from about 20 hours to about 1 day, from about 20 hours to about 28 days, from about 20 hours to about 26 days, from about 20 hours to about 24 days, from about 20 hours to about 22 days, from about 20 hours to about 20 days, from about 20 hours to about 18 days, from about 20 hours to about 16 days, from about 20 hours to about 14 days, from about 20 hours to about 12 days, from about 20 hours to about 10 days, from about 20 hours to about 8 days, from about 20 hours to about 7 days, from about 20 hours to about 6 days, from about 20 hours to about 5 days, from about 20 hours to about 4 days, from about 20 hours to about 3 days, from about 20 hours to about 2 days, from about 20 hours to about 1 day, from about 20 hours to about 22 hours From about 1 day to about 24 months, from about 1 day to about 22 months, from about 1 day to about 20 months, from about 1 day to about 18 months, from about 1 day to about 16 months, from about 1 day to about 14 months, from about 1 day to about 12 months, from about 1 day to about 10 months, from about 1 day to about 8 months, from about 1 day to about 6 months, from about 1 day to about 4 months, from about 1From daytime to about 2 months, from about 1 day to about 1 month, from about 1 day to about 3 weeks, from about 1 day to about 2 weeks, from about 1 day to about 1 week, from about 1 day to about 6 days, from about 1 day to about 4 days, from about 1 day to about 2 days, from about 1 day to about 1 day, from about 1 day to about 28 days, from about 1 day to about 26 days, from about 1 day to about 24 days, from about 1 day to about 22 days, from about 1 day to about 20 days, from about 1 day to about 18 days, from about 1 day to about 16 days, from about 1 day to about 14 days, from about 1 day to about 12 days, from about 1 day to about 10 days, from about 1 day to about 8 days, from about 1 day to about 7 days, from about 1 day to about 6 days, from about 1 day to about 5 days, from about 1 day to about 4 days, from about 1 day to about 3 days, from about 1 day to about 2 days, from about 2 days to about 24 months, from about 2 days to about 22 months, from about 2 days to about 20 months, from about 2 days to about 18 months, from about 2 days to about 16 months, from about 2 days to about 14 months, from about 2 days to about 12 months, from about 2 days to about 10 months, from about 2 days to about 8 months, from about 2 days to about 6 months, from about 2 days to about 4 months, from about 2 days to about 2 months, from about 2 days to about 1 month, from about 2 days to about 3 weeks, from about 2 days to about 2 weeks, from about 2 days to about 1 week, from about 2 days to about 6 days, from about 2 days to about 4 days, from about 2 days to about 2 days, from about 2 days to about 2 days, from about 2 days to about 28 days, from about 2 days to about 26 days, from about 2 days to about 24 days, from about 2 days to about 22 days, from about 2 days to about 20 days, from about 2 days to about 18 days, from about 2 days to about 16 days, from about 2 days to about 14 days, from about 2 days to about 12 days, from about 2 days to about 10 days, from about 2 days to about 8 days, from about 2 days to about 7 days, from about 2 days to about 6 days, from about 2 days to about 5 days, from about 2 days to about 4 days, from about 2 days to about 3 days, from about 4 days to about 24 months, from about 4 days to about 22 months, from about 4 days to about 20 months, from about 4 days to about 18 months, from about 4 days to about 16 months, from about 4 days to about 14 months, from about 4 days to about 12 months, from about 4 days to about 10 months, from about 4 days to about 8 months, from about 4 days to about 6 months, from about 4 days to about 4 months, from about 4 days to about 2 months, from about 4 days to about 1 month, from about 4 days to about 3 weeks, from about 4 days to about 2 weeks, from about 4 days to about 1 week, from about 4 days to about 6 days, from about 4 days to about 4 days, from about 4 days to about 2 days, from about 4 days to about 4 days, from about 4 days to about 28 days, from about 4 days to about 26 days, from about 4 days to about 24 days, from about 4 days to about 22 days, from about 4 days to about 20 days, from about 4 days to about 18 days, from about 4 days to about 16 days, from about 4 days to about 14 days, from about 4 days to about 12 days, from about 4 days to about 10 days, from about 4 days to about 8 days, from about 4 days to about 7 days, from about 4 days to about 6 daysFrom about 4 days to about 5 days, from about 7 days to about 24 months, from about 7 days to about 22 months, from about 7 days to about 20 months, from about 7 days to about 18 months, from about 7 days to about 16 months, from about 7 days to about 14 months, from about 7 days to about 12 months, from about 7 days to about 10 months, from about 7 days to about 8 months, from about 7 days to about 6 months, from about 7 days to about 4 months, from about 7 days to about 2 months, from about 7 days to about 1 month, from about 7 days to about 3 weeks, from about 7 days to about 2 weeks, from about 7 days to about 1 week, from about 7 days to about 6 days, from about 7 days to about 4 days, from about 7 days to about 2 days, from about 7 days to about 7 days, from about 7 days to about 28 days, from about 7 days to about 26 days, from about 7 days to about 24 days, from about 7 days to about 22 days, from about 7 days to about 20 days, from about 7 days to about 18 days, from about 7 days to about 16 days, from about 7 days to about 14 days, from about 7 days to about 12 days, from about 7 days to about 10 days, from about 7 days to about 8 days, from about 1 week to about 24 months, from about 1 week to about 22 months, from about 1 week to about 20 months, from about 1 week to about 18 months, from about 1 week to about 16 months, from about 1 week to about 14 months, from about 1 week to about 12 months, from about 1 week to about 10 months, from about 1 week to about 8 months, from about 1 week to about 6 months, from about 1 week to about 4 months, from about 1 week to about 2 months, from about 1 week to about 1 month, from about 1 week to about 3 weeks, from about 1 week to about 2 weeks, from about 2 weeks to about 24 months, from about 2 weeks to about 22 months, from about 2 weeks to about 20 months, from about 2 weeks to about 18 months, from about 2 weeks to about 16 months, from about 2 weeks to about 14 months, from about 2 weeks to about 12 months, from about 2 weeks to about 10 months, from about 2 weeks to about 8 months, from about 2 weeks to about 6 months, from about 2 weeks to about 4 months, from about 2 weeks to about 2 months, from about 2 weeks to about 1 month, from about 2 weeks to about 3 weeks, from about 3 weeks to about 24 months, from about 3 weeks to about 22 months, from about 3 weeks to about 20 months, from about 3 weeks to about 18 months, from about 3 weeks to about 16 months, from about 3 weeks to about 14 months, from about 3 weeks to about 12 months, from about 3 weeks to about 10 months, from about 3 weeks to about 8 months, from about 3 weeks to about 6 months, from about 3 weeks to about 4 months, from about 3 weeks to about 2 months, from about 3 weeks to about 1 month, From about 1 month to about 24 months, from about 1 month to about 22 months, from about 1 month to about 20 months, from about 1 month to about 18 months, from about 1 month to about 16 months, from about 1 month to about 14 months, from about 1 month to about 12 months, from about 1 month to about 10 months, from about 1 month to about 8 months, from about 1 month to about 6 months, from about 1 month to about 4 months, from about 1 month to about 2 months, from about 2 months to about 24 months, from about 2 months to about 22 months, from about 2 months to about 20 months, from about 2 months to about 18 months, from about 2 months to about 16 months, from about 2 months to about 14 months, from about 2 months to about Stable (e.g., HMW% by SEC ≤ 5%) (e.g., measured using high performance size exclusion chromatography) for 12 months, about 2 months to about 10 months, about 2 months to about 8 months, about 2 months to about 6 months, about 2 months to about 4 months, about 4 months to about 24 months, about 4 months to about 22 months, about 4 months to about 20 months, about 4 months to about 18 months, about 4 months to about 16 months, about 4 months to about 14 months, about 4 months to about 12 months, about 4 months to about 10 months, about 4 months to about 8 months, about 4 months to about 6 months, about 6 months to about 24 months, about 6 months to about 22 months, about 6 months to about 20 months, about 6 months to about 18 months, about 6 months to about 16 months, about 6 months to about 12 months, about 6 months to about 10 months, about 6 months to about 8 months, about 10 months to about 24 months, about 10 months to about 22 months, about 10 months to about 20 months, about 10 months to about 18 months, about 10 months to about 16 months, about 10 months to about 14 months, about 10 months to about 12 months, about 12 months to about 24 months, about 12 months to about 22 months, about 12 months to about 20 months, about 12 months to about 18 months, about 12 months to about 16 months, about 12 months to about 14 months, about 14 months to about 24 months, about 14 months to about 22 months, about 14 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 at 40 °C 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 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 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 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 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 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,From about 10 hours to about 6 weeks, from about 10 hours to about 4 weeks, from about 10 hours to about 2 weeks, from about 10 hours to about 1 week, from about 10 hours to about 6 days, from about 10 hours to about 4 days, from about 10 hours to about 2 days, from about 10 hours to about 1 day, from about 10 hours to about 22 hours, from about 10 hours to about 20 hours, from about 10 hours to about 18 hours, from about 10 hours to about 16 hours, from about 10 hours to about 14 hours, from about 10 hours to about 12 hours, from about 12 hours to about 8 weeks, from about 12 hours to about 6 weeks, from about 12 hours to about 4 weeks, from about 12 hours to about 2 weeks, from about 12 hours to about 1 week, from about 12 hours to about 6 days, from about 12 hours to about 4 days, from about 12 hours to about 2 days, from about 12 hours to about 1 day, from about 12 hours to about 22 hours, from 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, about 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) is stable (for example, the HMW% by SEC is ≦ 5%) (for example,Measured using high performance size exclusion chromatography).

[0096] In some embodiments, the formulation has a viscosity 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 45 cP, about 5 cP to about 40 cP, about 5 cP to about 35 cP, about 5 cP to about 30 cP, about 5 cP to about 25 cP, about 5 cP to about 20 cP, about 5 cP to about 15 cP, about 5 cP to about 10 cP, about 10 cP to about 50 cP, about 10 cP to about 45 cP, about 10 cP to about 40 cP, about 10 cP to about 35 cP, about 10 cP to about 30 cP, about 10 cP to about 25 cP, about 10 cP to about 20 cP, about 10 cP to about 15 cP, about 15 cP to about 50 cP, about 15 cP to about 45 cP, about 15 cP to about 40 cP, about 15 cP to about 35 cP, about 15 cP to about 30 cP, about 15 cP to about 25 cP, about 15 cP to about 20 cP, about 20 cP to about 50 cP, about 20 cP to about 45 cP, about 20 cP to about 40 cP, about 20 cP to about 35 cP, about 20 cP to about 30 cP, about 20 cP to about 25 cP, about 25 cP to about 50 cP, about 25 cP to about 45 cP, about 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 (e.g., measured using a viscometer), before and / or after the addition of a salt (e.g., any of the salts described herein).

[0097] In some embodiments, the formulation may be suitable for subcutaneous administration, intravenous administration, intra - arterial administration, intra - ocular administration, intra - peritoneal administration, intramuscular administration, intra - articular administration, or trans - pedicle administration.

[0098] Stabilizer 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 can be from about 0.01 mM to about 1500 mM (or any sub - range 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. Further examples of amino acids are known in the art. The final concentration of the amino acid (or the total final concentration of one or more amino acids) in any of the formulations described herein can be from about 0.01 mM to about 750 mM (or any sub - range of this range described herein).

[0100] Surfactant 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 monolinoate, 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, 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 stearic amide, sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, sodium polyoxyethylene lauryl sulfate, sodium lauryl sulfosuccinate, lecithin, glycerophospholipid, sphingophospholipid, 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 is 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), about 0.001 %(w / v) to about 1.2% (w / v), about 0.001% (w / v) to about 1.0% (w / v), about 0.001% (w / v) to about 0.9% (w / v), about 0.001% (w / v) to about 0.8% (w / v), about 0.001% (w / v) to about 0.7% (w / v), about 0.001% (w / v) to about 0.6% (w / v), about 0.001% (w / v) to about 0.5% (w / v), about 0.001% (w / v) to about 0.45% (w / v), about 0.001% (w / v) to about 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) to about 0.25% (w / v), about 0.001% (w / v) to about 0.20% (w / v), about 0.001% (w / v) to about 0.15% (w / v), about 0.001% (w / v) to about 0.10% (w / v), about 0.001% (w / v) to about 0.05% (w / v), about 0.001% (w / v) to about 0.01% (w / v), about 0.001% (w / v) to about 0.005% (w / v), about 0.005% (w / v) to about 2.0% (w / v), about 0.005% (w / v) to about 1.8% (w / v), about 0.005% (w / v) to about 1.6% (w / v), about 0.005% (w / v) to about 1.4% (w / v), about 0.005% (w / v) to about 1.2% (w / v), about 0.005% (w / v) to about 1.0% (w / v), about 0.005% (w / v) to about 0.9% (w / v), about 0.005% (w / v) to about 0.8% (w / v), about 0.005% (w / v) to about 0.7% (w / v), about 0.005% (w / v) to about 0.6% (w / v), about 0.005% (w / v) to about 0.5% (w / v), about 0.005% (w / v) to about 0.45% (w / v), about 0.005% (w / v) to about 0.40% (w / v), about 0.005% (w / v) to about 0.35% (w / v), about 0.005% (w / v) to about 0.30% (w / v), about 0.005% (w / v) to about 0.25% (w / v), about 0.005% (w / v) to about 0.20% (w / v), about 0.005% (w / v) to about 0.15% (w / v), about 0.005% (w / v) to about 0.10% (w / v), about 0.005% (w / v) to about 0.05% (w / v), about 0.005% (w / v) to about 0.01% (w / v), about 0.01% (w / v) to about 2.0% (w / v), about 0.01% (w / v) to about 1.8% (w / v), about 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 approximately 0.15% (w / v), approximately 0.05% (w / v) to approximately 0.10% (w / v), approximately 0.10% (w / v) to approximately 2.0% (w / v), approximately 0.10% (w / v) to approximately 1.8% (w / v), approximately 0.10% (w / v) to approximately 1.6% (w / v), approximately 0.10% (w / v) to approximately 1.4% (w / v), approximately 0.10% (w / v) to approximately 1.2% (w / v), approximately 0.10% (w / v) to approximately 1.0% (w. / v), from about 0.10% (w / v) to about 0.9% (w / v), from about 0.10% (w / v) to about 0.8% (w / v), from about 0.10% (w / v) to about 0.7% (w / v), from about 0.10% (w / v) to about 0.6% (w / v), from about 0.10% (w / v) to about 0.5% (w / v), from about 0.10% (w / v) to about 0.45% (w / v), from about 0.10% (w / v) to about 0.40% (w / v), from about 0.10% (w / v) to about 0.35% (w / v), from about 0.10% (w / v) to about 0.30% (w / v), from about 0.10% (w / v) to about 0.25% (w / v), from about 0.10% (w / v) to about 0.20% (w / v), from 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), from about 0.25% (w / v) to about 0.5% (w / v), from about 0.25% (w / v) to about 0.45% (w / v), from about 0.25% (w / v) to about 0.40% (w / v), from about 0.25% (w / v) to about 0.35% (w / v), from about 0.25% (w / v) to about 0.30% (w / v), from about 0.30% (w / v) to about 2.0% (w / v), from about 0.30% (w / v) to about 1.8% (w / v), from about 0.30% (w / v) to about 1.6% (w / v), from about 0.30% (w / v) to about 1.4% (w / v), from about 0.30% (w / v) to about 1.2% (w / v), from about 0.30% (w / v) to about 1.0% (w / v), from about 0.30% (w / v) to about 0.9% (w / v), from about 0.30% (w / v) to about 0.8% (w / v), from about 0.30% (w / v) to about 0.7% (w / v), from about 0.30% (w / v) to about 0.6% (w / v), from about 0.30% (w / v) to about 0.5% (w / v), from about 0.30% (w / v) to about 0.45% (w / v), from about 0.30% (w / v) to about 0.40% (w / v), from about 0.30% (w / v) to about 0.35% (w / v), from about 0.35% (w / v) to about 2.0% (w / v), from about 0.35% (w / v) to about 1.8% (w / v), from about 0.35% (w / v) to about 1.6% (w / v), from about 0.35% (w / v) to about 1.4% (w / v), from about 0.35% (w / v) to about 1.2% (w / v), from about 0.35% (w / v) to about 1.0% (w / v), from about 0.35% (w / v) to about 0.9% (w / v), from about 0.35% (w / v) to about 0.8% (w / v), from about 0.35% (w / v) to about 0.7% (w / v), from about 0.35% (w / v) to about 0.6% (w / v), 0.35%. (w / v) ~ about 0.5% (w / v), about 0.35% (w / v) ~ about 0.45% (w / v), about 0.35% (w / v) ~ about 0.40% (w / v), about 0.40% (w / v) ~ about 2.0% (w / v), about 0.40% (w / v) ~ about 1.8% (w / v), about 0.40% (w / v) ~ about 1.6% (w / v), about 0.40% (w / v) ~ about 1.4% (w / v), about 0.40% (w / v) ~ about 1.2% (w / v), about 0.40% (w / v) ~ about 1.0% (w / v), about 0.40% (w / v) ~ about 0.9% (w / v), about 0.40% (w / v) ~ about 0.8% (w / v), about 0.40% (w / v) ~ about 0.7% (w / v), about 0.40% (w / v) ~ about 0.6% (w / v), about 0.40% (w / v) ~ about 0.5% (w / v), about 0.40% (w / v) ~ about 0.45% (w / v), about 0.45% (w / v) ~ about 2.0% (w / v), about 0.45% (w / v) ~ about 1.8% (w / v), about 0.45% (w / v) ~ about 1.6% (w / v), about 0.45% (w / v) ~ about 1.4% (w / v), about 0.45% (w / v) ~ about 1.2% (w / v), about 0.45% (w / v) ~ about 1.0% (w / v), about 0.45% (w / v) ~ about 0.9% (w / v), about 0.45% (w / v) ~ about 0.8% (w / v), about 0.45% (w / v) ~ about 0.7% (w / v), about 0.45% (w / v) ~ about 0.6% (w / v), about 0.45% (w / v) ~ about 0.5% (w / v), about 0.5% (w / v) ~ about 2.0% (w / v), about 0.5% (w / v) ~ about 1.8% (w / v), about 0.5% (w / v) ~ about 1.6% (w / v), about 0.5% (w / v) ~ about 1.4% (w / v), about 0.5% (w / v) ~ about 1.2% (w / v), about 0.5% (w / v) ~ about 1.0% (w / v), about 0.5% (w / v) ~ about 0.9% (w / v), about 0.5% (w / v) ~ about 0.8% (w / v), about 0.5% (w / v) ~ about 0.7% (w / v), about 0.5% (w / v) ~ about 0.6% (w / v), From about 0.6% (w / v) to about 2.0% (w / v), from about 0.6% (w / v) to about 1.8% (w / v), from about 0.6% (w / v) to about 1.6% (w / v), from about 0.6% (w / v) to about 1.4% (w / v), from about 0.6% (w / v) to about 1.2% (w / v), from about 0.6% (w / v) to about 1.0% (w / v), from about 0.6% (w / v) to about 0.9% (w / v), from about 0.6% (w / v) to about 0.8% (w / v), from about 0.6% (w / v) to about 0.7% (w / v), from about 0.7% (w / v) to about 2.0% (w / v), from about 0.7% (w / v) to about 1.8% (w / v), from about 0.7% (w / v) to about 1.6% (w / v), from about 0.7% (w / v) to about 1.4% (w / v), from about 0.7% (w / v) to about 1.2% (w / v), from about 0.7% (w / v) to about 1.0% (w / v), from about 0.7% (w / v) to about 0.9% (w / v), from about 0.7% (w / v) to about 0.8% (w / v), from about 0.8% (w / v) to about 2.0% (w / v), from about 0.8% (w / v) to about 1.8% (w / v), from about 0.8% (w / v) to about 1.6% (w / v), from about 0.8% (w / v) to about 1.4% (w / v), from about 0.8% (w / v) to about 1.2% (w / v), from about 0.8% (w / v) to about 1.0% (w / v), from about 0.8% (w / v) to about 0.9% (w / v), from about 0.9% (w / v) to about 2.0% (w / v), from about 0.9% (w / v) to about 1.8% (w / v), from about 0.9% (w / v) to about 1.6% (w / v), from about 0.9% (w / v) to about 1.4% (w / v), from about 0.9% (w / v) to about 1.2% (w / v), from about 0.9% (w / v) to about 1.0% (w / v), from about 1.0% (w / v) to about 2.0% (w / v), from about 1.0% (w / v) to about 1.8% (w / v), from about 1.0% (w / v) to about 1.6% (w / v), from about 1.0% (w / v) to about 1.4% (w / v), from about 1.0% (w / v) to about 1.2% (w / v), from about 1.2% (w / v) to about 2.0% (w / v), from about 1.2% (w / v) to about 1.8% (w / v), from about 1.2% (w / v) to about 1.6% (w / v), from about 1.2% (w / v) to about 1.4% (w / v), from about 1.4% (w / v) to about 2.0% (w / v), from about 1.4% (w / v) to about 1.8% (w / v), from about 1.4% (w / v) to about 1.6% (w / v), from about 1.6% (w / v) to about 2.0% (w / v), from about 1.6% (w / v) to about 1.8% (w / v), or from 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 in this specification is 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, from about 0.001 mg / mL to about 20 mg / mL, from about 0.001 mg / mL to about 18 mg / mL, from about 0.001 mg / mL to about 16 mg / mL, from about 0.001 mg / mL to about 14 mg / mL, from about 0.001 mg / mL to about 12 mg / mL, from about 0.001 mg / mL to about 10 mg / mL, from about 0.001 mg / mL to about 8 mg / mL, from about 0.001 mg / mL to about 6 mg / mL, from about 0.001 mg / mL to about 5 mg / mL, from about 0.001 mg / mL to about 4 mg / mL, from about 0.001 mg / mL to about 3 mg / mL, from about 0.001 mg / mL to about 2 mg / mL, from about 0.001 mg / mL to about 1 mg / mL, from about 0.001 mg / mL to about 0.5 mg / mL, from about 0.001 mg / mL to about 0.1 mg / mL, from about 0.001 mg / mL to about 0.05 mg / mL, from about 0.001 mg / mL to about 0.005 mg / mL, from about 0.005 mg / mL to about 50 mg / mL, from about 0.005 mg / mL to about 45 mg / mL, from about 0.005 mg / mL to about 40 mg / mL, from about 0.005 mg / mL to about 35 mg / mL, from about 0.005 mg / mL to about 30 mg / mL, from about 0.005 mg / mL to about 28 mg / mL, from about 0.005 mg / mL to about 26 mg / mL, from about 0.005 mg / mL to about 24 mg / mL, from about 0.005 mg / mL to about 22 mg / mL, from about 0.005 mg / mL to about 20 mg / mL, from about 0.005 mg / mL to about 18 mg / mL, from about 0.005 mg / mL to about 16 mg / mL, from about 0.005 mg / mL to about 14 mg / mL, from about 0.005 mg / mL to about 12 mg / mL, from about 0.005 mg / mL to about 10 mg / mL, from about 0.005 mg / mL to about 8 mg / mL, from about 0.005 mg / mL to about 6 mg / mL, from about 0.005 mg / mL to about 5 mg / mL, from about 0.005 mg / mL to about 4 mg / mL, from about 0.005 mg / mL to about 3 mg / mL, from about 0.005 mg / mL to about 2 mg / mL, from about 0.005 mg / mL to about 1 mg / mL, from about 0.005 mg / mL to about 0.5 mg / mL, from about 0.005 mg / mL to about 0.1 mg / mL, from about 0.005 mg / mL to about 0.05 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 45 mg / mL, about 0.05 mg / mL to about 40 mg / mL, about 0.05 mg / mL to about 35 mg / mL, about 0.05 mg / mL to about 30 mg / mL, about 0.05 mg / mL to about 28 mg / mL, about 0.05 mg / mL to about 26 mg / mL, about 0.05 mg / mL to about 24 mg / mL, about 0.05 mg / mL to about 22 mg / mL, about 0.05 mg / mL to about 20 mg / mL, about 0.05 mg / mL to about 18 mg / mL, about 0.05 mg / mL to about 16 mg / mL, about 0.05 mg / mL to about 14 mg / mL, about 0.05 mg / mL to about 12 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 8 mg / mL, about 0.05 mg / mL to about 6 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.05 mg / mL to about 4 mg / mL, about 0.05 mg / mL to about 3 mg / mL, about 0.05 mg / mL to about 2 mg / mL, about 0.05 mg / mL to about 1 mg / mL, about 0.05 mg / mL to about 0.5 mg / mL, about 0.05 mg / mL to about 0.1 mg / mL, about 0.1 mg / mL to about 50 mg / 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 28 mg / mL, about 0.1 mg / mL to about 26 mg / mL, about 0.1 mg / mL to about 24 mg / mL, about 0.1 mg / mL to about 22 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 18 mg / mL, about 0.1 mg / mL to about 16 mg / mL, about 0.1 mg / mL to about 14 mg / mL, about 0.1 mg / mL to about 12 mg / mL, about 0.1 mg / mL to about 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, about 2 mg / mL to about 28 mg / mL, about 2 mg / mL to about 26 mg / mL, about 2 mg / mL to about 24 mg / mL, about 2 mg / mL to about 22 mg / mL, about 2 mg / mL to about 20 mg / mL, about 2 mg / mL to about 18 mg / mL, about 2 mg / mL to about 16 mg / mL, about 2 mg / mL to about 14 mg / mL, about 2 mg / mL to about 12 mg / mL, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 8 mg / mL, 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,About 6 mg / mL to about 40 mg / mL mL, about 6 mg / mL to about 35 mg / mL, about 6 mg / mL to about 30 mg / mL, about 6 mg / mL to about 28 mg / mL, about 6 mg / mL to about 26 mg / mL, about 6 mg / mL to about 24 mg / mL, about 6 mg / mL to about 22 mg / mL, about 6 mg / mL to about 20 mg / mL, about 6 mg / mL to about 18 mg / mL, about 6 mg / mL to about 16 mg / mL, about 6 mg / mL to about 14 mg / mL, about 6 mg / mL to about 12 mg / mL, about 6 mg / mL to about 10 mg / mL, about 6 mg / mL to about 8 mg / mL, about 8 mg / mL to about 50 mg / mL, about 8 mg / mL to about 45 mg / mL, about 8 mg / mL to about 40 mg / mL, about 8 mg / mL to about 35 mg / mL, about 8 mg / mL to about 30 mg / mL, about 8 mg / mL to about 28 mg / mL, about 8 mg / mL to about 26 mg / mL, about 8 mg / mL to about 24 mg / mL, about 8 mg / mL to about 22 mg / mL, about 8 mg / mL to about 20 mg / mL, about 8 mg / mL to about 18 mg / mL, about 8 mg / mL to about 16 mg / mL, about 8 mg / mL to about 14 mg / mL, about 8 mg / mL to about 12 mg / mL, about 8 mg / mL to about 10 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 28 mg / mL, about 10 mg / mL to about 26 mg / mL, about 10 mg / mL to about 24 mg / mL, about 10 mg / mL to about 22 mg / mL, about 10 mg / mL to about 20 mg / mL, about 10 mg / mL to about 18 mg / mL, about 10 mg / mL to about 16 mg / mL, about 10 mg / mL to about 14 mg / mL, about 10 mg / mL to about 12 mg / mL, about 12 mg / mL to about 50 mg / mL, about 12 mg / mL to about 45 mg / mL, about 12 mg / mL to about 40 mg / mL, about 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 / mLAbout 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 / mL, about 24 mg / mL to about... It can be 28 mg / mL, about 24 mg / mL to about 26 mg / mL, about 26 mg / mL to about 50 mg / mL, about 26 mg / mL to about 45 mg / mL, about 26 mg / mL to about 40 mg / mL, about 26 mg / mL to about 35 mg / 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 mg / 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] Injector device Furthermore, provided herein is an injector device comprising 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 injector device can be a pre-filled syringe. Non-limiting examples of such pre-filled syringes are known in the art.

[0104] Kit Furthermore, provided herein is a kit comprising any of the injector devices provided herein. Furthermore, provided herein is a kit comprising one or more vials containing any of the aqueous antibody formulations described herein. In some embodiments, any of the kits provided herein further comprises instructions for administering any of the aqueous antibody formulations to a subject in need thereof.

[0105] Method for preparing a formulation Furthermore, a method for preparing any of the aqueous antibody formulations described herein is provided, comprising the step of mixing or combining: (i) an antibody or an 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 any one or more of them); (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 (or any one or more of them); (iv) a stabilizer; (v) a surfactant; and (vi) water (e.g., sterile water), wherein (i)-(vi) are mixed or combined in an amount sufficient to produce any of the aqueous antibody formulations described herein.

[0106] Some embodiments of these methods may further comprise the step of filtering the mixed or combined (i)-(vi). Some embodiments of these methods may further comprise the step of placing or installing the formulation in 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 comprise adding or mixing with (i)-(vi) in an amount sufficient to result in any of the aqueous antibody formulations described herein one or more (e.g., two or three) of a stabilizer (e.g., any one or more of the exemplary stabilizers described herein or known in the art), an amino acid (e.g., any one or more of the exemplary amino acids described herein or known in the art), and a surfactant (e.g., any one or more of the exemplary surfactants described herein or known in the art).

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

[0109] As will be appreciated by those skilled in the art, the order in which the components of the formulation are added can be varied. For example, an antibody or antigen-binding antibody fragment can be a lyophilized solid that is dissolved in a buffered aqueous solution containing salts and buffers. In another example, a solid containing an antibody or antigen-binding antibody fragment (in the form of a lyophilized powder) and a salt can be dissolved in a buffered aqueous solution (containing a buffer). In some embodiments, a solid containing an antibody or antigen-binding fragment (in the form of a lyophilized powder), a buffer, and a salt is dissolved in water (e.g., sterile water).

[0110] 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 the methods described herein, the method does not include mixing or combining a buffer with (i)-(v) and the method results in a buffer-free aqueous antibody formulation.

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

[0112] Some embodiments of any of these methods may further include adding or mixing one or more (e.g., two or three) of a stabilizer (e.g., any one or more 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., any one or more of the exemplary surfactants described herein or known in the art) in an amount sufficient to result in any of the aqueous antibody formulations described herein or mixing with (i)-(vi).

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

[0114] Method for treating a subject Furthermore, provided herein is a method for treating a subject in need of treatment, the method 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 by intravenous administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, intraarterial administration, intraocular administration, intraarticular administration, or transforaminal epidural administration. 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 is identified or diagnosed (e.g., pre-identified or diagnosed as having a disease or condition that would benefit from treatment with an antibody or antigen-binding antibody fragment present in an aqueous antibody formulation).

[0116] In some embodiments of any of the methods described herein, one or more additional therapeutic agents may be administered to the subject. 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 administering the aqueous antibody formulation to the subject.

Examples

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

[0118] Exemplary Components of the Antibody Formulation 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 in conformational stability tests, kinetic stability tests, and viscosity measurements. Various formulations were prepared with 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 in combination and appropriate pH adjustment.

[0119] Exemplary Sample Preparation Sugars, polyols, amino acids, amino acid salts, and metal salt solutions were all prepared in 10 mM histidine buffer between pH 5.5 and pH 6.2. For measurement of thermal (conformational) stability, 1 mg / mL mAb formulations were prepared by adding the stock mAb solution to the excipient solution at a ratio of approximately 1 / 50 (volume / volume). For kinetic stability testing and viscosity measurement, a Vivaspin-20 30 kDa molecular weight cut-off (MWCO) membrane (General Electric) was used to concentrate the stock mAb solution and perform buffer exchange into various excipient solutions. The mAb formulations were concentrated to >180 mg / mL and then diluted to 150 mg / mL using the corresponding excipient solution.

[0120] Exemplary aqueous antibody formulations In some embodiments, the aqueous antibody formulation comprises from 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), from about 0 to about 100 mM of a buffer (e.g., any of the buffers described herein), from about 1 to about 750 mM of a stabilizing or viscosity salt (e.g., any of the stabilizing or viscosity salts described herein), from about 0.001 to about 0.2% of a surfactant (e.g., any of the surfactants described herein), from about 0% to about 10% of a sugar or polyol, and has a pH of from about 4 to about 8. See, e.g., embodiment A of Table 1.

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

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

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

[0124] [Table 1]

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

[0126] In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 200 mM of magnesium aspartate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 200 mM of magnesium glutamate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of histidine buffer, from about 100 to about 300 mM of magnesium sulfate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of histidine buffer, about 200 mM of magnesium sulfate, about 2% of sucrose, about 0.05% of polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 4 of Table 2.

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

[0130] In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 5 mM of a histidine buffer, about 200 mM of magnesium glutamate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of an acetate buffer, from about 100 to about 300 mM of magnesium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of an acetate buffer, about 200 mM of magnesium aspartate, about 2% of sucrose, about 0.05% of polysorbate 80, and has a pH of about 5.0. See, for example, embodiment 7 of Table 2.

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

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

[0134] In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), 10 mM of a histidine buffer, 200 mM of magnesium glutamate, 2% of sucrose, 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of lithium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), 10 mM of a histidine buffer, 200 mM of lithium aspartate, 2% of sucrose, 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of lithium glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 20 0 mM of lithium glutamate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of sodium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 200 mM of sodium aspartate, about 2% of sucrose, about 0.05% of polysorbate 80, and has a pH of about 5.5. See, for example, embodiment 13 of Table 2.

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

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

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

[0141] In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 200 to about 750 mM of lysine aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 30 0 mM of lysine aspartate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 200 to about 750 mM of lysine glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 300 mM of lysine glutamate, about 2% of sucrose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium aspartate, from about 1% to about 8% of trehalose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), about 10 mM of a histidine buffer, about 200 mM of magnesium aspartate, about 2% of trehalose, about 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium glutamate, from about 1% to about 8% of trehalose, from about 0.01% to about 0.1% of polysorbate 80, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), 10 mM of a histidine buffer, 200 mM of magnesium glutamate, 2% of trehalose, 0.05% of 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 from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of polysorbate 20, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), 10 mM of a histidine buffer, 200 mM of magnesium aspartate, 2% of sucrose, 0.05% of polysorbate 20, and has a pH of about 5.5. See, for example, embodiment 21 of Table 2.

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

[0147] In some embodiments, the aqueous antibody formulation comprises from 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), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium aspartate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of poloxamer 188, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from 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 of a histidine buffer, about 200 mM of magnesium aspartate, about 2% of sucrose, about 0.05% of poloxamer 188, and has a pH of about 5.5. See, for example, embodiment 23 of Table 2.

[0148] In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), from about 1 to about 100 mM of a histidine buffer, from about 100 to about 300 mM of magnesium glutamate, from about 1% to about 8% of sucrose, from about 0.01% to about 0.1% of poloxamer 188, and has a pH of from about 4.5 to about 7.5. In some embodiments, the aqueous antibody formulation comprises from about 0.1 to about 200 mg / mL of an antibody or an antigen-binding fragment thereof (e.g., any of the antibodies or antigen-binding fragments described herein), 10 mM of a histidine buffer, 200 mM of magnesium glutamate, 2% of sucrose, 0.05% of poloxamer 188, and has a pH of about 5.5. See, e.g., 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 melting temperature, T m1 m, of the mAb using a capillary-DSC system (Malvern). Both the identity and concentration of the different excipients were used to rank their effectiveness in improving conformational stability by their effect on the increase in the T m1 value. Measurements were performed 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 designated as T m1 m.

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

[0152] Viscosity measurement of mAb formulation 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 a single shear rate, and the pressure was measured at 20 °C.

Example

[0153] Stabilization of Fc mutant mAb An Fc-engineered mAb (antibody A) with a relatively low CH2 domain unfolding temperature (T m1 ) compared to a conventional mAb 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 evaluated by differential scanning calorimetry (DSC). Furthermore, solutions of the mAb were prepared at concentrations of 25 or 150 mg / mL in the same buffer-excipient-pH solutions, and the kinetic stability or storage stability, measured by the aggregation rate (k agg ), was evaluated at 5 °C, 25 °C, and 40 °C. Then , the increase in T m1 (ΔT m1 ) of antibody A in solution and / or k aggThe excipients were evaluated based on their effectiveness in the decrease. Based on the nature of the salts used, T m1 could be increased by about 7 °C with magnesium salts, which generally provided the greatest effect (Figure 1). Arginine salts generally provided the smallest but still significant increase with respect to antibody A. Among the anions, aspartate and glutamate were generally the most effective in the increase of T m1 . For k agg (antibody A at 40 °C, 150 mg / mL), a general decrease was observed along with the increase in ΔT m1 (Figure 2). Based on the nature of the salts, a decrease in the aggregation rate of approximately 35-fold was shown compared to the control formulation. Magnesium salts generally provided the highest decrease in k agg , followed by arginine, lysine, lithium, and sodium.

Example

[0154] Stabilization of another Fc mutant mAb Based on the results of Example 1, a subset of excipients was selected and their effectiveness as stabilizers was evaluated using another Fc-engineered mAb (antibody B) having a relatively low T m1 .

[0155] Solutions of antibody B (1 mg / mL) were prepared in 10 mM histidine buffer at pH 5.5 and 6.2 for conformational stability measurements. Solutions of antibody B (50 mg / mL) were prepared in the same buffer-excipient at pH 6.2 for kinetic stability (40 °C) analysis. Similar to the effects observed for antibody A, a salt-dependent increase in T m1 was observed for antibody B (Figure 3). Magnesium salts generally showed the greatest increase. For the anions, glutamate was found to be the most effective in the increase of T m1 , followed by aspartate and sulfate. Consistent with the effect on T m1 , a decrease in k agg was also shown in the presence of salts (Figure 4). Magnesium salts were generally the most effective in the increase of k agg .

Example

[0156] Stabilization of the Fc mutant mAb (antibody A) as a function of excipient concentration The excipients were evaluated at higher concentrations of 500 mM and 750 mM with respect to their stabilizing effect on antibody A in solution. All excipients were shown to improve the conformational stability of antibody A by increasing T m1 (Figure 5). Magnesium salts generally showed the largest increase in T m1 and showed approximately 15 °C at 750 mM for magnesium glutamate. Furthermore, the results of the kinetic stability tests (Figure 6) showed that these same excipients at 500 mM further reduced aggregation and k agg compared to 200 mM used in Example 1.

Example

[0157] Stabilization of wild-type mAb The same excipients used in Example 2 were further evaluated for their stabilizing effect on a conventional mAb (antibody C) having a much higher T m1 than the Fc mutants used in our tests. Except for sulfate, most excipients moderately improved the conformational stability with increasing concentration (200 mM, 500 mM, and 750 mM) (Figure 7). Aspartate and glutamate were generally superior in stabilizing the wild-type antibody.

Example

[0158] Stabilization of another wild-type mAb and its single and double amino acid mutants The aspartates and glutamates of magnesium, lithium, and sodium were evaluated at a concentration of 200 mM for their stabilizing effect on a wild-type anti-CEACAM5 antibody and its antibody D mutant, antibody E mutant, and antibody DE mutant. All salts improved the conformational stability of the four antibodies tested, and the effect was most prominent for the antibody DE mutant (Figure 8). Among the salts tested, the magnesium salt had the highest Tm1 was most effective in the increase.

Example

[0159] Effect of excipients on the viscosity and osmolality of the mAb solution The effect of the excipients at a concentration of 200 mM on the viscosity of the antibody solution was also evaluated. The viscosities of solutions of antibody A and antibody C (at approximately 150 mg / mL) were measured in the presence and absence of the excipients and compared to the viscosity in the presence of a conventional stabilizing excipient such as sucrose. The results showed that the selected excipients (i) significantly decreased the viscosity of the solution compared to the control solution (Figure 9) and / or (ii) resulted in solutions with lower viscosity (Figure 10) and lower osmolality (Figure 11) compared to sucrose at equipotent concentrations. For antibody C, the solution viscosity could be decreased by about 10-fold compared to the control, and arginine salts, lysine salts, and magnesium salts were most effective, followed by sodium and lithium (Figure 9). In contrast, the antibody A solution was not prohibitively viscous (control formulation in Figure 10). When sucrose was added to those solutions to improve conformational stability, especially at concentrations above 10%, the solution viscosity increased significantly. Such an increase in solution viscosity was not observed with any of the salts tested. The effect of the two excipient classes on solution viscosity was most apparent for solutions showing a ΔT m1 > 3°C. The results indicate that the viscosity trend associated with the use of sucrose at concentrations not too far from those generally used to stabilize protein formulations (about 8%) is not substantially present with the excipients listed in the present invention. A similar effect was also observed in relation to solution osmolality (Figure 11). Solutions containing 15% and 30% sucrose showed higher osmolality compared to a 200 mM salt solution without necessarily having a significantly higher stabilizing effect as measured by ΔT m1 .

[0160] Another embodiment Although the present invention has been described in connection with its detailed description, it should be understood that the foregoing description is intended as an illustration of the scope of the invention as defined by the appended claims and not as a limitation. Other aspects, advantages, and modifications are within the scope of the following claims.

[0161] Array information Provide the amino acid sequences corresponding to the heavy and light chains of the exemplary antibodies described herein.

[0162] Heavy chain of antibody A - anti - CXCR3 - DE(S239D, I332E) - Fc variant (SEQ ID NO: 1) EVQLLESGGGLVQPGGSLRLSCAASGFTFTSYAMSWVRQAPGKGLEWVATISHGGTYTYYPDSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARHPIYSGNYQGYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0163] Light chain of antibody A - anti - CXCR3 - DE(S239D, I332E) - Fc variant (SEQ ID NO: 2) DIQLTQSPSFLSASVGDRVTITCRASSGVNYLYWYQQKPGKAPKLWIYFTSTLASGVPSRFSGSGSGNEYTLTISSLQPEDFATYYCQQFTSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0164] Heavy chain of antibody C - anti - CD38 (Isatuximab) - wild - type IgG1 Fc (SEQ ID NO: 3) QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0165] Light chain of antibody C - anti - CD38 (Isatuximab) - wild - type IgG1 Fc (SEQ ID NO: 4) DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0166] Heavy chain of antibody B - anti - CD38 - ADE (G236A, S239D, I332E) - Fc variant (SEQ ID NO: 5) QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLAGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0167] Light chain of antibody B - anti - CD38 - ADE (G236A, S239D, I332E) - Fc variant (SEQ ID NO: 6) DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQ AEDLAVYYCQQHYSPPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0168] Heavy chain of anti-CEACAM5-wild type IgG1 Fc (SEQ ID NO: 7) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0169] Light chain of anti-CEACAM5-wild type IgG1 Fc (SEQ ID NO: 8) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0170] Heavy chain of antibody D-anti-CEACAM5(S239D)-Fc variant (SEQ ID NO: 9) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

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

[0172] Heavy chain of antibody E-anti-CEACAM5(I332E)-Fc variant (SEQ ID NO: 11) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0173] Light chain of antibody E-anti-CEACAM5(I332E)-Fc variant (SEQ ID NO: 12) DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0174] Heavy chain of antibody DE-anti-CEACAM5(S239D, I332E)-Fc variant (SEQ ID NO: 13) EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0175] Light chain (SEQ ID NO: 14) of the antibody DE-anti-CEACAM5 (S239D, I332E)-Fc variant 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 about 100 mM buffer; 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; wherein the aqueous antibody formulation has a pH of about 4 to about 8.

2. 1. 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; wherein the aqueous antibody formulation has a pH of about 4 to about 8.

3. 3. The formulation of claim 2, which is a buffer-free formulation.

4. The formulation of any one of claims 1 to 3, wherein the salt is magnesium glutamate, magnesium acetate, magnesium aspartate, or magnesium sulfate, or a combination thereof.

5. 5. The formulation of claim 4, wherein the salt is magnesium glutamate.

6. 5. The formulation of claim 4, wherein the salt is magnesium acetate.

7. 5. The formulation of claim 4, wherein the salt is magnesium aspartate.

8. 5. The formulation of claim 4, wherein the salt is magnesium sulfate.

9. The formulation of any one of claims 1 to 8, comprising from about 10 mM to about 750 mM of said salt.

10. 10. The formulation of claim 9 comprising from about 20 mM to about 750 mM of said salt.

11. The formulation of any one of claims 1 to 3, wherein the salt is sodium acetate, sodium aspartate, sodium glutamate or sodium sulfate.

12. 12. The formulation of claim 11, wherein the salt is sodium acetate.

13. 12. The formulation of claim 11, wherein the salt is sodium aspartate.

14. 12. The formulation of claim 11, wherein the salt is monosodium glutamate.

15. 12. The formulation of claim 11, wherein the salt is sodium sulfate.

16. 16. The formulation of any one of claims 11 to 15, comprising from about 10 mM to about 750 mM of said salt.

17. 17. The formulation of claim 16 comprising from about 20 mM to about 750 mM of said salt.

18. The formulation of any one of claims 1 to 3, wherein the salt is lithium acetate, lithium aspartate, lithium glutamate or lithium sulfate.

19. 20. The formulation of claim 18, wherein the salt is lithium acetate.

20. 19. The formulation of claim 18, wherein the salt is lithium aspartate.

21. 19. The formulation of claim 18, wherein the salt is lithium glutamate.

22. 19. The formulation of claim 18, wherein the salt is lithium sulfate.

23. 23. The formulation of any one of claims 18 to 22, comprising from about 10 mM to about 750 mM of said salt.

24. 24. The formulation of claim 23 comprising from about 20 mM to about 750 mM of said salt.

25. The formulation of any one of claims 1 or 4-24, wherein the buffer is selected from the group consisting of acetate, succinate, gluconate, histidine, citrate and phosphate.

26. 26. The formulation of claim 25, wherein the buffer is a histidine buffer.

27. 26. The formulation of claim 25, wherein the buffer is an acetate buffer.

28. 26. The formulation of claim 25, wherein the buffer is a citrate buffer.

29. 26. The formulation of claim 25, wherein the buffer is a phosphate buffer.

30. 30. The formulation of any one of claims 1 or 4-29, comprising from about 1 mM to about 100 mM of said buffer.

31. 31. The formulation of claim 30, comprising from about 1 mM to about 75 mM of said buffer.

32. 32. The formulation of claim 31 comprising from about 1 mM to about 50 mM of said buffer.

33. 33. The formulation of claim 32, comprising from about 1 mM to about 20 mM of said buffer.

34. 34. The formulation of any one of claims 1 to 33, having a pH of about 5 to about 6.

35. 35. The formulation of claim 34 having a pH of about 5.

5.

36. The formulation of any one of claims 1 to 35, comprising an antibody.

37. 37. The formulation of claim 36, wherein the antibody is a monoclonal antibody.

38. 38. The formulation of claim 37, wherein the monoclonal antibody is a human or humanized antibody.

39. 38. The formulation of claim 37, wherein the monoclonal antibody has an Fc amino acid substitution that reduces conformational stability compared to a similar antibody that does not contain that Fc amino acid substitution.

40. 38. The formulation of claim 37, wherein the monoclonal antibody is an IgG1 antibody or an IgG4 antibody.

41. 38. The formulation of claim 37, wherein the monoclonal antibody is an anti-C-X-C motif chemokine receptor 3 (CXCR3) monoclonal antibody.

42. 42. The formulation of claim 41, wherein the anti-CXCR3 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:

2.

43. 38. The formulation of claim 37, wherein the monoclonal antibody is an anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody.

44. The formulation of claim 43, wherein the anti-CEACAM5 monoclonal antibody comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising SEQ ID NO:

8.

45. 38. The formulation of claim 37, wherein the monoclonal antibody is an Fc-engineered anti-carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) monoclonal antibody.

46. 46. ​​The formulation of claim 45, wherein 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.

47. 46. ​​The formulation of claim 45, wherein 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.

48. 46. ​​The formulation of claim 45, wherein 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.

49. 49. The formulation of any one of claims 1-48, comprising about 0.1 mg / mL to about 400 mg / mL of the antibody or antigen-binding antibody fragment.

50. 50. The formulation of claim 49, comprising about 0.1 mg / mL to about 250 mg / mL of the antibody or antigen-binding antibody fragment.

51. 51. The formulation of claim 50, comprising about 0.1 mg / mL to about 200 mg / mL of the antibody or antigen-binding antibody fragment.

52. 52. The formulation of claim 51, comprising about 0.1 mg / mL to about 150 mg / mL of the antibody or antigen-binding antibody fragment.

53. 53. The formulation of claim 52, comprising about 0.1 mg / mL to about 100 mg / mL of the antibody or antigen-binding antibody fragment.

54. 54. The formulation of claim 53, comprising about 0.1 mg / mL to about 50 mg / mL of the antibody or antigen-binding antibody fragment.

55. 55. The formulation of claim 54, comprising about 0.1 mg / mL to about 25 mg / mL of the antibody or antigen-binding antibody fragment.

56. 56. The formulation of any one of claims 1 to 55, having a viscosity of about 1 cP to about 50 cP.

57. 57. The formulation of claim 56, having a viscosity of about 1 cP to about 40 cP.

58. 58. The formulation of claim 57 having a viscosity of about 1 cP to about 30 cP.

59. 59. The formulation of claim 58 having a viscosity of about 1 cP to about 20 cP.

60. 60. The formulation of any one of claims 1 to 59, having an osmolality of about 250 mOsm / kg to about 1500 mOsm / kg.

61. 61. The formulation of claim 60 having an osmolality of about 250 mOsm / kg to about 750 mOsm / kg.

62. 62. The formulation of claim 61 having an osmolality of about 250 mOsm / kg to about 500 mOsm / kg.

63. 63. The formulation of claim 62 having an osmolality of about 250 mOsm / kg to about 400 mOsm / kg.

64. 64. The formulation of any one of claims 1 to 63, which is stable at 25°C for about 1 hour to about 2 years.

65. 64. The formulation of any one of claims 1 to 63, which is stable at 40°C for about 1 hour to about 8 weeks.

66. 66. A formulation according to any one of claims 1 to 65, suitable for intravenous, intramuscular or subcutaneous administration.

67. 67. The formulation of claim 66, which is suitable for intravenous administration.

68. 67. The formulation of claim 66, which is suitable for subcutaneous administration.

69. 69. The formulation of any one of claims 1 to 68, further comprising one or more of a stabilizer, an antioxidant, a metal chelator, a viscosity modifier, an amino acid and a surfactant.

70. 70. The formulation of claim 69, wherein 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.

71. The antioxidant is methionine, ascorbic acid or N-acetylcysteine.

70. The formulation of claim 69.

72. 70. The formulation of claim 69, wherein the metal chelator is sodium ethylenediaminetetraacetate (EDTA), calcium EDTA, or diethylenetriaminepentaacetate (DTPA).

73. 70. The formulation of claim 69, wherein the viscosity modifier is arginine, histidine, lysine, proline, glycine or sodium chloride.

74. The surfactant may be 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, or polyoxyethylene lauryl ether.

70. The formulation of claim 69, wherein the fatty acid ester is selected from the group consisting of 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.

75. 70. The formulation of claim 69, wherein the amino acid is selected from the group consisting of arginine, lysine, histidine, proline, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, and aspartic acid.

76. 76. An injection device comprising a formulation according to any one of claims 1 to 75.

77. A kit comprising one or more vials containing the formulation according to any one of claims 1 to 75.

78. 78. The kit of claim 77, further comprising an injection device for administering the formulation to a subject in need thereof.

79. 1. A method of making an aqueous antibody formulation, comprising: (i) an antibody or antigen-binding fragment thereof; (ii) a buffer; and (iii) 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 a salt selected from the group consisting of tium; (iv) a stabilizer; (v) a surfactant; (vi) mixing or combining with sterile water; 76. A method of making the aqueous antibody formulation comprising mixing or combining (i)-(vi) in sufficient amounts to produce the formulation of any one of claims 1-75.

80. 80. The method of claim 79, further comprising the step of mixing or combining one or more of an antioxidant, a metal chelator, and a viscosity modifier with (i)-(vi).

81. 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, 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; (vi) mixing or combining with sterile water; 76. A method of making the aqueous antibody formulation comprising mixing or combining (i)-(v) in sufficient amounts to produce the formulation of any one of claims 1-75.

82. 82. The method of claim 81, which does not include the step of mixing or combining a buffer with (i)-(v).

83. 83. The method of claim 81 or 82, further comprising mixing or combining one or more of an antioxidant, a metal chelator, and a viscosity modifier with (i)-(vi).

84. 76. A method of treating a subject in need of treatment, comprising administering to said subject a therapeutically effective amount of a formulation according to any one of claims 1 to 75.

Images